Synthesis of C-glycosylmethyl isoxazoles via aerobic oxidation of ketoximes catalyzed by TEMPO

Article abstract of DOI:10.1016/j.tetlet.2017.03.005

An efficient and high yielding synthesis of C-glycosylmethyl isoxazoles by oxidation of ketoximes in the presence of oxygen and mediated by TEMPO is described.

Full text of DOI:10.1016/j.tetlet.2017.03.005

Accepted Manuscript
Synthesis of C-glycosylmethyl isoxazoles via aerobic oxidation of ketoximes
catalyzed by TEMPO
Helberth Llantén, Sebastian Barata-Vallejo, Alberto Postigo, Pedro A. Colinas
PII:
S0040-4039(17)30287-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.005
TETL 48706
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
8 February 2017
1 March 2017
Please cite this article as: Llantén, H., Barata-Vallejo, S., Postigo, A., Colinas, P.A., Synthesis of C-glycosylmethyl
isoxazoles via aerobic oxidation of ketoximes catalyzed by TEMPO, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.03.005
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Synthesis of C-glycosylmethyl isoxazoles via aerobic oxidation of ketoximes
catalyzed by TEMPO
Helberth Llantén,a Sebastian Barata-Vallejo,b Alberto Postigo,b Pedro A. Colinasa,*
aCEDECOR, Departamento de Química, Facultad de Ciencias Exactas, CONICET,
Universidad Nacional de La Plata. 47 y 115, La Plata, 1900, Argentina.
bDepartamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad
de Buenos Aires, Junín 954 CP 1113, Buenos Aires, Argentina.
e-mail: pcolinas@quimica.unlp.edu.ar
Abstract
An efficient and high yielding synthesis of C-glycosylmethyl isoxazoles by
oxidation of ketoximes in the presence of oxygen and mediated by TEMPO is
described.
Keywords: C-glycosides; heterocycle; radical; C-cinnamoyl glycosides
Chemistry of isoxazole derivatives has attracted increasing interest due to their
chemotherapeutic properties, such as hypoglycemic,1a anti-inflamatory,1b
cytotoxic,1c and anti-bacterial activity.1d One of the most useful strategies to
prepare 1,2-isoxazoles is the nitrile oxide cycloadditions to alkynes.2 Nitrile
oxides are normally obtained from oximes in two steps: halogenation of the
aldoxime to give a hydroximoyl halide and subsequent dehydrohalogenation by
base. It is also possible to combine both steps in one operation. Due to some
drawbacks of this methodology (use of oxidants, metal salts, high pressure)
several alternative preparations have been reported.
Dominguez et al. have described the high efficient synthesis of 4,5-
diarylisoxazoles by a “one-pot” reaction of enamino ketones with hydroxylamine

under oximation conditions.3 A mechanism was proposed involving an amine
exchange reaction followed by nucleophilic attack of the hydroxylamine
derivative to the carbonyl group. Then elimination afforded the isoxazoles with
high yields. Recently Liu reported an aqueous “one-pot” reaction of ethyl
acetoacetate, hydroxylamine and aromatic aldehydes in the presence of sodium
benzoate.4 The methodology involves an oximation reaction, further ring closing
and subsequent Knoevenagel reaction of the isoxazolone with aromatic
aldehydes gave the isoxazoles in good yields. A closed related synthesis has
been developed by reaction of α,β-unsaturated ketones or aldehydes and N-
hydroxyl-4-toluenesulfonamide in the presence of potassium carbonate to afford
the isoxazoles in good to moderate yields.5 Recently Chiba´s group has
described the synthesis of several pyrazoles and isoxazoles by the reaction of
hydrazones and oximes in the presence of TEMPO (2,2,6,6-
tetramethylpiperidin-1-oxyl) and K2CO3 under N2 atmosphere.6
During the last years one of our groups has been interested in the synthesis of
C-glycosides analogues of biologically active molecules. The replacement of the
naturally occurring O-glycoside bond by C-glycoside bond is an approach
practiced in the synthesis of carbohydrate-containing compounds for the
downstream biological applications.7 This isosteric replacement seeks to
enhance stability of the small molecule glycoside toward enzymatic hydrolysis
of the glycosidic bond while retaining vital molecular recognition interactions
with the biological target.8
Several glycosyl isoxazoles have been prepared by cycloaddition of nitrile
oxides to propargyl glycosides.9 Dondoni´s group has developed the synthesis
of C-glycosyl amino acids that feature an isoxazole heterocycle as a tether of

