Convenient synthetic method for 6-substituted derivatives of 4-methylumbelliferone

Article abstract of DOI:10.1007/s10600-012-0374-2

New 6-pyrazolyl-, isoxazolyl-, and pyrimidinylumbelliferones were synthesized from an analog of natural 6-acetyl-7-hydroxy-4-methylumbelliferone.

Full text of DOI:10.1007/s10600-012-0374-2

Chemistry of Natural Compounds, Vol. 48, No. 5, November, 2012 [Russian original No. 5, September–October, 2012]
CONVENIENT SYNTHETIC METHOD FOR 6-SUBSTITUTED
DERIVATIVES OF 4-METHYLUMBELLIFERONE
V. S. Moskvina,1* A. A. Ishchenko, and V. P. Khilya
2
1
UDC 547.587.51
New 6-pyrazolyl-, isoxazolyl-, and pyrimidinylumbelliferones were synthesized from an analog of natural
-acetyl-7-hydroxy-4-methylumbelliferone.
6
Keywords: benzopyran-2-one, umbelliferone, enaminoketone, heterocyclization.
Synthetic transformations of natural compounds, including coumarins, represent a critical direction of modern organic
chemistry that is related to the synthesis of compounds with broad applications. A critical area of research is the discovery of
new coumarin derivatives that contain a pharmacophore. This could be accomplished by combining several heterocyclic
moieties in a single molecule. Until now, such modification was carried out primarily at the pyran-2-one group of the benzopyran-
2
-one system. Thus, methods for preparing 3-hetarylcoumarin derivatives were broadly studied [1]. Synthetic procedures for
preparing 4-aryl(hetaryl)coumarins using cross-coupling reactions were recently developed. 4-Hetarylcoumarins were prepared
using a Suzuki-Miyaura reaction of 4-trifluoromethylsulfonyloxycoumarins [2, 3]; a Stille reaction of 4-stannylcoumarins
with 3-iodopyridine and 3-iodothiophene [4]; and of 4-trifluoromethylsulfonyloxycoumarins or 4-toluenesulfonyloxycoumarins
with tributyl(2-pyridyl-, furyl-, thienyl-)stannanes [5, 6]. Few examples of the preparation of coumarins containing heterocyclic
substituents in the benzene ring of the benzopyran-2-one system have been published. Thus, derivatives of
7
-phenylthiazolidinylbenzopyran-2-one exhibited antimicrobial properties [7]; 7-(indol-3-yl)coumarins were prepared via
Pd-catalyzed reaction of o-trifluoroacetanilides and coumarin triflate [8, 9]. However, the toxicity of organotin compounds
and the high cost of the starting triflates, tosylates, and Pd catalysts limited to a certain extent the application of these reactions
to the preparation of hetarylsubstituted coumarins. These circumstances also defined the goal of our study, i.e., to develop the
optimal and effective synthetic method for such compounds. We prepared previously [10] the first examples of 6- and
8
-hetarylsubstituted coumarins where enaminoketones, the precursors of which were 6- and 8-acetylneoflavones that were
prepared in three steps, were used successfully as the key intermediates.
In this respect, the synthesis of naturally occurring molecules and the use of such compounds as key intermediates are
especially interesting. Thus, 4-methylumbelliferone itself was isolated from Dalbergia volubilis [11]; liqcoumarin (6-acetyl-
5
-hydroxy-4-methylumbelliferone) was observed in Glycyrrhiza glabra [12], and 6-acetyl-7-hydroxy-4-methylcoumarin (1)
was found in seeds of Apium petroselinum [13].
We prepared 6-acetyl-7-hydroxy-4-methylcoumarin (1) in one step via condensation of resacetophenone with
acetoacetic ester in 75% yield (Scheme 1).
HO
O
OH
HO
O
O
O
HO
O
O
O
O
O
Me
N
DMFDMA
Me
+ Me
Me
Me
OEt
Me
Me
1
2
Scheme 1
) Kiev National Taras Shevchenko University, 01601, Kiev , Ul. Vladimirskaya, 60, e-mail: v.moskvina@gmail.com,
1
Ukraine; 2) Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 02094, Kiev, Ul. Murmanskaya, 5.
