Triflic anhydride: A mild reagent for highly efficient synthesis of 1,2-benzisoxazoles, isoxazolo, and isothiazolo quinolines without additive or base

Article abstract of DOI:10.1080/00397911.2013.821617

The synthetic utility of trifluoromethanesulphonic anhydride (triflic anhydride, TA) without additive or base for the high-yielding synthesis of a wide variety of 1,2-benzisoxazoles from 2-hydroxyaryl aldoximes and ketoximes under mild conditions has been carried out for the first time. As a continuation of our study, syntheses of isoxazolo and isothiazolo quinolones have also been demonstrated using triflic anhydride under similar conditions. This method is simple and has benefits from the easy way to isolate the products in excellent yields.

Full text of DOI:10.1080/00397911.2013.821617

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Triflic Anhydride: A Mild Reagent
for Highly Efficient Synthesis of
1,2-Benzisoxazoles, Isoxazolo, and
Isothiazolo Quinolines Without Additive
or Base
Rajesh G. Kalkhambkar a & H. Yuvaraj b
a Department of Chemistry , Karnatak University's Karnatak Science
College , Dharwad , Karnatak , India
b School of Display and Chemical Engineering , Yeungnam
University , Gyeongsan , Gyeoungbuk , Republic of Korea
Published online: 27 Dec 2013.
To cite this article: Rajesh G. Kalkhambkar & H. Yuvaraj (2014) Triflic Anhydride: A Mild Reagent
for Highly Efficient Synthesis of 1,2-Benzisoxazoles, Isoxazolo, and Isothiazolo Quinolines Without
Additive or Base, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:4, 547-555, DOI: 10.1080/00397911.2013.821617
To link to this article: http://dx.doi.org/10.1080/00397911.2013.821617
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Synthetic Communications1, 44: 547–555, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.821617
TRIFLIC ANHYDRIDE: A MILD REAGENT FOR HIGHLY
EFFICIENT SYNTHESIS OF 1,2-BENZISOXAZOLES,
ISOXAZOLO, AND ISOTHIAZOLO QUINOLINES
WITHOUT ADDITIVE OR BASE
Rajesh G. Kalkhambkar1 and H. Yuvaraj2
1Department of Chemistry, Karnatak University’s Karnatak Science College,
Dharwad, Karnatak, India
2School of Display and Chemical Engineering, Yeungnam University,
Gyeongsan, Gyeoungbuk, Republic of Korea
GRAPHICAL ABSTRACT
Abstract The synthetic utility of trifluoromethanesulphonic anhydride (triflic anhydride, TA)
without additive or base for the high-yielding synthesis of a wide variety of 1,2-benzisoxazoles
from 2-hydroxyaryl aldoximes and ketoximes under mild conditions has been carried out for
the first time. As a continuation of our study, syntheses of isoxazolo and isothiazolo
quinolones have also been demonstrated using triflic anhydride under similar conditions. This
method is simple and has benefits from the easy way to isolate the products in excellent yields.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Aldoximes; 1,2-benzisoxazoles; isothiazolo quinolones; isoxazolo quinolones;
ketoximes; triflic anhydride
Received April 24, 2013.
Address correspondence to Rajesh G. Kalkhambkar, Department of Chemistry, Karnatak
University’s Karnatak Science College, Dharwad, Karnatak 580001, India. E-mail: rgkalkhambkar@
gmail.com
547

