Reactivity of Condensed Isoflavone Derivatives for Hydrazine

Article abstract of DOI:10.1007/s10600-018-2439-3

Recyclization by hydrazine of furo[3,2-b]pyrano[2,3-f]chromen-4-ones, dipyrano[2,3-b:2,3-f]chromen4-ones, and pyrano[2,3-a]xanthen-4-ones derived from natural isoflavonoids and their analogs was studied. The reaction was shown to proceed selectively with opening of the chromone ring. Several substituted 4-arylpyrazoles containing furo[3,2-b]chromen-5-ol, pyrano[2,3-b]chromen-6-ol, and xanthen-8-ol fragments were synthesized.

Full text of DOI:10.1007/s10600-018-2439-3

DOI 10.1007/s10600-018-2439-3
Chemistry of Natural Compounds, Vol. 54, No. 4, July, 2018
REACTIVITY OF CONDENSED ISOFLAVONE
DERIVATIVES FOR HYDRAZINE
1
2
3
G. P. Mrug, N. V. Bondarenko, S. P. Bondarenko,
1*
and M. S. Frasinyuk
Recyclization by hydrazine of furo[3,2-b]pyrano[2,3-f]chromen-4-ones, dipyrano[2,3-b:2ꢀ,3ꢀ-f]chromen-
4-ones, and pyrano[2,3-a]xanthen-4-ones derived from natural isoflavonoids and their analogs was studied.
The reaction was shown to proceed selectively with opening of the chromone ring. Several substituted
4-arylpyrazoles containing furo[3,2-b]chromen-5-ol, pyrano[2,3-b]chromen-6-ol, and xanthen-8-ol
fragments were synthesized.
Keywords: isoflavone, pyrazole, furo[3,2-b]chromen-5-ol, pyrano[2,3-b]chromen-6-ol, xanthen-8-ol.
2,3-Condensed chromone derivatives occur among secondary metabolites of plants and fungi and are interesting
subjects in the chemistry of natural compounds. Unique xyloketals A-H in addition to widely distributed xanthone derivatives
were isolated from mangrove fungus Xylaria sp. [1–4]; alboatrin, from Verticillium albo-atrum [5]. These contained
furo[3,2-b]chromane moieties. Various methods for synthesizing the xyloketal core and its analogs have now been developed
based on construction of pyran and furan rings [6–10].
Me
Me
O
HO
O
O
O
Ac
H
H
Me
OH
OH
Xyloketal D
Me
Alboatrin
Benzopyrone derivatives can be precursors for synthesizing substituted pyrazoles [11, 12], pyrimidines [13, 14], or
isoxazoles [15, 16] because nucleophiles tend to cleave the chromone core. This prompted us to study the preparation of
4-arylpyrazoles containing xyloketal or analogous cores.
Condensed derivatives of natural isoflavonoids and their analogs were synthesized via an inverse electron-demand
Diels–Alder heteroreaction [17] and contained two substituted heterocyclic systems that could react with hydrazine or its
derivatives. Thus, furo[3,2-b]pyrano[2,3-f]chromen-4-ones 3a, c–e, g–i, and h and dipyrano[2,3-b:2ꢀ,3ꢀ-f]chromen-4-ones 4a
and 4b, which were produced via condensation of the Mannich bases of isoflavones 2a–j with 2,3-dihydrofuran or
3,4-dihydro-2H-pyran, contained a chromone fragment and an acetal that could react with hydrazine. Nucleophilic attack by
hydrazine of 3-aryl-8,9,10,12-tetrahydro-4H,11H-pyrano[2,3-a]xanthen-4,11-diones 5a–c, f–h, and j could occur at various
positions of the heterocyclic system, i.e., at the 4- or 11-carbonyls to form hydrazones and at heterocyclic 2- and 7a-ketones
resulting from opening of the pyrone rings.
As it turned out, the course of the reaction under the given conditions of the chromone derivatives with hydrazine was
not affected by the acetal moiety in 3 and 4. The stability of the acetals under weakly basic conditions may have been
responsible for this. As a result, the reaction afforded high yields of pyrazolyl-substituted 2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-
5-ols 6a, c–e, g–i, and h and 3,4,4a,10a-tetrahydro-2H,5H-pyrano[2,3-b]chromen-6-ols 7a and 7b.
1) Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1 Murmanskaya
St., Kiev, 02094, Ukraine, e-mail: mykhaylo.frasinyuk@ukr.net; 2) Taras Shevchenko Kiev National University,
64 Vladimirskaya St., Kiev, 01601, Ukraine; 3) National University of Food Technologies, 68 Vladimirskaya St., Kiev, 01601,
Ukraine. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August, 2018, pp. 554–558. Original article submitted
January 19, 2018.
