Efficient synthesis of isoxazoles and isoxazolines from aldoximes using Magtrieve (CrO2)

Article abstract of DOI:10.1016/j.tetlet.2009.04.073

Treatment of aldoximes 1 with Magtrieve (CrO₂) in presence of dipolarophile 3 or 4, furnished a variety of isoxazolines 5a-u and isoxazoles 6a-q as 1,3-dipolar cycloaddition (1,3-DC) products (38 examples; 63-90% isolated yields). In situ formation of a nitrile oxide intermediate was confirmed through isolation of the dimerization product furoxane 2a in absence of any dipolarophile. The methodology has been extended to intramolecular nitrile oxide cycloaddition (INOC) reactions to access highly useful chromane derivatives 7-8 (75-80% isolated yields). Magtrieve, as a new reagent for 1,3-DC reactions, has offered excellent substrate generality and at the same time demonstrated tolerance toward sensitive protecting groups and electron-rich functional groups.

Full text of DOI:10.1016/j.tetlet.2009.04.073

Tetrahedron Letters 50 (2009) 3948–3951
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of isoxazoles and isoxazolines from aldoximes using
TM
Magtrieve (CrO2)
Sandeep Bhosale a, Santosh Kurhade a, Uppuleti Viplava Prasad b, Venkata P. Palle a, Debnath Bhuniya a,
*
a Drug Discovery Facility, Advinus Therapeutics, Quantum Towers, Plot-9, Phase-I, MIDC, Hinjewadi, Pune 411 057, India
b Department of Organic Chemistry, Andhra University, Visakhapatnam 530 003, India
a r t i c l e i n f o
a b s t r a c t
TM
Article history:
Treatment of aldoximes 1 with Magtrieve (CrO2) in presence of dipolarophile 3 or 4, furnished a variety
of isoxazolines 5a–u and isoxazoles 6a–q as 1,3-dipolar cycloaddition (1,3-DC) products (38 examples;
63–90% isolated yields). In situ formation of a nitrile oxide intermediate was confirmed through isolation
of the dimerization product furoxane 2a in absence of any dipolarophile. The methodology has been
extended to intramolecular nitrile oxide cycloaddition (INOC) reactions to access highly useful chromane
Received 23 March 2009
Revised 15 April 2009
Accepted 21 April 2009
Available online 24 April 2009
TM
derivatives 7–8 (75–80% isolated yields). Magtrieve , as a new reagent for 1,3-DC reactions, has offered
excellent substrate generality and at the same time demonstrated tolerance toward sensitive protecting
groups and electron-rich functional groups.
Ó 2009 Elsevier Ltd. All rights reserved.
Isoxazoles and isoxazolines are very useful heterocycles1 in or-
ganic and medicinal chemistry.2a–e Isoxazoline rings have been used
by organic chemists for synthetic manipulation to access complex
molecular architectures.1b Drugs such as Isocarboxazid, Valdecoxib,
Oxacillin, Leflunomide, and Micafungin are the examples2f to sub-
stantiate the pharmaceutical acceptance of such heterocyclic sys-
tems. When suitably crafted within a small molecule, these
scaffolds have been often conceived as stable amide surrogates.3
Hence, new synthetic methodologies to construct these heterocy-
cles with varieties of substitutions are highly desired.
aromatic aldoximes. Moreover, aliphatic aldoximes were found to
be very poor substrates for that matter.
Recently we discovered Magtrieve (CrO2)9 as a very efficient
TM
reagent for the oxidation of aldoximes to nitrile oxides. Subse-
quently, a structurally diverse set of isoxazoline and isoxazole ring
systems were synthesized in high yields by reacting varieties of
TM
aldoximes and dipolarophiles in presence of Magtrieve . A preli-
minary account of this methodology is being reported in this
Letter.
Potential of CrO2 for the oxidation of aldoximes to nitrile oxides
was studied initially with 4-chlorobenzaldehyde oxime, 1a, chosen
as a model substrate. Using 10 mol equiv of CrO2, several reaction
conditions were scanned such as (a) dichloromethane at rt, (b)
chloroform at 65 °C, (c) MeCN at 80 °C, and (d) toluene at 80 °C.
