Electrophilic substitution in the dihydroquercitin system. Aminomethylation

Article abstract of DOI:10.1023/B:RUJO.0000045904.63368.06

Treating dihydroquercetin with formaldehyde and amines under conditions of Mannich reaction provided mono- and diaminomethyl derivatives of dihydroquercetin.

Full text of DOI:10.1023/B:RUJO.0000045904.63368.06

Russian Journal of Organic Chemistry, Vol. 40, No. 8, 2004, pp. 1190 -1193. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 8, 2004,
pp. 1237-1240.
Original Russian Text Copyright Ó 2004 by Kukhareva, Krasnova, Koroteev, Kaziev, Kuleshova, Korlyukov, Antipin, Nifant’ev.
Electrophilic Substitution in the Dihydroquercitin System.
Aminomethylation
T.S. Kukhareva1, V.A. Krasnova1, M.P. Koroteev1, G.Z. Kaziev1, L.N.Kuleshova2,
A.A. Korlyukov2, M.Yu. Antipin2, and E.E. Nifant’ev1
1Moscow State Pedagogical University, Moscow, 119992 Russia
e-mail: chemdept@mtu-net.ru
2Nesmeyanov Institute of Organoelemental Compounds, Moscow, 117813 Russia
e-mail: lukul@xrlab.ineos.ac.ru
Received December 5, 2003
Abstract—Treating dihydroquercetin with formaldehyde and amines under conditions of Mannich reaction
provided mono- and diaminomethyl derivatives of dihydroquercetin.
In extension of systematic investigations on the
chemical features of dihydroquercetin [1, 2] we started
to study its behavior in Mannich reaction. The process
is well documented by examples of versatile phenols [3–
5] and is widely used in syntheses. Yet important natural
polyhydric phenols, flavanoids, were not involved into
aminomethylation. We demonstrated that an available
flavanoid dihydroquercetin (I) readily reacted with
formaldehyde in the presence of secondary amines. The
structure of final reaction products depends on the
reagents ratio: both mono- and di(aminomethyl)di-
hydroquercetin can be obtained.
Reaction products II–VII are powdery solids. Their
composition and structure were proved by elemental
analysis and 1H and 13C NMR spectra.
It should be noted in particular, that the electrophilic
substitution occurred solely in A ring even at the large
excess of reagent and under more severe reaction
condutions.
Aminomethylated dihydroquercetin form crystalline
salts with mineral and organic acids soluble in water, for
instance, tosylate VIII.
The structure of compound VIII was investigated by
means of X-ray diffraction analysis. An independent part
2+
+2
5 1&+
2
2+
+15
2+
&+ 2
2+
2+
2
,, ,9
+2
2
2+
2+
2+
&+ 15
+2
5 1&+
2
2+
ꢀ+15 ꢁ
ꢀ&+ 2
+2
2
2+
2+
2
9 9,,
,
NR2 = morpholino (II, V), piperidino (III, VI), N(Et)2 (IV, VII).
1070-4280/04/4008-1190Ó2004 MAIK “Nauka/Interperiodica”