©
654
0009-3130/18/5404-0654 2018 Springer Science+Business Media, LLC

NMe
O
2
HO
O
R
HO
R
a
Ar
Ar
O
O
1a-j
2a-j
b
c
d
Me
O
9
Me
9
11
O
8
O
11
12
12
1
O
1
O
1
O
O
R
7 O
R
7 O
R
6
Ar
Ar
Ar
4
4
4
5
5
O
O
O
5a-c,f-h,j
Me
3a,c-e,g-i,k
4a,b
e
e
e
3
1
O
Me
1O
9 O
1
O
4
9
8
5
OH
N
10 O
6
OH
10O
OH
N
Ar
Ar
Ar
9
5
5'
5'
5'
R
R
R
N
NH
NH
NH
7a,b
8a-c,f-h,j
6a,c-e,g-i,k
a: R = H, Ar = C H OMe-4; b: R = H, Ar = C H (OMe) -3,4; c: R = H, Ar = C H (OCH O)-3,4
6
4
6
3
2
6
3
2
d: R = H, Ar = C H Cl-4; e: R = H, Ar = C H (OCH CH O)-3,4; f: R = H, Ar = C H F-2; g: R = Me, Ar = Ph
6
4
6
3
2
2
6 4
h: R = Me, Ar = C H OMe-4; i: R = Me, Ar = C H (OMe) -3,4; j: R = Me, Ar = C H F-4; k: R = Me, Ar = C H Cl-4
6
4
6
3
2
6
4
6 4
a. CH (NMe ) , i-PrOH; b. 2,3-dihydrofuran, DMF; c. 3,4-dihydro-2H-pyran, DMF;
2
2 2
d. 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, DMF; e. N H , EtOH
2
4
Reaction of hydrazine with 3-aryl-8,9,10,12-tetrahydro-4H,11H-pyrano[2,3-a]xanthene-4,11-diones 5a–c, f–h, and
j under these same conditions gave the major products 8-hydroxy-3-[4-arylpyrazol-3-yl]-3,3-dimethyl-2,3,4,9-tetrahydro-
1H-xanthen-1-ones 8a–c, f–h, and j. Moreover, prolonged heating of compounds 5 with hydrazine formed insignificant
quantities of the hydrazones of 8, as confirmed by HPLC-MS.
As noted in our previous work, the reactivity toward binucleophiles decreased noticeably for natural isoflavone
derivatives with electron-donating methoxyls on ring B, especially 2-methyl-substituted isoflavones 3g–i and k and 5g, h, and
j, recyclization of which by hydrazine took several hours.
13
The pyrazole structure of 6–8 was confirmed by PMR and C NMR spectroscopy. PMR spectra of 6–8 exhibited
diamagnetic shifts by 0.7–0.8 and 1.2–1.3 ppm for the protons of the oxygen-containing aromatic heterocycle as compared
with the positions of these proton resonances in starting compounds 3–5. However, the positions and SSCCs of acetal protons
in 6 and 7 were practically unchanged. Also, prototropic tautomerism of the pyrazole ring broadened resonances in both the
13
PMR and C NMR spectra.
13
The C NMR spectrum of 8b can be used as examples to demonstrate the presence of a xanthenone fragment. Thus,
the resonance at 196.78 ppm was indicative of a carbonyl; a weak-field resonance at 163.99 ppm, to C-4a.
Thus, polycyclic oxygen-containing heterocycles prepared under inverse electron-demand Diels–Alder reaction
conditions via cycloaddition of electron-rich dienes to o-quinone methides could be convenient intermediates for preparing
derivatives of natural compounds.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Silufol UV-254 plates (Merck, Germany)
f
13
using CH Cl –MeOH (9:1, 95:5). PMR and C NMR spectra were recorded in CDCl or DMSO-d vs. TMS internal
2
2
3
6
standard on the ꢁ-scale on Varian M400 (400 and 100 MHz, respectively) and Bruker 500 instruments (500 and 125 MHz,
655

respectively). GC-MS used an Agilent 1100 Series HPLC-MS equipped with an Agilent LC\MSD SL mass-selective diode-
array detector and chemical ionization at atmospheric pressure (APCI). Elemental analyses of all compounds agreed with
those calculated.
General Method for Preparing 8-Dimethylaminomethyl-7-hydroxyisoflavones 2a–j. A suspension of
7-hydroxyisoflavone (1a–j, 2 mmol) in i-PrOH (20 mL) was stirred, refluxed, treated with bis(dimethylamino)methane
(2.4 mmol), refluxed for 6–8 h until the starting isoflavone was completely dissolved (end of reaction determined by TLC),
and cooled. The precipitated Mannich base was filtered off, rinsed with hexane, and dried. If crystallization did not occur, the
solvent and excesses of reagents were evaporated at reduced pressure. The solid was crystallized from i-PrOH–hexane. Data
for synthesized Mannich bases 2a–e, g–i, and k were reported by us earlier [17, 18].
