Trichloroisocyanuric Acid Promoted Cascade Cyclization/Trifluoromethylation of Allylic Oximes: Synthesis of Trifluoromethylated Isoxazolines

Article abstract of DOI:10.1021/acs.orglett.6b03582

Cheap and commercially available trichloroisocyanuric acid has been used to promote trifluoromethylation by using TMSCF₃ as the trifluoromethyl source. The method provides a novel and efficient protocol for the construction of CF₃-containing 4,5-dihydroisoxazoles from allylic oximes in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.6b03582

Letter
pubs.acs.org/OrgLett
Trichloroisocyanuric Acid Promoted Cascade Cyclization/
Trifluoromethylation of Allylic Oximes: Synthesis of
Trifluoromethylated Isoxazolines
Weigang Zhang,† Yingpeng Su,† Ke-Hu Wang,† Lili Wu,† Bingbing Chang,† Ya Shi,† Danfeng Huang,†
and Yulai Hu*,†,‡
†College of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning East Road, Lanzhou 730070, P. R.
China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: Cheap and commercially available trichloroisocyanuric acid
has been used to promote trifluoromethylation by using TMSCF3 as the
trifluoromethyl source. The method provides a novel and efficient protocol
for the construction of CF3-containing 4,5-dihydroisoxazoles from allylic
oximes in good to excellent yields.
approach toward CF3-containing isoxazolines involves the
cyclization/trifluoromethylation of β,γ-unsaturated oximes.
For instance, Liang’s and Chen’s groups successively reported
the synthesis of CF3-containing isoxazolines from β,γ-
unsaturated oximes compounds by using Togni’s reagent and
Umemoto’s reagent as the trifluoromethylating reagents,
respectively.7d,9c However, these protocols suffer from moder-
ate yields of the products, high price, and nonavailability of the
trifluoromethylating reagents on large scale in industry.
Therefore, it is highly desirable to develop new protocols for
incorporation of the CF3 group into isoxazolines.
Trichloroisocyanuric acid (TCCA) is used as a versatile and
innocuous oxidant or chlorinating reagent with high stability in
industry.10 In the realm of synthetic organic chemistry, TCCA
has been widely applied in a variety of reactions due to its low
price, ready availability, environmentally benign attributes, and
ability to serve as a source of three chlorine atoms for a variety
of reactions.11 However, the TCCA-promoted strategy to
achieve highly functionalized fluorine-containing compounds is
quite limited (Scheme 1).12 Until now, only halofluorination of
alkenes and trifluoromethylthiolation promoted by TCCA have
been reported. TCCA-mediated trifluoromethylation of allylic
oximes remains unexplored. Herein, we report the TCCA-
promoted cyclization/trifluoromethylation of allylic oximes by
using TMSCF3 as trifluoromethyl source, which provided a
concise and efficient method for preparation of trifluoromethyl-
substituted 4,5-dihydroisoxazoles.
soxazolines are important structural motifs existing in
1
pharmaceuticals,2 and agro-
Inumerous natural products,
chemicals.3 They also serve as important building blocks in
organic synthesis as well as chiral ligands in asymmetric
catalysis.4 Therefore, it is not surprising that many efforts have
been devoted to the construction of the isoxazoline scaffold
over the past decades.5 On the other hand, the incorporation of
fluorinated moieties, particularly the CF3 group, into drug
candidates can significantly alter their lipophilicity, metabolic
stability, and bioavailability owing to the unique properties of
the CF3 group.6 Thus, the synthesis of CF3-containing
compounds has attracted considerable research interest in
recent years. To date, a series of trifluoromethylating reagents
have been developed and successfully employed to introduce
the CF3 group into organic compounds.7
Recently, CF3-substituted isoxazolines have been proven to
exhibit remarkable biological activities (Figure 1).7d,8 There-
fore, it is highly desirable to develop efficient methods for the
synthesis of CF3-containing isoxazoline compounds. However,
efficient methods for the introduction of the CF3 group into
isoxazolines have previously been scarce.7d,9 A general synthetic
We initially tested the feasibility of the cyclization/
trifluoromethylation of oxime 1a with TMSCF3 in the presence
of CsF, CuCl, and TCCA in CH3CN under argon atmosphere.
