Regioselective synthesis of 2,6-dimethyl-3,5-bis[(3-aryl-5-trifluoromethyl) -isoxazol-4-carbonyl]-pyridine derivatives

Article abstract of DOI:10.1002/cjoc.201300366

Ethyl 4,4,4-trifluoro-3-oxo-butyrate reacted with 2,6-dimethyl-3,5- diacetyl-pyridine 1 in the presence of NaOC₂H₅ at 0°C to give 2,6-dimethyl-3,5-bis(4,4,4-trifluoro-1,3-oxo-butyl)-pyridine (2a) in good yield. Cyclization reaction o

Full text of DOI:10.1002/cjoc.201300366

FULL PAPER
DOI: 10.1002/cjoc.201300366
Regioselective Synthesis of 2,6-Dimethyl-3,5-bis[(3-aryl-5-
trifluoromethyl)-isoxazol-4-carbonyl]-pyridine Derivatives
Yindi Yang,a Min Zhang,*,a Yiwen Zhu,a Li Zhang,a Qiqiang Xie,a
Liping Song,*,a,b and Hongmei Dengc
a School of Science, Shanghai University, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
c Laboratory for Microstructures, Shanghai University, Shanghai 200444, China
Ethyl 4,4,4-trifluoro-3-oxo-butyrate reacted with 2,6-dimethyl-3,5-diacetyl-pyridine 1 in the presence of
NaOC2H5 at 0 ℃ to give 2,6-dimethyl-3,5-bis(4,4,4-trifluoro-1,3-oxo-butyl)-pyridine (2a) in good yield. Cycliza-
tion reaction of 2a and aryl imidoyl chlorides 5a－5i, obtained from chlorination of aryl oximes with N-chlorosuc-
cimide, afforded 2,6-dimethyl-3,5-bis[(3-aryl-5-trifluoromethyl)-isoxazol-4-carbonyl]-pyridine derivatives 6a－6i.
Keywords cyclization reaction, trifluoromethyl-1,3-diketones, aryl imidoyl chlorides, regioselective, 3,5-bis(5-
trifluoromethyl-isoxazol)-pyridine derivatives
Introduction
Experimental
1H NMR spectra were recorded at 500 MHz with
tetramethylsilane as internal reference. 13C NMR spec-
tra were recorded at 125 MHz with deuterated chloro-
form as internal reference. 19F NMR spectra were re-
corded at 470 MHz with CFCl3 as internal reference.
Deuterated chloroform was the solvent in all cases.
Mass spectra were obtained by using Waters Micromass
GCT. Elemental analysis data were obtained by using
Vario ELIII Analyzer. X-ray crystal structure data were
collected by using BRUKER APEX-Ⅱ CCD.
Pyridine derivatives are useful pharmaceutical inter-
mediates. For example, some benzoxepin [4,3-b] pyri-
dine derivatives have been reported having important
pharmacology properties, such as antitumor, analgesic,
antimicrobial activities.[1-4] Fluorinated organic com-
pounds, in particular, trifluoromethylated compounds,
have received considerable attention due to their unique
biological properties,[5-7] and been used as excellent
building blocks for the construction of more complex
CF3-containing heterocyclic compounds.[8-12] The isoxa-
zole ring system is an major class of five-membered
nitrogen heterocycle and an important core component
in natural products, which is particularly interesting
since it is readily transformed into various biodynamic
agents, including those with antithrombotic, PAF an-
tagonist, and hypolipidemic properties.[13-16]
Therefore, tremendous synthetic approaches for the
construction of the 5-trifluoromethyl isoxazole frame-
work have been actively reported, for example, cycliza-
tion reaction between trifluoromethyl-1,3-dione with
imidoyl chlorides,[17,18] or with hydroxylamine.[19]
However, to date, few reports have appeared on the si-
multaneous construction of bis-5-trifluoromethyl-isoxa-
zole ring systems in one molecule. Herein, we wish to
report a new synthesized pyridine derivatives bearing
bis-5-trifluoromethyl isoxazole ring system via cyclo-
addition reaction of trifluoromethyl-1,3-dione with aryl
imidoyl chlorides.