It was found that the starting material 1a disappeared after 2 h
when heated at 80 °C in MeCN or toluene solvent, and it led to
the formation of corresponding furoxane 2a (dimerization product
of in situ formed nitrile oxide) as a major product along with a
trace amount (less than 10%) of 4-chlorobenzaldehyde as deoxima-
tion product (Scheme 1, Path-A). As reported in the literature,
treatment of 1a with excess MnO2 (added in batches) led to a very
sluggish reaction in dichloromethane at rt.8bi When the same reac-
tion was carried out in chloroform at 65 °C, it resulted in almost
equal distribution of 1a, 2a, and the deoximation product after
6 h. Interestingly, excess MnO2 in toluene at 80 °C led to disappear-
ance of the starting material within 2 h leading to the formation of
The most convenient synthesis of isoxazoline and isoxazole ring
systems has been executed in the literature via 1,3-dipolar cyclo-
addition (1,3-DC) reactions4 of alkenes or alkynes with nitrile oxi-
des,5 generated in situ from aldoximes. Two different classes of
reagents have been used in the literature for the conversion of
aldoximes to nitrile oxides: (i) halogenating agents6 or hypervalent
iodine7 to produce hydroximoyl halides or equivalent molecule as
the reactive intermediates, and (ii) direct oxidizing agents8 such as
K3[Fe(CN)6], Ceric ammonium nitrate (CAN), Pb(OAc)4, and MnO2.
8b
Use of MnO2 has offered advantages over many other choices
mainly because of two reasons: (a) avoidance of additional base
treatment that is required in the case of conventional halogenating
agents and (b) mild reaction conditions compared to other direct
oxidizing agents. However, the MnO2 methodology has been
essentially limited to aldoximes bearing strong electron-with-
drawing groups such as carboxylate. In addition, only moderate
yields of cycloaddition products along with the formation of signif-
icant amount of corresponding aldehydes have been reported for
4-chlorobenzaldehyde as major product along with
a minor
amount of 2a (Scheme 1, Path-B). The above observations
TM
prompted us to explore the potential use of Magtrieve for the syn-
thesis of isoxazoline and isoxazole ring systems via 1,3-DC
reactions.
* Corresponding author. Tel.: +91 20 66539600; fax: +91 20 66539620.
E-mail address: debnath.b@advinus.com (D. Bhuniya).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.073

S. Bhosale et al. / Tetrahedron Letters 50 (2009) 3948–3951
3949
CrO2 (10 eq), MeCN or Toluene,
80 ºC, 2h
SO2Ph
3a
SO2Ph
Trace
Major
R1
O
N
5a
Path-A
OH
N
R1
CrO2 (10 eq), MeCN,
80 ºC, 2 h
86%
O
R1
+
CO2Et
N
N
R1
O
O
R1
1a: R1: 4-Cl-Ph
Path-B
Path-C
CO2Et
4a
2a: R1: 4-Cl-Ph
O
6a
81%
MnO2 (3x3 eq), CH2Cl2,
RT, 9 h
N
Little conversion
R1
almost equal distribution
MnO2 (3x2 eq), CHCl3,
65 ºC, 6 h
Minor
Major
MnO2 (10 eq), Toluene,
80 ºC, 2 h
Scheme 1. Fate of aldoxime 1a when treated with CrO2 in presence or absence of dipolarophiles.
Table 2
To execute 1,3-DC reactions, adoxime 1a was treated with
dipolarophiles 3a and 4a separately in presence of 10 mol equiv
of CrO2 in either toluene or MeCN at 80 °C for 2 h. The desired
products 5a and 6a were obtained in high yields (Scheme 1,
Path-C) along with minor amount of deoximation product in each
case. An attempt to accomplish these reactions by using 5 mol e-
quiv of CrO2 led to incomplete reactions even after 6 h.
Following the typical procedure described for 5a and 6a, the
present methodology was elaborated to a variety of aldoximes 1
and various choices of alkenes 3 or alkynes 4. These reactions were
carried out using stoichiometric amounts of aldoximes and dipol-
arophiles, except in the case of volatile substrates (3 equiv excess
used). The corresponding cycloaddition products 5b–u and 6b–q
were obtained in high yields after column or preparative thin layer
chromatography (Table 1 and 2 and Fig. 1). While the aromatic and
heteroaromatic aldoximes led to higher yields of cycloaddition
products (80–90%), relatively less yields were obtained from the
aliphatic aldoximes (e.g., 5g–i, 5u and 6g–j: 63–78%) due to the
formation of 15–25% of deoximation products. The regiochemistry
of cycloaddition products 5 and 6 was established based on 1H
NMR analysis and literature precedence available for this class of
compounds. Small amounts of other regioisomers (less than 10%)
were also obtained in the case of 5e–i, 5k, 5q, and 6g–i.
