Synthesis of 6-Isoxazolyl Derivatives of 4-Methylumbelliferone

Article abstract of DOI:10.1007/s10600-017-2080-6

A two-step synthesis of 6-(5-isoxazolyl)coumarins was developed. Recyclization of 7-hydroxychromones by hydroxylamine into 4-(5-isoxazolyl)-1,3-benzenediols followed by condensation with acetoacetic ester produced 6-(5-isoxazolyl)-4-methylumbelliferone de

Full text of DOI:10.1007/s10600-017-2080-6

DOI 10.1007/s10600-017-2080-6
Chemistry of Natural Compounds, Vol. 53, No. 4, July, 2017
SYNTHESIS OF 6-ISOXAZOLYL DERIVATIVES
OF 4-METHYLUMBELLIFERONE
1*
1
T. V. Shokol, N. V. Gorbulenko,
2
1
M. S. Frasinyuk, and V. P. Khilya
A two-step synthesis of 6-(5-isoxazolyl)coumarins was developed. Recyclization of 7-hydroxychromones by
hydroxylamine into 4-(5-isoxazolyl)-1,3-benzenediols followed by condensation with acetoacetic ester
produced 6-(5-isoxazolyl)-4-methylumbelliferone derivatives with aryl and hetaryl substituents on the
isoxazole ring.
Keywords:
7-hydroxychromones,
4-methylumbelliferone,
4-(5-isoxazolyl)-1,3-benzenediols,
6-(5-isoxazolyl)coumarins.
Benzopyran-2- and -4-one derivatives (coumarins and chromones) from plants are natural bioregulators. The
coexistence in Dalbergia volubilis extract of formononetin (7-hydroxy-4ꢀ-methoxyflavone) and 4-methylumbelliferone
(7-hydroxy-4-methylcoumarin) is of biogenetic interest [1]. Mutual transformations of ꢁ- and ꢂ-benzopyrone derivatives are
a research topic for natural-products and heterocyclic chemists.
Previously, we proposed recyclization of chromones through the action of hydrazine hydrate into pyrazoles followed
by Pechmann cyclization with acetoacetic ester to transform 7-hydroxyisoflavones and their heterocyclic analogs into
4-methylumbelliferone derivatives with a 6-pyrazole substituent [2]. Herein, a similar approach is taken to synthesize
6-(5-isoxazolyl) derivatives of 4-methylumbelliferone.
Isoxazolylcoumarins are known to be potential anti-inflammatory agents [3]. 6-(5-Isoxazolyl) derivatives of
4-methyl- and 4-phenylumbelliferone emitted fluorescence and were proposed as bases for fluorescent probes of pH [4] and
water content in organic solvents [5].
The main synthetic method for 6-isoxazolylcoumarins involves a reaction with hydroxylamine to fuse an isoxazole
ring to a coumarin core with a 1,3-diketone or enaminoketone fragment [6–8]. 6-(5-Isoxazolyl)coumarins were also prepared
via recyclization of 4H,8H-pyrano[2,3-f]chromen-4,8-diones through the action of hydroxylamine [9].
R
1
R
1
R
1
O
O
OH
HO
O
R
R
HO
OH
2
b
a
O
O
R
4
R
4
3
N
N
CH
O
3
R
3
R
3
R
2
R
2
2a-g
1a,2a,3a: R = R = R = H, R = Ph; 1b,2b,3b: R = R = R = H, R = 4-CH OC H
6 4
3a-d,f,g
1a-g
1
2
4
3
1
2
4
3
3
1c,2c,3c: R = R =H, R = Me, R = 4-CH OC H ; 1d,2d,3d: R = R = H, R = Me, R = 3,4-(CH O) C H
1
4
2
3
3
6
4
1
4
2
3
3
2 6 3
1e,2e: R = H, R = Me, R =3,4-(CH O) C H , R = CH O
1
2
3
3
2
6
3
4
3
1f,2f,3f: R = R = H, R = Me, R = 4-BrC H ; 1g,2g,3g: R = R =Me, R = 4-methylthiazol-2-yl, R = H
1
4
2
3
6
4
1
2
3
4
a. N H ; b. CH COCH COOEt, H SO
4
2
4
3
2
2
1) Taras Shevchenko Kiev National University, 64/13 Vladimirskaya St., Kiev, 01601, Ukraine, e-mail:
shokol_tv@univ.kiev.ua; 2) Institute of Bioorganic Chemistry and Petroleum Chemistry, National Academy of Sciences of
Ukraine, 1 Murmanskaya St., Kiev-94, 02660, Ukraine. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August,
2017, pp. 547–549. Original article submitted November 4, 2016.