Melting points were determined in open capillary
tubes and are uncorrected. Flash chromatography was
performed on silica gel (200－300 mesh) with ethyl
acetate/petroleum ether as the eluent.
General procedure for the preparation of 2,6-di-
methyl-3,5-bis[(5-trifluoromethyl)-isoxazol-4-carbon-
yl]-pyridines (one-pot, two-step procedure)
N-Chlorosuccimide (1.9 mmol) was added to a solu-
tion of 4a－4i (1.8 mmol) in DMF (15 mL). The resul-
tant mixture was stirred at 60 ℃ for 1 h, then cooled to
room temperature. The compound 2a (0.9 mmol) and
KHCO3 (2.2 mmol) were added to the above solution at
room temperature. The mixture was continuously stirred
at r.t. and the reaction was monitored by TLC. Until the
completion of the reaction, the mixture was extracted
with ethyl acetate and water three times, the oil lay was
dried over MgSO4 and evaporated under vacuum. The
*
E-mail: mzhang@shu.edu.cn (M. Zhang); lpsong@shu.edu.cn (L. P. Song)
Received April 29, 2013; accepted June 20, 2013; published online July 5, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300366 or from the author.
950
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 950—954

2,6-Dimethyl-3,5-bis[(3-aryl-5-trifluoromethyl)-isoxazol-4-carbonyl]-pyridine Derivatives
crude residue was purified by flash column chromatog-
raphy on silica gel to afford the pure product 6a－6i.
2,6-Dimethyl-3,5-bis[3-(4-nitro-phenyl)-5-trifluoro-
methyl-isoxazol-4-carbonyl]-pyridine (6a): Yellow solid,
(s, 6H); 13C NMR (125 HMz, CDCl3) δ: 185.9, 165.5,
2
164.2, 163.5, 160.4, 157.2 (q, JC-F＝43.0 Hz), 141.6,
1
130.2, 130.1, 128.2, 122.0, 121.9, 118.9, 117.3 (q, JC-F
＝271.0 Hz), 116.9, 116.8, 25.4; 19F NMR (470 MHz,
CDCl3) δ: −62.7 (s, 6F), −107.2 (m, 2F); IR (KBr) ν:
3054, 2998, 1689, 1321, 1211, 1156, 885 cm−1; MS (EI,
70 eV) m/z (%): 621 (M＋, 20), 552 (100), 293 (23), 258
(44), 161 (23), 95 (34). Anal. calcd for C29H15F8N3O4: C
56.05, H 2.43, N 6.76; found C 56.04, H 2.44, N 6.73.
2,6-Dimethyl-3,5-bis[3-(4-methyl-phenyl)-5-trifluo-
romethyl-isoxazol-4-carbonyl]-pyridine (6f): Yellow
1
m.p. 194.2－195.6 ℃; H NMR (500 MHz, CDCl3) δ:
8.23 (d, J＝8.5 Hz, 4H), 7.65 (d, J＝8.5 Hz, 4H), 7.64
(s, 1H), 2.81 (s, 6H); 13C NMR (125 MHz, CDCl3) δ:
2
185.4, 164.3, 160.1, 157.6 (q, JC-F＝43.0 Hz), 149.5,
140.9, 131.8, 129.3, 128.6, 124.5, 119.0, 116.2 (q,
19
1JC-F＝275.0 Hz), 25.4; F NMR (470 MHz, CDCl3) δ:
−62.3 (s, 6F); IR (KBr) ν: 3085, 2861, 1676, 1526, 852,
692 cm−1; MS (EI, 70 eV) m/z (%): 675 (M＋, 14), 658
(23), 606 (100), 235 (22), 76 (23). Anal. calcd for
C29H15F6N5O8: C 51.57, H 2.24, N 10.37; found C 51.60,
H 2.41, N 10.27.
