Convenient synthesis of 4,5-unsubstituted 3-aroylisoxazoles from methyl aryl ketones and (vinylsulfonyl)benzene in water

Article abstract of DOI:10.1016/j.tetlet.2020.152739

A convenient synthesis of 3-aroylisoxazoles from methyl ketones and (vinylsulfonyl)benzene in 2%TPGS-750-M/H₂O has been developed. This reaction proceeds via tandem tert-butyl nitrite-promoted Csp³-H functionalization of methyl ketones, 1,3-dipolar cycloaddition and base-catalyzed aromatization, providing the corresponding products in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2020.152739

Tetrahedron Letters 64 (2021) 152739
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient synthesis of 4,5-unsubstituted 3-aroylisoxazoles from
methyl aryl ketones and (vinylsulfonyl)benzene in water
⇑
⇑
Liang Wang , Yu Tao, Nana Zhang, Shubai Li
School of Chemical and Pharmaceutical Engineering, Changzhou Vocational Institute of Engineering, Changzhou 213164, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of 3-aroylisoxazoles from methyl ketones and (vinylsulfonyl)benzene in 2%TPGS-
750-M/H2O has been developed. This reaction proceeds via tandem tert-butyl nitrite-promoted Csp3-H
functionalization of methyl ketones, 1,3-dipolar cycloaddition and base-catalyzed aromatization, provid-
ing the corresponding products in moderate to good yields.
Received 19 October 2020
Revised 26 November 2020
Accepted 2 December 2020
Available online 2 January 2021
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
3-Aroylisoxazoles
1,3-Dipolar cycloaddition
Aromatization
Green solvent
Isoxazole motifs exist in many biologically important com-
pounds possessing a variety of biological and pharmaceutical activ-
ities such as antiinflammatory, antifungal, and anticancer activities
[1–4].
The most direct and effective method for the synthesis of isox-
azoles is the 1,3-dipolar cycloaddition of nitrile oxides and alkynes
[5]. Following Huisgen’s classic work, a series of contributions have
been reported using various catalysts [6]. Alternatively, isoxazoles
can be synthesized via the reaction of N-hydroxyl-4-toluenesulfon-
CuBr/K2S2O8 to give benzoylisoxazoles. Recently, the Zhang group
and Wang group independently developed a metal-free Csp3-H
bond functionalization of ketones and tandem cyclization reaction
for the formation of 3-acyl-isoxazoles (Scheme 1b) [17,18].
Inspired by their contributions and in continuation of our inter-
est in green chemistry [19], we herein report a convenient synthe-
sis of 4,5-unsubstituted 3-aroylisoxazoles from methyl arylketones
and (vinylsulfonyl)benzene under mild reaction conditions in
water (Scheme 1c).
amide with
a
,b-unsaturated carbonyl compounds [7], oxidation of
Initially, acetophenone 1a and (vinylsulfonyl)benzene 2 were
chosen as the model substrate to optimize the reaction conditions
for 1,3-dipolar cycloaddition (Table 1).
isoxazolines [8], and the Machetti-De Sarlo reaction [9]. Moreover,
nitro alkanes [10], alkynes [11], primary amines [12], and diazo
compounds have also been employed as nitrile oxide precursors
in the 1,3-dipolar cycloaddition [13].
Although significant progress has been made in this area, the
synthesis of 3-acyl-isoxazoles, particularly 4,5-unsubstituted 3-
aroylisoxazoles, is still less exploited. In 2002, Kai and co-workers
[14] reported the synthesis of 3-benzoylisoxazoles (Scheme 1a).
