Click-chemistry approach to isoxazole-containing α-CF 3-substituted α-aminocarboxylates and α-aminophosphonates

Article abstract of DOI:10.1039/c1ob06040f

A convenient strategy for the synthesis of isoxazole-containing α-CF₃-substituted α-aminocarboxylates and α-aminophosphonates have been developed. The method is based on copper-catalyzed 1,3-dipolar cycloaddition of different aromatic nitrile o

Full text of DOI:10.1039/c1ob06040f

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PAPER
Click-chemistry approach to isoxazole-containing a-CF3-substituted
a-aminocarboxylates and a-aminophosphonates
Daria V. Vorobyeva,*a Natalya M. Karimova,a Irina L. Odinets,a Gerd-Volker Ro¨schenthaler*b and
Sergey N. Osipova
Received 28th June 2011, Accepted 29th July 2011
DOI: 10.1039/c1ob06040f
A convenient strategy for the synthesis of isoxazole-containing a-CF3-substituted a-aminocarboxylates
and a-aminophosphonates have been developed. The method is based on copper-catalyzed 1,3-dipolar
cycloaddition of different aromatic nitrile oxides to functionalized acetylenes.
Many synthetic approaches have been reported for the for-
mation of the isoxazole core, including reactions of hydroxy-
lamine with 1,3-dicarbonyl compounds, a,b-unsaturated carbonyl
compounds, and a,b-unsaturated nitriles as well as (3 + 2)-
Introduction
The development of new methods for the synthesis of five
membered heterocyclic compounds is an ever-expanding area in
cycloadditions of nitrile oxides to alkynes.6 Although, these
strategies are highly convergent, in many cases either strong
bases or strong mineral acids are required, or prolonged heating
at elevated temperatures is necessary. In addition, the observed
regioselectivities of the heterocyclization are often poor. Recently,
Fokin and co-workers have described an elegant approach to 3,5-
and 3,4-disubstituted isoxazoles based on “click” methodology.7
The method includes transition-metal-catalyzed regioselective 1,3-
dipolar cycloaddition of highly energetic nitrile oxides to alkynes.
On the other hand, fluorinated a-aminocarboxylic and a-
aminophosphonic acids derivatives, which can function as selec-
tive inhibitors of variety biologically active enzymes, have been
attracting considerable interest.8 Moreover, it is known, that the in-
corporation of a-trifluoromethyl-a-amino acids (a-CF3-AA) and
their phosphate analogues into strategically important positions
of peptides retards proteolytic degradation, induces a secondary
structure motif, and improves the lipophilicity9 enhancing in vivo
absorption, thus improving permeability through certain body
barriers. Therefore, the combination of the isoxazole and a-amino
acid (or a-amino phosphonic acid) pharmacophores within the
same molecule appears to be an attractive challenge for diversity-
oriented synthesis of potent drugs.
bioorganic and medicinal chemistry. Specifically, those containing
the isoxazole ring have been widely used as key building blocks
for drugs. Its derivatives are endowed with a broad spectrum
of pharmacological properties, for example, hypoglycemic, anal-
gesic, anti-inflammatory, antibacterial, anti-HIV, and anticancer
activity.1 In addition, they also can be used as agrochemicals
with herbicidal and soil fungicidal activity.2 Recently, isoxazoles
bearing carboxamide moieties demonstrated to have significant
pharmacological applications. For examples, the cyclooxygenase-
2 (COX-2) selective inhibitor valdecoxib A is currently pre-
scribed for the treatment of arthritis and inflammatory diseases.3
This compound exhibit anti-inflammatory activity with reduced
gastrointestinal side effects. Oxacillin and its derivatives B are
useful compounds because of their narrow spectrum antibiotic
properties.4 The isoxazoles C containing trifluoromethyl and aryl
groups were also shown to be potent in vivo antithrombotic
efficacy5 (Fig. 1).
aA.N. Nesmeyanov Institute of Organoelement compounds, Russian Academy
of Sciences, 119991, Moscow, Russia. Vavilov str. 28, Russia. E-mail:
vorobyeva-daria@yandex.ru; Fax: +7 495 135 5085
bJacobs University Bremen gGmbH, P.O. Box 750 561, D-28725, Bremen,
Germany. E-mail: g.roeschenthaler@jacobs-university.de
Fig. 1
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Herein, we report an efficient synthetic approach to
novel isoxazole-containing a-CF3-a-aminocarboxylates and a-
aminophosphonates (Fig. 2).
essentially affect the yield of the products; in all cases isoxazole-
containing derivatives 4a–e were isolated in good yields. However,
the usage of too much excess of nitrile oxides may cause side
reactions leading to a decrease in yields of the desired products. In
all cases, the purification of the final isoxazoles has been achieved
by column chromatography on silica gel or recrystallization.
The cycloadditions of propargyl-containing aminocarboxylates
1b and aminophosphonate 2b to organic nitrile oxides have
been investigated under similar conditions. As it turned out the
reactions of 1b and 2b with the highly reactive nitrile oxides (e.g. p-
CH3O–C6H4-, C6H5-, p-F–C6H4-derivatives) unexpectedly led to
formation of a mixture of two possible 3,5- and 3,4-substituted
regioisomers in a ~5 : 1 ratio, respectively (NMR-analysis), which
could not be separated chromatographically. At the same time, in
the case of electron-deficient nitrile oxides derived from p-NO2-
and p-CF3-benzaldehydes the reaction occurs regioselectively to
yield the desired 3,5-disubstituted isoxazoles 5a–f (Entries 1–6,
Scheme 3, Table 3).