Translated from Khimiya Prirodnykh Soedinenii, No. 5, September–October, 2012, pp. 674–678. Original article submitted
February 10, 2012.
0
009-3130/12/4805-0751 ©2012 Springer Science+Business Media New York
751

Subsequent reaction of 1 with dimethylformamide dimethylacetal (DMFDMA) in refluxing toluene gave the
corresponding (dimethylamino)propenone 2 in 79% yield (Scheme 1) that was used successfully in heterocyclization reactions
with hydrazines, hydroxylamine, and guanidine.
Reaction of 2 with hydrazine hydrate (3 eq.) in refluxing EtOH produced 6-(pyrazol-5-yl)coumarin 3 in 79% yield
(
Scheme 2). Despite the fact that the coumarin ring is known to be destroyed by the action of nucleophiles, in this instance it
was not affected. This was confirmed by PMR spectroscopy. The H-3 resonance at 6.05 ppm was located in the region
characteristic of it. Two characteristic doublets for H-4ꢀ and H-5ꢀ of the pyrazole ring were observed at 6.9 and 7.5 ppm,
3
respectively, with J = 2.0 Hz. The exchangeable NH resonance appeared at 13.15 ppm. Because of the lability of this proton,
especially in solution, we could not draw an unambiguous conclusion about the regioselectivity of this transformation.
HO
O
O
HO
O
O
HO
O
O
a
b
Me
N
N
2
N
+
N
HN
Me N
Me
Me
Me
3
4 (type A)
5 (type B)
a. N H , EtOH; b. MeNHNH , EtOH
2
4
2
Scheme 2
We expanded the studies using methylhydrazine in various mole ratios in order to understand the mechanism of this
reaction.
The formation of two possible regioisomers of the N-methylpyrazoles, 1-methyl-1H-pyrazol-3-yl (type A) [14–17]
and 1-methyl-1H-pyrazol-5-yl (type B) [18, 19] has been reported in the literature.
Exclusively 6-(pyrazol-3-yl)coumarin 4 (typeA) was formed in 54% yield during the reaction of 2 with methylhydrazine
in a 1:1 mole ratio. Use of a 1:2 mole ratio resulted in the formation of regioisomers 6-(pyrazol-3-yl)coumarin (4) (typeA) and
6
-(pyrazol-5-yl)coumarin (5) (type B) in an 8:2 ratio (Scheme 2). The formation of regioisomeric products was confirmed by
TLC in which two spots with different R values were observed. One of the spots gave a dark-green color with an alcoholic
f
solution of FeCl . This indicated that an intramolecular H-bond had formed, which is possible for 4. This hypothesis was
3
confirmed by PMR spectroscopy of 4 and 5. Thus, the resonance of the 7-OH group in 5 was observed at 9.5 ppm. The
corresponding resonance in 4 was shifted to weak field and was found at 11.7 ppm. Compounds 4 and 5 were separated by
column chromatography and characterized.
Based on the results, we proposed the following formation mechanism for the targeted pyrazolylcoumarins (Scheme 3).
In the first step, the carbonyl was attacked by methylhydrazine with subsequent elimination of dimethylamine if a 1:1 mole
ratio of the reagents was used. This led to the formation of a single reaction product (4, Scheme 2). If an excess of
methylhydrazine was used, a competing exchange reaction of amino groups and then nucleophilic attack at the carbonyl could
also occur. In turn, this would produce 5 (Scheme 2). This proposed mechanism would explain the formation of
pyrazolylcoumarin 4 as the main reaction product.
Me
NH
Me
N
NHMe
NH
+
+
R
+
H
+
+H
N
NHNHMe
HN
NHNHMe
N
NMe
+
-H
+
R
R
R
+
5
NH
2
-NH NHMe, -H
2
NHMe
-HNMe
2 2
, H O
1: 2
NH
2
NHMe
O
NHMe
NHMe
+
N
N
Me
N
R
R
NMe
1 : 1
H
2
N
+
R
NMe
R
N HMe
2
2
2
NH NHMe
-
H O
+
4
2
-HNMe
2
-H
Scheme 3
752

Subsequent reaction of 2 with a slight excess of hydroxylamine hydrochloride (1.2 eq.) produced exclusively
-(isoxazol-5-yl)coumarin 6 in 83% yield (Scheme 4). The appearance of an H-3 resonance in the PMR spectrum indicated
6
that the coumarin system was intact. Doublets for H-3ꢀ and H-4ꢀ of the isoxazole ring were observed in the characteristic
3
region at 6.7 and 8.4 ppm, respectively, with J = 1.2 Hz.