the carbohydrate and glycinyl moiety.10 Interesting some glycosyl isoxazoles
showed to be good inhibitors of galectins.11 Ismael´s group has reported the
synthesis of furanosyl isoxazoles by intramolecular oxidative cyclization of α,β-
unsaturated oximes with iodine, potassium iodide and sodium hydrogen
carbonate.12 Somzák´s group reported the synthesis of one C-glycosyl
isoxazole by reaction of a glucopyranosyl alkynyl ketone with hydroxylamine.
The compound was tested as inhibitor of glycogen phosphorylase b showing no
activity.13
Recently we have described the synthesis and biological activities of several C-
glycosides, which have been prepared by aldol
condensation of β-C-glucosyl and β-C-galactosyl ketones with
aryl aldehydes at room temperature in the presence of pyrrolidine as
catalyst.14 It could be envisioned that the ketoximes of those glycosides could
be used in the synthesis of the corresponding C-glycosylmethyl isoxazoles
(Scheme 1). Here we describe the synthesis of C-glycosyl isoxazoles via
aerobic oxidation of glycosyl ketoximes.
1-(β-D-Glycosyl)-propan-2-ones were prepared by Knoevenagel condensation
with 2,4-pentanedione in the presence of sodium carbonate using water as
solvent.15 Crude mixtures containing the C-glycosyl ketones were acetylated
and then purified to afford the peracetylated compounds 2 in good yields. C-

cinnamoyl glycosides 3 have been prepared by aldol condensation of β-C-
glucosyl or β-C-galactosyl ketones with different aromatic aldehydes at room
temperature in the presence of pyrrolidine as catalyst.14 Then the reaction of the
C-glycosides with hydroxylamine hydrochloride under oximation conditions
afforded the corresponding ketoximes 4 in very good yields (Scheme 2).
We have studied several reactions conditions to obtain the desired C-
glycosylmethyl isoxazoles. We have employed She´s methodology5 using the
deprotected C-cinnamoyl glycoside 6 (Scheme 3), easily prepared from
compound 3a by reaction with triethylamine in methanol/water. Unfortunately
the product was not observed and only starting material was recovered.
Recently Joshi´s group has prepared several isoxazoles by reaction of
chalcones with hydroxylamine hydrochloride and sodium acetate in the
presence of glacial acetic acid.1d We applied this methodology to the per-O-
acetylated C-glycoside 3a but only the corresponding ketoxime 4a could be
isolated from the reaction mixture (Scheme 4).

Next we applied the conditions developed by Ismael´s group to the deprotected
oxime 6 (Scheme 5).12 Although it was possible to obtain the desire isoxazole,
the yield was low and the purification step was complicated due to the presence
of several compounds in the reaction mixture.
In view of the methodology reported by Chiba´s group6 and that steric hindrance
around the double bond of oximes decreases the O-H bond dissociation
energy,16 we decided to study if an iminoxyl radical generated from the oximes
of C-cinnamoyl glycosides by TEMPO could led to the corresponding C-
glycosylmethyl isoxazoles through an intramolecular cyclization (Scheme 6).
We began studying the preparation of C-glycosylmethyl isoxazole 5a from
ketoxime 4a under different reaction conditions (Table 1).

Table 1. Preparation of C-glycosylmethyl isoxazole 5a a
entry
1b
Solvent
Temp (°C) Additives
time(h) Yield(%)
TEMPO
(equiv)
3
DMF
140
2
80
K2CO3 (2
equiv)
O2 (1 atm)
2
3
4
5
6
7
8
3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
140
140
140
140
140
120
80
3
5
99
99
99
99
99
99
99
1
O2 (1 atm)
0.5
0.2
0.05
0.05
0.05
O2 (1 atm) 13
O2 (1 atm) 18
O2 (1 atm) 26
O2 (1 atm) 32
O2 (1 atm) 40
a The reactions were performed using 0.04 mmol of 4a en 0.2 mL of solvent. b
Under argon and with degassed solvent.
When 4a was heated with TEMPO (3 equiv.) in DMF at 140 oC under argon in
the presence of potassium carbonate (2 equiv) the reaction afforded a good
yield of the C-glycosyl isoxazole 5a (entry 1). Unfortunately purification of the
product was very difficult due to the presence of partial deacetylated
derivatives. It is very well known that TEMPO could be regenerated by oxygen
thus we decided to perform the reaction under 1 atm of oxygen.17 Under those
conditions the best yield is found using 0.05 equiv. of TEMPO at 140 oC (entry
6) with full conversion and shorter reaction times (entries 7-8).
Based on the results shown in Table 1, it is possible to conclude that the
reaction rate depends on amount of TEMPO and the temperature.
With this knowledge in hand, the selected conditions were applied to a variety of
C-glycosyl ketoximes to examine the scope of the reaction.