Synthesis of isoxazolines 5j–n and isoxazoles 6k–o from 1a and various alkenes 3 or
alkynes 4
X
CrO2, MeCN,
80 ºC, 2 h
X
HO
N
X
or
O
N
X
O
N
or
+
R1
R1
6k-o
6a (% yield)
R1
1a
3 or 4
5j-n
3
X
5a (% yield)
4
X
3b
3c
3d
3e
3f
Ph–
5j (82)
5k (80)
5l (84)
5m (89)
5n (88)
4b
4c
4d
4e
4f
Ph–
6k (85)
6l (80)
6m (80)
6n (85)
6o (86)
–CO2Et
–CN
–CH2–OTBS
–CH2–OTHP
–CH2N(H)Boc
TMS–
–Bn
AcO–
a
Major regioisomer formed.
Substrate generality of the present methodology was further
established through the construction of trisubstituted ring systems
(e.g., 5p–t and 6p–q). Chosen examples with commonly used pro-
tecting groups, for example, –OTBS, –OTHP, –N(H)Boc, –TMS, and
acetonide (e.g., 6l–o, 6j, and 5u), as well as cases with electron-rich
Table 1
OH
Me
CO2Et
R1
Br
O
Synthesis of isoxazolines 5b–i and isoxazoles 6b–j from various aldoximes 1 and
respective 1,3-dipolarophile 3a or 4a
N
CO2Me
R1
O
N
O
N
O
N
F
O
N
CO2Et
SO2Ph
O2N
CrO2, MeCN,
80 ºC, 2 h
CO2Et
R1
HO
O
N
O
N
R1
or
5r (75%)
(1:2 diast. mix)
+
3a or 4a
N
5o (90%)
5p (85%)
5q (80%)
R
R
R
1
5b-i
6b-j
Ph
CO2Me
CO2Et
Me
1
R
Description
5a (% yield)
6a (% yield)
H
CO2Me
O
O
H
O
N
1b
1c
1d
1e
R2
R3
R4
R5
R6
R7
R8
R9
4-Br–Ph–
5b (85)
5c (80)
5d (83)
5e (82)
5f (84)
5g (70)
5h (67)
5i (65)
6b (83)
6c (78)
6d (85)
6e (87)
6f (80)
6g (68)
6h (65)
6i (63)
O
N
O
N
O
N
N
Thiophen-2-yl–
Pyridin-2-yl–
4-(MeS)–Ph–
4-(MeO)–Ph–
2-Phenylethyl–
2-Methylpropyl–
Cyclohexyl–
H
R1
R1
H
R10
R1
R1
1f
5u (78%)
1gb
1hb
1ib
5s (85%)
6q (84%)
5t (87%)
6p (90%)
(1:1 dist. mix)
O
N
O
N
Br
Br
O
O
1jb
R10
6j (75)
O
O
7 (80%)
8 (75%)
BnO
Major regioisomer formed.
ꢀ60:40 mixture of E and Z isomers used.
O
a
Figure 1. Additional examples of isoxazoles and isoxazolines synthesized using
b
TM
Magtrieve methodology.

3950
S. Bhosale et al. / Tetrahedron Letters 50 (2009) 3948–3951
groups, for example, 5c–e and 6c–e further proved the mildness of
stirred under heating at 80 °C for 2 h. The reaction mixture was fil-
tered through Celite bed. Magtrieve was washed with ethyl acetate
TM
the method.
TM
When compared to MnO2, Magtrieve showed clear advantages
(20 ml  2). The combined filtrate was condensed to give the crude
product, which was purified by silica gel prep. TLC (20% ethyl ace-
tate in hexanes) to obtain 5a (163 mg, 86%). Rf-value: 0.4 (20% ethyl
acetate in hexanes). Mp: 142–144 °C. 1H NMR (400 MHz; CDCl3): d
3.81 (dd, J = 18.3, 10.8 Hz, 1H); 4.08 (dd, J = 18.3, 4.5 Hz, 1H); 5.59
(dd, J = 10.8, 4.5 Hz, 1H); 7.42 (d, J = 8.6 Hz, 2H); 7.58 (d, J = 8.6 Hz,
2H); 7.63 (t, J = 7.6 Hz, 2H); 7.73 (t, J = 7.5 Hz, 1H); 8.03 (d,
J = 7.7 Hz, 2H). 13C NMR (100 MHz; CDCl3): d 36.46, 93.13, 125.58,
128.12 (2C), 129.01(2C), 129.12(2C), 129.54(2C), 134.51, 134.86,
137.03, 155.88. LC–MS (m/z): 322 [M(35Cl)+1], 339 [M(35Cl)+18]
base peak. HPLC purity: 98.4%.
in (i) overcoming the substrate limitation (ii) avoiding inconve-
nience that is caused by successive addition of reagent, and of
course longer reaction time, (iii) controlling the formation of deox-
imation product. In addition to above advantages, CrO2 did not lead
to overoxidation of isoxazolines to isoxazoles which otherwise was
reported10 for MnO2 at higher temperature. Therefore, it is evident
TM
that Magtrieve has clearly overcome the limitations of MnO2 as
reagent for 1,3-DC reactions.
