Reaction of methyl 3-[(dimethylamino)methylidene]-6-fluoro-4-oxo -3,4-dihydrochroman-2-carboxylate with primary and secondary amines

Article abstract of DOI:10.1007/s10593-011-0859-0

A method was developed for substitution of the dimethylamino group by bioisosteric fragments by the action of various primary and secondary amines on methyl 3-[(dimethylamino)methylidene]-6-fluoro-4-oxo-3,4-dihydrochroman-2- carboxylate.

Full text of DOI:10.1007/s10593-011-0859-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 8, November, 2011 (Russian Original Vol. 47, No. 8, August, 2011)
REACTION OF METHYL 3-[(DIMETHYLAMINO)METHYLIDENE]-
6-FLUORO-4-OXO -3,4-DIHYDROCHROMAN-2-CARBOXYLATE
WITH PRIMARY AND SECONDARY AMINES*
A. I. Kysil1, V. S. Moskvina1**, A. V. Turov1, Z. V. Voitenko1, and V. P. Khilya1
A method was developed for substitution of the dimethylamino group by bioisosteric fragments by the
action of various primary and secondary amines on methyl 3-[(dimethylamino)methylidene]-6-fluoro-
4-oxo-3,4-dihydrochroman-2-carboxylate.
Keywords: 3-aminomethylidenechroman-4-one, primary and secondary amines, chroman, bioisosteric
displacements.
The chemical design of biologically active substances, including analogs of natural oxygen-containing
heterocycles, is achieved by the combination of several pharmacophoric fragments in the molecule. This often
leads to an increase in some therapeutic effect but sometimes also leads to the appearance of unexpected types
of activity.
The interest in derivatives of chromans, very important oxygen-containing heterocycles, arises from a
series of factors. Compounds of this class, which are present in the vegetable kingdom, have a broad spectrum
of biological activity and are used in medical practice. The high reactivity of these compounds makes them
attractive subjects for synthetic organic chemistry [1, 2].
The present work was devoted to the development of a method for the production of methyl 3-[(di-
methylamino)methylidene]-6-fluoro-4-oxo-chroman-2-carboxylate 2 and study of its reaction with primary and
secondary amines.
N,N-Disubstituted 3-aminomethylenechroman-4-ones were obtained earlier by the reaction of the
corresponding 3-hydroxymethylenechroman-4-ones with dimethylamine [3, 4], diethylamine [5], pyrrolidine
[6, 7], piperidine [3], N-methylaniline [3] and by the action of secondary amines on chroman-containing
Morita–Baylis–Hillman adducts [8].
We first obtained methyl 3-[(dimethylamino)methylidene]-6-fluoro-4-oxochroman-2-carboxylate 2 by
the reaction of methyl 6-fluoro-4-oxo-3,4-dihydro-2H-chroman-2-carboxylate (1) with N,N-dimethylformamide
dimethyl acetal (DMF-DMA) in DMF. It is known that the insertion of the residues of a secondary or tertiary
amine into the structure of the molecule leads to promising compounds for medical use. Thus, in order to obtain
potential biologically active substances we then used compound 2 in reactions with various primary and
secondary amines.
_______
*Dedicated to the happy memory of M. O. Lozinskii.
** To whom correspondence should be addressed, e-mail: v.moskvina@gmail.com.
1Taras Shevchenko Kyiv National University, 64 Volodymyrska St., Kyiv 01601, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1154-1161, August, 2011.
Original article submitted March 11, 2011.
946
0009-3122/11/4708-0946©2011 Springer Science+Business Media, Inc.

The high reactivity of the β-position of the enamino ketone fragment in compound 2 toward
N-nucleophiles made it possible to obtain a wide range of 3-aminomethylidenechromanones 4. For this purpose,
we used the bioisosteric exchange method – the exchange of groups with similar physicochemical
characteristics, like those with similar pharmacological effects [9].
O
CO2Me
O
O
CO2Me
DMF–DMA
DMF
F
F
O
N
Me
Me
1
2
When heated with primary and secondary amines 3a-p in dioxane, compound 2 gave compounds 4a-p.
For the isolation of compounds 4a-i we used preparative column chromatography, and for the less soluble
tertiary amines 4j-p we used crystallization from acetonitrile.
O
CO2Me
O
CO2Me
R
Dioxane
3–8 h
+
HN
F
F
R1
O
Me
N
O
N
R
R1
Me
4а–р
3а–р
2
3, 4 a–i R1 = H; а R = n-Pr, b R = i-Pr, c R = BocNH(CH2)2, d R = morpholin-4-yl(CH2)2,
e R = morpholin-4-yl(CH2)3, f R = Ph(CH2)2, g R = 1-benzylpiperidin-4-yl,
h R = cyclo-C5H9, i R = pyridin-3-yl(CH2); j NRR1 = piperidin-1-yl,
k NRR1 = morpholin-4-yl;
N
N
N
N
l NRR1 =
; m NRR1 =
; n NRR1 =
;
N
N
N
O
F
F
O
Cl
o NRR1 =
; p NRR1 =
N
N
N
N
S
N
The reaction of the 3-dimethylaminomethylidenechromanone 2 with the primary amines 3a-i proceeds
more quickly than the reaction with the secondary amines 3j-p, and the formation of the desired products is
complete after 3-4 and 4-8 h respectively (Table 1). The rate of substitution of the dimethylamino group by the
respective amine residue also depends on the size of the substituent. For example, the reaction with tert-butyl-
(2-aminoethyl)carbamate (3c) takes 8 h, while the reaction with the less bulky pyridin-3-ylmethylamine (3i)
takes 6 h.
1
Compounds 4a-p can exist in the form of two geometric (Z,E)-isomers. According to the H NMR
spectra of the obtained compounds, with the exception of compound 4i, one isomer is formed preferentially. In
1
the H NMR spectrum of compound 4i, the signals of protons close to the exocyclic double bond are doubled,
indicating the formation of a mixture of the isomers.
947