©
642
0009-3130/17/5304-0642 2017 Springer Science+Business Media New York

The goal of the present work was to synthesize 6-isoxazolyl-4-methylumbelliferone derivatives via an alternate method,
i.e., formation of a coumarin ring from substituted isoxazoles.
The starting materials for implementing this approach to synthesizing derivatives of 6-(5-isoxazolyl)-4-
methylumbelliferone were the natural isoflavones 7-hydroxyisoflavone (1a) (isolated from Echinops echinatus [10]), formononetin
(1b), 7-hydroxy-2-methyl-4ꢀ-methoxyisoflavone (1c) (isolated from Butea monosperma [11]), and their analogs 1d–f.
Oximation of 3-aryl(hetaryl)chromones with hydroxylamine hydrochloride is known to occur with opening of the
ꢁ-pyrone ring and subsequent cyclization of the intermediates into derivatives of regioisomeric isoxazoles or only one of them,
3-aminochromones, and 3-aminoisoxazoles. The direction of the reaction depends on the substituents in the 2- and 3-positions
of the chromone ring and the used base [12–14].
The reaction of 2-methylchromones 1c–g with hydroxylamine hydrochloride occurred with refluxing in Py;
of 2-unsubstituted isoflavones 1a and 1b, in EtOH in the presence of N-methylmorpholine. In both instances under such
conditions, the reaction occurred regioselectively to afford exclusively 4-(5-isoxazolyl)benzene-1,3-diols 2a–g. This was
confirmed by PMR spectra recorded in DMSO-d (3-OH resonances were observed at 9.5–9.8 ppm) and the lack of a
6
characteristic color reaction with alcoholic FeCl solution. The singlet for the 1-OH proton appeared in practically the same
3
region. The PMR spectrum of 2g, which contained a thiazole substituent in the isoxazole 4-position, that was recorded in less
polar CDCl gave 1-OH (8.92 ppm) and 3-OH (11.47 ppm) resonances that were very different. The shift of the 3-OH
3
resonance to weak field was due to an intramolecular H-bond between the 3-OH and thiazole N atom and; therefore,
a conformation change in favor of chelated structure 2gꢀ.
H C
3
CH
3
CH
3
CH
3
OH
OH
O
N
N
N
O
O
HO
S
S
CH
3
CH
3
O
CH
3
N
2g'
3g'
Compounds 2 were convenient synthons for Pechmann syntheses of coumarins because of the resorcinol fragment
without substituents in the 6-position. The reaction of 2a–d, –f, and –g with acetoacetic ester in the presence of H SO formed
2
4
6-(5-isoxazolyl)coumarins 3a–d, –f, and –g with aromatic and heterocyclic substituents in the 4-position of the isoxazole ring.
The fact that 6-methoxy derivative 2e did not undergo a Pechmann reaction (the starting isoxazole was isolated) confirmed
that the electrophile attacked at the 6-position of the 4-(5-isoxazolyl)-1,3-benzenediols.
Coumarins 3a–d, –f, and –g were colorless crystalline compounds that did not form colored complexes with FeCl
3
solution. PMR spectra of 3 showed a singlet for the 4-methyl at 2.30–2.33 ppm and a singlet for H-3 at 6.04–6.15 ppm.
A singlet for the 7-OH proton was observed at 10.28 (3g) and 10.78–10.92 ppm (3a–d and –f) (in DMSO-d –CCl , 1:1).
6
4
PMR spectra in CCl of 3g had the 7-OH resonance shifted to weak field to 11.68 ppm because the chelate 3gꢀ formed.
4
Thus, natural and synthetic 7-hydroxychromones were transformed in two steps into derivatives of 6-(5-isoxazolyl)-
4-methylumbelliferone. These were recyclization of the starting chromones through the action of hydroxylamine into
4-(5-isoxazolyl)-1,3-benzenediols followed by condensation with acetoacetic ester. A resorcinol with a free 6-position in the
isoxazole derivatives was required for Pechmann synthesis of the coumarins. This approach could be used to create combinatory
libraries of 6-hetarylcoumarins with various substituents in both heterocyclic rings. In turn, this would make them more
available and allow their spectra of applications to expand.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck 60 F plates using CHCl –MeOH
254
3
(9:1). Melting points were measured on a Kofler block. PMR spectra were recorded vs. TMS (internal standard) in DMSO-d or
6
DMSO-d –CCl (1:1), CDCl , or CCl on a Varian Mercury-400 spectrometer. Elemental analyses obtained using a Vario
6
4
3
4
MicroCube instrument agreed with those calculated. Compounds 2b–d were prepared by us earlier [14].