After brief optimization of the mole ratio of the reactants, we
Received: December 1, 2016
Figure 1. Examples of biologically active CF3-containing isoxazolines.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03582
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Organic Letters
Letter
elevated any more when the amount of TCCA was further
increased (Table 1, entry 8). Other additives such as N-
chlorophthalimide or NCS were also examined in the reaction,
but the yield of 5a was not improved (Table 1, entries 9 and
10). Considering that in situ produced CuCF3 may be unstable,
1,10-phenanthroline was added to form a complex [(phen)-
CuCF3] to stabilize in situ formed CuCF3 according to the
literature.14 To our delight, the yield of 5a was greatly increased
to 93% (Table 1, entry 11). Finally, the effects of CuOAc and
TCCA on the reaction were studied. It was found that both of
them were essential to the reaction because no desired product
5a was observed in the absence of CuOAc or TCCA (Table 1,
entries 12 and 13).
Scheme 1. TCCA-Promoted Reactions To Access Fluorine-
Containing Compounds
With the optimal reaction conditions in hand, we next
explored the scope of the reactions with a variety of β,γ-
unsaturated oximes 1. As shown in Scheme 2, all of the
found that the mole ratio of 1:3:3.6:3.6:0.5 for oxime 1a/CuCl/
CsF/TMSCF3/TCCA seemed to be the best one to give the
product 5a in 60% yield and the byproduct 6a in 32% yield,
which was then used to optimize other reaction conditions.
Because of their high efficiency and the relatively low cost,
copper salts are usually used to promote trifluoromethylation
via in situ formation of CuCF3.13 Thus, we screened other
copper salts such as CuCN, CuI, CuCl2, and Cu(OAc)2 (Table
1, entries 2−5). When CuCN was used in the reaction, no
a,b
Scheme 2. Substrate Scope of Reaction
a
Table 1. Optimization of Reaction Conditions
b
yield (%)
entry
copper salt 2
additive (equiv)
TCCA (0.5)
5a
60
6a
32
1
2
CuCl
CuCN
CuI
TCCA (0.5)
TCCA (0.5)
TCCA (0.5)
TCCA (0.5)
TCCA (0.5)
TCCA (0.67)
TCCA (0.84)
N-Cl-phthalimide (2.0)
NCS (2.0)
trace
24
nd
nd
51
82
32
80
19
93
nd
nd
trace
51
c
3
4
CuCl2
98
5
Cu(OAc)2
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
97
a
All reactions were carried out using 0.3 mmol of 1a, 0.67 equiv of
6
nd
TCCA, 3 equiv of CuOAc, 3 equiv of 1,10-phen, 3.6 equiv of
7
nd
b
TMSCF3, 3.6 equiv of CsF, and 8 mL of CH3CN. Isolated yields.
8
54
c
1
The ratio of diastereomers was determined by crude H NMR and
9
nd
19F NMR.
10
66
d
11
TCCA (0.67)
TCCA (0.67)
nd
d
12
d
trace
nd
aromatic oximes 1 with electron-donating or electron-with-
drawing groups on their phenyl rings afforded the desired
isoxazolines 5a−k in excellent yields (85−93%), except for 4-
cyano-substituted oximes 1l, which gave a complex mixture.
Naphthal- and heteroaryl-substituted substrates were also
transformed into the desired products 5m,o in good yields.
The reaction could also be applied to aliphatic oximes such as
1u and 1v, which produced 5u and 5v in 67% and 78% yields,
respectively. The oximes with different allylic groups produced
the products 5q−5t in good yields (85−92%), and substrates
1p gave a mixture of diastereoisomers 5p (dr =1.2:1) in 91%
yield.
In order to further examine the generality of the reaction,
compounds 1w−y were exposed in the optimized reaction
conditions (Scheme 3). The bis-oxime 1w afforded the
monotrifluoromethylated product 5w instead of the bis-
trifluoromethylated one. When oxime 1x was used in the
reaction, no trifluoromethylated product was produced, and
13
CuOAc
a
b
All reactions were carried out by using 0.3 mmol of 1a. Isolated
c
yields. Yield for 5-(iodomethyl)-3-phenyl-4,5-dihydroisoxazole (6aa).
d
3 equiv of 1,10-phen was added to the reaction mixture. nd = not
detected.