This protocol involved in situ generation of nitrile oxides from
chloro-oxime derivatives in the presence of NaHCO3, 1,3-dipolar
cycloaddition of nitrile oxides with butyl vinyl ether, and aromati-
zation (10% H2SO4, toluene, reflux). In 2014, Liang and co-workers
disclosed an iron-catalyzed aerobic oxidative reaction to synthe-
size benzoylisoxazoles from homopropargylic alcohol, tert-butyl
nitrite (TBN), and H2O [15]. Later, Yang and co-workers [16]
reported the Csp3-H functionalization of 2-ethylazaarenes with
The solvent played an important role in the reaction. Trace
amount of the desired product 3a was observed in DMF at 80 °C
after 6 h (Entry 1). Switching the solvents to CH3CN, DMSO, toluene
and 1,4-dioxane led to moderate yields (Entries 2–5). This reaction
was also conducted in water; however, 3a was obtained in only
10% yield (entry 6). Then, reactions in water employing different
surfactants including tetrabutylammonium bromide (TBAB), tetra-
butylammonium chloride (TBAC), Tween-80, Triton-X-100, sodium
dodecyl sulfate (SDS), PTS and TPGS were evaluated (Entries 7–13).
⇑
Corresponding authors.
E-mail addresses: 8000000993@czie.edu.cn (L. Wang), sbli@czie.edu.cn (S. Li).
https://doi.org/10.1016/j.tetlet.2020.152739
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

L. Wang, Y. Tao, N. Zhang et al.
Tetrahedron Letters 64 (2021) 152739
equivalents of TBN led to a slightly decrease in the yield, while a
moderate yield was obtained in the presence of one equivalent of
TBN (Entries 16 and 17).
Next, we investigated the aromatization reaction of 3a under
either acidic or basic conditions (Table 2). In contrast to the litera-
ture [14], treatment of 3a with protic acids such as HCl, H2SO4,
TfOH, and TsOH at 80 °C afforded much lower yields of 4a (Entries
1–4). The use of Lewis acids such as BF3ÁOEt2 and FeCl3 also led to
unsatisfactory yields (Entries 5 and 6). We then turned our atten-
tion to examining various bases (Entries 7–15). Generally, bases
are far more effective than acids and showed good catalytic activ-
ities for this transformation, giving 4a in moderate to excellent
yields. Among which, K2CO3 provided the best yield (90%, Entry
8), while KOH, Et3N and DMAP gave poor yields (Entries 10–12).
Finally, the reaction temperature was also checked, and 100 °C
was selected as the best choice (Entries 8, 16 and 17).
With the above optimized reaction conditions in hand, we then
explored the substrate scope [22]. After the 1,3-dipolar cycloaddi-
tion reaction, K2CO3 was added to neutralize the reaction system.
An extra amount of K2CO3 (10 mol%) was then added and the mix-
ture was further stirred at 80 °C. Thus, the purification of com-
pound 3 was avoided. Generally, most of the methyl ketones
reacted with (vinylsulfonyl)benzene to afford compounds 3 with
good conversion as monitored by TLC. The following aromization
reaction also proceeded smoothly, providing the desired products
4 in good yields (4a-4m, 55–82%). Functional groups including
alkyl, methoxy, trifluomethyl, nitro, cyano and halogen were all
well tolerated. The effect of steric hindrance was evaluated, and
both the ortho-and meta-substituted substrates provided the
desired products in good yields. Heteroaryl methyl ketones such
as 2-acetylthiophene, 3-acetylpyridine and 2-acetylpyridine were
Scheme 1. Synthesis of 3-acyl-isoxazoles.
It was worth noting that the yields were significantly increased in
either 2% PTS/H2O or 2% TPGS-750-M/H2O (Entries 12 and 13, 73%
and 86% yield, respectively). These results might be attributed to
the fact that the non-ionic amphiphiles PTS [19a,20] and TPGS-
750-M [19d,21] served as a ‘‘solubilizer” for organic molecules in
water. In addition, Lipshutz’s group have demonstrated reaction
acceleration phenomenon in such micelle systems. Varying the
temperature to 60 °C or 100 °C afforded 3a in 74% and 87% yield,
respectively (Entries 14 and 15). Finally, the use of three
Table 1
Optimization of 1,3-dipolar cycloaddition reaction.a
Entry
Solvent
TBN (eq.)