ELECTROPHILIC SUBSTITUTION IN THE DIHYDROQUERCITIN SYSTEM
1191
9ꢀꢀꢁꢁ7V2+
2
1+
2+
2+
+ &
+ 2
+2
2
2
ꢂ7V2ꢀꢀꢃ
+ &
2+
Fig. 1. Comparison of geometry of the dihydroquercetin
fragments in salt VIII and compound I (the molecules are
superimposed along the phenol group plane; molecule VIII is
shown by dashed lines).
1+ 2+
2
9,,,
of its unit cell consists of two molecules of protonated
dihydroquercetin derivative (cation), two tosylate anions,
and three hydrate water molecules. Hence one of the p-
toluenesulfonic acid molecules in preparation of salt VIII
acts only as protonating agent and does not take part
directly in building up the structure under study.
The conformation of dihydroquercetin fragment in
salt VIII where into positions 6 and 8 are introduced
1-aza-4-oxacyclohexyl substituents remained the same
as in the initial flavanoid I (Fig. 1). In the crystal of
compound VIII the molecules of cation, tosylate anion,
and hydrate water form a three-dimensional framework
of hydrogen bonds. It is noteworthy that in the crystal
packing of compound VIII are present cation-anion pairs
...
bound by strong N–H O bonds (Fig. 2).Amore detailed
analysis of salt VIII geometry and crystal packing will
be published elsewhere.
EXPERIMENTAL
1H NMR spectra were registered from solutions in
DMSO-d6 on spectrometer Bruker AM-250 at operating
frequency 250 MHz; chemical shifts were measured with
respect to HMDS as external reference. 13C NMR spectra
were obtained on spectrometer Bruker AC-200 at
operating frequency 50.32 MHz from solutions in
DMSO-d6, internal reference TMS. Adsorption
chromatography was carried out on column packed with
silica gel L100/250 or L 40/100 mm. TLC was performed
on Silufol UV-254 plates. The reaction progress was
monitored and homogeneity of compounds obtained was
checked by TLC, eluent benzene-dioxane, 1:3.
Fig. 2. General view of cation-anion pair in salt. VIII.
17.687(4) , b110.939(5)°, V 7350(3) 3, Z 8, M 699.71,
–3
–1
r
calc 1.256 g/cm , m(MoKa) 1.52 cm , F(000) 2930. In-
tensities of 22030 reflections were measured on diffracto-
meter Smart CCD 1000K at 110 K [l(MoKa) 0.71072
,
w-scanning, 2q<50°], 11745 independent reflections (Rint
0.0342) were used for further refining. Structure VIII
was solved by the direct method and refined by a least-
squares procedure in full-matrix anisotropic-isotropic
X-ray diffraction study. Crystals C32H39N2O13.5
S
monoclinic, space group Cc, a 22.890(4), b 19.439(4), c
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 8 2004