reaction occurred (Table 1, entry 2). When CuCl2 and
Cu(OAc)2 were used, only chlorinated byproduct 6a was
obtained in almost quantitative yields. CuI led to the desired
product 5a in only 24% yield, while another iodinated
byproduct 6aa instead of chlorinated 6a was formed in 51%
yield. Encouragingly, the addition of CuOAc made the reaction
produce solely the product 5a in 51% yield without formation
of any byproducts, and 40% of starting material was recovered
(Table 1, entry 6). Encouraged by this result, the amount of
TCCA was increased to 0.67 equiv, and the yield of 5a reached
82% (Table 1, entry 7). Unfortunately, the yield of 5a was not
B
DOI: 10.1021/acs.orglett.6b03582
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TEMPO was added into the reaction mixture under the
standard reaction conditions. TEMPO−CF3 adduct 9 was
obtained only in 12% yield (Scheme 5, b). This meant the
trifluoromethyl radical was not the major intermediate in the
reaction. However, when TEMPO was added into the reaction
mixture with oxime 1a as substrate, products 5a and 9 were
formed in 15% and 9% yield, respectively; another product 10
was obtained in 71% yield. This meant that radical 15 was the
major intermediate (Scheme 5, c).
Scheme 3. Scope of Other Substrates
Consequently, a mechanism was suggested on the basis of
experimental results and the literature5e,i,15 (Scheme 6). As
Scheme 6. Proposed Mechanism
only isomerized product 5x was obtained in 80% yield. If oxime
1y was applied as substrate, acetoxylation at the hydroxyl group
occurred to give the product 5y instead of the desired
cyclization/trifluoromethylation reaction.
Isoxazolines are often used as important synthetic building
blocks in organic synthesis.4a,c,f To demonstrate the synthetic
utility of trifluoromethylation products, further transformation
of isoxazolines was examined. For instance, 5a was applied to
reductive ring-opening reactions (Scheme 4). When 5a was
illustrated in Scheme 6, when TMSCF3 was stirred with
CuOAc, CsF, and 1,10-phenanthroline, a complex 11 was
formed first.14 Addition of TCCA and oxime 1a into the
reaction mixture produced radical 12, which abstracted a
proton from the hydroxyl group in oxime 1a to produce radical
14. TCCA was finally converted into isocyanuric acid, which
was detected from the reaction mixture. Cyclization of radical
14 gave another carbon radical 15, which abstracted a
trifluoromethyl group from complex 11 to give the final
product 5a.
In conclusion, cheap and commercially available trichlor-
oisocyanuric acid has been used to promote the first
trifluoromethylation by using TMSCF3 as the CF3 source.
Allylic oximes were efficiently converted to trifluoromethylated
4,5-dihydroisoxazoles in good to excellent yields by cascade
cyclization/trifluoromethylation. The related products, trifluor-
omethyl-containing 4,5-dihydroisoxazoles, could be easily
converted into 1,3-amino alcohol and β-hydroxy ketone by
reductive ring-opening reactions. Further studies on TCCA-
promoted trifluoromethylation reactions are currently under-
way in our laboratory.
Scheme 4. Synthetic Applications of Current Method
reacted with NaBH4 in the presence of NiCl2·6H2O, 1,3-amino
alcohol 8 was obtained in 97% yield. If 5a was stirred with Fe
and NH4Cl in EtOH/H2O, β-hydroxy ketone 7 could be
obtained in 92% yield. During these ring-opening reactions, the
trifluoromethyl groups remained unchanged.
To probe the reaction mechanism, some control experiments
were conducted as shown in Scheme 5. Chlorinated product 6a
was obtained as a byproduct at the beginning of our studies.
Thus, the pure 6a was exposed to the standard reaction
conditions, but there was no trifluoromethylated product 5a
formed. These indicated that desired product 5a did not come
from the byproduct 6a (Scheme 5, a). In the second
experiment, the substrate oxime 1a was taken away, and
ASSOCIATED CONTENT
* Supporting Information
Scheme 5. Control Experiments for Mechanism
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03582.
Experimental procedures and compound characterization
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: huyl@nwnu.edu.cn.
ORCID
Yingpeng Su: 0000-0002-4396-4198
Yulai Hu: 0000-0002-9630-4150
C
DOI: 10.1021/acs.orglett.6b03582
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
McTier, T. L.; Pullins, A.; Zinser, E. W.; Meeus, P. F. M.; Woods, D. J.;
Hedges, L.; Stuk, T.; Price, J. E.; Koch, J. D.; Menon, S. R. Bioorg. Med.
Chem. Lett. 2016, 26, 1831.
Notes
The authors declare no competing financial interest.
(9) (a) Furukawa, T.; Nishimine, T.; Tokunaga, E.; Hasegawa, K.;
Shiro, M.; Shibata, N. Org. Lett. 2011, 13, 3972. (b) Kawai, H.; Tachi,
K.; Tokunaga, E.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2011,
50, 7803. (c) He, Y.-T.; Li, L.-H.; Yang, Y.-F.; Wang, Y.-Q.; Luo, J.-Y.;
Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2013, 49, 5687.