Temp. (°C)
Yield 3a (%)b
1
2
3
4
5
6
7
8
DMF
MeCN
DMSO
toluene
1,4-dioxane
H2O
TBAC/H2O
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
1.0
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
Trace
34
52
40
41
10
21
25
18
15
16
73
86
74
87
84
54
TBAB/H2O
9
Tween-80/H2O
Triton-X-100/H2O
SDS/H2O
10
11
12
13
14
15
16
17
PTS/H2O
TPGS-750-M/H2O
TPGS-750-M/H2O
TPGS-750-M/H2O
TPGS-750-M/H2O
TPGS-750-M/H2O
a
Reagents and conditions: 1a (0.2 mmol, 1 equiv.), 2 (0.4 mmol, 2 equiv.), TBN, solvent (2 mL, with 2% surfactant if necessary), 6 h.
Isolated yield.
b
2

L. Wang, Y. Tao, N. Zhang et al.
Tetrahedron Letters 64 (2021) 152739
Table 2
Table 3
Optimization of the aromatization reaction.a
Substrate scope.a
Entry
Catalyst
Temp. (°C)
Yield 4a (%)b
1
2
3
4
5
6
7
8
HCl
H2SO4
TfOH
TsOH
BF3ꢀOEt2
FeCl3
Na2CO3
K2CO3
K3PO4
KOH
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
22
48
23
25
31
19
68
90
70
trace
21
16
45
65
40
81
96
9
10
11
12
13
14
15
16
17
Et3N
DMAP
DIPEA
DBU
DBACO
K2CO3
K2CO3
a
Reagents and conditions: 3a (0.2 mmol, 1 equiv.), catalyst (10 mol%), 2%TPGS-
750-M/H2O (2 mL), 6 h.
b
Isolated yield.
also tolerated, giving the corresponding products (4m-4o) in mod-
erate yields. In contrast, aromatic methyl ketone 1p reacted with
(vinylsulfonyl)benzene, while the aromization reaction failed. Only
trace amounts of 4p was observed. In addition, the aliphatic methyl
ketone acetone was also checked; similarly, only intermediate 3q
was observed (Table 3).
To gain insight into the mechanism, selected control experi-
ments were conducted (Scheme 2). None of the desired product
3a was obtained when two equivalents of 2,2,6,6-tetram-
ethylpiperidine N-oxide (TEMPO) was added (Scheme 2a), which
indicated that a radical reaction pathway might be involved in this
process. Treatment of phenyl ethyl ketone 5 with TBN afforded
products 6 and 7 (Scheme 2b). Finally, we tried the one-step reac-
tion by adding K2CO3 before the aromization reaction. However,
only trace amount of 4a was observed (Scheme 2c). This might
be attributed to the K2CO3 being neutralized by the in situ gener-
ated nitrous acid in the first step.
A plausible mechanism was also proposed (Scheme 3). Initially,
thermal hemolysis of TBN generates NO and t-BuO radicals. The
NO2 radical can also be generated during this process via oxidation
or disproportionation [23]. Then, a hydrogen atom of methyl
ketone 1 is abstracted by the t-BuO radical, which is further
attacked by NO or NO2 radicals to give intermediates A or D [18].
Based on the control experiments (Scheme 2b), two pathways
might be involved. First, intermediate A is converted to B by tau-
tomerization, which is further attacked by the t-BuO radical and
NO2 radical to give nitrile oxide C upon releasing nitrous acid. Sec-
ond, intermediate D is attacked by the t-BuO radical to give E.