4-(4-Phenyl-5-isoxazolyl)-1,3-benzenediol (2a). A solution of isoflavone 1a (0.480 g, 2 mmol) in EtOH (10 mL)
was treated with hydroxylamine hydrochloride (0.280 g, 4 mmol) and N-methylmorpholine (0.4 mL). The mixture was
refluxed for 6–8 h (end of reaction determined by TLC), poured into H O (100 mL), and acidified to pH 6 using dilute HCl.
2
643

The resulting precipitate was filtered off and crystallized from MeOH. Yield 0.42 g (83%). C H NO , mp 179–180ꢃÑ (lit. [15]:
15 11
3
1
mp 185–186ꢃÑ). Í NMR spectrum (DMSO-d , ꢄ, ppm, J/Hz): 6.34 (1Í, dd, J = 8.4, 2.2, H-6), 6.44 (1Í, d, J = 2.2, H-2), 7.09
(1Í, d, J = 8.4, Í-5), 7.20–7.43 (5H, m, Ñ Í ), 8.79 (1Í, s, Í-3ꢀ), 9.83 and 9.84 (1H each, s, 1, 3-OÍ). C NMR spectrum
6
13
6
5
(DMSO-d , ꢄ, ppm): 103.6, 106.5, 107.9, 116.8, 127.3, 127.7, 129.2, 130.9, 132.2, 151.2, 157.6, 161.2, 163.9.
6
4-(3-Methyl-5-isoxazolyl)-1,3-benzenediols (2e–g) (General Method). A solution of the appropriate chromone 1e,
f, or g (2 mmol) in Py (3 mL) was treated with hydroxylamine hydrochloride (0.42 g, 6 mmol), heated at 80–90°C for 3 h
(course of reaction monitored by TLC), diluted with H O (50 mL), and acidified with HCl to pH 6. The resulting precipitate
2
was filtered off.
4-[4-(3,4-Dimethoxyphenyl)-3-methylisoxazol-5-yl]-6-methoxybenzene-1,3-diol (2e). Yield 0.64 g (89%),
1
C H NO , mp 200–201ꢃÑ. Í NMR spectrum (DMSO-d , ꢄ, ppm, J/Hz): 2.28 (3H, s, 3ꢀ-CH ), 3.57, 3.62, 3.74 (3H each,
19 19
6
6
3
s, 6, 3ꢀꢀ, 4ꢀꢀ-OCH ), 6.41 (1H, s, Í-2), 6.69 (1H, s, Í-6), 6.77–6.96 (3H, m, H-2ꢀꢀ, 5ꢀꢀ, 6ꢀꢀ), 9.28 and 9.47 (1H each, s, 1, 3-OÍ).
3
13
C NMR spectrum (DMSO-d , ꢄ, ppm): 11.5, 56.0, 57.0, 104.6, 105.3, 112.4, 113.3, 115.1, 117.0, 121.7, 123.9, 141.4, 148.7,
6
149.1, 150.2, 151.1, 159.0, 164.6.
4-[4-(4-Bromophenyl)-3-methylisoxazol-5-yl]benzene-1,3-diol (2f). Yield 0.59 g (85%), C H BrNO ,
16 12
3
1
mp 223–224ꢃÑ. Í NMR spectrum (DMSO-d , ꢄ, ppm, J/Hz): 2.26 (3H, s, 3ꢀ-CH ), 6.28 (1Í, dd, J = 8.4, 2.3, H-5), 6.33 (1Í,
6
3
d, J = 2.3, H-2), 7.03 (1H, d, J = 8.4, Í-6), 7.19 (2H, d, J = 8.5, H-3ꢀꢀ, 5ꢀꢀ), 7.54 (2H, d, J = 8.5, H-2ꢀꢀ, 6ꢀꢀ), 9.70 and 9.76 (1H
13
each, s, 1, 3-OÍ). C NMR spectrum (DMSO-d , ꢄ, ppm): 10.8, 102.9, 105.8, 107.2, 115.2, 120.4, 130.6, 130.7, 131.4, 131.4,
6
156.7, 158.3, 160.5, 164.6.