1
solid, m.p. 195－197 ℃; H NMR (500 MHz, CDCl3)
δ: 7.38 (s, 1H), 7.16 (d, J＝8 Hz, 4H), 7.07 (d, J＝8 Hz,
4H), 2.82 (s, 6H), 2.28 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ: 186.1, 164.0, 161.0, 157.1 (q, 2JC-F＝43.0 Hz),
142.0, 141.9, 130.1, 127.7, 122.8, 119.1, 117.4 (q,
1JC-F＝271.0), 25.3, 21.4; 19F NMR (470 MHz, CDCl3)
δ: −62.8 (s, 6F); IR (KBr) ν: 3031, 3006, 2968, 2925,
1676, 1320, 1204, 1140, 881, 748 cm−1; MS (EI, 70 eV)
m/z (%): 613 (M＋, 78), 544 (80), 254 (48), 204 (48), 91
(100). Anal. calcd for C31H21F6N3O4: C 60.69, H 3.45,
N 6.85; found C 60.83, H 3.67, N 6.71.
2,6-Dimethyl-3,5-bis[3-(4-cyano-phenyl)-5-trifluoro-
methyl-isoxazol-4-carbonyl]-pyridine (6b): White solid,
1
m.p. 165.7－167.2 ℃; H NMR (500 MHz, CDCl3) δ:
7.69 (d, J＝8.5 Hz, 4H), 7.58 (d, J＝8.5 Hz, 4H), 7.58
(s, 1H), 2.81 (s, 6H); 13C NMR (125 MHz, CDCl3) δ:
2
185.5, 164.2, 160.3, 157.5 (q, JC-F＝43.0 Hz), 140.8,
133.1, 130.1, 128.9, 128.6, 119.0, 117.5, 117.2 (q,
1JC-F＝271.0 Hz), 115.4, 25.3; 19F NMR (470 MHz,
CDCl3) δ: −62.3 (s, 6F); IR (KBr) ν: 3105, 2988, 2235,
1675, 1168, 879 cm−1; MS (EI, 70 eV) m/z (%): 635
(M＋, 6), 620 (29), 566 (100), 265 (28), 215 (40), 128
(31), 102 (30). Anal. calcd for C31H15F6N5O4: C 58.59,
H 2.38, N 11.02; found C 58.42, H 2.69, N 10.72.
2,6-Dimethyl-3,5-bis[3-(4-methoxy-phenyl)-5-triflu-
oromethyl-isoxazol-4-carbonyl]-pyridine (6g): White
1
solid, m.p. 155.8－157.5 ℃; H NMR (500 MHz,
CDCl3) δ: 7.45 (s, 1H), 7.23 (d, J＝8.5 Hz, 4H), 6.78 (d,
J＝8.5 Hz, 4H), 3.75 (s, 6H), 2.84 (s, 6H); 13C NMR
(125 MHz, CDCl3) δ: 186.3, 164.1, 161.9, 160.7, 156.9
2
2,6-Dimethyl-3,5-bis[3-(4-bromo-phenyl)-5-trifluoro-
methyl-isoxazol-4-carbonyl]-pyridine (6c): Yellow solid,
(q, JC-F＝43.0 Hz), 142.2, 129.4, 127.9, 118.9, 117.8,
1
117.4 (q, JC-F＝271.0 Hz), 114.9, 55.4, 25.4; 19F NMR
1
m.p. 183.7－185.2 ℃; H NMR (500 MHz, CDCl3) δ:
(470 MHz, CDCl3) δ: −62.8 (s, 6F); IR (KBr) ν: 3013,
2941, 1678, 1263, 1176, 883, 840 cm−1; MS (EI, 70 eV)
m/z (%): 645 (M＋, 100), 305 (26), 270 (33), 133 (28),
77 (27). Anal. calcd for C31H21F6N3O6: C 57.68, H 3.28,
N 6.51; found C 57.59, H 3.56, N 6.52.