Intermediate E reacts with the NO or NO2 radical to give F. Inter-
mediate F is converted to nitrile oxide C upon releasing nitrous
acid. Finally, C and 2 undergo the 1,3-dipolar cycloaddition reac-
tion to give 3. Deprotonation and aromization of 3 provides the
desired product 4.
a
Reagents and conditions: 1 (0.2 mmol, 1 equiv.), 2 (0.4 mmol, 2 equiv.), TBN
(0.4 mmol, 2 equiv.), 2%TPGS-750-M/H2O (2 mL), 80 °C, 6 h. Then adjust the pH = 7,
K2CO3 (0.1 equiv.), 100 °C, 6 h. bOverall yield.
In summary, a convenient synthesis of 3-aroylisoxazoles from
methyl ketones and (vinylsulfonyl)benzene in 2%TPGS-750-M/
H2O has been developed. This reaction proceeded via tandem
tert-butyl nitrite-promoted Csp3-H functionalization of methyl
ketones, 1,3-dipolar cycloaddition and base-catalyzed aromatiza-
tion, providing the corresponding products in moderate to good
yields. Control experiments showed that two pathways might be
involved. Both
are crucial for this reaction.
a-nitro ketone and a-nitroso ketone intermediates
3

L. Wang, Y. Tao, N. Zhang et al.
Tetrahedron Letters 64 (2021) 152739
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152739.
References
[1] M.P. Giovannoni, C. Vergelli, C. Ghelardini, N. Galeotti, A. Bartolini, V. Dal Piaz,
J. Med. Chem. 46 (2003) 1055.
[2] J. Kaffy, R. Pontikis, D. Carrez, A. Croisy, C. Monneret, J.-C. Florent, Bioorg. Med.
Chem. 14 (2006) 4067.
[3] A. Kamal, J. Surendranadha Reddy, M. Janaki Ramaiah, D. Dastagiri, E. Vijaya
Bharathi, M. Ameruddin Azhar, F. Sultana, S. Pushpavalli, M. Pal-Bhadra, A.
Juvekar, Eur. J. Med. Chem. 45 (2010) 3924.
[4] A. Kamal, E.V. Bharathi, J.S. Reddy, M.J. Ramaiah, D. Dastagiri, M.K. Reddy, A.
Viswanath, T.L. Reddy, T.B. Shaik, S. Pushpavalli, M.P. Bhadra, Eur. J. Med.
Chem. 46 (2011) 691.
Scheme 2. Control experiments.
[5] R. Huisgen, Angew. Chem. Int. Ed. 2 (1963) 565.
[6] (a) F. Himo, T. Lovell, R. Hilgraf, V.V. Rostovtsev, L. Noodleman, K.B. Sharpless,
V.V. Fokin, J. Am. Chem. Soc. 127 (2005) 210;
(b) T.V. Hansen, P. Wu, V.V. Fokin, J. Org. Chem. 70 (2005) 7761;
(c) J.P. Waldo, R.C. Larock, Org. Lett. 7 (2005) 5203;
(d) M.P. Bourbeau, J.T. Rider, Org. Lett. 8 (2006) 3679;
(e) J.P. Waldo, R.C. Larock, J. Org. Chem. 72 (2007) 9643;
(f) J. Xu, A.T. Hamme II, Synlett (2008) 919;
(g) B. Willy, F. Rominger, T. Müller, Synthesis (2008) 293;
(h) J.A. Crossley, D.L. Browne, J. Org. Chem. 75 (2010) 5351;
(i) C. Praveen, A. Kalyanasundaram, P.T. Perumal, Synlett (2010) 777;
(j) E. Gayon, O. Quinonero, S. Lemouzy, E. Vrancken, J.-M. Campagne, Org. Lett.
13 (2011) 6418;
(k) O. Jackowski, T. Lecourt, L. Micouin, Org. Lett. 13 (2011) 5664;
(l) A. Yoshimura, K.R. Middleton, A.D. Todora, B.J. Kastern, S.R. Koski, A.V.