HO
O
O
HO
O
O
O
HO
O
O
Me
N
a
a
N
O
Me
O
N
Me
Me
Me
6
(type C)
2
7 (type D)
a. NH OH4HCl, EtOH
2
Scheme 4
Because hydroxylamine is less nucleophilic than hydrazine derivatives, it could be assumed that exchange of the
amino group with subsequent nucleophilic attack at the carbonyl would occur in the first step.
Two cyclization pathways of enaminoketones with hydroxylamine to form isomeric isoxazol-5-yl (type C) [15, 20–
2
2] and isoxazol-3-yl (type D) products [16, 17] were reported in the literature. A reliable signature for differentiating the
isoxazole regioisomers (C or D) is the chemical shift of the phenol hydroxyl proton in PMR spectra recorded in CDCl [23].
3
The hydroxyl of isomer D can form an intramolecular bond with the isoxazole N atom, as a result of which its resonance will
be observed at weak field of 9.5–12.0 ppm. On the other hand, such a bond cannot be formed in isomer C. The OH resonance
should be found in the range 6.5–8.5 ppm. The resonance of the 7-OH in 6 was observed at 7.4 ppm, which was consistent
with the type C structure.
The reaction of 2 with guanidine occurred with heating of a reaction mixture in DMF and a catalytic amount of
3
K CO at 80°C to form a pyrimidine ring (Scheme 5). Resonances at 6.62 and 8.23 ppm with J = 5.2 Hz in PMR spectra of
2
3
8
corresponded to H-5ꢀ and H-4ꢀ of the pyrimidine ring. The amine resonance was observed at 7.2 ppm.
HO
O
O
HO
O
O
Me
N
a
H N
2
N
Me
O
Me
N
Me
2
8
a. NH C(NH)NH , DMF/K CO
2
2
2
3
Scheme 5
We performed quantum-chemical calculations of the energies E for conformers of 3, 6, and 7.
The calculations for 6 suggested the two most probable coplanar conformers 6a and 6b. Acomparison of the E values
showed that the first was more favorable by 6.11 kJ/mol. This could be explained by the formation of a strong H-bond
between the oppositely charged hydroxyl H atom and isoxazole O atom. A stable six-membered ring was formed. The
°
distance of 1.81 A provided evidence that the H-bond was strong because it is very effective at this distance.
HO
O
O
HO
O
O
HO
O
O
H
N
N
HN
N
Me
N
Me
Me
HN
O
3
a
3b
HO
3c
HO
1
HO
0
9
O
1
8
O
O
O
O
8a
4a
O
HO
O
7
N
1
'
5'
3
O
O
4
5
Me
N
Me
N
Me
N
O
Me
O
3
'
6a
6b
7a
7b
Electrostatic interactions of the hydroxyl O atom and the C-4ꢀ H atom in addition to those of O-1ꢀ and the C-5 H atom
were involved in stabilizing conformer 6b. These interactions could be considered weak H-bonds because, firstly, the H atoms
°
on the C atoms were very weakly acidic. Secondly, the interaction occurred at a significantly greater distance (2.40 A for
°
O-10–C-4ꢀ and 2.36 A for O-1ꢀ–C-5) than that for conformer 6a. As a result, the electrostatic stabilization of conformer 6b
between the pairs of atoms indicated above was weaker than that from O-1ꢀ and the H atom on O-10 in conformer 6a.
753

With respect to conformers 7a and 7b, which were isomeric with the corresponding conformers 6a and 6b, 7a was
more favorable than 7b for reasons analogous to those for the last pair. However, the difference between them was much
greater and reached 6 kJ. This was due to the fact that, in contrast with conformers 6a and 6b, a N atom instead of an O atom
was involved in the H-bonds of conformers 7a and 7b. Because of the greater fluxionality of its electron pair than that of an
O atom, it formed stronger H-bonds. For this reason, such bonds should be stronger for conformer 7a than for 6a. This was
°
confirmed by the significant shortening of the H-bond in the former compared with the latter. The length was 1.74 A for 7a.
