Features of the aminomethylation of 7-hydroxy-4'-fluoroisoflavones with primary amines

Article abstract of DOI:10.1007/s10593-010-0485-2

The behavior of 7-hydroxy-4'-fluoroisoflavones under the conditions of the Mannich reaction with primary amines was studied. New 9-alkyl-substituted 3-(4-fluorophenyl)-9,10-dihydro-4H,8H-chromeno-[8,7-e][1,3]oxazin-4-ones were synthesized. A method was developed for the synthesis of 8-amino- methyl derivatives of isoflavones.

Full text of DOI:10.1007/s10593-010-0485-2

Chemistry of Heterocyclic Compounds, Vol. 46, No. 2, 2010
FEATURES OF THE AMINOMETHYLATION
OF 7-HYDROXY-4'-FLUOROISOFLAVONES
WITH PRIMARY AMINES
S. P. Bondarenko1, M. S. Frasinyuk1*, and V. P. Khilya1
The behavior of 7-hydroxy-4'-fluoroisoflavones under the conditions of the Mannich reaction with primary
amines was studied. New 9-alkyl-substituted 3-(4-fluorophenyl)-9,10-dihydro-4H,8H-chromeno-
[8,7-e][1,3]oxazin-4-ones were synthesized. A method was developed for the synthesis of 8-amino- methyl
derivatives of isoflavones.
Keywords: 8-aminomethylisoflavones, 3-(4-fluorophenyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxa-
zin-4-ones, aminomethylation, electrophilic substitution.
The derivatives of oxygen-containing heterocycles are some of the most widely distributed classes of
natural compounds. An important position among them is occupied by isoflavones. The low toxicity of these
compounds, together with their selective pharmacological action on the human organism, makes it possible to
use them widely in the creation of medicines.
The derivatives of isoflavones substituted with fluorine in ring B exhibit various types of biological
activity. Thus, derivatives of 4'- and 2'-fluoroisoflavones exhibit hypoglycemic and anabolic activity, while
4'-fluoroisoflavones in addition exhibit hypotensive, anti-inflammatory, hypolipidemic, hepatoprotective, and
antioxidant activity [1].
It is well known that N-substituted aminomethyl derivatives of isoflavones and flavones are stimulants
of the central nervous system, respiratory stimulants, are anesthetics, and also exhibit high anticonvulsive and
antiallergic activity [2, 3]. The interest of investigators in the chemistry of Mannich bases is constantly
increasing, and this is due not only to their valuable pharmacological characteristics but also to the possibility of
the formation of water-soluble salts suitable for study of their biological activity.
The aim of our work was to develop the procedures and to synthesize new aminomethyl derivatives of
4'-fluoro-7-hydroxyisoflavone (1a) and its 2-methyl derivative 1b. The choice of compounds 1a,b was based on
their pharmacological activity and also on the possibility of synthesizing tertiary amines by substitution of the
fluorine atom as demonstrated for the case of 4'-fluoroflavones [4].
Earlier in the reaction of 3-hetaryl(aryl)-7-hydroxychromones with aminals (1,1'-methylenebisamines)
we obtained their 8-dialkylaminomethyl and 8-(N-heteryl)methyl derivatives respectively [5-13].
_______
* To whom correspondence should be addressed, e-mail: mfras@i.kiev.ua.
1Taras Shevchenko Kiev National University, Kiev 01033, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 180-186, February, 2010. Original
article submitted January 30, 2009. Revision submitted October 28, 2009.
146
0009-3122/10/4602-0146©2010 Springer Science+Business Media, Inc.

As known, under the conditions of the Mannich reaction with equivalent amounts of the substituted
phenol and primary amine and also with a twofold excess of formalin in the presence of a catalyst [KOH or
N,N-dimethylaminopyridine (DMAP)] derivatives of 3,4-dihydro-1,3-benzoxazine are formed as a result of
electrophilic substitution (e.g., see [14, 15]).
Annelation of the oxazine ring to the coumarin ring by the reaction of 7-hydroxycoumarins and
previously synthesized N,N-bis(hydroxymethyl)amines in the presence of DMAP leads to the formation of
derivatives of 9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-one [16], while the isomeric derivatives of
9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-ones were obtained by the condensation of derivatives of
isoflavones with the esters of α-amino acids and an excess of formalin [17].
In the present work we showed that the reaction of 4'-fluoro-7-hydroxyisoflavones 1a,b with primary
aliphatic amines and formalin by boiling the reaction mixture in 2-propanol (3-5 h) in the presence of a catalytic
amount of DMAP leads to derivatives of 3-(4-fluorophenyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-
4-one 3a-e (yields 68-84%).
R1
N
HO
O
R
10
1
H2NR1
CH2O
+
+
O
O
R
7
 , DMAP
2a–d
3
O
F
5
1a,b
O
F
3a–e
1a, 3ac R = H, 1b, 3d,e R = Me, 2a,3a R1 = Pr, 2b,3b R1 = i-Pr,
2c,3c,d R1 = (CH2)3OMe, 2d,3e R1 = CH2CH2OMe
TABLE 1. Characteristics of Compounds 3a-e and 4a-f
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
N
F
Cl
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f*
C20H18FNO3
4.27
4.13
4.02
4.13
4.02
3.79
3.58
3.65
3.67
3.79
3.68
3.56
3.68
3.71
3.33
3.47
5.58
5.60
5.71
5.60
5.01
5.14
5.11
4.95
5.10
5.14
4.76
4.82
4.95
5.03
4.65
4.70
116-117
136-137
108-109
124-125
142-143
211-212
194-195
234-235
181-182
225-226
199-200
68
76
80
84
78
76
65
78
82
68
79
C20H18FNO3
C21H20FNO4
C22H22FNO4
C21H20FNO4
C20H20FNO4HCl
C20H20FNO3HCl
C22H22FNO3HCl
C23H18FNO3HCl
C24H19ClFNO3HCl
C22H18FNO3SHCl
9.27
9.00
9.20
9.38
8.56
8.78
8.78
8.61
16.02
15.40
7.95
8.21
3.47
3.40
2.95
3.04
3.07
3.24
4.82
4.61
4.04
4.13
4.32
4.40
_______
* Found, %: S 7.22. Calculated, %: S 7.42.
147