(10) (a) Tilstam, U.; Weinmann, H. Org. Process Res. Dev. 2002, 6,
384. (b) Mendonca̧ , G. F.; Sindra, H. C.; de Almeida, L. S.; Esteves, P.
ACKNOWLEDGMENTS
■
We are thankful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21262031 and
21662030) and the State Key Laboratory of Applied Organic
Chemistry, Lanzhou University.
M.; de Mattos, M. C. S. Tetrahedron Lett. 2009, 50, 473. (c) Mishra, A.
K.; Nagarajaiah, H.; Moorthy, J. N. Eur. J. Org. Chem. 2015, 2015,
2733. (d) Gaspa, S.; Porcheddu, A.; De Luca, L. Adv. Synth. Catal.
2016, 358, 154.
(11) (a) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001,
3, 3041. (b) Ye, J.; Wang, Y.; Chen, J.; Liang, X. Adv. Synth. Catal.
2004, 346, 691. (c) Sniady, A.; Morreale, M. S.; Wheeler, K. A.;
Dembinski, R. Eur. J. Org. Chem. 2008, 2008, 3449. (d) Jing, Y.;
Daniliuc, C. G.; Studer, A. Org. Lett. 2014, 16, 4932. (e) Raihan, M. J.;
Rajawinslin, R. R.; Kavala, V.; Kuo, C.-W.; Kuo, T.-S.; He, C.-H.;
Huang, H.-N.; Yao, C.-F. J. Org. Chem. 2013, 78, 8872.
(12) (a) Crespo, L.; Ribeiro, R.; Mattos, M.; Esteves, P. M. Synthesis
2010, 2010, 2379. (b) Xiang, H.; Yang, C. Org. Lett. 2014, 16, 5686.
(c) Zhu, X.-L.; Xu, J.-H.; Cheng, D.-J.; Zhao, L.-J.; Liu, X.-Y.; Tan, B.
Org. Lett. 2014, 16, 2192.
(13) (a) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262.
(b) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.;
Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 20901. (c) Hu, M.; Ni, C.;
Hu, J. J. Am. Chem. Soc. 2012, 134, 15257. (d) Hu, M.; He, Z.; Gao, B.;
Li, L.; Ni, C.; Hu, J. J. Am. Chem. Soc. 2013, 135, 17302. (e) Han, G.;
Wang, Q.; Liu, Y.; Wang, Q. Org. Lett. 2014, 16, 5914.
(14) (a) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2011, 50, 3793. (b) Litvinas, N. D.; Fier, P. S.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 536. (c) Oishi, M.;
Kondo, H.; Amii, H. Chem. Commun. 2009, 14, 1909. (d) Weng, Z.;
Lee, R.; Jia, W.; Yuan, Y.; Wang, W.; Feng, X.; Huang, K.-W.
Organometallics 2011, 30, 3229. (e) Shimizu, N.; Kondo, H.; Oishi, M.;
Fujikawa, K.; Komoda, K.; Amii, H. Org. Synth. 2016, 93, 147.
(15) (a) Pratt, D. A.; Blake, J. A.; Mulder, P.; Walton, J. C.; Korth,
H.-G.; Ingold, K. U. J. Am. Chem. Soc. 2004, 126, 10667. (b) Liu, Y.-Y.;
Yang, J.; Song, R.-J.; Li, J.-H. Adv. Synth. Catal. 2014, 356, 2913.
REFERENCES
■
(1) Kaur, K.; Kumar, V.; Sharma, A. K.; Gupta, G. K. Eur. J. Med.
Chem. 2014, 77, 121.
(2) (a) Castellano, S.; Kuck, D.; Viviano, M.; Yoo, J.; Lopez-Vallejo,
́
F.; Conti, P.; Tamborini, L.; Pinto, A.; Medina-Franco, J. L.; Sbardella,
G. J. Med. Chem. 2011, 54, 7663. (b) Jewett, J. C.; Sletten, E. M.;
Bertozzi, C. R. J. Am. Chem. Soc. 2010, 132, 3688. (c) Jullien, N.;
Makritis, A.; Georgiadis, D.; Beau, F.; Yiotakis, A.; Dive, V. J. Med.
Chem. 2010, 53, 208. (d) Poutiainen, P. K.; Palvimo, J. J.; Hinkkanen,
A. E.; Valkonen, A.; Vaisanen, T. K.; Laatikainen, R.; Pulkkinen, J. T. J.
Med. Chem. 2013, 56, 1064.