7.47 (s, 1H), 7.46 (d, J＝8.5 Hz, 4H), 7.20 (d, J＝8.5
Hz, 4H), 2.83 (s, 6H); 13C NMR (125 MHz, CDCl3) δ:
2
185.8, 164.4, 160.5, 157.2 (q, JC-F＝43.0 Hz), 141.6,
132.9, 129.3, 128.1, 126.4, 124.7, 118.8, 117.3 (q,
19
1JC-F＝270.0 Hz), 25.4; F NMR (470 MHz, CDCl3) δ:
2,6-Dimethyl-3,5-bis[3-(5-bromo-pyridin-2-yl)-5-tri-
fluoromethyl-isoxazol-4-carbonyl]-pyridine (6h): Yel-
−62.7 (s, 6F); IR (KBr) ν: 3053, 1682, 1313, 1165, 880
cm−1; MS (EI, 70 eV) m/z (%): 743 (M＋, 19), 674 (100),
320 (38), 275 (61), 155 (43), 102 (37), 75 (30). Anal.
calcd for C29H15Br2F6N3O4: C 46.86, H 2.03, N 5.65;
found C 46.87, H 2.03, N 5.57.
1
low solid, m.p. 155－156 ℃; H NMR (500 MHz,
CDCl3) δ: 8.21－8.20 (m, 2H), 7.91－7.86 (m, 4H),
7.54 (s, 1H), 2.95 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ: 185.1, 163.1, 160.2, 156.3 (q, 2JC-F＝43.0 Hz), 150.5,
143.6, 141.2, 140.3, 128.6, 123.2, 123.1, 119.3, 117.4 (q,
2,6-Dimethyl-3,5-bis[3-(4-chloro-phenyl)-5-trifluoro-
methyl-isoxazol-4-carbonyl]-pyridine (6d): Yellow solid,
19
1JC-F＝270.0 Hz), 24.9; F NMR (470 MHz, CDCl3) δ:
1
m.p. 179.9－181.5 ℃; H NMR (500 MHz, CDCl3) δ:
−63.1 (s, 6F); IR (KBr) ν: 3082, 1676, 1316, 1157, 843
cm−1; MS (EI, 70 eV) m/z (%): 745 (M＋, 5), 676 (100),
158 (78), 156 (78), 76 (34). Anal. calcd for C27H13-
Br2F6N5O4: C 43.52, H 1.76, N 9.40; found C 43.54, H
1.83, N 9.38.
7.47 (s, 1H), 7.29 (d, J＝8.5 Hz, 4H), 7.27 (d, J＝8.5
Hz, 4H), 2.83 (s, 6H); 13C NMR (125 MHz, CDCl3) δ:
2
185.8, 164.3, 160.4, 157.2 (q, JC-F＝43.0 Hz), 141.6,
136.0, 129.8, 129.2, 128.1, 124.2, 118.9, 117.3 (q,
19
1JC-F＝271.0 Hz), 25.4; F NMR (470 MHz, CDCl3) δ:
2,6-Dimethyl-3,5-bis[3-(6-bromo-pyridin-3-yl)-5-tri-
fluoromethyl-isoxazol-4-carbonyl]-pyridine (6i): Yellow
−62.7 (s, 6F); IR (KBr) ν: 3055, 1681, 1313, 1165, 881
cm−1; MS (EI, 70 eV) m/z (%): 653 (M＋, 16), 584 (100),
274 (38), 224 (41), 111 (39), 75 (19). Anal. calcd for
C29H15Cl2F6N3O4: C 53.23, H 2.31, N 6.42; found C
53.27, H 2.41, N 6.46.