2-Methyl-4-[3-methyl-4-(4-methyl-1,3-thiazol-2-yl)-5-isoxazolyl]-1,3-benzenediol (2g). Yield 0.50 g (83%),
1
C H N O S, mp 169–170ꢃÑ (EtOAc). Í NMR spectrum (DMSO-d –CCl , ꢄ, ppm, J/Hz): 2.04 (3H, s, CH -2), 2.41 (3H,
15 14
2
3
6
4
3
s, CH -4ꢀꢀ), 2.55 (3H, s, CH -3ꢀ), 6.47 (1Í, d, J = 8.4, H-6), 6.88 (1Í, d, J = 8.4, H-5), 7.01 (1Í, s, H-5ꢀꢀ), 9.11 (1Í, s, 1-OÍ),
3
3
1
9.53 (1Í, s, 3-OÍ). Í NMR spectrum (CDCl , ꢄ, ppm, J/Hz): 2.27 (3H, s, CH -2), 2.46 (3H, s, CH -4ꢀꢀ), 2.57 (3H, s,
3
3
3
CH -3ꢀ), 6.05 (1Í, br.s, 1-OÍ), 6.51 (1Í, d, J = 8.0, H-6), 6.94 (1Í, s, H-5ꢀꢀ), 7.18 (1Í, d, J = 8.0, H-5), 11.47 (1Í, s, 3-OÍ).
3
13
C NMR spectrum (DMSO-d , ꢄ, ppm): 9.6, 12.5, 17.3, 106.9, 108.2, 112.8, 113.0, 114.9, 128.7, 152.2, 155.5, 157.7, 158.6,
6
159.7, 167.9.
7-Hydroxy-4-methyl-6-(5-isoxazolyl)-2H-2-chromenones (3a–d, f, g) (General Method). A suspension of the
appropriate 1,3-benzenediol 2a–d, f, or g (1 mmol) in acetoacetic ester (1 mL, 7.8 mmol) was treated with H SO (0.5 mL),
2
4
heated on a water bath for 20 min, left overnight, and worked up with H O. The precipitate was filtered off and recrystallized
2
from MeOH (3a), i-PrOH (3b), or EtOH (3c, d, f, g).
7-Hydroxy-4-methyl-6-(4-phenyl-5-isoxazolyl)-2H-2-chromenone (3a). Yield 0.11 g (34%), C H NO ,
19 13
4
1
mp 189–190ꢃÑ. Í NMR spectrum (DMSO-d –CCl , ꢄ, ppm, J/Hz): 2.32 (3Í, s, ÑÍ -4), 6.07 (1Í, s, H-3), 6.87 (1H, s, Í-8),
7.29–7.33 (5H, m, Ph), 7.63 (1Í, s, Í-5), 8.71 (1Í, s, H-3ꢀ), 10.78 (1Í, s, OH). C NMR spectrum (DMSO-d , ꢄ, ppm): 18.6,
6
4
3
13
6
103.7, 111.9, 113.1, 113.4, 118.4, 127.5, 128.1, 128.8, 129.3, 130.4, 151.4, 153.7, 156.4, 159.6, 160.4, 161.8.
7-Hydroxy-4-methyl-6-[4-(4-methoxyphenyl)-5-isoxazolyl]-2H-2-chromenone (3b). Yield 0.11 g (32%),
1
C H NO , mp 240–241ꢃÑ. Í NMR spectrum (DMSO-d –CCl , ꢄ, ppm, J/Hz): 2.33 (3Í, s, ÑÍ -4), 3.74 (3Í, s, ÑÍ O),
20 15
5
6
4
3
3
6.07 (1Í, s, H-3), 6.81 (2H, d, J = 8.4, Í-2ꢀꢀ, 6ꢀꢀ), 6.85 (1H, s, Í-8), 7.24 (2H, d, J = 8.4, Í-3ꢀꢀ, 5ꢀꢀ), 7.62 (1Í, s, Í-5), 8.73 (1Í,
13
s, H-3ꢀ), 10.92 (1Í, s, OH). C NMR spectrum (DMSO-d , ꢄ, ppm): 18.7, 55.8, 103.6, 111.9, 113.1, 113.5, 114.8, 118.1,
6
122.6, 128.8, 128.9, 151.4, 153.9, 156.3, 159.3, 159.6, 160.4, 160.8.
7-Hydroxy-4-methyl-6-[4-(4-methoxyphenyl)-3-methyl-5-isoxazolyl]-2H-2-chromenone (3c). Yield 0.14 g (39%),
1
C H NO , mp 229–230ꢃÑ. Í NMR spectrum (DMSO-d –CCl , ꢄ, ppm, J/Hz): 2.30 (6Í, s, ÑÍ -4, 3ꢀ), 3.76 (3Í, s, ÑÍ O),
21 17
5
6
4
3
3
6.04 (1Í, s, H-3), 6.78 (1H, s, Í-8), 6.84 (2H, d, J = 8.4, Í-2ꢀꢀ, 6ꢀꢀ), 7.12 (2H, d, J = 8.4, Í-3ꢀꢀ, 5ꢀꢀ), 7.51 (1Í, s, Í-5), 10.79
13
(1Í, s, OH). C NMR spectrum (DMSO-d , ꢄ, ppm): 11.2, 18.6, 55.7, 103.7, 111.8, 112.8, 113.5, 114.7, 118.4, 122.9, 128.8,
6
130.5, 153.7, 156.1, 157.5, 159.3, 159.5, 160.4, 162.5.