7-Hydroxy-8-[(dimethylamino)methyl]-3-(2-fluorophenyl)-4H-chromen-4-one (2f). Yield 73%, C H FNO ,
18 16
3
1
mp 165–167ꢂC. Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 2.43 (6H, s, N(CH ) ), 3.99 (2H, s, H-8), 6.90 (1H, d,
3
3 2
J = 8.8, Í-6), 7.12–7.23, 7.31–7.40, 7.46–7.53 (2H, 1H, 1H, 3m, 3-C H F-o), 7.94 (1H, s, Í-2), 8.12 (1H, d, J = 8.8, Í-5),
6
4
13
10.60 (1H, s, 7-ÎÍ). C NMR spectrum (100 MHz, CDCl , ꢁ, ppm, J/Hz): 44.60, 55.16, 107.61, 115.74, 115.78 (d, J(C/F) = 22.4),
3
116.91, 119.61 (d, J(C/F) = 14.9), 119.64 (d, J(C/F) = 1.3), 124.00 (d, J(C/F) = 3.7), 126.79, 129.93 (d, J(C/F) = 8.2), 132.14 (d,
19
J(C/F) = 3.1), 153.34 (d, J(C/F) = 3.5), 155.01, 160.26 (d, J(C/F) = 247.4), 164.29, 175.03. F NMR spectrum (377 MHz,
+
CDCl , ꢁ, ppm): 115.17. MS (CI) m/z 314.0 (MH , 100).
3
7-Hydroxy-8-[(dimethylamino)methyl]-3-(4-fluorophenyl)-2-methyl-4H-chromen-4-one (2j). Yield 69%,
1
C H FNO , mp 160–162ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 2.24 (3H, s, H-2), 2.35 (6H, s, N(CH ) ),
19 18
3
6
3 2
13
3.94 (2H, s, H-8), 6.83 (1H, d, J = 8.8, H-6), 7.19–7.39 (4H, m, Í-2ꢀ, 3ꢀ, 5ꢀ, 6ꢀ), 7.80 (1H, d, J = 8.8, H-5). C NMR spectrum
(100 MHz, DMSO-d , ꢁ, ppm, J/Hz): 19.14, 44.04, 53.30, 108.19, 114.67, 114.90 (d, J(C/F) = 21.1), 114.97, 120.96, 125.56,
6
19
129.63 (d, J(C/F) = 3.3), 132.61 (d, J(C/F) = 8.1), 154.68, 161.52 (d, J(C/F) = 243.8), 162.25, 163.86, 174.88. F NMR
spectrum (377 MHz, DMSO-d , ꢁ, ppm): –115.06. MS (CI) m/z 328.2 (MH , 100).
+
6
9,9-Dimethyl-3-(2-fluorophenyl)-8,9,10,12-tetrahydro-4H,11H-pyrano[2,3-a]xanthene-4,11-dione (5f). Asolution
of Mannich base (314 mg, 1 mmol) and 3-(dimethylamino)-5,5-dimethylcyclohex-2-en-1-one (344 mg, 2 mmol) in DMF (10 mL)
was refluxed for 4-6 h, cooled, and evaporated at reduced pressure. The solid was triturated with MeOH. The resulting
1
precipitate was filtered off and crystallized from MeOH–MeCN. Yield 330 mg (85%), C H FO , mp 285–287ꢂC. Í NMR
24 19
4
spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz): 1.15 (6H, s, CH -9), 2.37 (2H, s, H-10), 2.49 (2H, s, H-8), 3.64 (2H, s, H-12), 7.05
3
3
(1H, d, J = 8.8, Í-6), 7.11–7.28, 7.32–7.42, 7.42–7.51 (2H, 1H, 1H, 3m, 3-C H F-o), 8.05 (1H, s, Í-2), 8.13 (1H, d, J = 8.8,
6
4
13
Í-5). C NMR spectrum (100 MHz, CDCl , ꢁ, ppm, J/Hz): 16.63, 28.52, 32.31, 41.24, 50.68, 108.39, 110.21, 114.71, 115.98
3
(d, J(C/F) = 22.2), 119.27 (d, J(C/F) = 14.9), 120.67, 121.01, 124.21 (d, J(C/F) = 3.6), 125.75, 130.37 (d, J(C/F) = 8.3), 132.04
(d, J(C/F) = 3.0), 153.35, 154.40 (d, J(C/F) = 3.1), 154.79, 160.38 (d, J(C/F) = 247.9), 164.37, 174.96, 197.80. MS (CI)
+
m/z 391.2 (MH , 100).