2,6-Dimethyl-3,5-bis[3-(4-fluoro-phenyl)-5-trifluoro-
methyl-isoxazol-4-carbonyl]-pyridine (6e): Yellow solid,
m.p. 160－161 ℃; 1H NMR (500 MHz, CDCl3) δ: 7.46
(s, 1H), 7.37－7.34 (m, 4H), 7.04－7.00 (m, 4H), 2.83
1
solid, m.p. 151.6－153.2 ℃; H NMR (500 MHz,
CDCl3) δ: 8.43 (d, J＝3.0 Hz, 2H), 7.72 (dd, J1＝3.0 Hz,
J2＝8.0 Hz, 2H), 7.67 (s, 1H), 7.57 (d, J＝8.0 Hz, 2H),
2.80 (s, 6H); 13C NMR (125 MHz, CDCl3) δ: 185.3,
164.2, 158.7, 157.6 (q, 2JC-F＝43.0), 148.9, 145.5, 140.7,
137.7, 128.9, 128.6, 121.6, 118.7, 117.2 (q, 1JC-F＝271.0
Hz), 25.4; 19F NMR (470 MHz, CDCl3) δ: −62.2 (s, 6F);
IR (KBr) ν: 3084, 3054, 1676, 1311, 1144, 882 cm−1;
Chin. J. Chem. 2013, 31, 950—954
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951

Yang et al.
FULL PAPER
MS (EI, 70 eV) m/z (%): 745 (M＋, 7), 730 (100), 676
(43), 608 (51), 319 (34), 271 (50), 158 (60), 103 (84),
76 (61). Anal. calcd for C27H13Br2F6N5O4: C 43.52, H
1.76, N 9.40; found C 43.65, H 1.81, N 9.49.
1, Entry 6). However, the reaction at elevated tempera-
ture resulted in the complicated products, TLC analysis
showed that only a trace of desired product was detected,
and a large amounts of unidentified by-products were
formed (Table 1, Entry 7).
Results and Discussion
Table 1 Optimization of reaction conditions for the cycloaddi-
tion reaction of 5a and 2a
The synthetic route for preparation of 2,6-dimethyl-
3,5-bis(4,4,4-trifluoro-1,3-oxo-butyl)-pyridine (2a) was
illustrated in Scheme 1. 2 equiv. of ethyl 4,4,4-trifluoro-
3-oxo-butyrate was added dropwise to a stirring solution
of 2,6-dimethyl-3,5-diacetyl-pyridine (1) in the presence
of NaOC2H5 in EtOH at 0 ℃. After the completion of
the reaction (monitored by TLC), the solvent was then
evaporated and the residue was purified by flash column
chromatography on silica gel to afford the pure product
2a.
Aryl imidoyl chlorides 5 were readily synthesized by
chlorination of the corresponding aryl oximes, obtained
from the acidic catalytic dehydration of aromatic alde-
hydes 3a－3i and hydroxylamine, with NCS in high
yields according to the reported methods (Scheme
2).[20-24]
Entry
Base
Et3N
T/℃
25
25
25
25
25
5
Solvent
DMF
Yielda/%
b,d
1
2
3
4
5
6
7
－
NaOH
DMF
traced
30.2c
27.5c
29.3c
23.0c
traced
KHCO3
KHCO3
KHCO3
KHCO3
DMF
THF
95% EtOH
DMF
KHCO3
60
DMF
b
c
a Isolated yield. No product was detected. Reaction conditions:
5a－5i (2 mmol) and 2a (1 mmol), 6 h. d Reaction conditions:
5a－5i (2 mmol) and 2a (1 mmol), 12 h.
After briefly screening the reaction conditions, we
next investigated the possibility of the above-reaction in
one-pot, two-step manner. It was found that the cycliza-
tion reaction could be performed by one-pot, two-step
reaction in DMF without further purification of the re-
action intermediates aryl imidoyl chlorides 5. The de-
sired products 6a－6i could be readily obtained by
one-pot procedure from the corresponding compounds
4a－4i without obviously loss of the products yields
(Scheme 3).
Scheme 1
O
O
O
O
O
O
CF3CO2Et (2 equiv.)
NaOC2H5
F3C
CF3
C2H5OH, 0 o
C
N
N
85%
2a
1
Scheme 2
With the suitable reaction conditions in hand, the
scope and limitation of this cyclization reaction was
explored to establish the generality of the process using
one-pot, two-step reaction. The corresponding pyridine
derivatives bearing bis-5-trifluoromethyl isoxazole ring
6a－6i were obtained. The reaction facilitated the vari-
ous aryl imidoyl chlorides bearing either electron-with-
drawing groups such as fluoro, chloro, cyano and nitro
(Table 3, Entries 1－4, 8) or electron-donating groups
such as alkyl and alkoxyl (Table 3, Entries 6, 7). For
other aromatic analogues bearing heteroaryl groups (ie:
pyridin-2-yl, pyridine-3-yl), we also obtained the corre-
sponding products (Table 3, Entries 5, 9).