Table 2. Preparation of C-glycosylmethyl isoxazoles a
entry
C-glycosyl
C-glucosyl
R3
Product
5a
Time
Yield(%)
1
26
99
5b
5c
5d
2
3
15
10
99
99
O
O
O
F
4
35
77
Cl
Cl
5e
5f
5
6
22
8
99
99
O
C-galactosyl
O
O
5g
7
33
86
O
Br
a All the reactions were performed using 1 equiv of ketoxime 4, 0.05 equiv of TEMPO, O2 (1
atm) in DMF at 140 oC.
By varying the substituent R3, various isoxazoles containing electron donating
and electron withdrawing groups could be prepared. As can be seen in Table 2
the different groups on the aromatic moiety have almost no effect on the
reaction and the corresponding isoxazoles were obtained in very good to
excellent yields. Only in the compounds 5d and 5g the large steric hindrance of
halogen atoms at ortho positions resulted in moderate yields (entries 4 and 7).

The products were easily purified by flash chromatography. The 1H and 13C
NMR experiments and mass spectral data of the C-glycosyl isoxazoles were in
full accordance with their structure.
Based on these results, a mechanism of this preparation of isoxazoles from
ketoximes is suggested in Scheme 7. TEMPO induces generation of iminoxyl
radical A, that undergoes 5-endo trig cyclization to give the isoxazolinyl radical
B, this radical could participate in a disproportionation reaction with TEMPO or
could be directly oxidized by oxygen.18 Also an ionic pathway that involves
trapping of C-radical B by TEMPO and successive elimination of TEMPO-H to
afford the isoxazole 5, could be suggested. However, in our conditions we have
not been able to isolate or observe an intermediate that supports this pathway.
R2
R2
OAc
OAc
R3
TEMPO (0.05 eq.)
O2
O
O
R1
AcO
R1
AcO
R3
OAc
OAc
DMF, 140 o
C
N
N
O
4
5
OH
O
OH
N
N
or O2
O2
O2
HO
O
N
N
R2
OAc
OAc
R2
R3
O
O
R1
AcO
R1
R3
AcO
OAc
OAc
N
H
N
O
B
A
O
R1= OAc, R2= H or
R1=H, R2= OAc
R3= aryl
Proposed mechanism for the preparation of C-glycosylmethyl isoxazoles
Scheme 7.
In conclusion, we have developed an efficient approach for the synthesis of C-
glycosylmethyl isoxazoles from ketoximes that is quite simple and high yielding.
In addition this methodology circumvents the use of metal catalysts. The
reaction mechanism of our methodology includes the 5-endo trig cyclization of
an iminoxyl radical generated from the ketoxime with TEMPO as initiator.
Further applications of the above method for the synthesis of other C-glycosyl
isoxazoles will be presented in due course.

A. Supplementary information
Experimental details including procedures, characterization, and spectra data.
Supplementary data associated with this article can be found, in the online
version, at
Acknowledgements
This work was financed by UNLP and CONICET (PIP 0701). H.L. is holder of a
fellowship from CONICET. S.B.; A.P. and P.A.C. are members of the Scientific
Research Career of CONICET.
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OAc
O
OAc
O
R2
R2
R1
AcO
O2
R1
AcO
R3
R3
TEMPO
AcO
AcO
N
N
O
OH

Highlights
. An efficient and high yielding synthesis of C-glycosylmethyl isoxazoles
is described.
. A reaction mechanism for our methodology is proposed
. Use of metal catalysts is avoided.