548
R. G. KALKHAMBKAR AND H. YUVARAJ
INTRODUCTION
Because of their profound biological and pharmacological applications,
1,2-benzisoxazoles are useful intermediates in medicinal chemistry.[1–6] In view of
their extensive biological and pharmacological applications, many synthetic methods
have been developed to construct these nitrogen–oxygen heterocycles,[7] such as
cycloaddition of benzynes and nitrile oxides,[8] copper-catalyzed cyclization of
Z-oximes,[9] and the reaction of hydroxylamine-o-sulfonic acid with 2-hydroxyphenyl
carbonyl compounds.[10] In the past decade, many catalysts have also been developed
for the synthesis of 1,2-benzisoxazoles, which includes the base-catalyzed cyclization
of 2-hydroxyaryl aldoximes and ketoximes with Ac2O,[11,12] SOCl2,[13] Ga(OTf)3,[14]
Ph3P,[15] and trichloroacetyl isocyanate.[16] Although some benefits are there for each
of the reported methods, the limitations and drawbacks associated with the synthesis
of 1,2-benzisoxazoles in these reports,[17,18] directed us to find a new and simple way
of accessing the target molecules.
Generally, many benzo=hetero fused isoxazole derivatives and isothiazole deri-
vatives exhibit a wide variety of pharmacological properties, as the structural units of
many molecules consisting of 1,2-benzisoxazole moiety.[20] In particular, isothiazolo
quinolines are known to possess antibacterial activity.[21] A number of methods are
available in the literature for the synthesis of these heterocycles because of their great
synthetic and medicinal importance.[22–26] However, triflic anhydride–mediated
simple synthesis of isoxazolo and isothiazolo quinolines without additive or base
has not been reported yet. Recently, we have demonstrated the synthesis of simple
1,2-benzisoxazole by the utility of N-triflylimidazole, an in situ–generated reagent
by the reaction of triflic anhydride and imidazole,[19] which prompted us to synthe-
size a series of such compounds in the absence of imidazole. Hence, in continuation
of our work on the use of triflic anhydride (TA), we now report the synthesis of
1,2-benzisoxazoles, isoxazolo quinolines, and isothiazolo quinolines under mild
and neutral reaction conditions at room temperature without the formation of any
side products.
RESULTS AND DISCUSSION
To optimize the reaction conditions such as temperature, solvent, and amount of
reagent, and to study the feasibility of TA-mediated synthesis of 1,2-benzisoxazoles,
the cyclization of salicylaldoxime to its corresponding 1,2-benzisoxazole (Scheme 1)
was selected as a model.
The reaction was carried out at room temperature with equivalent amount of
TA in dichloromethane (DCM). Addition of the TA produced the corresponding
1,2-benzisoxazole at rt in moderate yield in 4 h (Table 1, entry 1). The successful
synthesis of 1,2-benzisoxazole derivatives via the cyclization of different aldoximes
Scheme 1. Synthesis of 1,2-benzisoxazole (1) from salicylaldoxime using TA.

SYNTHESIS OF 1,2-BENZISOXAZOLES
549
Table 1. Synthesis of 1,2-benzisoxazoles using TA
Isolated
yielda (%)
Entry
1
Compound
Substrate
Product
Time (h)
4
1
72
2
3
2
3
3
3
93
90
4
5
4
5
3
5
88
97
6
7
8
6
7
8
4
4
3
90
86
91 (88b)
9
9
3
2
86 (82b)
10
10
85
(Continued )

550
R. G. KALKHAMBKAR AND H. YUVARAJ
Table 1. Continued
Isolated
yielda (%)
Entry
11
Compound
Substrate
Product
Time (h)
11
2
83
94
12
12
4
aIsolated yields of pure products.
bThe reaction was carried out in EDC.
prompted us to investigate the applicability of this procedure for the generation of
other 1,2-benzisoxazoles via the cyclization of variety of ketoximes (Scheme 2).
A similar trend of reaction was observed in the cyclization of oxime of 2-
hydroxyacetophenone to the corresponding 1,2-benzisoxazoles (Table 1, entry 5).
The reaction was completed in 5 h at rt with 96% isolated yield. Thus, the cyclization
of a wide range of structurally varied 2-hydroxyaryl aldoximes and ketoximes in the
presence of TA was carried out under the optimized reaction conditions described
previously. The results (Table 1) show that a variety of structurally varied 2-
hydroxyaryl aldoximes and ketoximes cyclized smoothly in DCM to give the
corresponding 1,2-benzisoxazoles in excellent yield (82% to 96%) and purity.
To evaluate the reactivity of the system with another solvent, we also carried
out the reaction using ethylene dichloride (EDC). With EDC, in two different experi-
ments the cyclization was completed in 3 h at rt with 88 and 82% yields (Table 1,
entries 8 and 9 respectively) and almost the same results were obtained at 80 ꢀC.
Because the results obtained with EDC in terms of reaction time and isolated yield
were not so encouraging in comparison with those of DCM and because EDC is
potentially carcinogenic (cat. 1B), we thought to demonstrate the cyclization in
DCM. As shown in Table 1, the use of this method at room temperature and under
Scheme 2. Synthesis of various substituted 1,2-benzisoxazoles (1–12) from 2-hydroxyaryl aldoximes and
ketoximes using TA.