Fig. 2
Results and discussion
The highly reactive nitrile oxides were generated in situ in order to
avoid dimerization from the corresponding hydroxymoyl chlorides
derived by a two step procedure from different commercially
available aromatic aldehydes.7a The synthesis of the starting a-
alkynyl-a-CF3-a-aminocarboxylates 1a (n = 0), 1b (n = 1) and
a-alkynyl-a-CF3-a-aminophosphonates 2a (n = 0), 2b (n = 1) was
accomplished according to earlier methodology reported based
on the addition of C-nucleophiles to electrophilic imines.10,11
The 1,3-dipolar cycloaddition of highly energetic nitrile oxides
to alkynes 1 and 2 have been investigated using in situ generation
of Cu(I) moiety from CuSO4 pentahydrate (5 mol%) and sodium
ascorbate (30 mol%) in a mixture of tert-butanol/water in a ratio
of 1 : 1.7a,12
Thus, we found that ethynyl-substituted aminocarboxylates 1a
with different protecting groups on the amino group easily reacted
with the corresponding nitrile oxides at room temperature to
afford 3,5-disubstituted isoxazoles 3a–j in good yields, the reaction
goes to completion within 1–2 h (Entries 1–10, Table 1, Scheme 1).
The small excess of nitrile oxides (1.1 equiv.) provides the best
conversion of the starting acetylenes.
Scheme 3
One possible further synthetic application of the obtained
compounds has been also demonstrated. Thus, we have elaborated
the methods for the selective removal of protecting groups from
the amino group for 3e, 3f and 5e. As a result it was found that
the Boc-group can be easily removed by treatment of 3f or 5e with
trifluoroacetic acid in CH2Cl2 at room temperature to furnish the
corresponding aminoesters 6 and 7. However, attempting to obtain
the aminoester 6 from 3e using the classical palladium-catalyzed
hydrogenation in methanol the simultaneous cleavage of the labile
N–O bond of the isoxazole-ring13 occurs to give the corresponding
iminoenol 8 in excellent yield (Scheme 4).
Conclusion
In summary, we have developed an effective procedure for the
synthesis of novel a-CF3-substituted a-aminocarboxylic and a-
aminophosphonic acid derivatives bearing the isoxazole pharma-
cophore. The method is based on copper-catalyzed 1,3-dipolar
cycloaddition of different aromatic nitrile oxides to functionalized
acetylenes. The compounds obtained can be regarded as promising
drug candidates. Their biological activity is under current investi-
gation and will be published somewhere in due course.
Scheme 1
It turned out that ethynyl-substituted aminophosphonate
2a demonstrates comparable reactivity towards different ni-
trile oxides under the above-mentioned conditions yield-
ing the corresponding isoxazole-containing a-trifluoromethyl-
a-aminophosphonate derivatives in good yield (Entries 1–5,
Scheme 2, Table 2). It should be noted, that the variation of
substituents (Ar) in the starting hydroxymoyl chlorides did not
Experimental
General information
All solvents used in reactions were freshly distilled from appropri-
ate drying agents before use. All other reagents were recrystallized
or distilled as necessary. Analytical TLC was performed with
Merck silica gel 60 F254 plates. Visualization was accomplished
by UV light or spraying by Ce(SO4)2, solution in 5% H2SO4.
Flash chromatography was carried out using Merck silica gel 60
(230–400 mesh ASTM) and ethyl acetate/hexanes as eluent. NMR
Scheme 2
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Table 1 Synthesis of isoxazole-containing a-CF3-a-aminocarboxylates
Entry
1
Alkyne
Ar
Product
Yield (%)a
60
4-CH3O-C6H4
2
3
4
4-CH3O-C6H4
77
70
68
C6H5
C6H5
5
4-F-C6H4
89
6
7
8
4-F-C6H4
62
78
77
4-CF3-C6H4
4-CF3-C6H4
9
4-NO2-C6H4
4-NO2-C6H4
67
70
10
a Isolated yields after purification by column chromatography or recrystallization.
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Table 2 Synthesis of isoxazole-containing a-CF3-a-aminophosphonates
(br s, 2H, CH2), 6.32 (br s, 1H, NH), 6.86 (s, 1H, CH), 6.99 (d,
J = 8.8 Hz, 2H, CHAr), 7.35 (br s, 5H, Ph), 7.75 (d, J = 8.8 Hz,
2H, CHAr); 19F NMR (376.2 MHz, CDCl3) d 2.31 (s, 3F, CF3);
13C NMR (151 MHz, CDCl3) d 54.8, 55.4, 64.1 (q, J = 31.0 Hz,
>C<), 68.0, 103.8, 114.4, 120.6, 122.6 (q, J = 283.0 Hz, CF3),
128.4, 128.5, 128.6, 128.7, 135.4, 153.9, 161.4, 161.6, 162.6, 163.9;
Calcd for C22H19N2F3O6 (464.39): C, 56.90; H, 4.12; N, 6.03; found:
C, 56.87; H, 3.99; N, 5.94.
Entry
Ar
Product
Yield (%)a
55
1
4-CH3O-C6H4
2
3
C6H5
65
58
Methyl N-(tert-butoxycarbonyl)-3,3,3-trifluoro-2-[3-(4-metho-
xyphenyl)isoxazol-5-yl]alaninate (3b). Yield 77% as a white
◦
1
solid; M.p. 133–135 C; H NMR (300 MHz, CDCl3) d 1.48 (s,
9H, 3CH3), 3.92 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 5.99 (s, 1H,
NH), 6.91 (s, 1H, CH), 7.04 (d, J = 8.7 Hz, 2H, CHAr), 7.82 (d,
J = 8.7 Hz, 2H, CHAr); 19F NMR (282 MHz, CDCl3) d 4.39 (s,
3F, CF3); 13C NMR (151 MHz, CDCl3) d 27.9, 54.5, 55.3, 64.1
(q, J = 31.2 Hz, >C<), 82.1, 103.4, 114.4, 120.6, 122.3 (q, J =
288.6 Hz, CF3), 128.3, 153.1, 161.3, 161.9, 162.5, 163.7; Calcd for
C19H21N2F3O6 (430.37): C, 53.02; H, 4.92; N, 6.51; found: C, 53.10;
H, 4.99; N, 6.39.
4-F-C6H4
4
5
4-CF3-C6H4
4-NO2-C6H4
80
68
Methyl
N-[(benzyloxy)carbonyl]-3,3,3-trifluoro-2-(3-phenyli-
soxazol-5-yl)alaninate (3c). Yield: 70% as white solid; M.p.