̈
̈
(3) (a) García-Reynaga, P.; Zhao, C.; Sarpong, R.; Casida, J. E. Chem.
Res. Toxicol. 2013, 26, 514. (b) Hwang, I. T.; Kim, H. R.; Jeon, D. J.;
Hong, K. S.; Song, J. H.; Cho, K. Y. J. Agric. Food Chem. 2005, 53,
8639. (c) Hwang, K.-H.; Lim, J.-S.; Kim, S.-H.; Jeon, M.-S.; Lee, D.-G.;
Chung, K.-H.; Koo, S.-J.; Kim, J.-H. J. Agric. Food Chem. 2013, 61,
9285.
(4) (a) Kozikowski, A. P.; Stein, P. D. J. Am. Chem. Soc. 1982, 104,
4023. (b) Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1, 1795.
(c) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001,
123, 2907. (d) Marotta, E.; Micheloni, L. M.; Scardovi, N.; Righi, P.
Org. Lett. 2001, 3, 727. (e) Muthiah, C.; Arai, M. A.; Shinohara, T.;
Arai, T.; Takizawa, S.; Sasai, H. Tetrahedron Lett. 2003, 44, 5201.
(f) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. J. Am. Chem. Soc.
2005, 127, 5376. (g) Wakita, K.; Bajracharya, G. B.; Arai, M. A.;
Takizawa, S.; Suzuki, T.; Sasai, H. Tetrahedron: Asymmetry 2007, 18,
372.
(5) (a) Lohse-Fraefel, N.; Carreira, E. M. Org. Lett. 2005, 7, 2011.
(b) Adamo, M. F. A.; Nagabelli, M. Org. Lett. 2008, 10, 1807.
(c) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. J. Org. Chem. 2010, 75,
1961. (d) Minakata, S.; Okumura, S.; Nagamachi, T.; Takeda, Y. Org.
Lett. 2011, 13, 2966. (e) Han, B.; Yang, X.-L.; Fang, R.; Yu, W.; Wang,
C.; Duan, X.-Y.; Liu, S. Angew. Chem., Int. Ed. 2012, 51, 8816.
(f) Schmidt, E. Y.; Tatarinova, I. V.; Ivanova, E. V.; Zorina, N. V.;
Ushakov, I. A.; Trofimov, B. A. Org. Lett. 2013, 15, 104. (g) Tripathi,
C. B.; Mukherjee, S. Angew. Chem., Int. Ed. 2013, 52, 8450. (h) Han,
L.; Zhang, B.; Zhu, M.; Yan, J. Tetrahedron Lett. 2014, 55, 2308.
(i) Yang, X.-L.; Chen, F.; Zhou, N.-N.; Yu, W.; Han, B. Org. Lett. 2014,
16, 6476. (j) Dong, K.-Y.; Qin, H.-T.; Liu, F.; Zhu, C. Eur. J. Org.
Chem. 2015, 2015, 1419. (k) Li, C.; Deng, H.; Li, C.; Jia, X.; Li, J. Org.
Lett. 2015, 17, 5718. (l) Chen, F.; Yang, X.-L.; Wu, Z.-W.; Han, B. J.
Org. Chem. 2016, 81, 3042.
(6) (a) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011,
111, 455. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (c) Muller, K.; Faeh, C.; Diederich, F.
̈
Science 2007, 317, 1881.
(7) (a) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 10875. (b) Charpentier, J.; Fruh, N.; Togni, A. Chem.
̈
Rev. 2015, 115, 650. (c) Dai, J.-J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu,
Z.-J.; Lu, X.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 8436. (d) Wei,
Q.; Chen, J.-R.; Hu, X.-Q.; Yang, X.-C.; Lu, B.; Xiao, W.-J. Org. Lett.
2015, 17, 4464. (e) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev.
2015, 115, 683. (f) Nagib, D. A.; MacMillan, D. W. C. Nature 2011,
480, 224.
(8) (a) Cheng, J.-F.; Huang, Y.; Penuliar, R.; Nishimoto, M.; Liu, L.;
Arrhenius, T.; Yang, G.; O’Leary, E.; Barbosa, M.; Barr, R.; Dyck, J. R.
B.; Lopaschuk, G. D.; Nadzan, A. M. J. Med. Chem. 2006, 49, 4055.
(b) Kumar, V.; Kaur, K. J. Fluorine Chem. 2015, 180, 55. (c) Curtis, M.
P.; Vaillancourt, V.; Goodwin, R. M.; Chubb, N. A. L.; Howson, W.;
D
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