2,9,9-Trimethyl-3-(4-fluorophenyl)-8,9,10,12-tetrahydro-4H,11H-pyrano[2,3-a]xanthene-4,11-dione (5j) was
1
prepared analogously to 5f. Yield 85%, C H FO , mp 271–273ꢂC. Í NMR spectrum (400 MHz, CDCl , ꢁ, ppm, J/Hz):
25 21
4
3
1.16 (6H, s, CH -9), 2.33 (3H, s, CH -2), 2.38 (2H, s, H-10), 2.49 (2H, s, H-8), 3.64 (2H, s, H-12), 7.00 (1H, d, J = 8.7, Í-6),
3
3
13
7.06–7.17 (2H, m, Í-3ꢀꢀ, 5ꢀꢀ), 7.20–7.30 (2H, m, Í-2ꢀꢀ, 6ꢀꢀ), 8.06 (1H, d, J = 8.7, Í-5). C NMR spectrum (100 MHz, CDCl , ꢁ,
3
ppm, J/Hz): 16.59, 19.65, 28.54, 32.32, 41.34, 50.76, 108.45, 109.73, 114.23, 115.58 (d, J(C/F) = 21.4), 120.04, 122.93,
125.64, 128.78 (d, J(C/F) = 3.4), 132.24 (d, J(C/F) = 8.3), 153.17, 154.40, 162.53 (d, J(C/F) = 246.9), 163.52, 164.55, 176.15,
+
197.95. MS (CI) m/z 405.1 (MH , 100).
General Method for Preparing Pyrazoles 6–8. A hot solution of the appropriate polycyclic 3–6 (1 mmol) in the
minimal amount of EtOH was treated with hydrazine hydrate (0.5 mL, 10 mmol), refluxed for 0.5–2 h (end of reaction
determined by TLC), poured into H O (100–150 mL), and acidified to pH 7. The resulting precipitate was filtered off and
2
crystallized from MeOH–H O.
2
6-[4-(4-Methoxyphenyl)-1H-pyrazol-3-yl]-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-5-ol (6a). Yield 73%,
1
C H N O , mp 206–208ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.40–1.59 (1H, m, H-3ꢃ), 1.95–2.12
21 20
2
4
6
(1H, m, H-3ꢄ), 2.60–2.70 (1H, m, H-3a), 2.79 (1H, dd, J = 17.2, 6.1, H-4ꢃ), 2.86 (1H, dd, J = 17.2, 2.5, H-4ꢄ), 3.76 (3H, s,
4ꢀꢀ-OÑÍ ), 3.79–3.87 (1H, m, H-2ꢃ), 3.87–3.97 (1H, m, H-2ꢄ), 5.53 (1H, d, J = 4.4, H-9a), 6.15 (1H, d, J = 8.6, Í-8),
3
13
6.87–6.95 (3H, m, Í-7, 3ꢀꢀ, 5ꢀꢀ), 7.22 (2H, d, J = 8.6, Í-2ꢀꢀ, 6ꢀꢀ), 7.88 (1H, s, Í-5ꢀ). C NMR spectrum (125 MHz, CDCl , ꢁ,
3
ppm): 20.37, 28.22, 36.65, 55.48, 67.73, 100.60, 107.43, 108.41, 110.57, 114.40, 118.89, 126.19, 130.18, 130.71, 130.83,
+
146.29, 153.38, 154.65, 158.70. MS (CI) m/z 365.2 (MH , 100).
656

6-[4-(1,3-Benzodioxol-5-yl)-1H-pyrazol-3-yl]-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-5-ol (6c). Yield 62%,
1
C H N O , mp 105–107ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.41–1.59 (1H, m, H-3ꢃ), 1.96–2.11
21 18
2
5
6
(1H, m, H-3ꢄ), 2.60–2.70 (1H, m, H-3a), 2.79 (1H, dd, J = 17.1, 6.1, H-4ꢃ), 2.83–2.91 (1H, m, H-4ꢄ), 3.78–3.88 (1H, m,
H-2ꢃ), 3.87–3.97 (1H, m, H-2ꢄ), 5.54 (1H, d, J = 4.4, H-9a), 6.01 (2H, s, OCH O), 6.20 (1H, d, J = 8.6, Í-8), 6.77 (1H, d,
2
+
J = 8.0, Í-7ꢀꢀ), 6.82 (1H, s, Í-6ꢀꢀ), 6.84–6.94 (2H, m, Í-7, 4ꢀꢀ), 7.87 (1H, s, H-5ꢀ). MS (CI) m/z 379.2 (MH , 100).
6-[4-(4-Chlorophenyl)-1H-pyrazol-3-yl]-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-5-ol (6d). Yield 69%,
1
C H ClN O , mp 238–240ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.41–1.58 (1H, m, H-3ꢃ), 1.97–2.13
20 17
2
3
6
(1H, m, H-3ꢄ), 2.59–2.72 (1H, m, H-3a), 2.73–2.92 (2H, m, H-4), 3.78–3.89 (1H, m, H-2ꢃ), 3.87–3.97 (1H, m, H-2ꢄ), 5.54
(1H, s, H-9a), 6.11–6.25 (1H, m, Í-8), 6.85 (1H, d, J = 8.5, H-7), 7.19–7.47 (4H, m, Í-2ꢀꢀ, 3ꢀꢀ, 5ꢀꢀ, 6ꢀꢀ), 8.01 (1H, s, H-5ꢀ), 10.86
+
(1H, s, 5-OH), 13.35 (1H, s, NH-1ꢀ). MS (CI) m/z 369.2 (MH , 100).