86–88 ◦C; 1H NMR (300 MHz, CDCl3) d 3.80 (3H, OCH3),
4.99–5.07 (m, 2H, CH2), 6.17 (br s, 1H, NH), 6.84 (s, 1H, CH),
7.27 (br s, 5H, Ph), 7.39–7.41 (3H, CHAr), 7.74–7.75 (m, 2H,
CHAr); 19F NMR (282 MHz, CDCl3) d 4.64 (s, 3F, CF3); 13C
NMR (151 MHz, CDCl3) d 54.6, 63.9 (q, J = 31.2 Hz, >C<),
67.8, 103.8, 122.1 (q, J = 287.6 Hz, CF3), 126.7, 127.9, 128.1,
128.3, 128.4, 128.8, 130.3, 135.1, 153.6, 161.6, 162.7, 163.2; Calcd
for C21H17N2F3O5 (434.36): C, 58.07; H, 3.94; N, 6.45; found: C,
58.11; H, 3.95; N, 6.52.
a Isolated yields after purification by column chromatography or recrys-
tallization.
Methyl
N-(tert-butoxycarbonyl)-3,3,3-trifluoro-2-(3-phenyli-
spectra were obtained on a Bruker AV-300, AV-600 and on a Jeol
ECX-400 spectrometers operating at 300 MHz, 400 MHz and
600 MHz respectively (TMS) for 1H; 100 MHz and 151 MHz for
13C; 282 MHz and 376.2 MHz for 19F (CF3COOH); 121 MHz
and 161 MHz for 31P (H3PO4). High resolution mass spectra
(HRMS) were recorded using a Bruker Daltonics (MicroTOF-Q).
Electrospray ionization (ESI) mass spectra (MS) were obtained
from methanol solution.
soxazol-5-yl)alaninate (3d). Yield 68% as a white solid; M.p.
◦
1
115–116 C; H NMR (300 MHz, CDCl3) d 1.48 (s, 9H, 3CH3),
3.96 (s, 3H, OCH3), 5.99 (s, 1H, NH), 6.98 (s, 1H, CH), 7.51–7.54
(m, 3H, CHAr), 7.86–7.90 (m, 2H, CHAr); 19F NMR (282 MHz,
CDCl3) d 4.43 (s, 3F, CF3); 13C NMR (100 MHz, CDCl3) d 27.9,
54.5, 64.1 (q, J = 28.7 Hz, >C<), 82.1, 103.8, 122.3 (q, J =
287.8 Hz, CF3), 126.9, 128.2, 128.9, 130.4, 153.1, 162.3, 162.8,
163.6; Calcd for C18H19N2F3O5 (400.34): C, 54.00; H, 4.78; N,
7.00; found: C, 53.94; H, 4.77; N, 7.01.
General procedure for the synthesis of isoxazoles
Methyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoro-2-[3-(4-fluoro-
phenyl)isoxazol-5-yl] alaninate (3e). Yield: 89% as a colorless oil;
1H NMR (300 MHz, CDCl3) d 3.94 (3H, OCH3), 5.16 (br s, 2H,
CH2), 6.32 (br s, 1H, NH), 6.95 (s, 1H, CH), 7.22 (t, J = 8.5 Hz,
To a solution of the corresponding acetylene 1 or 2 (1.0 mmol)
in t-BuOH–H2O (1 : 1 ratio) (5 ml) was added the corresponding
hydroxymoyl chloride (1.1 mmol), sodium ascorbate (0.3 mmol)
and 0.5 M copper sulfate pentahydrate (0.05 mmol), KHCO3
(4 mmol), sequentially. The reaction mixture was stirred at room
temperature for 1.5–2 h until the completion of the reaction
monitored by TLC. After evaporation of the mixed solvent under
reduced pressure, water (5 ml) was added to a residue and the
aqueous mixture was extracted with ethyl acetate (2 ¥ 10 ml). The
organic layer was dried over MgSO4 and evaporated to dryness.
The residue was purified by flash chromatography on silica gel
eluting by ethyl acetate–hexanes (1 : 8) or by recrystallization.
2H, CHAr), 7.41 (br s, 5H, Ph), 7.86 (t, J = 7.1 Hz, 2H, CHAr); 19
F
NMR (282 MHz, CDCl3) d -31.96, 4.65 (s, 3F, CF3); 13C NMR
(100 MHz, CDCl3) d 54.9, 64.1 (q, J = 31.2 Hz, >C<), 68.0, 103.9,
116.1 (d, J = 21.6 Hz, CAr-m), 122.2 (q, J = 288.1 Hz, CF3), 124.3,
128.4, 128.5, 128.6, 128.9 (d, J = 8.8 Hz, CAr-o), 135.3, 153.8, 161.9,
162.0, 163.3, 164.1 (d, J = 250.7 Hz, CAr-p); Calcd for C21H16N2F4O5
(452.35): C, 55.75; H, 3.54; N, 6.19; found: C, 56.02; H, 3.73; N,
5.88.
Methyl N-(tert-butoxycarbonyl)-3,3,3-trifluoro-2-[3-(4-fluoro-
phenyl)isoxazol-5-yl] ◦ alaninate (3f). Yield 62% as a white
Methyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoro-2-[3-(4-metho-
xyphenyl)isoxazol-5-yl] alaninate (3a). Yield: 60% as colorless
1
solid; M.p. 119–121 C; H NMR (300 MHz, CDCl3) d 1.48 (s,
1
oil; H NMR (300 MHz, CDCl3) d 3.87 (s, 6H, 2OCH3), 5.12
9H, 3CH3), 3.96 (s, 3H, OCH3), 5.99 (s, 1H, NH), 6.96 (s, 1H,
7338 | Org. Biomol. Chem., 2011, 9, 7335–7342
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Table 3 Isoxazole-containing a-CF3-a-aminocarboxylates and a-CF3-a-aminophosphonates
Entry
1
Alkyne
Ar
Product
Yield (%)a
62
4-CF3-C6H4
2
3
4-CF3-C6H4
4-CF3-C6H4
64
58
4
5
4-NO2-C6H4
4-NO2-C6H4
68
72
6
4-NO2-C6H4
65
a Isolated yields after purification by column chromatography or recrystallization.