TM
In some instances, Magtrieve was found to be more efficient
than previously known halogenating or equivalent reagents. For
example, the synthesis of 5r needed overnight reaction when
NaOCl was used11 as reagent whereas CrO2 treatment required
only 2 h. In addition, NaOCl was found to be a very poor reagent
for S-containing substrates 1c and 1e leading to intractable reac-
tion mixtures whereas CrO2 led to smooth reactions. Similarly,
use of N-chlorosuccinimide (NCS) and a recently reported hyperva-
lent iodine reagent di-acetoxyiodobenzene (DIB) provided only
modest yields of cycloaddition products from (p-thiomethyl)ben-
zaldoxime 1e. On the other hand, the examples with thiophene
compounds 5c and 6c in the present study suggested that Mag-
Typical synthesis of 6a:14b Using 4-chlorobenzaldoxime (100 mg,
0.64 mmol, 1 equiv), ethyl propiolate (190 mg, 1.93 mmol,
TM
3.0 equiv), and 10 equiv of Magtrieve in 3.2 mL acetonitrile, the
reaction was carried out as described for 5a to obtain the desired
product 6a (130 mg, 81%). Rf-value: 0.7 (20% ethyl acetate in hex-
anes). Mp: 136–138 °C (lit.14b 136–138 °C). 1H NMR (400 MHz;
CDCl3): d 1.47 (t, J = 7.1 Hz, 3H); 4.49 (q, J = 7.1 Hz, 2H); 7.25 (s,
1H); 7.49 (d, J = 8.4 Hz, 2H); 7.81 (d, J = 8.4 Hz, 2H). 13C NMR
(100 MHz; CDCl3): d 13.94, 62.23, 106.95, 126.24, 127.90 (2C),
129.18 (2C), 136.46, 156.44, 160.97, 161.77. LC–MS (m/z): 252
[M(35Cl) +1] base peak, 269 [M(35Cl)+18]. HPLC purity: 99%.
Typical synthesis of 7:14c Using 2-allyloxy-5-bromobenzalde-
TM
trieve would be the choice for substrates that were reported to
be sensitive for partial aromatic halogenation when Cl2, NCS, or
N-bromosuccinimide (NBS) was used as reagent.6d
hyde oxime (400 mg, 1.56 mmol, 1.0 equiv) and Magtrieve
TM
Intramolecular nitrile oxide cycloaddition (INOC) is a powerful
tool to construct often complex chemical structures.12 Robustness
of the current methodology was further established by accom-
plishing such reactions by treatment of oximes derived from
(1.31 g, 15.6 mmol, 10 equiv) in MeCN (8 mL), the reaction was
carried out as described for 5a to obtain the desired product 7
(320 mg, 80%) after silica gel column chromatography (5–20% ethyl
acetate in hexanes). Rf-value: 0.3 (20% ethyl acetate in hexanes).
Mp: 108–109 °C. 1H NMR (400 MHz; CDCl3): d 3.88–4.02 (m, 2H);
4.07–4.14 (m, 1H); 4.71–4.78 (m, 2H); 6.88 (d, J = 8.8 Hz, 1H);
7.45 (dd, J = 8.8, 1.76 Hz, 1H); 7.95 (d, J = 1.76 Hz, 1H). 13C NMR
(100 MHz; CDCl3): d 45.10, 69.08, 70.63, 113.85, 114.48, 119.06,
127.69, 134.89, 151.51, 154.24. LC–MS (m/z): 254 [M(79Br)+1] base
peak., 256 [M(81Br)+1]. HPLC purity: 98%.
2-allyloxy-5-bromobenzaldehyde and 2-propargyloxy-5-bromo-
TM
benzaldehyde with Magtrieve Corresponding chromane deriva-
.
tives 7–813 (Fig. 1) were obtained as intramolecular cycloaddition
products in high yields (see the typical procedure for the synthesis
of 7).
