Unprecedented formation of Δ2-isoxazoline and/or 1-nitroso-pyrazoline from α-bromoketone oximes and diazo compounds

Article abstract of DOI:10.1016/j.tetlet.2008.12.032

Reaction of α-bromoketone oximes with diazo compounds in the presence of a metal catalyst and base led to the unprecedented formation of two types of rings: Δ²-isoxazolines and 1-nitrosopyrazolines.

Full text of DOI:10.1016/j.tetlet.2008.12.032

Tetrahedron Letters 50 (2009) 933–935
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Tetrahedron Letters
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Unprecedented formation of
D
2-isoxazoline and/or 1-nitroso-pyrazoline
from
a-bromoketone oximes and diazo compounds
*
*
Jianhua Guo , John Gaudette, Jie-Fei Cheng
Department of Chemistry, Tanabe Research Laboratories USA, Inc.; 4540 Towne Centre Court, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of
a-bromoketone oximes with diazo compounds in the presence of a metal catalyst and base
led to the unprecedented formation of two types of rings:
D
2-isoxazolines and 1-nitrosopyrazolines.
Received 10 September 2008
Revised 3 December 2008
Accepted 5 December 2008
Available online 13 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
D
2-Isoxazoline
1-Nitrosopyrazolines
Cycloaddition
Metal-catalyzed
Nitrosoalkenes are usually generated through 1,4-elimination of
We report here our efforts to extend nitrosoalkene reaction with
a diazo compound, which gives
2-isoxazoline and 1-nitroso-4,5-
dihydropyrazole derivatives (Scheme 1). Neither of these
formations is known in the literature.
2-Isoxazolines are versatile
a
a-haloketone oxime or
a-haloaldoxime with an organic or inor-
D
ganic base such as sodium carbonate.1 It is isolated occasionally
as a relatively stable compound, but in general, it is unstable and
was most often characterized through in situ trapping with certain
reagents. For instance, reaction of a nitrosoalkene with a variety of
electron-rich dienophiles such as silyl enol ethers,2 silylated ole-
fins,3 and alkoxyallens4 provides a hetero Diels–Alder product,5
which could be further modified to produce 1,4-hydroxylamine
derivatives. The flexibility and versatility of this hetero Diels–Alder
reaction have attracted much attention in the past decade, and its
scope and limitations were extensively investigated.1c Trapping
nitrosoalkene with a one-carbon unit represents a novel and attrac-
tive strategy to construct five-member ring systems. However, only
a few such [4+1] annulation reactions were reported to date,6 one
example being the reaction of nitrosoalkene with an isocyanide to
provide 2-aminoisoxazole products in moderate yields.6a
D
intermediates for the synthesis of a wide variety of complex natural
products or pharmaceutical agents.11 The ring system itself has
been incorporated into a number of pharmaceutically important
compounds or drug candidates.12 They were typically prepared
through a 1,3-dipolar cycloaddition of a nitrile oxide, which could
be generated from a hydroximic acid chloride13 or primary nitroalk-
anes,14 with a dipolarophile in either solution phase or on solid sup-
port.15,16 Although [3+2] dipolar cycloaddition in general gave rise
to the desired D
2-isoxazoline products efficiently and in good yields,
one of the common limitations was the difficulty in controlling the
stereoselectivity.17 On the other hand, 1-nitrosopyrazolines could
be prepared from pyrazoline under nitrite oxidation condition.18 It
can be converted into the corresponding dihydropyrazoles or pyra-
zoles which are found frequently in pharmaceutical agents.
Diazo compounds have been widely used as a carbene source in
organic synthesis.7 Transition metal-catalyzed decomposition of
diazoalkanes followed by cycloadditions has been extensively
studied.8 Highly stereoselective cyclopropanation catalyzed by chi-
ral metal complexes using diazo compounds as carbene sources
has been achieved.9 There are also some reports on copper-cata-
R1
R2
R2CHN2
Base
N O
+
R1
lyzed [4+1] cycloaddition of
a,b-unsaturated ketones with diazo
Br
compounds.10 However, a [4+1] cycloaddition of diazo compounds
with nitrosoalkene has never been reported.
CH2Cl2
[M]
N
HO
R1
R2
NO
N N
* Corresponding authors. Tel.: +1 858 622 7053 (J.G.).
E-mail addresses: jguo@trlusa.com (J. Guo), jaycheng2008@gmail.com (J.-F.
Cheng).
Scheme 1. Reaction of a nitrosoalkene and a diazo compound.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.032