Scheme 4
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CH), 7.16 (t, J = 8.6 Hz, 2H, CHAr), 7.85–7.90 (m, 2H, CHAr); 19
F
5.1 (dAB, JAB = 12.0 Hz, 1H, CH2), 5.99 (d, J = 8.0 Hz, 1H, NH),
6.74 (s, 1H, CH), 6.98 (d, J = 8.3 Hz, 2H, CHAr), 7.33 (br s, 5H,
Ph), 7.76 (d, J = 8.3 Hz, 2H, CHAr); 19F NMR (376.2 MHz,
CDCl3) d 8.31 (s, 3F, CF3); 31P NMR (161 MHz, CDCl3) d 11.55;
13C NMR (151 MHz, CDCl3) d 16.3, 55.4, 61.8 (dq, J = 141.5,
32.4 Hz, >C<), 65.8 (d, J = 6.6 Hz, OCH2-), 65.9 (d, J = 6.6 Hz,
OCH2-), 67.9, 103.1, 114.3, 120.8, 123.3 (q, J = 287.8 Hz, CF3),
128.3, 128.4, 128.6, 135.4, 153.6, 161.1, 161.2, 162.2; Calcd for
C24H26N2F3O7P (542.44): C, 53.15; H, 4.83; N, 5.16; found: C,
53.19; H, 4.75; N, 5.21.
NMR (282 MHz, CDCl3) d -32.08, 4.45 (s, 3F, CF3); 13C NMR
(100 MHz, CDCl3) d 27.9, 54.6, 64.1 (q, J = 30.2 Hz, >C<), 82.2,
103.7, 116.1 (d, J = 21.6 Hz, CAr-m), 122.2 (q, J = 287.5 Hz, CF3),
124.4, 128.9 (d, J = 8.8 Hz, CAr-o), 153.1, 161.9, 162.6, 163.6, 164.0
(d, J = 250.7 Hz, CAr-p); Calcd for C18H18N2F4O5 (418.34): C, 51.67;
H, 4.31; N, 6.70; found: C, 51.59; H, 4.37; N, 6.54.
Methyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoro-2-{3-[4-(trifluo-
romethyl)phenyl]isoxazol-5-yl}alaninate (3g). Yield: 78% as a
1
colorless oil; H NMR (400 MHz, CDCl3) d 3.88 (3H, OCH3),
5.10 (br s, 2H, CH2), 6.34 (br s, 1H, NH), 6.98 (s, 1H, CH),
7.34 (br s, 5H, Ph), 7.72 (d, J = 8.0 Hz, 2H, CHAr), 7.92 (d, J =
4.0 Hz, 2H, CHAr); 19F NMR (376.2 MHz, CDCl3) d 3.66 and
13.74 (both s, 3F, CF3); 13C NMR (100 MHz, CDCl3) d 54.9,
64.2 (q, J = 31.3 Hz, >C<), 68.0, 104.1, 122.2 (q, J = 287.5 Hz,
CF3), 123.8 (q, J = 272.4 Hz, CF3), 125.9, 127.3, 128.1, 128.2,
128.5, 131.6, 132.2 (q, J = 32.8 Hz, CAr-p), 135.3, 153.8, 161.7,
162.6, 163.2; Calcd for C22H16N2F6O5 (502.36): C, 52.60; H, 3.21;
N, 5.58; found: C, 52.88; H, 3.20; N, 5.27.
Diethyl [1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-(3-
phenylisoxazol-5-yl)ethyl] phosphonate diethyl {1-{[(benzyloxy)-
carbonyl]amino}-2,2,2-trifluoro-1-[3-(4-methoxyphenyl)isoxazol-
5-yl]ethyl}phosphonate (4b). Yield: 65% as white solid; M.p.
95–97 ◦C; 1H NMR (300 MHz, CDCl3) d 1.26 (t, J = 7.1 Hz, 6H,
2CH3), 4.00–4.24 (m, 4H, 2OCH2), 4.98 (dAB, JAB = 12.1 Hz, 1H,
CH2), 5.04 (dAB, JAB = 12.1 Hz, 1H, CH2), 5.96 (d, J = 10.3 Hz,
1H, NH), 6.75 (s, 1H, CH), 7.25 (br s, 5H, Ph), 7.37–7.40 (m, 3H,
CHAr), 7.72–7.75 (m, 2H, CHAr); 19F NMR (282 MHz, CDCl3) d
9.28 (s, 3F, CF3); 31P NMR (121 MHz, CDCl3) d 10.28; 13C NMR
(100 MHz, CDCl3) d 16.0 (d, J = 4.3 Hz, 2CH3-), 61.6 (dq, J =
142.2, 31.9 Hz, >C<), 65.7 (t, J = 7.9 Hz, 2OCH2-), 67.7, 103.1,
123.1 (q, J = 288.7 Hz, CF3), 126.7, 128.1, 128.2, 128.3, 128.4,
128.7, 130.1, 135.2, 153.3, 161.2, 162.4; Calcd for C23H24N2F3O6P
(512.41): C, 53.91; H, 4.72; N, 5.47; found: C, 53.69; H, 4.73; N,
5.17.
Methyl N-(tert-butoxycarbonyl)-3,3,3-trifluoro-2-{3-[4-(trifluo-
romethyl)phenyl]isoxazol-5-yl}alaninate (3h). Yield 77% as a
1
colorless oil; H NMR (400 MHz, CDCl3) d 1.41 (s, 9H, 3CH3),
3.90 (s, 3H, OCH3), 6.00 (br s, 1H, NH), 6.99 (s, 1H, CH), 7.72
(d, J = 8.0 Hz, 2H, CHAr), 7.94 (d, J = 8.0 Hz, 2H, CHAr); 19F
NMR (376.2 MHz, CDCl3) d 3.66 and 13.74 (both s, 3F, CF3);
13C NMR (151 MHz, CDCl3) d 27.9, 54.6, 64.2 (q, J = 31.7 Hz,
>C<), 82.2, 103.9, 122.2 (q, J = 287.8 Hz, CF3), 123.8 (q, J =
272.4 Hz, CF3), 125.9, 127.3, 131.7, 132.2 (q, J = 32.8 Hz, CAr-p),
153.1, 161.7, 163.1, 163.5; Calcd for C19H18N2F6O5 (468.34): C,
48.73; H, 3.87; N, 5.98; found: C, 48.59; H, 3.41; N, 5.67.