It has been reported in the literature that only (E)-aldoximes
could be oxidized to nitrile oxides when treated with Pb(OAc)4.8a
On the other hand, MnO2 has been shown to produce nitrile oxides
from both (E)-aldoximes and (Z)-aldoximes.8bi In the present work
high yields of cycloaddition products, obtained from the mixture of
(E)- and (Z)-aliphatic oximes 1g–j, indicated that both the regioi-
somers were oxidized to nitrile oxides. Based on the above obser-
vation, a plausible mechanism can be invoked for CrO2-mediated
oxidation of aldoximes to nitrile oxides following Kiegiel’s pro-
posal.8bi Since the formation of aldehydes was found to be signifi-
cantly less under CrO2 treatment than under MnO2, a separate
mechanistic study of CrO2-mediated oxidation of aldoximes has
been undertaken in our laboratory and the results will be reported
in due course.
Acknowledgments
We thank Professor Y. L. N. Murthy (Andhra University), Ma-
hesh Mone (Analytical Dept.), and Vinod P. Vyavahare for their
help. We are grateful to Drs. Rashmi Barbhaiya and Kasim Mookh-
tiar for their support and encouragement.
Supplementary data
Supplementary data (spectral characterization data of 5b–u,
6b–q, and 8) associated with this paper can be found, in the online
version, at doi:10.1016/j.tetlet.2009.04.073.
TM
In conclusion, Magtrieve (CrO2) has been proven to be an effi-
cient reagent for direct oxidation of variety of aldoximes to nitrile
oxides in situ. Using Magtrieve , this Letter has revealed a new pro-
References and notes
TM
}
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the same time demonstrated tolerance toward various protecting
groups and electron-rich functional groups. The methodology has
been shown to be equally versatile for intramolecular nitrile oxide
cycloaddition (INOC) reactions. Hence, the current method should
be the choice for direct oxidation of oximes to nitrile oxides which
are useful intermediates in the organic synthesis.
Taylor, E. C., Ed.; John Wiley & Sons: New York, 1991; Vol. 49, (b) Kozikowski, A.
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Typical synthesis of 5a:14a Phenyl vinyl sulfone (100 mg,
0.59 mmol, 1.0 equiv) and 4-chlorobenzaldoxime (110 mg,
0.71 mmol, 1.2 equiv) were dissolved in 3 mL acetonitrile. Mag-
TM
trieve (Aldrich cat. No. 480037; CAS No. 12018-01-8; 500 mg,
5.95 mmol, 10 equiv) was added and the reaction mixture was

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3951
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´
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TM
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Torssell, K. B. G. Tetrahedron 1984, 40, 2985–2988; (b) Kim, J. N.; Ryu, E. K.
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Tetrahedron Lett. 2006, 47, 1457–1460. and references cited herein.
7. For aldoximes to nitrile oxides using hypervalent iodine reagent
diacetoxybenzene (DIB), see: (a) Das, B.; Holla, H.; Mahender, G.; Banerjee, J.;
Reddy, M. R. Tetrahedron Lett. 2004, 45, 7347–7350; (b) Prakash, O.; Pannu, K.
10. Barco, A.; Benetti, S.; Pollini, G. P. Synthesis 1977, 837.
11. This is in agreement with the literature report for 5r-like compounds prepared
in an overnight reaction using NaOCl procedure: Sammelson, R. E.; Gurusinghe,
C. D.; Kurth, J. M.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 2002, 67, 876–882.
12. (a) Beebe, X.; Chiappari, C. L.; Kurth, M. J.; Schore, N. E. J. Org. Chem. 1993, 58,
7320–7321; (b) Yip, C.; Handerson, S.; Jordan, R.; Tam, W. Org. Lett. 1999, 1,
791–794; (c) Kambe, M.; Arai, E.; Suzuki, M.; Tokuyama, H.; Fukuyama, T. Org.
Lett. 2001, 3, 2575–2578; (d) Shing, T. K. M.; Wong, W. F.; Cheng, H. M.; Kwok,
W. S.; So, K. H. Org. Lett. 2007, 9, 753–756.
13. For similar compounds, see: (a) Lee, G. A. Synthesis 1982, 508–509; (b) Vaidya,
V. V.; Wankhede, K. S.; Salunkhe, M. M.; Trivedi, G. K. Synth. Commun. 2008, 38,
2392–2403; (c) Hassner, A.; Rai, K. M. L. Synthesis 1989, 57–59.
14. (a) For des-Cl 5a: see Ref. 6g.; (b) For 6a, see: Wang, Y.-G.; Xu , W.-M.; Huang,
X.; Synthesis 2007 28–32; (c) For des-Br 7: see Ref. 13c.