6-[4-(2,3-Dihydro-1,4-benzodioxan-6-yl)-1H-pyrazol-3-yl]-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-5-ol
1
(6e). Yield 74%, C H N O , mp 109–111ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm): 1.43–1.55 (1H, m, H-3ꢃ),
22 20
2
5
6
1.99–2.14 (1H, m, H-3ꢄ), 2.62–2.71 (1H, m, H-3a), 2.74–2.95 (2H, m, H-4), 3.78–3.87 (1H, m, H-2ꢃ), 3.87–4.00 (1H, m,
H-2ꢄ), 4.24 (4H, s, OCH CH O), 5.54 (1H, s, H-9a), 6.16 (1H, s, Í-8), 6.67–7.01 (4H, m, Í-7, 5ꢀꢀ, 7ꢀꢀ, 8ꢀꢀ), 7.90 (1H, s, H-5ꢀ),
2
2
+
11.15 (1H, s, 5-OH), 13.25 (1H, s, NH-1ꢀ). MS (CI) m/z 393.2 (MH , 100).
6-(5-Methyl-4-phenyl-1H-pyrazol-3-yl)-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-5-ol (6g). Yield 85%,
1
C H N O , mp 263–265ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.41–1.57 (1H, m, Í-3ꢃ), 1.95–2.09
21 20
2
3
6
(1H, m, H-3ꢄ), 2.15 (3H, s, CH -5ꢀ), 2.59–2.67 (1H, m, H-3a), 2.78 (1H, dd, J = 17.3, 6.0, H-4ꢃ), 2.85 (1H, dd, J = 17.3, 2.5,
3
Í-4ꢄ), 3.77–3.86 (1H, m, Í-2ꢃ), 3.87–3.95 (1H, m, Í-2ꢄ), 5.50 (1H, d, J = 4.4, Í-9a), 6.02 (1H, d, J = 8.6, Í-8), 6.70 (1H,
d, J = 8.6, Í-7), 7.24 (2H, d, J = 6.8, Í-3ꢀꢀ, 5ꢀꢀ), 7.32–7.48 (3H, m, Í-2ꢀꢀ, 4ꢀꢀ, 6ꢀꢀ), 11.67 (1H, s, 5-OH), 13.05 (1H, s, NH-1ꢀ).
+
MS (CI) m/z 349.2 (MH , 100).
5-Methyl-6-[4-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-5-ol (6h).
1
Yield 91%, C H N O , mp 213–215ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.39–1.61 (1H, m, Í-3ꢃ),
22 22
2
4
6
1.94–2.10 (1H, m, Í-3ꢄ), 2.13 (3H, s, CH -5ꢀ), 2.58–2.71 (1H, m, Í-3a), 2.78 (1H, dd, J = 17.3, 6.0, Í-4ꢃ), 2.81–2.92 (1H,
3
m, Í-4ꢄ), 3.79 (3H, s, 4ꢀꢀ-OÑÍ ), 3.80–3.87 (1H, m, Í-2ꢃ), 3.86–3.97 (1H, m, Í-2ꢄ), 5.49 (1H, d, J = 4.3, Í-9a), 6.04 (1H, d,
3
J = 8.7, Í-8), 6.76 (1H, d, J = 8.7, Í-7), 6.99 (2H, d, J = 8.1, Í-3ꢀꢀ, 5ꢀꢀ), 7.15 (2H, d, J = 8.1, Í-2ꢀꢀ, 6ꢀꢀ), 11.71 (1H, s, 5-OH),
+
13.04 (1H, s, NH-1ꢀ). MS (CI) m/z 379.2 (MH , 100).
6-[4-(3,4-Dimethoxyphenyl)-5-methyl-1H-pyrazol-3-yl]-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-5-ol (6i).