Diethyl {1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-[3-
(4-fluorophenyl)isoxazol-5-yl]ethyl}phosphonate (4c). Yield: 58%
◦
1
as white solid; M.p. 105–107 C; H NMR (400 MHz, CDCl3)
d 1.33 (t, J = 8.0 Hz, 6H, 2CH3), 4.11–4.30 (m, 4H, 2OCH2),
5.05 (dAB, JAB = 12.0 Hz, 1H, CH2), 5.10 (dAB, JAB = 12.0 Hz, 1H,
CH2), 6.02 (d, J = 8.0 Hz, 1H, NH), 6.77 (s, 1H, CH), 7.15 (t, J =
Methyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoro-2-[3-(4-nitroph-
enyl)isoxazol-5-yl] alaninate (3i). Yield 67% as a white solid; M.p.
116–118 ◦C; 1H NMR (300 MHz, CDCl3) d 3.82 (s, 3H, OCH3),
5.03 (br s, 2H, CH2), 6.22 (br s, 1H, NH), 6.96 (s, 1H, CH), 7.27
(br s, 5H, Ph), 7.94 (d, J = 7.2 Hz, 2H, CHAr), 8.26 (d, J = 7.2 Hz,
8.0 Hz, 2H, CHAr), 7.32 (br s, 5H, Ph), 7.78 (br s, 2H, CHAr); 19
F
NMR (376.2 MHz, CDCl3) d -33.35, 8.26 (s, 3F, CF3); 31P NMR
(161 MHz, CDCl3) d 10.28 (d, J = 3.6 Hz). 13C NMR (100 MHz,
CDCl3) d 16.3 (d, J = 2.0 Hz, CH3-), 16.4 (d, J = 2.0 Hz, CH3-),
61.8 (dq, J = 142.0, 30.0 Hz, >C<), 65.9 (d, J = 7.0 Hz, OCH2-),
66.1 (d, J = 8.0 Hz, OCH2-), 68.0, 103.3, 116.1 (d, J = 22.0 Hz,
2H, CHAr); 19F NMR (282 MHz, CDCl3) d 4.76 (s, 3F, CF3); 13
C
NMR (100 MHz, CDCl3) d 55.1, 63.7 (q, J = 30.0 Hz, >C<),
68.1, 104.3, 122.4 (q, J = 289.4 Hz, CF3), 124.3, 127.9, 128.3,
128.6, 128.7, 134.2, 135.2, 148.9, 153.7, 161.0, 163.1, 163.2; Calcd
for C21H16N3F3O7 (479.36): C, 52.61; H, 3.34; N, 8.77; found: C,
52.68; H, 3.32; N, 8.51.
C
Ar-m), 123.3 (q, J = 287.0 Hz, CF3), 124.6, 128.4, 128.5, 128.7,
128.9 (d, J = 8.0 Hz, CAr-o), 135.4, 153.6, 161.7, 161.8, 164.0 (d,
J = 249.0 Hz, CAr-p); Calcd for C23H23N2F4O6P (530.41): C, 52.08;
H, 4.37; N, 5.84; found: C, 52.19; H, 4.34; N, 5.19.
Methyl N-(tert-butoxycarbonyl)-3,3,3-trifluoro-2-[3-(4-nitroph-
enyl)isoxazol-5-yl]alaninate (3j). Yield 70% as a white solid; M.p.
Diethyl (1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-{3-
[4-(trifluoromethyl)phenyl] isoxazol-5- yl}ethyl)phosphonate (4d).
Yield: 80% as white solid; M.p. 132–134 ◦C; 1H NMR (400 MHz,
CDCl3) d 1.33 (t, J = 8.0 Hz, 6H, 2CH3), 4.12–4.30 (m, 4H,
◦
1
142–144 C; H NMR (300 MHz, CDCl3) d 1.48 (s, 9H, 3CH3),
3.98 (s, 3H, OCH3), 5.99 (br s, 1H, NH), 7.11 (s, 1H, CH), 8.09 (d,
J = 8.8 Hz, 2H, CHAr), 8.40 (d, J = 8.6 Hz, 2H, CHAr); 19F NMR
(282 MHz, CDCl3) d 4.57 (s, 3F, CF3); 13C NMR (100 MHz,
CDCl3) d 27.9, 54.6, 64.2 (q, J = 30.1 Hz, >C<), 82.3, 104.1,
122.1 (q, J = 289.7 Hz, CF3), 124.2, 127.8, 134.3, 148.9, 153.2,
161.0, 163.4, 163.7; Calcd for C18H18N3F3O7 (445.35): C, 48.54; H,
4.07; N, 9.44; found: C, 48.39; H, 4.02; N, 9.61.