As a result, the energy gain on going from 6a to 7a was 9.12 kJ/mol.
The strengthening of the H-bond in the pyrazolyl-containing compounds compared with that in the isoxazole analogs
also caused a greater difference in the energies of conformers 3a and 3b than in 6a and 6b. According to the calculations,
conformer 3a was more favorable than 3b by 28.83 kJ/mol whereas the E value for conformer 6a was less than that of 6b by
only 6.11 kJ/mol.
Tautomer 3c was less favorable than 3a by 25.52 kJ/mol. This could be explained by the different lengths of H-bonds
formed by O and N atoms.
°
°
The O…H bond length of 3c was 2.055 A; N…H of 3a, 1.743 A. Therefore, the latter was stronger than the former,
as a result of which 3a was more favorable than 3c.
Thus, the corresponding enaminoketone was synthesized from 6-acetyl-7-hydroxy-4-methylumbelliferone.
Transformation of the enaminoketone via reaction with N,N- and N,O-binucleophiles produced new 4-methylumbelliferone
derivatives containing pyrazole, isoxazole, and pyrimidine heterocycles in the 6-position. Quantum-chemical calculations
enabled the most energetically favorable conformers to be identified.
EXPERIMENTAL
Solvents were purified and dried by standard methods. The course of reactions and purity of products were monitored
by TLC on Merck 60 F254 plates using CHCl :MeOH (9:1) and EtOAc:hexane (7:3) as eluents. Column chromatography was
3
carried over silica gel (63–200 mesh, Merck). Melting points were measured on a Boetius block. NMR spectra were measured
1
relative to TMS (internal standard) on a Varian Mercury spectrometer at operating frequency 400 MHz ( H) and 100 MHz
1
3
(
C). Mass spectra were recorded on an Agilent 1100 LC/MSD spectrometer (chemical ionization).
Quantum-chemical calculations of energies E of conformers of 3, 6, and 7 were performed using the PC GAMESS/
Firefly programs and a non-empirical DFT method in basis set B3LYP/6-31G (d,p) with preliminary geometry optimization in
the same basis set.
6
-Acetyl-7-hydroxy-4-methyl-2H-chromen-2-one (1). Amixture of resacetophenone (50 mmol, 8 g) and acetoacetic
ester (50 mmol, 6 g) was treated with anhydrous POCl (2 mL) and anhydrous benzene (20 mL). The mixture was heated on
3
a water bath for 7 h, cooled, and poured into cold H O (200 mL). The benzene layer was separated. The aqueous layer was
2
extracted with benzene (2 ꢁ 30 mL). The benzene fractions were combined and evaporated in a rotary evaporator. The solid
+
was crystallized from EtOH. Yield 8.8 g (75%), C H O (218.21), mp 209–210°C. MS (m/z, I , %): 219 (100) [M + 1] .
1
2
10
4
rel
PMR spectrum (400 MHz, DMSO-d , ꢂ, ppm): 2.46 (3H, s, 4-CH ), 2.71 (3H, s, 6-COCH ), 6.16 (1H, s, H-3), 6.77
6
3
3
(
1H, s, H-8), 8.13 (1H, s, H-5), 12.34 (1H, s, OH).
1
3
C NMR spectrum (100 MHz, DMSO-d , ꢂ, ppm): 19.4, 26.6, 106.8, 112.7, 113.5, 124.4, 127.2, 152.6, 159.4,
6
1
60.8, 164.3, 202.8.
6
-[(2Z,E)-3-(Dimethylamino)prop-2-enoyl]-7-hydroxy-4-methyl-2H-chromen-2-one (2). A mixture of
acetylcoumarin 1 (3.5 mmol, 0.76 g) and DMFDMA (1 mL, 7 mmol) in toluene (10 mL) was refluxed for 5–7 h. The course
of the reaction was monitored by TLC. After the reaction was complete, the mixture was cooled. The solvent was evaporated
in vacuo. The solid was crystallized from propanol-2. Yield 0.75 g (79%), C H NO (273.28), mp 259–260°C.