1
Yield 89%, C H N O , mp 231–233ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.42–1.57 (1H, m, Í-3ꢃ),
23 24
2
5
6
1.94–2.10 (1H, m, Í-3ꢄ), 2.15 (3H, s, CH -5ꢀ), 2.58–2.69 (1H, m, Í-3a), 2.78 (1H, dd, J = 17.3, 6.1, Í-4ꢃ), 2.81–2.90 (1H,
3
m, Í-4ꢄ), 3.67 (3H, s, 3ꢀꢀ-OÑÍ ), 3.79 (3H, s, 4ꢀꢀ-OÑÍ ), 3.79–3.88 (1H, m, Í-2ꢃ), 3.86–3.95 (1H, m, Í-2ꢄ), 5.50 (1H, d,
3
3
J = 4.3, Í-9a), 6.07 (1H, d, J = 8.7, Í-8), 6.66–6.90 (3H, m, Í-7, 2ꢀꢀ, 6ꢀꢀ), 7.00 (1H, d, J = 8.2, Í-5ꢀꢀ), 11.74 (1H, s, 5-OH),
+
13.03 (1H, s, NH-1ꢀ). MS (CI) m/z 409.2 (MH , 100).
6-[5-Methyl-4-(4-chlorophenyl)-1H-pyrazol-3-yl]-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-5-ol (6k). Yield
1
90%, C H ClN O , mp 245–247ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.41–1.58 (1H, m, Í-3ꢃ),
21 19
2
3
6
1.94–2.10 (1H, m, Í-3ꢄ), 2.16 (3H, s, CH -5ꢀ), 2.57–2.70 (1H, m, Í-3a), 2.72–2.89 (2H, m, H-4), 3.78–3.87 (1H, m, Í-2ꢃ),
3
3.86–3.97 (1H, m, Í-2ꢄ), 5.50 (1H, d, J = 4.3, Í-9a), 6.08 (1H, d, J = 8.6, Í-8), 6.69 (1H, d, J = 8.6, Í-7), 7.26 (2H, d, J = 7.9,
+
Í-3ꢀꢀ, 5ꢀꢀ), 7.47 (2H, d, J = 7.9, Í-2ꢀꢀ, 6ꢀꢀ), 11.46 (1H, s, 5-OH), 13.15 (1H, s, NH-1ꢀ). MS (CI) m/z 383.0 (MH , 100).
7-[4-(4-Methoxyphenyl)-1H-pyrazol-3-yl]-3,4,4a,10a-tetrahydro-2H,5H-pyrano[2,3-b]chromen-6-ol (7a). Yield
1
59%, C H N O , mp 245–247ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.45–1.70 (4H, m, H-3, 4),
22 22
2
4
6
2.03–2.17 (1H, m, Í-4a), 2.57 (1H, dd, J = 17.2, 5.0, Í-5ꢃ), 2.74 (1H, dd, J = 17.1, 6.4, Í-5ꢄ), 3.54–3.65 (1H, m, Í-2ꢃ),
3.62–3.89 (4H, m, 4ꢀꢀ-OÑÍ , Í-2ꢄ), 5.26 (1H, d, J = 2.3, Í-10a), 6.15 (1H, d, J = 8.6, Í-9), 6.90 (1H, d, J = 8.6, Í-8), 6.95
3
(2H, d, J = 8.3, Í-3ꢀꢀ, 5ꢀꢀ), 7.23 (2H, d, J = 8.3, Í-2ꢀꢀ, 6ꢀꢀ), 7.91 (1H, s, Í-5ꢀ), 11.24 (1H, s, 6-OH), 13.26 (1H, s, NH-1ꢀ).
+
MS (CI) m/z 379.2 (MH , 100).
7-[4-(3,4-Dimethoxyphenyl)-1H-pyrazol-3-yl]-3,4,4a,10a-tetrahydro-2H,5H-pyrano[2,3-b]chromen-6-ol (7b).
1
Yield 90%, C H N O , mp 170–172ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.42–1.70 (4H, m, H-3, 4),
23 24
2
5
6
2.05–2.16 (1H, m, Í-4a), 2.57 (1H, dd, J = 17.3, 5.1, Í-5ꢃ), 2.74 (1H, dd, J = 17.3, 6.3, Í-5ꢄ), 3.56–3.65 (1H, m, Í-2ꢃ), 3.67
(3H, s, 3ꢀꢀ-OÑÍ ), 3.77 (3H, s, 4ꢀꢀ-OÑÍ ), 3.80–3.88 (1H, m, Í-2ꢄ), 5.26 (1H, s, Í-10a), 6.18 (1H, d, J = 8.6, Í-9), 6.73–7.07
3
3
+
(4H, m, Í-8, 2ꢀꢀ, 5ꢀꢀ, 6ꢀꢀ), 7.93 (1H, s, Í-5ꢀ), 11.24 (1H, s, 6-OH), 13.25 (1H, s, NH-1ꢀ). MS (CI) m/z 409.2 (MH , 100).
657

8-Hydroxy-7-[4-(4-methoxyphenyl)-1H-pyrazol-3-yl]-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (8a).