2OCH2), 5.05 (dAB, JAB = 12.0 Hz, 1H, CH2), 5.10 (dAB, JAB
=
12.0 Hz, 1H, CH2), 6.03 (d, J = 8.0 Hz, 1H, NH), 6.84 (s, 1H,
CH), 7.32 (br s, 5H, Ph), 7.72 (d, J = 8.0 Hz, 2H, CHAr), 7.93 (d,
J = 8.0 Hz, 2H, CHAr); 19F NMR (376.2 MHz, CDCl3) d 8.28 and
13.76 (both s, 3F, CF3); 31P NMR (161 MHz, CDCl3) d 10.73;
13C NMR (100 MHz, CDCl3) d 16.3 (d, J = 2.0 Hz, CH3-), 16.4
(d, J = 2.0 Hz, CH3-), 61.8 (dq, J = 140.0, 30.0 Hz, >C<), 65.9
(d, J = 7.0 Hz, OCH2-), 66.1 (d, J = 8.0 Hz, OCH2-), 68.1, 103.4,
123.3 (q, J = 287.0 Hz, CF3), 123.9 (q, J = 270.0 Hz, CF3), 125.9,
127.3, 128.4, 128.5, 128.7, 131.9, 132.2 (q, J = 33.0 Hz, CAr-p),
Diethyl {1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-[3-
(4-methoxyphenyl)isoxazol-5-yl]ethyl}phosphonate (4a). Yield:
◦
55% as white solid; M.p. 103–104 C;1H NMR (400 MHz,
CDCl3) d 1.32 (t, J = 7.1 Hz, 6H, 2CH3), 3.86 (s, 3H, OCH3),
4.09–4.29 (m, 4H, 2OCH2), 5.05 (dAB, JAB = 12.0 Hz, 1H, CH2),
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135.4, 153.6, 161.5, 162.3; Calcd for C24H23N2F6O6P (580.41): C,
49.66; H, 3.99; N, 4.83; found: C, 49.58; H, 3.95; N, 4.77.
162.7; Calcd for C25H25N2F6O6P (594.44): C, 50.51; H, 4.24; N,
4.71; found: C, 50.37; H, 4.28; N, 4.44.
Diethyl {1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-[3-
(4-nitrophenyl)isoxazol-5-yl] ethyl}phosphonate (4e). Yield: 68%
as white solid; M.p. 145–147 ◦C; 1H NMR (300 MHz, CDCl3) d
1.41 (t, J = 6.7 Hz, 6H, 2CH3), 4.15–4.39 (m, 4H, 2OCH2), 5.12
(dAB, JAB = 11.9 Hz, 1H, CH2), 5.17 (dAB, JAB = 11.9 Hz, 1H, CH2),
6.1 (d, J = 8.8 Hz, 1H, NH), 6.94 (s, 1H, CH), 7.39 (br s, 5H, Ph),
8.06 (d, J = 8.5 Hz, 2H, CHAr), 8.39 (d, J = 8.2 Hz, 2H, CHAr);
19F NMR (282 MHz, CDCl3) d 9.22 (d, J = 3.0 Hz, 3F, CF3);
31P NMR (161 MHz, CDCl3) d 10.09 (d, J = 3.3 Hz); 13C NMR
(100 MHz, CDCl3) d 16.3, 61.7 (dq, J = 142.6, 30.9 Hz, >C<),
65.9 (d, J = 6.6 Hz, OCH2-), 66.1 (d, J = 6.6 Hz, OCH2-), 68.0,
103.4, 123.2 (q, J = 288.9 Hz, CF3), 124.2, 127.8, 128.4, 128.6,
134.4, 135.3, 148.8, 153.6, 160.8, 162.8; Calcd for C23H23N3F3O8P
(557.41): C, 49.56; H, 4.16; N, 7.54; found: C, 49.58; H, 4.19; N,
7.54.
Methyl 2-{[(benzyloxy)carbonyl]amino}-3,3,3-trifluoro-2-{[3-
(4-nitrophenyl)isoxazol-5-yl]methyl}propanoate (5d). Yield 68%
as a white solid; M.p. 125–127 ◦C; 1H NMR (300 MHz, CDCl3) d
3.68 (dAB, JAB = 14.3 Hz, 1H, CH2), 3.93 (s, 3H, OCH3), 4.55 (dAB
,
JAB = 15.3 Hz, 1H, CH2), 4.95 (dAB, JAB = 11.3 Hz, 1H, CH2), 5.16
(dAB, JAB = 12.1 Hz, 1H, CH2), 5.95 (br s, 1H, NH), 6.25 (s, 1H,
CH), 7.19–7.26 (m, 5H, Ph), 7.72 (d, J = 8.5 Hz, 2H, CHAr), 8.23
(d, J = 9.1 Hz, 2H, CHAr); 19F NMR (282 MHz, CDCl3) d 3.19
(s, 3F, CF3); 13C NMR (100 MHz, CDCl3) d 26.4, 55.9, 64.7 (q,
J = 29.8 Hz, >C<), 62.2, 102.9, 123.3 (q, J = 288.6 Hz, CF3),
124.1, 127.7, 128.2, 128.4, 128.6, 134.7, 135.8, 148.7, 153.9, 160.7,
165.9, 167.2; Calcd for C22H18N3F3O7 (493.37): C, 53.56; H, 3.68;
N, 8.52; found: C, 53.56; H, 3.47; N, 8.41.
Methyl 2-[(tert-butoxycarbonyl)amino]-3,3,3-trifluoro-2-{[3-(4-
nitrophenyl)isoxazol-5-yl] methyl}propanoate (5e). Yield 72% as
◦
1
Methyl 2-{[(benzyloxy)carbonyl]amino}-3,3,3-trifluoro-2-({3-
[4-(trifluoromethyl)phenyl] isoxazol-5-yl}methyl)propanoate (5a).
Yield 62% as a white solid; M.p. 129–131 ◦C; 1H NMR (400 MHz,
CDCl3) d 3.72 (dAB, JAB = 12.0 Hz, 1H, CH2), 3.99 (s, 3H, OCH3),
4.60 (dAB, JAB = 12.0 Hz, 1H, CH2), 5.01 (dAB, JAB = 12.0 Hz, 1H,
CH2), 5.21 (dAB, JAB = 12.0 Hz, 1H, CH2), 6.02 (br s, 1H, NH),
6.30 (s, 1H, CH), 7.24–7.36 (m, 5H, Ph), 7.69 (d, J = 8.0 Hz, 2H,
CHAr), 7.74 (d, J = 8.0 Hz, 2H, CHAr); 19F NMR (376.2 MHz,
CDCl3) d 2.17 and 13.79 (both s, 3F, CF3); 13C NMR (151 MHz,
CDCl3) d 26.4, 55.9, 64.6 (q, J = 29.8 Hz, >C<), 62.2, 102.9,
123.3 (q, J = 288.2 Hz, CF3), 123.9 (q, J = 272.4 Hz, CF3), 124.1,
127.7, 128.2, 128.4, 128.6, 134.6, 135.8, 148.6, 153.8, 160.6, 165.8,
167.2; Calcd for C23H18N2F6O5 (516.39): C, 53.05; H, 3.51; N,
5.42; found: C, 53.56; H, 3.58; N, 4.98.