934
J. Guo et al. / Tetrahedron Letters 50 (2009) 933–935
Table 1
Influence of metal catalyst on the reaction yield
Si
N N
HO
Catalyst
Yielda (3a, %)
O
N
catalyst
(20% equiv.)
Br
(Ph2PC5H4)2Fe
Ag(CF3CO2)
AgO
31
34
47
52
13
37
9
30
54
22
28
7
37
57
0
29
22
19
27
6
O
O
Si
Na2CO3 (3 equiv.)
DCM, r.t., 24h
N
O
O
AgOAc
Cu(acac)2
Cu(OAc)2
Cu(OTf) C6H6
Cu(OTf)2
Cu2O
CuBr
CuBr2
CuCl
CuI
CuO
FeCl3
MgCl2
MgO
Pd(OAc)2
Rh2(OAc)2
Sc(OTf)3
ZnCl2
3a
1a
Scheme 2. Formation of
D
2-isoxazoline.
We started to test the reaction of nitrosoalkenes and diazo com-
pounds with 3-bromo-2-hydroxyimino-propionic acid ester (1a)
and trimethylsilyldiazomethane (Scheme 2). Dichloromethane
was chosen as solvent based on previous reports on the unstable
nature of nitrosoalkene.1,6a 1a was treated with freshly ground so-
dium carbonate in dichloromethane at room temperature under
nitrogen to generate nitrosoalkene. Trimethylsilyldiazomethane
was added dropwise in the presence of metal catalyst at room tem-
perature. Isoxazoline 3a was formed, and many metal catalysts are
effective in catalyzing this reaction. However, copper-based cata-
lysts turned to be slightly more effective (Scheme 2, Table 1).
CuO was chosen as the catalyst for reactions with different oxi-
mes and diazo compounds (Table 2).19,20 For reaction of oxime 1a
with t-butyl diazoacetate, isoxazoline 3a0 was obtained similarly.
But products with an unusual 1-nitroso-4,5-dihydropyrazole ring
were obtained when oximes 1b and 1c were used. Formation of
isoxazoline in these reactions is either trace amount or undetect-
able. Without adding metal catalyst, reaction of 1b with t-butyl
diazoacetate generated 4b in 36% yield, but no isoxazoline at all.
In these reactions, the products are formed with other uncharac-
terized materials. Yields of the separated products from these reac-
tions varied from 10% to 48%. The structure of compound 4c0, one
4
a
Yields by HPLC.
of the 1-nitroso-4,5-dihydropyrazole compounds, was solved by
X-ray crystallographic study (Fig. 1).21
Based on these results, we propose a possible mechanism for the
formation of these products (Scheme 3). a-Bromoketone oxime re-
acts with base to generate nitrosoalkene A. Diazo compound was
decomposed by metal catalyst (CuO or catalysts listed in Table 1)
to form metal carbene complex B. A concert [4+1] cycloaddition be-
tween nitrosoalkene A and metal carbene B produces
line 3. Nitrosoalkene A could also undergo a [3+2] reaction with
D
2-isoxazo-
Table 2
The reactions between oximes and diazomethane
Entry
Reactant 1
Reactant 2
TMSCHN2
Isoxazoline (yield)
Nitrosopyrazoline (yield)
HO
O
N
N
O
O
Br
Br
1
Si
N
O
O
1a
3a (48%)
O
HO
O
O
O
2
3
N2CHCOOt-Bu
N2CHCOOt-Bu
N
O
O
O
1a
3a’ (16%)
HO
N
O
Br
N
N
O
NO
1b
4b (45%, 36%*)
HO
N
Br
Br
4
5
TMSCHN2
Si
N
N
N
O
NO
1c
3c (10%)
4c (23%)
HO
N
O
O
N2CHCOOt-Bu
N
N
NO
1c
4c’ (25%)
*Reaction without CuO. All yields are separated yields.