1
Yield 89%, C H N O , mp 252–254ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm): 1.05 (6H, s, CH -3), 2.27 (2H,
25 24
2
4
6
3
s, H-4), 2.43 (2H, s, H-2), 3.26 (2H, s, H-9), 3.77 (3H, s, 4ꢀꢀ-OÑÍ ), 6.31–6.44 (1H, m, Í-5), 6.83–7.04 (3H, m, Í-6, 3ꢀꢀ, 5ꢀꢀ),
3
+
7.14–7.30 (2H, m, Í-2ꢀꢀ, 6ꢀꢀ), 7.95 (1H, s, Í-5ꢀ), 11.40 (1H, s, 8-OH), 13.37 (1H, s, NH-1ꢀ). MS (CI) m/z 417.2 (MH , 100).
8-Hydroxy-3,3-dimethyl-7-[4-(3,4-dimethoxyphenyl)-1H-pyrazol-3-yl]-2,3,4,9-tetrahydro-1H-xanthen-1-one
1
(8b). Yield 89%, C H N O , mp 252–254ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.04 (6H, s, CH -3),
26 26
2
5
6
3
2.26 (2H, s, H-4), 2.43 (2H, s, H-2), 3.25 (2H, s, H-9), 3.66 (3H, s, 3ꢀꢀ-OÑÍ ), 3.76 (3H, s, 4ꢀꢀ-OÑÍ ), 6.43 (1H, d, J = 8.7,
3
3
13
H-5), 6.79–6.92 (2H, m, Í-2ꢀꢀ, 6ꢀꢀ), 6.95 (1H, d, J = 8.2, Í-5ꢀꢀ), 7.06 (1H, d, J = 8.7, Í-6), 7.95 (1H, s, Í-5ꢀ). C NMR
spectrum (125 MHz, DMSO-d , ꢁ, ppm): 16.80, 27.77, 31.74, 40.25, 49.98, 55.38, 55.46, 106.38, 107.72, 108.77, 111.93,
6
112.63, 113.56, 119.07, 120.86, 125.74, 126.57, 130.75, 144.02, 147.82, 148.58, 149.33, 154.14, 163.99, 196.78. MS (CI)
+
m/z 447.1 (MH , 100).
7-[4-(1,3-Benzodioxol-5-yl)-1H-pyrazol-3-yl]-8-hydroxy-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (8c).
1
Yield 88%, C H N O , mp 272–274ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.04 (6H, s, CH -3), 2.26
25 22
2
5
6
3
(2H, s, H-4), 2.43 (2H, s, H-2), 3.25 (2H, s, H-9), 6.02 (2H, s, OCH O), 6.36–6.49 (1H, m, Í-5), 6.70–6.94 (3H, m, Í-4ꢀꢀ, 6ꢀꢀ, 7ꢀꢀ),
2
+
7.01 (1H, d, J = 8.7, Í-6), 7.89–8.00 (1H, s, Í-5ꢀ), 11.29 (1H, s, 5-ÎÍ), 13.37 (1H, s, NH-1ꢀ). MS (CI) m/z 431.1 (MH , 100).
8-Hydroxy-3,3-dimethyl-7-[4-(2-fluorophenyl)-1H-pyrazol-3-yl]-2,3,4,9-tetrahydro-1H-xanthen-1-one (8f).
1
Yield 82%, C H FN O , mp 284–286ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.04 (6H, s, CH -3), 2.26
24 21
2
3
6
3
(2H, s, H-4), 2.42 (2H, s, H-2), 3.26 (2H, s, H-9), 6.39 (1H, d, J = 8.6, Í-5), 6.86 (1H, d, J = 8.6, Í-6), 7.19–7.32, 7.31–7.48
+
(2H each, m, 4ꢀ-C H F-o), 8.03 (1H, s, Í-5ꢀ). MS (CI) m/z 405.1 (MH , 100).
6
4
8-Hydroxy-3,3-dimethyl-7-(5-methyl-4-phenyl-1H-pyrazol-3-yl)-2,3,4,9-tetrahydro-1H-xanthen-1-one (8g).
1
Yield 63%, C H N O , mp 292–294ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.04 (6H, s, CH -3), 2.17
25 24
2
3
6
3
(3H, s, CH -5ꢀ), 2.26 (2H, s, H-4), 2.41 (2H, s, H-2), 3.24 (2H, s, H-9), 6.28 (1H, d, J = 8.7, Í-5), 6.80 (1H, d, J = 8.7, Í-6), 7.25
3
+
(2H, d, J = 7.3, Í-3ꢀꢀ, 5ꢀꢀ), 7.32–7.49 (3H, m, Í-6, 2ꢀꢀ, 6ꢀꢀ), 11.80 (1H, s, 5-ÎÍ), 13.23 (1H, s, NH-1ꢀ). MS (CI) m/z 401.1 (MH , 100).