SYNTHESIS OF 1,2-BENZISOXAZOLES
551
Scheme 3. Synthesis of various substituted isoxazolo and isothiazoloquinolines (13–19) using TA.
neutral conditions gave 83 to 94% yields of various substituted 1,2-benzisoxazoles
(Table 1, entries 6, 7, and 10–12).
In view of the synthetic importance of isoxazolo and isothiazolo quinolines,[20–22]
and as a continuation of this work, we have also demonstrated the synthesis of a
variety of isoxazolo and isothiazolo quinolines via the cyclization of variety of substi-
tuted oximes of 2-chloro-3-formylquinoline and 2-mercapto-3-formylquinoline in the
presence of TA (Scheme 3).
Under the present optimized reaction conditions, a comparatively long reaction
time was observed with substrates such as the oximes of 2-chloro-3-formyl-
7-methoxy-quinolin and 2-chloro-3-formyl-7-methyl-quinolin (Table 2, entries 3 and
Table 2. Synthesis of substituted isoxazolo and isothiazolo quinolines using TA
Isolated
yielda (%)
Entry
1
Compound
Substrate
Product
Time (h)
6
13
84
2
14
6
92
3
4
5
6
7
15
16
17
18
19
8
7
6
5
5
84 (80b)
84 (78b)
74
85
90
aIsolated yields of pure products.
bThe reaction was carried out in EDC.

552
R. G. KALKHAMBKAR AND H. YUVARAJ
Scheme 4. Plausible mechanism of formation of 1,2-benzisoxazole (1) using TA.
4 respectively). Nevertheless, all the oximes of quinoline are cyclized in 5 to 8 h with
excellent yields of 74 to 92%. In comparison with the observed yield of various
products as depicted in Table 2, excellent yields of products are obtained when the
oximes of 2-chloro-3-formyl-4-methyl quinoline (Table 2, entry 2) and 2-mercapto-3-
formyl-7-methyl quinoline (Table 2, entry 7) are subjected to cyclization.
The plausible mechanism of formation of various 1,2-benzisoxazoles is
depicted in Schemes 4–6. The initial step is the reaction between phenolic OH and
Tf2O, which is favored because of high nucleophilicity of phenolic OH and facile
cleavage of the S-O bond. The resulting phenyl trifluoromethyl sulfonate acts as a
better leaving group and facilitates an intramolecular ipso attack by the oxime
hydroxyl group, leading to the expulsion trifluoromethane sulfonic acid and the for-
mation of 1,2-benzisoxazole 1 (Scheme 4).
In the reaction of 2-chloroquinoline-3-aldoxime, the oxime forms a trifluoro-
methane sulfonate, which again brings intramolecular ipso chloro displacement at
C-2 of quinoline by the expulsion of trifluoromethane sulfonylchloride, leading to the
formation of isoxazole-fused quinoline (13) (Scheme 5). Similar structurally analogous
intramolecular reactions have been observed in the formation of pyrazoloquinolines.[28]
In the reaction of 2-mercaptoquinoline-3-aldoximes, the free oxime acts as a
better nucleophile than the tautomeric thiol. The oxime has now been converted into
a better leaving group. The N-S bond formation is triggered by the deprotonation at
the ring N and the nucleophillic attack on the azomethine nitrogen. The N-S bond
formation is facilitates by the facile cleavage of the N-O bond with the loss of
Scheme 5. Plausible mechanism of formation of isoxazoloquinoline (13) using TA.