a white solid; M.p. 114–116 C; H NMR (400 MHz, CDCl3) d
1.42 (s, 9H, 3CH3), 3.73 (dAB, JAB = 12.0 Hz, 1H, CH2), 3.97 (s, 3H,
OCH3), 4.54 (dAB, JAB = 12.0 Hz, 1H, CH2), 5.71 (s, 1H, NH), 6.53
(s, 1H, CH), 7.91 (d, J = 8.5 Hz, 2H, CHAr), 8.30 (d, J = 8.5 Hz,
2H, CHAr); 19F NMR (376.2 MHz, CDCl3) d 2.12 (s, 3F, CF3); 13
C
NMR (100 MHz, CDCl3) d 26.7, 28.0, 54.9, 64.7 (q, J = 29.0 Hz,
>C<), 81.2, 103.1, 123.5 (q, J = 288.0 Hz, CF3), 124.3, 127.6,
134.9, 148.8, 153.3, 160.7, 166.3, 167.9; Calcd for C19H20N3F3O7
(459.37): C, 49.68; H, 4.39; N, 9.15; found: C, 49.74; H, 4.34; N,
9.16.
Diethyl (1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-{[3-
(4-nitrophenyl)isoxazol-5-yl]methyl}ethyl)phosphonate
(5f).
Yield: 65% as white solid; M.p. 143–145 ◦C; 1H NMR (300 MHz,
CDCl3) d 1.22–1.31 (m, 6H, 2CH3), 3.82–3.90 (m, 1H, CH2),
4.15–4.27 (m, 4H, 2OCH2, 1H, CH2), 5.12 (dAB, JAB = 11.7 Hz,
1H, CH2), 5.23 (dAB, JAB = 12.3 Hz, 1H, CH2), 5.59 (d, J = 7.9 Hz,
1H, NH), 6.39 (s, 1H, CH), 7.37 (br s, 5H, Ph), 7.81 (d, J = 7.3 Hz,
2H, CHAr), 8.27 (d, J = 8.1 Hz, 2H, CHAr); 19F NMR (282 MHz,
CDCl3) d 7.38 (3F, CF3); 31P NMR (161 MHz, CDCl3) d 14.78;
13C NMR (151 MHz, CDCl3) d 16.2, 25.8, 61.6 (dq, J = 152.5,
29.1 Hz, >C<), 64.6 (d, J = 6.6 Hz, OCH2-), 64.8 (d, J = 5.5 Hz,
OCH2-), 67.5, 102.6, 124.2 (q, J = 287.8 Hz, CF3), 124.1, 127.6,
128.4, 128.5, 128.7, 135.1, 135.8, 148.6, 154.5, 160.6, 167.9; Calcd
for C24H25N3F3O8P (571.44): C, 50.44; H, 4.41; N, 7.35; found: C,
49.77; H, 4.31; N, 7.14.
Methyl 2-[(tert-butoxycarbonyl)amino]-3,3,3-trifluoro-2-({3-[4-
(trifluoromethyl)phenyl] isoxazol-5-yl}methyl)propanoate (5b).
Yield 64% as a white solid; M.p. 117–119 ◦C; 1H NMR (400 MHz,
CDCl3) d 1.43 (s, 9H, 3CH3), 3.73 (dAB, JAB = 12.0 Hz, 1H, CH2),
3.98 (s, 3H, OCH3), 4.54 (dAB, JAB = 12.0 Hz, 1H, CH2), 5.73 (br s,
1H, NH), 6.51 (s, 1H, CH), 7.71 (d, J = 8.0 Hz, 2H, CHAr), 7.86
(d, J = 8.0 Hz, 2H, CHAr); 19F NMR (376.2 MHz, CDCl3) d 2.14
and 13.73 (both s, 3F, CF3); 13C NMR (151 MHz, CDCl3) d 26.6,
28.1, 54.7, 64.7 (q, J = 29.4 Hz, >C<), 81.1, 103.1, 123.5 (q, J =
287.7 Hz, CF3), 123.8 (q, J = 272.5 Hz, CF3), 126.0, 127.0, 132.1
(q, J = 31.1 Hz, CAr-p), 132.2, 153.3, 161.3, 166.3, 167.3; Calcd
for C20H20N2F6O5 (482.37): C, 49.80; H, 4.18; N, 5.81; found: C,
49.66; H, 4.14; N, 5.62.
General procedure for the removing of the Boc-protecting group
Diethyl [1-{[(benzyloxy)carbonyl]amino}-2,2,2-trifluoro-1-({3-
[4-(trifluoromethyl)phenyl] isoxazol-5-yl}methyl)ethyl]phosphonate
(5c). Yield: 58% as white solid; M.p. 120–122 ◦C; 1H NMR
(400 MHz, CDCl3) d 1.25–1.27 (m, 6H, 2CH3), 3.81–3.89 (m,
A solution of 3f and 5e (1 mmol) in a biphasic mixture of
trifluoroacetic acid/dichlormethane (2 ml/5 ml) was stirred at
room temperature for 50 min. After evaporation of solvents under
reduced pressure, water (5 ml) was added to the residue and the
resulting water solution was neutralized with saturated solution of
sodium bicarbonate until pH 7. Then the mixture was extracted
with diethyl ether (3 ¥ 10 ml). The organic layer was dried over
MgSO4 and evaporated to dryness. The residue was purified by
column chromatography on silica gel eluting by ethyl acetate–
hexanes (1 : 8) or by recrystallization.