8-Hydroxy-5-methyl-7-[4-(4-methoxyphenyl)-1H-pyrazol-3-yl]-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-
1
one (8h). Yield 58%, C H N O , mp 251–253ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.04 (6H, s,
26 26
2
4
6
CH -3), 2.14 (3H, s, CH -5ꢀ), 2.26 (2H, s, H-4), 2.42 (2H, s, H-2), 3.24 (2H, s, H-9), 3.80 (3H, s, 4ꢀꢀ-OÑÍ ), 6.32 (1H, d,
3
3
3
J = 8.7, Í-5), 6.86 (1H, d, J = 8.7, Í-6), 7.00 (2H, d, J = 8.0, Í-3ꢀꢀ, 5ꢀꢀ), 7.16 (2H, d, J = 8.0, Í-2ꢀꢀ, 6ꢀꢀ), 11.89 (1H, s, 5-ÎÍ),
+
13.18 (1H, s, NH-1ꢀ). MS (CI) m/z 431.1 (MH , 100).
8-Hydroxy-3,3-dimethyl-5-methyl-7-[4-(4-fluorophenyl)-1H-pyrazol-3-yl]-2,3,4,9-tetrahydro-1H-xanthen-1-one
1
(8j). Yield 47%, C H FN O , mp 284–286ꢂC. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.04 (6H, s, CH -3),
25 23
2
3
6
3
2.16 (3H, s, CH -5ꢀ), 2.26 (2H, s, H-4), 2.41 (2H, s, H-2), 3.24 (2H, s, H-9), 6.33 (1H, d, J = 8.6, Í-5), 6.77 (1H, d, J = 8.6, Í-6),
3
+
7.14–7.40 (4H, m, 4ꢀ-C H F-p), 11.71 (1H, s, 5-ÎÍ), 13.24 (1H, s, NH-1ꢀ). MS (CI) m/z 419.1 (MH , 100).
6
4
REFERENCES
1.
2.
Y. Lin, X. Wu, S. Feng, G. Jiang, J. Luo, S. Zhou, L. L. P. Vrijmoed, E. B. G. Jones, K. Krohn, K. Steingrover,
and F. Zsila, J. Org. Chem., 66, 6252 (2001).
X. Y. Wu, X. H. Liu, Y. C. Lin, J. H. Luo, Z. G. She, L. Houjin, W. L. Chan, S. Antus, T. Kurtan, B. Elsasser,
and K. Krohn, Eur. J. Org. Chem., 2005, 4061 (2005).
3.
4.
5.
X. Wu, X. Liu, G. Jiang, Y. Lin, W. Chan, and L. L. P. Vrijmoed, Chem. Nat. Compd., 41, 27 (2005).
X. Liu, F. Xu, Y. Zhang, L. Liu, H. Huang, X. Cai, Y. Lin, and W. Chan, Russ. Chem. Bull., 55, 1091 (2006).
A. Ichihara, M. Nonaka, S. Sakamura, R. Sato, and A. Tajimi, Chem. Lett., 17, 27 (1988).
D. Sarkar and R. V. Venkateswaran, Tetrahedron, 67, 4559 (2011).
6.
7.
8.
S. R. Graham, J. A. Murphy, and A. R. Kennedy, J. Chem. Soc., Perkin Trans. 1, 3071 (1999).
K. Krohn, M. Riaz, and U. Floerke, Eur. J. Org. Chem., 1261 (2004).
9.
B. Panda and T. K. Sarkar, J. Org. Chem., 78, 2413 (2013).
10.
11.
12.
13.
J. D. Pettigrew and P. D. Wilson, Org. Lett., 8, 1427 (2006).
S. P. Bondarenko, M. S. Frasinyuk, V. I. Vinogradova, and V. P. Khilya, Chem. Nat. Compd., 50, 889 (2014).
Z.-T. Zhang, D.-J. Tan, and D. Xue, Helv. Chim. Acta, 90, 2096 (2007).
M. S. Frasinyuk, S. P. Bondarenko, and V. P. Khilya, Chem. Nat. Compd., 42, 673 (2006).
658

14.
15.
16.
17.
F. Xie, H. Zhao, L. Zhao, L. Lou, and Y. Hu, Bioorg. Med. Chem. Lett., 19, 275 (2009).
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya, Chem. Nat. Compd., 43, 402 (2007).
S. P. Bondarenko, O. N. Miroshnikov, M. S. Frasinyuk, and V. P. Khilya, Chem. Nat. Compd., 49, 826 (2013).
M. S. Frasinyuk, G. P. Mrug, S. P. Bondarenko, V. P. Khilya, V. M. Sviripa, O. A. Syrotchuk, W. Zhang, X. Cai,
M. V. Fiandalo, J. L. Mohler, C. Liu, and D. S. Watt, ChemMedChem, 11, 600 (2016).
M. Frasinyuk, G. P. Mrug, S. P. Bondarenko, V. M. Sviripa, W. Zhang, X. Cai, M. Fiandalo, J. L. Mohler, C. Liu,
and D. Watt, Org. Biomol. Chem., 13, 11292 (2015).
18.
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