Maskaev, V.V. Zhdankin, Org. Lett. 15 (2013) 4010;
(m) R. Harigae, K. Moriyama, H. Togo, J. Org. Chem. 79 (2014) 2049;
(n) W. Chen, B. Wang, N. Liu, D. Huang, X. Wang, Y. Hu, Org. Lett. 16 (2014)
6140;
(o) Y. Jeong, B. Kim, J.K. Lee, J.-S. Ryu, J. Org. Chem. 79 (2014) 6444;
(p) M. Hu, X. He, Z. Niu, Z. Yan, F. Zhou, Y. Shang, Synthesis 46 (2014) 510;
(q) K.S. Kadam, T. Gandhi, A. Gupte, A.K. Gangopadhyay, R. Sharma, Synthesis
48 (2016) 3996;
(r) K.N. Tu, J.J. Hirner, S.A. Blum, Org. Lett. 18 (2016) 480;
(s) Y. Ning, Y. Otani, T. Ohwada, J. Org. Chem. 83 (2018) 203;
(t) P.V. Khairnar, T.-H. Lung, Y.-J. Lin, C.-Y. Wu, S.R. Koppolu, A. Edukondalu, P.
Karanam, W. Lin, Org. Lett. 21 (2019) 4219;
(u) C. Li, J. Li, F. Zhou, C. Li, W. Wu, J. Org. Chem. 84 (2019) 11958;
(v) E. Kobayashi, H. Togo, Synthesis 51 (2019) 3723;
(w) C. Chen, S. Cui, J. Org. Chem. 84 (2019) 12157.
[7] S. Tang, J. He, Y. Sun, L. He, X. She, Org. Lett. 11 (2009) 3982.
[8] (a) Q.-F. Jia, P.M.S. Benjamin, J. Huang, Z. Du, X. Zheng, K. Zhang, A.H. Conney, J.
Wang, Synlett 24 (2013) 79;
(b) S.-R. Sheng, X.-L. Liu, Q. Xu, C.-S. Song, Synthesis (2003) 2763.
[9] M. Vadivelu, S. Sampath, K. Muthu, K. Karthikeyan, C. Praveen, J. Org. Chem. 84
(2019) 13636.
[10] L. Cecchi, F. De Sarlo, F. Machetti, Eur. J. Org. Chem. (2006) 4852.
[11] Z. Lai, Z. Li, Y. Liu, P. Yang, X. Fang, W. Zhang, B. Liu, H. Chang, H. Xu, Y. Xu, J.
Org. Chem. 83 (2018) 145.
[12] X.-W. Zhang, W.-L. Hu, S. Chen, X.-G. Hu, Org. Lett. 20 (2018) 860.
[13] X.-D. Wang, L.-H. Zhu, P. Liu, X.-Y. Wang, H.-Y. Yuan, Y.-L. Zhao, J. Org. Chem.
84 (2019) 16214.
[14] H. Kai, M. Tomida, T. Nakai, A. Takase, Heterocycles 57 (2002) 2299.
[15] P. Gao, H.-X. Li, X.-H. Hao, D.-P. Jin, D.-Q. Chen, X.-B. Yan, X.-X. Wu, X.-R. Song,
X.-Y. Liu, Y.-M. Liang, Org. Lett. 16 (2014) 6298.
[16] G.-W. Wang, M.-X. Cheng, R.-S. Ma, S.-D. Yang, Chem. Commun. 51 (2015)
6308.
Scheme 3. Proposed mechanism.
[17] P. Dai, X. Tan, Q. Luo, X. Yu, S. Zhang, F. Liu, W. Zhang, Org. Lett. 21 (2019) 5096.
[18] X. Guo, G. Xu, L. Zhou, H. Yan, X. Hao, Q. Wang, Org. Chem. Front. 7 (2020)
2467.