SYNTHESIS OF 1,2-BENZISOXAZOLES
553
Scheme 6. Plausible mechanism of formation of isothiazoloquinoline (17) using TA.
trifluoromethane sulfonet moiety, leading to the formation of isothiazole fused
quinolines (17) (Scheme 6).
The commen features in this reaction seem to be the formation of
O-trifluoromethanesulfonate and the leaving ability favoring the formation of O-C
and S-N bonds by an intramolecular ipso SN-Ar pathway.
EXPERIMENTAL
The reagents employed were high-purity commercial samples, which were used
as received from vendors without further purification. Reactions were carried out in
an oven-dried round-bottom flask. Column chromatography was performed on
silica gel (200–400 mesh). Thin-layer chromatography (TLC) was performed on
alumina silica gel 60F254 (Fischer) detected by ultraviolet (UV) light (254 nm) and
iodine vapors. The melting points were determined by open capillaries on a Buchi
apparatus and are uncorrected. The infrared (IR) spectra were recorded on a
Nicolet-Impact-410 FT-IR spectrometer, using KBr pellets. 1H NMR and 13C
NMR spectra were recorded on a Bruker AC-300F 300-MHz, spectrometer in
dimethylsulfoxide (DMSO-d6) using tetramethylsilane (TMS) as an internal standard
1
with H resonance frequency of 300 MHz and 13C resonance frequency of 75 MHz.
Gas chromatographic (GC) analyses were performed on an Nucon 5700 series gas
chromatograph. GC-MS analyses were performed on a Shimadzu 2010 series mass
selective detector instrument. Elemental analysis was carried out by using Heraus
CHN rapid analyzer. All the compounds gave C, H, and N analysis within Æ0.4%
of the theoretical values. Dry DCM and EDC were obtained from commercial
sources by the standard procedure.[27]
Typical Procedure for the Synthesis of 1,2-Benzisoxazole Using
Triflic Anhydride
The desired 2-hydroxyaryl aldoxime or ketoxime (2.0 mmol) in 5 mL dry DCM
was taken in an oven-dried round-bottom flask. To the reaction mixture was added
dropwise triflic anhydride (2.0 mmol) in DCM under nitrogen for 15 min. The reac-
tion mixture was stirred at rt and the progress of the reaction was monitored by TLC

554
R. G. KALKHAMBKAR AND H. YUVARAJ
and GC-MS (Table 1). After completion of reaction, the contents were poured on to
crushed ice (100 mL), neutralized with 10% NaHCO3 solution (20 mL), and extracted
with DCM (3 Â 15 mL). The pure products were obtained by column chromato-
graphy with hexane–ethyl acetate mixture (80:20). All the 1,2-benzisoxazole
derivatives were characterized by GC-MS, 1H and 13C NMR, and elemental
analysis, and the results are compared with authentic samples.
Supporting Information
Full experimental details, IR, 1H and 13C NMR spectra, and elemental analysis
can be found via the ‘‘Supplementary Content’’ section of this article’s Web page.
CONCLUSIONS
In conclusion, we have successfully demonstrated the mild, convenient method
for the synthesis of a wide variety of 1,2-benzisoxazoles, from 2-hydroxyaryl aldox-
imes and ketoximes using triflic anhydride. Further we have also demonstrated the
synthesis of different substituted isoxazolo and isothiazolo quinolines using triflic
anhydride at room temperature. This practical and simple method led to good yields
with high purity of 1,2-benzisoxazoles under mild conditions without addition of
external base or additive. This protocol could serve as a valuable alternative to
the known reaction systems.
Further work, including the development of synthetic applications of aryl and
heteroaryl oximes and exploration of the enormous potential of triflic anhydride as a
triflyl source in organic synthesis, is under way in our laboratory.
ACKNOWLEDGMENTS
The authors thank the University Sophisticated Instrument Center, KUD, for
1
IR, GC, GC-MS, H NMR, and 13C NMR and G. Aridoss for useful discussions.
REFERENCES
1. (a) Quilico, A. Isoxazoles and Related Compounds in the Chemistry of Heterocyclic
Compounds; A. Weissberger (Ed.); Interscience: New York, 1962; p. 17; (b) Swinbourne,
J. F.; Hunt, H. J.; Klinkert, G. Adv. Heterocycl. Chem. 1987, 23, 103.
2. Shutske, G. M.; Setescak, L. L.; Allen, R. C.; Davis, L.; Effland, R. C.; Ranbom, K.;
Kitzen, J. M.; Wilker, J. C.; Novick, W. J. J. Med. Chem. 1982, 25, 36.
3. Rangappa, K. S.; Basappa, S. J. Phys. Org. Chem. 2005, 18, 773.
4. Veera Reddy, A.; Rajendiran, C.; Vaishali, N. WO Patent 2005=030738, Sep. 29, 2003;
Chem. Abstr. 2005, 142, 33849.
5. Struczewski, J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B. L.; Glamkovski, E. J.; Jones,
M. C.; Ellis, D. B.; Huger, F. P.; Dunn, R. W. J. Med. Chem. 1985, 28, 761.
6. Grunanger, P.; Vita-Finzi, P. Isoxazoles in the Chemistry of Heterocyclic Compounds; E.
C. Taylor (Ed.); Interscience: New York, 1991; p. 49.
7. Smalley, R. K. Methoden der organischen Chemie, Band E 8 a Hetarene III; Georg Thieme:
Stuttgart, Germany, 1993; vol. 1, p. 226.
8. Crossley, J. A.; Browne, D. L. Tetrahedron Lett. 2010, 51, 2271.