J. Guo et al. / Tetrahedron Letters 50 (2009) 933–935
935
336033 or e-mail: deposit@ccdc.cam.ac.Uk) Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.12.032.
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Figure 1. ORTEP of compound 4c0.
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H
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N
N
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NO
H
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N
MLn
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4
3
2
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2-isoxazolines:(a)Cheng, J.-F.;Mjalli, A. M. Tetrahedron
Scheme 3. Proposed reaction mechanisms.
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diazo compound to provide the nitrosopyrrolidine intermediate C,
which could form N-nitrosopyrrolizine product 4 through 1,3-ni-
troso migration.22 In reactions using trimethylsilyldiazaomethane,
the trimethylsilyl group (R2) in product 4 seems to easily fall off
and is replaced by a proton. In reactions with base and metal cata-
lyst, electron-deficient nitrosoalkene A reacts with metal carbene
complex exclusively, while electron-rich nitrosoalkene favors
cycloaddition with diazo compounds directly. In reactions without
16. Recent reports on new synthetic methods of
D
2- isooxazoline: (a) Cecchi, L.;
Sarlo, F. D.; Machetti, F. Tetrahedron Lett. 2005, 46, 7877; (b) Jiang, D.; Peng, J.;
Chen, Y. Org. Lett. 2008, 10, 1695.
17. (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863; (b) Lohse-Fraefel, N.;
Carreira, E. M. Org. Lett. 2005, 7, 2011; (c) Serizawa, M.; Ukaji, Y.; Inomata, K.
Tetrahedron: Asymmetry 2006, 17, 3075; (d) Lee, C. K. Y.; Herlt, A. J.; Simpson, G.
W.;Willis, A. C.; Easton, C. J. J. Org. Chem. 2006, 71, 3221;(e) Thomas, P. J.; Axtell, A.
T.; Klosin, J.; Peng, W.; Rand, C. L.; Clark, T. P.; Landis, C. R.; Abboud, K. A. Org. Lett.
2007, 9, 2665;(f)Norman,A. L.;Mosher,M. D. TetrahedronLett. 2008, 49, 4153;For
stereoselective synthesis of isoxazoline through cycloaddition of aliphatic chiral
nitrle oxide and optically active allylic alcohol,see: (g) Kanemasa, S.; Nishiuchi,
M.; Kamimura, A.; Hori, K. J. Am. Chem. Soc. 1994, 116, 2324; (h) Bode, J. W.;
Fraefel, N.; Muri, D.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 2001, 40, 2082.
18. Auwers, K. V.; Heimke, P. Liebigs Ann. Chem. 1927, 458, 209.
19. General procedure: The oxime (1 mmol), freshly grounded Na2CO3 (3 mmol)
and CuO (0.1 mmol) were mixed in a flask with a stir bar. The flask was
vacuumed/filled with nitrogen twice before adding 10 mL of dry
dichloromethane and trimethylsilyl diazomethane (ether solution, 2.0 M,
2.5 mmol) or tert-butyl diazoacetate (2.5 mmol). The mixture was stirred at
room temperature for 24 h under nitrogen. The solution was filtered, and the
solvent was removed under reduced pressure. The residue was purified by
column chromatography on silica gel to afford the product.
20. Some of the compounds listed in Table 2 have been reported previously using
different synthetic methods. Compound 3a: (a) Conti, D.; Rodriquez, M.; Sega, A.;
Taddei, M. Tetrahedron Lett. 2003, 44, 5327; (b) Lukevics, E.; Dirnens, V.; Kemme,
A.; Popelis, J. J. Organomet. Chem. 1996, 521, 235; Compound 3c: (c) Kolokol’tseva,
I. G. J. Gen. Chem. USSR1970, 40, 2605;Compound4c:(d)Freudenberg, K.;Stoll, W.
Liebigs Ann. Chem. 1924, 440, 38; (e) Auwers, K. V.; Heimke, P. Liebigs Ann. Chem.
1927, 458, 186; (f) Vecchio, G. L.; Crisafulli, M.; Aversa, M. C. Tetrahedron Lett.
1966, 7, 1909; (g) Nagarajan, K.; Rajagoplan, P. Tetrahedron Lett. 1966, 7, 5525.
21. CCDC 701669 contains the supplementary crystallographic data for this letter.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
metal catalysts, there is no metal carbene complex thus no
D
2-isox-
azoline formation, and nitrosopyrrolizine product formed through
the cycloaddition between nitrosoalkene and diazo compounds.
In summary, reaction of nitrosoalkene with a diazo compound
can proceed smoothly in the presence of an inorganic base and/
or metal catalyst to provide unique products,
D
2-isoxazoline and
1-nitroso-4,5-dihydropyrazole derivatives, in modest yields. The
reaction may be useful for developing metal-catalyzed asymmetric
synthesis of
D
2-isoxazolines.
Acknowledgments
We thank Prof. Arnold L. Rheingold at University of California,
San Diego for providing the X-ray crystal structure of compound 4c0.
Supplementary data
Synthetic, spectroscopic, and X-ray diffraction details (PDF, CIF).
This material is available free of charge via the Internet. Crystallo-
graphic data (excluding structure factors) for the structure in this
letter have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication nos. CCDC. Copies of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-
22. 1, 3-migration of nitroso group in the ON–X–CH@X systems (X = O, S, Se, NH,
CH2) has been reported: Avakyan, V. E.; Kletskii, M. E.; Minyaev, R. M. Russ. J.
Org. Chem. 2005, 41, 1467.