Declaration of Competing Interest
[19] (a) L. Wang, W. Zhou, S. Chen, M. He, Q. Chen, Adv. Synth. Catal. 354 (2012)
839;
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
(b) Z. Li, L. Wang, Adv. Synth. Catal. 357 (2015) 3469;
(c) L. Wang, J. Shen, S. Yang, W. Liu, Q. Chen, M. He, Green Chem. 20 (2018)
1290;
(d) L. Wang, H. Wang, G. Li, S. Min, F. Xiang, S. Liu, W. Zheng, Adv. Synth. Catal.
360 (2018) 4585.
[20] (a) For selected examples of reactions in PTS/H2O, see: B.H. Lipshutz, S. Ghorai
Aldrichimica Acta 45 (2012) 3;
Acknowledgements
(b) S. Minkler, B.H. Lipshutz, N. Krause, Angew. Chem. Int. Ed. 50 (2011) 7820;
(c) B.H. Lipshutz, S. Ghorai, W. Leong, B.R. Taft, J. Org. Chem. 76 (2011) 5061;
(d) B.H. Lipshutz, S. Ghorai, W. Leong, R. Moser, B.R. Taft, J. Org. Chem. 76
(2011) 5061;
(e) A. Krasovskiy, C. Duplais, B.H. Lipshutz, Org. Lett. 12 (2010) 4742;
(f) T. Nishikata, B.H. Lipshutz, Org. Lett. 2010 (1972) 12;
(g) B.H. Lipshutz, D.W. Chung, B. Rich, Adv. Synth. Catal. 351 (2009) 1717.
We gratefully acknowledge financial support from China Post-
doctoral Science Foundation (2018M632289) and Research Fund
of
Changzhou
Vocational
Institute
of
Engineering
(11120101120002, 11130300120001 and 11130900120004).
4

L. Wang, Y. Tao, N. Zhang et al.
Tetrahedron Letters 64 (2021) 152739
[21] (a) For selected examples of reactions in TPGS/H2O in the last three years, see:
B.S. Takale, R.R. Thakore, F. Kong, B.H. Lipshutz Green Chem. 21 (2019) 6258;
(b) G. Vaidya, S. Fiske, H. Verma, S. Lokhande, D. Kumar, Green Chem. 21
(2019) 1448;
[22] General procedure for the synthesis of 4: A sealed tube equipped with a
magnetic stirrer bar was charged with substrate 1 (0.2 mmol, 1 equiv.), 2 (0.4
mmol, 2 equiv.), TBN (0.4 mmol, 2 equiv.) and 2%TPGS-750-M/H2O (2 mL)
under air. The reaction mixture was then heated to 80 °C and stirred for 6 h.
Upon reaction completion, the solution was neutralized by adding K2CO3, and
an extra amount of K2CO3 (10 mol%) was then added. The mixture was further
stirred at 100 °C for another 6 h. Upon reaction completion, the mixture was
extracted with EtOAc (5 mL Â 3). The collected organic extracts were dried
over Na2SO4. The solvent was then removed under reduced pressure and the
residue was purified by silica gel column chromatography.
(c) N.R. Lee, R. Linstadt, D.J. Gloisten, F. Gallou, B.H. Lipshutz, Org. Lett. 20
(2018) 2902;
(d) M.P. Andersson, F. Gallou, P. Klumphu, B.S. Takale, B.H. Lipshutz, Chem.
Eur. J. 24 (2018) 6778;
(e) B.H. Lipshutz, S. Ghorai, M. Cortes-Clerget, Chem. Eur. J. 24 (2018) 6672;
(f) S. Handa, J.D. Smith, Y. Zhang, B.S. Takale, F. Gallou, B.H. Lipshutz, Org. Lett.
20 (2018) 542;
[23] Y. Liang, X. Li, X. Wang, Y. Yan, P. Feng, N. Jiao, ACS Catal. 2015 (1956) 5.
(g) H. Pang, F. Gallou, H. Sohn, J. Camacho-Bunquin, M. Delferro, B.H. Lipshutz,
Green Chem. 20 (2018) 130.
5