SYNTHESIS OF 1,2-BENZISOXAZOLES
555
´
9. Udd, S.; Jokela, R.; Franzen, R.; Tois, J. Tetrahedron Lett. 2010, 51, 1030.
10. Suwinski, J.; Walczak, K. Pol. J. Chem. 1992, 66, 777.
11. Roman, G.; Comanita, E.; Comanita, B. Tetrahedron 2002, 58, 1617.
12. Jain, M.; Kwon, C. J. Med. Chem. 2003, 46, 5428.
13. Kalkote, U. R.; Goswami, D. D. Aust. J. Chem. 1977, 30, 1847.
14. Yan, P.; Batamack, P.; Surya Prakash, G. K.; Olah, G. A. Catal Lett. 2005, 101, 141.
15. Iranpoor, N.; Firouzabadi, H.; Nowrouzi, N. Tetrahedron Lett. 2006, 47, 8247.
16. Stokker, G. J. Org. Chem. 1983, 48, 2613.
17. Bode, J. W.; Uesuka, H.; Suzuki, K. Org. Lett. 2003, 5, 395.
18. Suwinski, J.; Walczak, K. Pol. J. Chem. 1993, 67, 1267.
19. Kalkhambkar, R. G.; Bunge, S. D.; Laali, K. K. Tettrahedron. Lett. 2011, 52, 5184.
20. (a) Cutri, C. C. C.; Garozzo, A.; Siracusa, M. A.; Castro, A.; Tempera, G.; Sarva, M. C.;
Guerrera, F. Antiviral Res. 2002, 55, 357; (b) Aebi, J.; Ackermann, J.; Dehmlow, H.;
Maerki, H. P.; Morand, O. PCT Int. Appl. WO Patent 0236584, 2002.
21. Chu, D. T. W.; Ferandes, P. B.; Claiborne, A. K.; Shen, L.; Pernet, A. G. Drugs Exp. Clin.
Res. 1998, 14, 378.
22. (a) Dieter, R. K.; Chang, H. J. J. Org. Chem. 1989, 54, 1088; (b) Laaman, S. M.;
Meth-Cohn, O.; Recs, C. W. Synthesis 1999, 757.
23. Zlotin, S. G.; Kislitsin, P. G.; Podgursky, A. I.; Samet, A. V.; Buchana, A. C.; Gakh, A.
A. J. Org. Chem. 2000, 65, 8439.
24. Crenshaw, R. E.; Luke, G. M.; Siminoff, P. J. Med. Chem. 1976, 19, 262.
25. Choi, J. H.; Choi, E. B.; Pak, C. S. Synlett 2003, 166.
26. Nadaraj, V.; Thamarai, S. S. J. Chem. Pharm. Res. 2012, 4(6), 2850.
27. Vogel, A. Practical Organic Chemistry; Longman: New York, 1989.
28. (a) Mali, J. R.; Pratap, U. R.; Jawale, D. V.; Mane, R. A. Tettrahedron. Lett. 2010, 51,
3980; (b) Kedjadga, A.; Moussaoui, F.; Debache, A.; Rhouati, S.; Belfaith, A. J. Soc.
Alger. Chim. 2004, 14, 225.