1
5
15
4
+
MS (m/z, I , %): 274 (96.76) [M + 1] .
rel
PMR spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 3.09 (3H, s, CH N), 3.11 (3H, s, CH N), 2.28 (1H, s, 4-CH ),
6
3
3
3
3
3
5
1
.96 (1H, d, J = 11.6, COCH), 6.07 (1H, s, H-3), 6.62 (1H, s, H-8), 7.93 [1H, d, J = 11.6, CHN(CH ) ], 8.06 (1H, s, H-5),
3 2
5.30 (1H, br.s, OH).
1
3
C NMR spectrum (100 MHz, DMSO-d , ꢂ, ppm): 19.3, 44.3, 44.4, 92.87, 106.4, 112.6, 114.2, 119.4, 128.2, 152.7,
6
1
55.1, 156.1, 160.9, 164.8, 189.8.
754

General Method for Preparing Pyrazolylcoumarins. A solution of enaminoketone 2 (3 mmol) in EtOH (15 mL)
was treated with hydrazine hydrate (3-9 mmol) or N-methylhydrazine (3–6 mmol) and refluxed for 2-3 h. The course of the
reaction was monitored by TLC. After the reaction was complete, the mixture was cooled. The solvent was evaporated in
vacuo. The solid was treated with H O, filtered, and crystallized from an appropriate solvent or isolated by column
2
chromatography over silica gel.
7
-Hydroxy-4-methyl-6-(1H-pyrazol-3-yl)-2H-chromen-2-one (3). Yield 79.4%, crystallized from aqueous MeOH
+
(
1:5), C H N O (242.23), mp >300°C. MS (m/z, I , %): 243 (100) [M + 1] .
1
3
10
2
3
rel
PMR spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.45 (3H, s, 4-CH ), 6.05 (1H, s, H-3), 6.78 (1H, s, H-8), 6.89
6
3
3
3
(
1H, d, J = 2, H-4ꢀ), 7.75 (1H, d, J = 2, H-5ꢀ), 7.94 (1H, s, H-5), 11.79 (1H, br.s, OH), 13.15 (1H, br.s, NH).
1
3
C NMR spectrum (100 MHz, DMSO-d , ꢂ, ppm): 18.8, 104.8, 103.8, 112.6, 114.4, 115.4, 117.3, 126.8, 139.8,
6
1
53.1, 154.1, 156.2, 160.1.
-Hydroxy-6-(1-methyl-1H-pyrazol-3-yl)-4-methyl-2H-chromen-2-one (4) was prepared using N-methylhydrazine
3 mmol). Yield 54%, crystallized from acetone, C H N O (256.26), mp 250–251°C. Prepared in a mixture with 5 using
7
(
1
4 12 2 3
N-methylhydrazine (6 mmol). Yield 64%, R 0.37 (EtOAc:hexane, 3:7), C H N O (256.26), mp 250–251°C. MS (m/z,
f
14 12 2 3
+
I , %): 257 (100) [M] .
rel
PMR spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.44 (3H, s, 4-CH ), 3.96 (3H, s, CH N), 6.09 (1H, s, H-3), 6.76
6
3
3
3
3
(
1H, s, H-8), 6.93 (1H, d, J = 2, H-4ꢀ), 7.77 (1H, d, J = 2, H-5ꢀ), 7.92 (1H, s, H-5), 11.72 (1H, br.s, OH).
1
3
C NMR spectrum (100 MHz, DMSO-d , ꢂ, ppm): 19.8, 39.9, 105.3, 112.3, 114.1, 114.7, 117.4, 127.8, 130.9,
6
1
50.4, 152.7, 154.5, 154.8, 160.6.