148

1
The structure of the obtained compounds 3a-e is confirmed by the data from their H NMR spectra:
Compared with the spectra of the initial isoflavones 1a,b the signal of the H-8 proton is absent, but there are
signals for the protons of the C(10)H2 and C(8)H2 groups in the region of 4.18-4.26 and 4.96-5.06 ppm
respectively and also the protons of the amine residue. The presence of a signal for the methylene group in the
downfield region (4.96-5.06 ppm) indicates the formation of compounds of semiaminal structure, which is also
confirmed by the structure of the synthesized compounds 3a-e.
As known, compounds with acetal, semiaminal, and aminal structures are unstable toward acids. Thus,
we obtained the hydrochloride of the Mannich base 4a by heating compound 3c in a 10% alcohol solution of
1
HCl. As expected, the H NMR spectrum of 4a did not contain a two-proton singlet at 4.95-5.06 ppm,
confirming the opening of the 1,3-oxazine ring in compound 3c.
The instability of the derivatives of 3,4-dihydro-1,3-benzoxazine 3 in an acidic medium made it possible
to develop a simple preparative method for the synthesis of Mannich bases of a series of isoflavones.
Thus, compounds 3c,f-j with a 3,4-dihydro-1,3-benzoxazine ring were synthesized by boiling
7-hydroxyisoflavones 1a,b with primary amines 2c,e-i and an excess of formalin in the presence of a catalytic
amount of DMAP. A 36% aqueous solution of HCl was then added to the reaction mixture, and further boiling led
to formation of 65-82% yields of the hydrochlorides of 8-aminomethyl-4'-fluoro-7-hydroxyisoflavones (4a-f)
containing the residues of primary aliphatic amines, cyclopentylamine, arylmethylamines, and 2-thienylmethyl-
amine. The process was monitored by TLC.
1
The structure of the synthesized compounds 4a-f was confirmed by the data from the H NMR spectra.
They do not contain the signal of the H-8 proton of the chromones ring, whereas signals for the 8-CH2 group are
observed in the region of 4.22-4.28 ppm and also for the protons of the amine residue characteristic for
aminomethyl derivatives. The signal of the 7-OH group has the form of a narrow singlet at 11.58-12.21 ppm,
while the signal for the protons of the ammonium group is a broad two-proton singlet in the region of 9.06-9.74
ppm since the fast exchange processes lead to disappearance of the spin–spin coupling with the protons of the
aliphatic methylene and methine groups.
R1
+
–
Cl
NH2
O
HO
R
HCl
H2NR1 + CH2O
2c,e–i
3c,f–j
1a,b
+
 , DMAP
O
F
4a–f
4 a,b,d R = H, c,e,f R = Me; 4a R1 = (CH2)3OMe; 2e,3f,4b R1 = Bu;
2f,3g,4c R1 = cyclopentyl; 2g,3h,4d R1 = CH2Ph; 2h,3i,4e R1 = CH2C6H4Cl-p;
2i,3j,4f R1 = 2-thienylmethyl
Thus, we have synthesized new substituted 9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-ones
containing alkyl substituents at position 9. We also developed a simple and effective method for the synthesis of
8-aminomethyl derivatives of isoflavones with various substituents at the amino group.
EXPERIMENTAL
The progress of the reactions and the purity of the obtained compounds were monitored by TLC on
Sorbfil UV-254 (Russia) and Merck (Germany) plates. As eluant we used 9:1 and 19:1 mixtures of toluene and
ethanol. The 1H NMR spectra were recorded on Varian VXR-300 and Mercury M-400 instruments (300 and 400
MHz respectively) with TMS as internal standard.
149

The initial 7-hydroxyisoflavones (1a,b) were obtained as described earlier [17, 18].
2-R-9-R1-3-(4-Fluorophenyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-ones
3a-e
(General Method). To a hot solution of 7-hydroxyisoflavone 1a,b (2 mmol) in 2-propanol (20 ml), the primary
amine (2.2 mmol), 37% solution of formalin (1.2 ml), and DMAP (5 mg) were added. The reaction mixture was
boiled for 3-5 h and was then cooled, and the solvent was evaporated under vacuum. The residue was
crystallized from a mixture of 2-propanol and hexane.
Hydrochlorides of 2-R-8-(R1-Aminomethyl)-3-(4-fluorophenyl)-7-hydroxy-4H-chromen-4-ones 4a-f
(General Method). The reaction mixture obtained as described above was boiled for 2-8 h, after which 36%
aqueous solution of HCl (0.5 ml) was added to it, and the boiling was continued for a further 1-2 h. After
cooling the solvent was evaporated under vacuum. The residue was crystallized from acetone or 2-propanol.
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