1192
KUKHAREVA et al.
approximation along F2. Hydrogen atoms of hydroxy
groups and those linked to nitrogen were found from the
difference Fourier syntheses of electron density and
refined in the framework of rider model. Other hydrogen
atoms were calculated from geometrical considerations
and were refined in the framework of rider model. The
final parameters of refinement: wR2 0.2002 (for all
reflections), GOF 1.073, R1 0.0938 [for 9434 reflections
with I > 2s(I)].All calculations were carried out on IBM
PC using SHELXTL-97 V5.10 software package [6].
172.60 (C7), 195.53 (C4). Found, %: C 62.84; H 5.62;
N 3.49. C21H23NO7. Calculated, %; C 62.95; H 5.74;
N 3.54.
6-(Diethylaminomethyl)dihydroquercetin (IV).
1
Yield 45%, mp 200–202°C. H NMR spectrum, d, ppm
(J, Hz): 1.14 t (6H, NCH2CH3), 2.86 q (4H, NCH2CH3),
3.89 s (2H, CH2), 4.38 d [1H, C2H, J(HH) 10.96], 4.93 d
[1H, C3H, J(HH) 11.01], 5.10 s (1H, C7OH), 5.52 s (1H,
C8H), 6.73 s (2H, C5',6'H), 6.86 s (1H, C2'H), 7.97 s (1H,
C4'OH), 8.10 s (1H, C3'OH), 11.05 s (1H, C3OH), 12.00 s
(1H, C5OH). 13C NMR spectrum, d, ppm: 25.51
[2(CH2CH3)], 45.89 [2(CH2CH3)], 47.54 (NCH2), 71.32
(C3), 82.74 (C2), 96.69 (C8), 97.18 (C6), 99.28 (C10),
115.10 (C5'), 115.31 (C2'), 119.25 (C6'), 128.54 (C1'),
145.02 (C3'), 145.72 (C4'), 161.16 (C9), 161.58 (C5),
172.60 (C7), 195.55 (C4). Found, %: C 61.98; H 6.02;
N 3.48. C20H23NO7. Calculated, %: C 61.70; H 5.91;
N 3.60.
6-(Morpholinomethyl)dihydroquercetin (II). A
mixture of 0.05 g (1.6 mmol) of paraformaldehyde,
0.15 g (1.6 mmol) of morpholine, and 10 ml of 2-propanol
was stirred at 60°C till complete homogenization. The
solution obtained was added slowly to a solution of 0.5 g
(1.6 mmol) of compound I in 2-propanol, and the reaction
mixture was stirred at heating for 1.5 h. The reaction
product gradually precipitated as light-yellow powder
that was filtered off and washed in succession with
ethanol, dioxane, benzene, and hexane, then it was dried
in a vacuum till constant weight, yield 40%, mp 160–
6,8-Di(morpholinomethyl)dihydroquercetin (V). A
mixture of 0.1 g (3.2 mmol) of paraformaldehyde, 0.3 g
(3.2 mmol) of morpholine, and 10 ml of 2-propanol was
stirred at 60°C till complete homogenization. The
solution obtained was added slowly to a solution of
0.5 g (1.6 mmol) of compound I in 2-propanol, and the
reaction mixture was stirred at slight heating for 1.5 h.
The reaction product gradually precipitated as light-
yellow powder that was filtered off and washed in
succession with ethanol, dioxane, benzene, and hexane,
then it was dried in a vacuum till constant weight. Yield
71%, mp 195–197°C. 1H NMR spectrum, d, ppm (J, Hz):
2.49 s [8H, N(CH2)2], 3.56 s (4H, CH2), 3.58 s [8H,
O(CH2)2], 4.45 d [1H, C2H, J(HH) 10.97], 4.95 d [1H,
C3H, J(HH) 10.96], 5.23 s (1H, C7OH), 6.75 s (2H,
C5',6'H), 6.88 s (1H, C2'H), 8.00 s (2H, C3',4'OH), 11.30 s
(1H, C3OH), 11.52 s (1H, C5OH). 13C NMR spectrum,
d, ppm: 50.57 (C6CH2N), 52.51 [4(NCH2)], 60.39
(C8CH2N), 66.02 [4(OCH2)], 71.55 (C3), 82.95 (C2),
99.24 (C8), 100.80 (C6), 101.64 (C10), 115.17 (C2', 5'),
119.13 (C6'), 128.22 (C1'), 144.96 (C3'), 145.72 (C4'),
159.21 (C9), 160.48 (C5), 167.99 (C7), 197.71 (C4).
Found, %: C 59.64; H 6.02; N 5.48. C25H30N2O9.
Calculated, %: C 59.76; H 5.98; N 5.58.
1
162°C. H NMR spectrum, d, ppm (J, Hz): 2.62 s [4H,
N(CH2)2], 3.58 s (2H, CH2), 3.78 s [4H, (CH2)2], 4.58 d
[1H, C2H, J(HH) 10.45], 5.00 d [1H, C3H, J(HH) 10.41],
5.12 s (1H, C7OH), 5.84 s (1H, C8H), 6.86 s (1H, C5'H),
6.91 s (1H, C6'H), 7.05 s (1H, C2'H), 7.93 s (1H, C4'OH),
8.10 s (1H, C3'OH), 10.95 s (1H, C3OH), 11.90 s (1H,
C5OH). 13C NMR spectrum, d, ppm: 50.56 (C6CH2–N),
52.39 [2(NCH2)], 66.02 [2(OCH2)], 71.55 (C3), 82.96
(C2), 99.24 (C8), 100.80 (C6), 101.64 (C10), 115.17 (C2',5'),
119.14 (C6'), 128.22 (C1'), 144.96 (C3'), 145.72 (C4'),
159.21 (C9), 160.48 (C5), 167.99 (C7), 197.71 (C4).
Found, %: C 59.64; H 5.07; N 3.57. C20H21NO8.
Calculated, %: C 59.55; H 5.21; N 3.47.
Compounds III and IV were prepared in a similar
way.
6-(Piperidinomethyl)dihydroquercetin (III). Yield
75%, mp 200–202°C. 1H NMR spectrum, d, ppm (J,
Hz): 1.50 s [2H, CH2(CH2)2], 1.59 s [4H, CH2(CH2)2],
2.71 s [4H, N(CH2)2], 3.79 s (2H, CH2), 4.40 d [1H, C2H,
J(HH) 10.44], 4.89 d [1H, C3H, J(HH) 10.40], 5.05 s
(1H, C7OH), 5.63 s (1H, C8H), 6.74 s (2H, C5',6'H),
6.87 s (1H, C2'H), 8.01 s (1H, C4'OH), 8.10 s (1H, C3'OH),
10.90 s (1H, C3OH), 12.00 s (1H, C5OH). 13C NMR
spectrum, d, ppm: 22.66 [(CH2)2CH2(CH2)2], 24.27
(CH2CH2CH2), 52.28 [2(NCH2)], 66.31 (C6CH2), 71.36
(C3), 82.77 (C2), 96.22 (C8), 97.91 (C6), 99.59 (C10),
115.07 (C5'), 115.29 (C2'), 119.25 (C6'), 128.38 (C1'),
144.96 (C3'), 145.69 (C4'), 161.18 (C9), 161.60 (C5),
Compounds VI and VII were prepared in a similar
way.
6,8-Di(piperidinomethyl)dihydroquercetin (VI).
1
Yield 70%, mp 201–203°C. H NMR spectrum, d, ppm
(J, Hz): 1.58 s [12H, CH2(CH2)2], 2.82 s [8H, N(CH2)2],
3.81 s (4H, CH2), 4.36 d [1H, C2H, J(HH) 11.00], 4.90 d
[1H, C3H, J(HH) 10.95], 5.00 s (1H, C7OH), 6.74 s (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 8 2004