1H, CH2), 4.02–4.29 (m, 4H, 2OCH2, 1H, CH2), 5.11 (dAB, JAB
=
12.0 Hz, 1H, CH2), 5.23 (dAB, JAB = 12.0 Hz, 1H, CH2), 5.61 (d, J =
8.0 Hz, 1H, NH), 6.38 (s, 1H, CH), 7.32–7.47 (br s, 5H, Ph), 7.67
(d, J = 8.0 Hz, 2H, CHAr), 7.76 (d, J = 8.0 Hz, 2H, CHAr); 19F NMR
(282 MHz, CDCl3) d 7.38 (3F, CF3); 31P NMR (161 MHz, CDCl3)
d 14.78; 13C NMR (100 MHz, CDCl3) d 16.3, 26.5, 61.7 (dq, J =
142.4, 30.2 Hz, >C<), 66.1, 68.0, 103.4, 123.1 (q, J = 288.5 Hz,
CF3), 123.7 (q, J = 272.4 Hz, CF3), 126.1, 127.3, 128.3, 128.5,
128.6, 132.1 (q, J = 31.2 Hz, CAr-p), 134.3, 135.3, 153.6, 161.3,
Methyl
3,3,3-trifluoro-2-[3-(4-fluorophenyl)isoxazol-5-yl]-
alaninate (6). Yield 78% as a colorless oil; 1H NMR (400 MHz,
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CDCl3) d 2.52 (br s, 2H, NH2), 3.91 (s, 3H, OCH3), 6.77 (s, 1H,
Rozhkova, N. M. Przheval’skii, S. Rogelj and A. Kornienko, J. Med.
Chem., 2007, 50, 5183–5192.
CH), 7.16 (t, J = 8.0 Hz, 2H, CHAr), 7.78–7.82 (m, 2H, CHAr); 19
F
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Tartari, M. Manfrini and G. Forlani, J. Agric. Food Chem., 2004, 52,
1898–1906.
NMR (282 MHz, CDCl3) d -33.02, 0.84 (s, 3F, CF3); 13C NMR
(100 MHz, CDCl3) d 54.5, 64.2 (q, J = 30.0 Hz, >C<), 102.6,
116.2 (d, J = 21.9 Hz, CAr-m), 123.1 (q, J = 285.0 Hz, CF3), 124.5,
128.9 (d, J = 8.6 Hz, CAr-o), 161.9, 165.4, 164.1 (d, J = 229.0 Hz,
C
Ar-p), 165.7; Calcd for C11H8N2F4O3 (318.22): C, 49.07; H, 3.17;
N, 8.80; found: C, 49.05; H, 3.17; N, 8.79.
3 J. A. Talley, D. L. Brown, J. S. Carter, M. J. Masferrer, W. E. Perkins,
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Lemyre, BMC Pediatr., 2005, 5, 49–53; (b) N. G. Miranda, M. B. E.
Leanos, P. M. Vilchis and S. F. Solorzano, Ann. Clin. Microbiol.
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Rolinson, Br. Med. J., 1970, 4, 455–460.
Methyl 2-amino-3,3,3-trifluoro-2-{[3-(4-nitrophenyl)isoxazol-5-
yl]methyl}propanoate (7). Yield 80% as white solid; M.p. 88–
◦
1
90 C; H NMR (400 MHz, CDCl3) d 1.94 (br s, 2H, NH2),
3.27 (dAB, JAB = 16.0 Hz, 1H, CH2), 3.70 (dAB, JAB = 16.0 Hz,
1H, CH2), 3.87 (s, 3H, OCH3), 6.59 (s, 1H, CH), 7.96 (d, J =
8.0 Hz, 2H, CHAr), 8.31 (d, J = 12.0 Hz, 2H, CHAr); 19F NMR
(376.2 MHz, CDCl3) d -1.43 (s, 3F, CF3); 13C NMR (100 MHz,
CDCl3) d 30.8, 53.9, 64.1 (q, J = 28.0 Hz, >C<), 102.5, 124.4 (q,
J = 287.2 Hz, CF3), 124.2, 127.7, 134.9, 148.7, 160.9, 168.0; Calcd
for C14H12N3F3O5 (359.26): C, 46.80; H, 3.37; N, 11.70; found: C,
46.68; H, 3.29; N, 11.58.
5 J. R. Pruitt, D. J. Pinto, M. J. Estrella, L. L. Bostrom, R. M. Knabb,
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Methyl 3-[2-(4-fluorophenyl)-2-iminoethylidene]-2-(trifluorome-
thyl)serinate (8). To a solution of Cbz-protected aminoester 3e
(1.5 mmol) in methanol (20 ml) 10% Pd/C (5%- mol) was added
and a slow stream of hydrogen was bubbled through the mixture
at room temperature. When TLC indicated no starting material
(about 2 h), the mixture was filtered and the solvent was evaporated
to dryness. Yield 96% as a yellow oil; 1H NMR (400 MHz, CDCl3)
d 2.48 (br s, 2H, NH2), 3.85 (s, 3H, OCH3), 5.72 (s, 1H, CH), 5.77
(br s, 1H, NH), 7.15 (dt, J = 8.0, 1.0 Hz, 2H, CHAr), 7.52–7.56
(m, 2H, CHAr); 19F NMR (376.2 MHz, CDCl3) d -31.19, 3.82
(s, 3F, CF3); 13C NMR (100 MHz, CDCl3) d 53.8, 71.1 (q, J =
27.0 Hz, >C<), 90.0, 116.2 (d, J = 21.9 Hz, CAr-m), 123.6 (q, J =
282.1 Hz, CF3), 128.8 (d, J = 8.9 Hz, CAr-o), 132.1, 164.5, 164.6 (d,
J = 250.8 Hz, CAr-p), 167.8, 183.4; MS(ESI) calcd for C13H12N2F4O3
[M+Na]+ 343.2294, found 343.2287.
Acknowledgements
This work was supported by Deutsche Forschungsgemeinschaft
(RO 362/42-1) and Russian Foundation of Basic Research (grant
No. 06-03-04003).
Notes and references
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