-Hydroxy-6-(1-methyl-1H-pyrazol-5-yl)-4-methyl-2H-chromen-2-one (5) was prepared in a mixture with 4 using
N-methylhydrazine (6 mmol). Yield 14%, R 0.09 (EtOAc:hexane, 3:7), C H N O (256.26), mp 234–235°C. MS (m/z,
7
f
14 12 2 3
+
I , %): 257 (100) [M] .
rel
PMR spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.43 (3H, s, 4-CH ), 3.95 (3H, s, CH N), 6.11 (1H, s, H-3), 6.88
6
3
3
3
3
(
1H, s, H-8), 6.96 (1H, d, J = 2, H-4ꢀ), 7.57 (1H, d, J = 2, H-5ꢀ), 7.84 (1H, s, H-5), 9.56 (1H, br.s, OH).
1
3
C NMR spectrum (100 MHz, DMSO-d , ꢂ, ppm): 19.6, 32.5, 104.8, 107.4, 112.5, 114.3, 117.2, 128.8, 138.9,
6
1
40.6, 152.6, 154.7, 154.8, 160.9.
-Hydroxy-6-(isoxazol-5-yl)-4-methyl-2H-chromen-2-one (6). A solution of the corresponding enaminoketone 2
7
(
(
0.27 g, 1 mmol) in EtOH (10 mL) was treated with a suspension of hydroxylamine hydrochloride (0.08 g, 1.2 mmol) in H O
1 mL). The mixture was refluxed for 2–3 h. The course of the reaction was monitored by TLC. After the reaction was
2
complete, the mixture was cooled. The solvent was evaporated in vacuo. The solid was treated with H O. The solid was
2
+
filtered off and crystallized from MeOH. Yield 0.2 g (83%), C H NO (243.21), mp >300°C. MS (m/z, I , %): 244 (100) [M] .
1
3
9
4
rel
3
PMR spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.46 (3H, s, 4-CH ), 6.06 (1H, s, H-3), 6.71 (1H, d, J = 1.2,
H-4ꢀ), 6.81 (1H, s, H-8), 8.03 (1H, s, H-5), 8.44 (1H, d, J = 1.2, H-3ꢀ), 11.43 (1H, br.s, OH).
PMR spectrum (400 MHz, CDCl , ꢃꢂ, ppm, J/Hz): 2.43 (3H, s, 4-CH ), 6.04 (1H, s, H-3), 6.73 (1H, d, J = 1.2,
6
3
3
3
3
3
3
H-4ꢀ), 6.85 (1H, s, H-8), 7.43 (1H, s, OH), 8.05 (1H, s, H-5), 8.46 (1H, d, J = 1.2, H-3ꢀ).
1
3
C NMR spectrum (100 MHz, DMSO-d , ꢂ, ppm): 18.6, 96.9, 104.5, 112.3, 112.8, 114.2, 126.4, 151.3, 152.7,
6
1
1
54.7, 155.1, 159.8, 164.6.
6
-(2-Aminopyrimidin-4-yl)-7-hydroxy-4-methyl-2H-chromen-2-one (8). A solution of enaminoketone 2 (0.27 g,
mmol) in anhydrous DMF (10 mL) was treated with guanidinium carbonate (0.2 g, 1.1 mmol) and freshly calcined K CO .
2
3
The reaction mixture was refluxed for 7 h. The course of the reaction was monitored by TLC. After the reaction was complete,
the mixture was cooled. The solvent was evaporated in vacuo. The solid was treated with H O acidified with HCl to pH 6.
2
The resulting precipitate was filtered off, washed with H O, and crystallized from MeOH. Yield 0.22 g (82.7%), C H N O
2
14 11
3
3
+
(
269.25), mp >300°C. MS (m/z, I , %): 270 (100) [M + 1] .
rel
3
PMR spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.42 (3H, s, 4-CH ), 6.09 (1H, s, H-3), 6.62 (1H, d, J = 5.2,
6
3
3
H-5ꢀ), 6.88 (1H, s, H-8), 7.21 (2H, br.s, NH ), 7.78 (1H, s, H-5), 8.23 (1H, d, J = 5.2, H-4ꢀ), 15.2 (1H, br.s, OH).
2
1
3
C NMR spectrum (100 MHz, DMSO-d , ꢂ, ppm): 19.6, 104.8, 105.1, 112.6, 114.1, 117.3, 127.8, 152.8, 154.0,
6
1
54.6, 154.8, 160.3, 161.4, 164.3.
755

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