ELECTROPHILIC SUBSTITUTION IN THE DIHYDROQUERCITIN SYSTEM
1193
C5',6'H), 6.86 s (1H, C2'H), 7.73 s (1H, C4'OH), 8.30 s
(1H, C3'OH), 11.05 s (1H, C3OH), 11.97 s (1H, C5OH).
13C NMR spectrum, d, ppm: 22.65[2(CH2)2CH2(CH2)2],
24.30 [2(CH2CH2CH2)], 52.61 [2(NCH2)], 66.35
(C6CH2), 66.50 (C8CH2), 71.00 (C3), 82.67 (C2), 96.50
(C8), 97.41 (C6), 99.19 (C10), 115.37 (C5'), 115.78 (C2'),
119.84 (C6'), 128.77 (C1'), 144.73 (C3'), 145.19 (C4'),
161.19 (C9), 161.63 (C5), 161.79 (C7), 193.71 (C4).
Found, %: C 64.97; H 6.77; N 5.73. C27H34N2O7.
Calculated, %: C 65.06; H 6.83; N 5.62.
N.93. C25H30N2O7. Calculated, %: C 63.35; H 7.17;
N 5.08.
Tosylate VIII. 0.5 g (1 mmol) of compound V was dis-
solved in a water solution of 0.35 g (2 mmol) of p-tolu-
enesulfonic acid. Salt VIII was separated from solution
as light-yellow crystals, mp 275–276°C.
REFERENCES
1. Nifantyev, E., Koroteev, M., Kaziev, G., Kukhareva, T.,
Dzgoeva, Z., and Zakharova, I., Phoshorus Sulfur Silicon
Other Elements, 2002, vol. 177, p. 1981.
2. Nifantyev, E.E., Kukhareva, T.S., Dzgoeva, Z.M., Vasyani-
na, L.K., Koroteev, M.P., and Kaziev, G.Z., Heteroatom.
Chem., 2003, vol. 14, no. 4, p. 1.
3. Kolka,A.J., Tai, W.T., and Mouit, R.H., US Patent 3504040,
1970.
4. Omura, Y., Taruno, Y., Irisa, Y., Morimoto, M., Saimoto,
H., and Shigemasa, Y., Tetrahedron Lett., 2001, vol. 42,
p. 7273.
5. Yarmukhamedov, N.N., Baibulatova, N.Z., Dokichev, V.A.,
Tomilov, Yu.V., and Yunusov, M.S., Izv. Akad. Nauk, Ser.
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6. Sheldrick, G.M., SHELXTL-97, V5.10, Bruker AXS Inc.,
Madison, WI-53719, USA, 1997.
6,8-Bis(diethylaminomethyl)dihydroquercitin
1
(VII). Yield 46%, mp 205–207°C. H NMR spectrum,
d, ppm (J, Hz): 1.18 t (12H, CH3), 2.85 q [8H, N(CH2)2],
3.56 s (1H, C7OH), 3.85 s (4H, CH2), 4.44 d [1H, C2H,
J(HH) 10.89], 4.87 d [1H, C3H, J(HH) 10.89], 6.73 s
(2H, C5',6'H), 6.87 s (1H, C2'H), 8.79 s (1H, C4'OH),
9.33 s (1H, C3'OH), 11.05 s (1H, C3OH), 13.27 s (1H,
C5OH). 13C NMR spectrum, d, ppm: 25.64 [4(CH2CH3)],
45.95 [4(CH2CH3)], 47.54 (NCH2C6), 47.53 (NCH2C8),
71.32 (C3), 82.74 (C2), 96.69 (C8), 97.18 (C6), 99.30
(C10), 115.10 (C5'), 115.31 (C2'), 119.27 (C6'), 128.54
(C1'), 145.0 (C3'), 145.72 (C4'), 161.16 (C9), 161.55 (C5),
172.60 (C7), 195.54 (C4). Found, %: C 63.29; H 7.25;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 8 2004