It was noteworthy that we have made great efforts to
improve the yields of this reaction by screening of vari-
ous inorganic and tertiary amine bases, solvent, reaction
temperatures and by varying of molecular ratio of the
starting materials, unfortunately, all attempts were failed.
The fairly low yields of products were attributed to the
formation of nitrile oxide dimers as major byproducts
under the present reaction conditions[25] and a sterically
demanding of the desired products. XRD analysis
showed that the product 6d adopted a torsional configu-
ration (Figure 1).
.
NH2OH HCl
H
C
NCS
DMF, 60 oC
Ar CHO
3a 3i
Ar
N OH
-
-
95% C2H5OH
4a 4i
Cl
Ar
C
N OH
-
5a 5i
Ar＝p-NO2C6H4, p-NCC6H4, p-BrC6H4, p-ClC6H4, 5-bromo-pyridin-2-
yl, 4-CH3C6H4, 4-CH3OC6H4, 4-FC6H4, 6-bromo-pyridin-3-yl
We initiated our investigation with the cyclization of
2 and 5 in the presence of base (Scheme 3). We firstly
attempted the reaction of 5a and 2a in DMF in the
presence of a little bit excess of Et3N at ambient tem-
perature. However, the desired product was not detected
(Table 1, Entry 1). When the reaction was performed in
the presence of NaOH as base (Table 1, Entry 2), only a
trace of desired product was detected by TLC analysis.
It was found that the reaction in KHCO3 as base gave
the desired product 6a in 30.2% yield (Table 1, Entry 3).
We next examined the same reaction in THF or 95%
EtOH in the presence of the KHCO3 to afford a little bit
lower yields (Table 1, Entries 4, 5). The reaction pro-
ceeded smoothly at ambient temperature, whereas the
reaction at low temperature decreased the yields (Table
952
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 950—954

2,6-Dimethyl-3,5-bis[(3-aryl-5-trifluoromethyl)-isoxazol-4-carbonyl]-pyridine Derivatives
Scheme 3
to nitrile oxides generated in situ form 5.[26]
H
Ar
N
OH
-
C
Conclusions
4a 4i
NCS
DMF
Cl
In conclusion, we have synthesized a series of new
pyridine derivatives 6 bearing bis-5-trifluoromethyl-
isoxazole ring systems with high regioselectivity, which
are potentially important and widely applicable for the
syntheses of pharmaceuticals and agrochemicals. The
simultaneous construction of bis-5-trifluoromethyl-
isoxazole ring systems in one molecule is a practical
way to more complex molecules.
O
O
O
O
Ar
C
N
OH
-
5a 5i
F3C
CF3
O
DMF, r.t.,
O
N
KHCO3
Ar
2a
Ar
N
N
O
O
Acknowledgement
N
CF3
F3C
-
6a 6i
The authors thank the National Natural Science
Foundation of China (NNSFC) (Nos. 21072128,
21272153), the Key Laboratory of Organofluorine
Chemistry, Shanghai Institute of Organic Chemistry for
financial support.
Ar＝p-NO2C6H4, p-NCC6H4, p-BrC6H4, p-ClC6H4, 5-bromo-pyridin-2-
yl, 4-CH3C6H4, 4-CH3OC6H4, 4-FC6H4, 6-bromo-pyridin-3-yl
Table 2 Synthesis of pyridine derivatives 6a－6i
Entry
Ar
p-NO2C6H4
Product
Yielda/%
References
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
30.2
34.5
33.3
29.5
29.2
31.7
20.0
35.5
33.7
p-NCC6H4
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It should be note that the reaction was the regiose-
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the regioisomer (3-CF3 isoxazole ring) of the products 6
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954
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 950—954