7-Hydroxy-6-[4-(3,4-dimethoxyphenyl)-3-methyl-5-isoxazolyl]-4-methyl-2H-2-chromenone (3d). Yield 0.15 g
1
(38%), C H NO , mp 224–225ꢃÑ. Í NMR spectrum (DMSO-d –CCl , ꢄ, ppm, J/Hz): 2.31 (3Í, s, ÑÍ -4), 2.33 (3Í, s,
22 19
6
6
4
3
ÑÍ -3ꢀ), 3.68 (3Í, s, ÑÍ O), 3.78 (3Í, s, ÑÍ O), 6.07 (1Í, s, H-3), 6.73–6.86 (4H, m, Í-8, 2ꢀꢀ, 5ꢀꢀ, 6ꢀꢀ), 7.58 (1Í, s, Í-5),
3
3
3
13
10.85 (1Í, s, OH). C NMR spectrum (DMSO-d , ꢄ, ppm): 11.3, 18.5, 56.1, 103.4, 112.6, 112.8, 113.3, 113.6, 118.6, 121.8,
6
123.1, 128.7, 149.0, 149.3, 153.7, 156.1, 159.3, 159.7, 160.3, 162.6.
6-[4-(4-Bromophenyl)-3-methyl-5-isoxazolyl]-7-hydroxy-4-methyl-2H-2-chromenone (3f). Yield 0.17 g (41%),
1
C H BrNO , mp 250–251ꢃÑ. Í NMR spectrum (DMSO-d , ꢄ, ppm, J/Hz): 2.32 (6Í, s, ÑÍ -4, 3ꢀ), 6.07 (1Í, s, H-3), 6.77 (1H,
20 14
4
6
3
644

13
s, Í-8), 7.17 (2H, d, J = 8.4, Í-2ꢀꢀ, 6ꢀꢀ), 7.47 (2H, d, J = 8.4, Í-3ꢀꢀ, 5ꢀꢀ), 7.53 (1Í, s, Í-5), 10.83 (1Í, s, OH). C NMR spectrum
(DMSO-d , ꢄ, ppm): 11.2, 18.6, 55.8, 103.5, 111.9, 113.0, 117.6, 121.6, 128.7, 130.5, 131.3, 131.9, 132.2, 153.7, 156.2, 159.2,
6
160.3, 161.1, 163.1.
7-Hydroxy-4,8-dimethyl-6-[3-methyl-4-(4-methyl-1,3-thiazol-2-yl)-5-isoxazolyl]-2H-2-chromenone (3g). Yield
1
0.16 g (43%), C H N O S, mp 222–223ꢃÑ. Í NMR spectrum (DMSO-d –CCl , ꢄ, ppm, J/Hz): 2.30 (3Í, s, ÑÍ -4), 2.38
19 16
2
4
6
4
3
(3Í, s, ÑÍ -8), 2.42 (3Í, s, ÑÍ -4ꢀꢀ), 2.59 (3Í, s, ÑÍ -3ꢀ), 6.15 (1Í, s, H-3), 7.05 (1H, s, Í-5 ), 7.58 (1Í, s, Í-5), 10.28
3
3
3
Th
1
(1Í, s, OH). Í NMR spectrum (CCl , ꢄ, ppm, J/Hz): 2.61 (3Í, s, ÑÍ -4), 2.65 (3Í, s, ÑÍ -8), 2.73 (3Í, s, ÑÍ -4ꢀꢀ), 2.81
4
3
3
3
13
(3Í, s, ÑÍ -3ꢀ), 6.25 (1Í, s, H-3), 7.18 (1H, s, Í-5 ), 7.70 (1Í, s, Í-5), 11.68 (1Í, s, OH). C NMR spectrum (DMSO-d –CCl ,
3
Th
6
4
ꢄ, ppm): 9.3, 12.3, 17.2, 18.8, 112.1, 112.8, 113.4, 113.7, 114.3, 114.6, 125.4, 152.4, 152.9, 154.9, 156.9, 157.7, 158.5, 160.0,
165.4.
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