TABLE 1. Physicochemical Properties of Compounds 4a-p
Found, %
Calculated, %
m/z
——————
Empirical
Com- formula
pound
mp.,
°С
Reaction Yield,
(Irel, %),
time, h
%
[M+H]+
С
Н
N
4а
C15H16FNO4
C15H16FNO4
61.43 5.50
61.36 5.43
4.78
4.61
96–97
294
3
4
89
82
(100)
4b
61.43 5.50
61.35 5.44
4.78
4.63
157–158
292*
(100)
4c
С19Н23FN2O6
57.86 5.88
57.71 5.73
7.10
7.02
126–128
144–145
395
8
73
80
(100)
4d
C18H21FN2O5
59.33 5.81
59.21 5.73
365
(100)
3.5
7.69
7.62
4e
4f
C19H23FN2O5
C20H18FNO4
C24H25FN2O4
C17H18FNO4
C18H15FN2O4
C17H18FNO4
C16H16FNO5
C29H25F3N2O4
C21H20FN3O4
C23H21FN2O6
C22H20ClFN2O4
C23H20FN3O4S
60.31 6.13
60.24 6.06
7.40
7.33
107–108
117–118
132–133
86–87
379
3.5
4
80
94
(100)
67.60 5.11
67.53 5.04
3.94
3.86
356
(100)
4g
4h
4i
67.91 5.94
67.86 5.87
6.60
6.53
425
(100)
4
73
63.94 5.68
63.85 5.61
4.39
4.34
320
(100)
3.5
4.5
3–3.5
3.5–4
8
93
63.15 4.42
63.08 4.36
8.18
8.12
151–152
134–135
141–142
210–212
185–187
104–105
145–147
156–158
343
(100)
84*2
90
4j
63.94 5.68
63.87 5.61
4.39
4.33
320
(99)
4k
4l
59.81 5.02
59.75 4.93
4.36
4.29
320*
(100)
93
66.66 4.82
66.54 4.76
5.36
5.28
523
(100)
92
4m
4n
4o
4р
63.47 5.07
63.39 5.01
10.57
10.02
398
(100)
7
94
62.87 4.59
62.82 4.54
6.38
6.33
440
(100)
6
85
61.47 4.46
61.39 4.37
6.52
6.46
430
(100)
6.5–7
8
92
60.92 4.45
60.86 4.39
9.27
9.21
452*
(100)
81
_______
*[M-H]+
*2Ratio of isomers Z:E = 7:3.
1
Since the assignment of the series of signals in the H NMR spectrum of compound 4i constitutes a
difficulty, we measured its correlation spectrum (COSY), which made it possible to assign the signals of both
isomers (Fig. 1). For the minor component, the chemical shifts are only given for the signals of the protons
whose chemical shifts differ from the chemical shifts of the main component.
It was possible to determine the geometric structure of the isomers by experiments employing the
homonuclear Overhauser effect (NOE). The additional irradiation of the singlet corresponding to the H-2 proton
of the chroman ring leads to a significant increase in the intensity of the doublet of the olefinic proton,
absorbing at 7.49 ppm. This shows that the indicated protons are sterically close, i.e., that the double bond in the
main isomer has the (Z)-configuration. This is also confirmed by the fact that the multiplet of the NH signal of
this isomer is in the downfield region at 10.28 ppm on account of the formation of a strong intramolecular
hydrogen bond with the carbonyl group of the chroman ring. In the minor isomer in the NOE experiment with
additional irradiation of the signal of the H-2 proton, which absorbs at 6.02 ppm, a significant NOE is observed
for the NH group located at 8.40 ppm. From this it follows that the exocyclic double bond in the given isomer
has the (E)-configuration.
948

9%
10%
5.64
H
6.02
H
3.57
OMe
OMe
7.05
7.30
O
O
O
7.38
F
O
H
O
N
8.40
H
7.49
4.57
4.65
F
N
O
H
H
7.88
10.28
7.38
7.41
N
8.56
N
8.52
Main isomer
Minor isomer
Data from experiments on the homonuclear Overhauser effect for the isomers of compound 4i.
1
In the H NMR spectra of 3-aminomethylidenechromans 4a-h, the signal for the proton of the amino
group appears in the form of a multiplet in the region of 10.01-10.26 ppm; the signal for the proton of the
methylene group is characterized by a doublet in the region of 7.17-7.42 ppm (3J = 14.0 Hz, Table 2). In
compounds 4j-p, this signal is observed in the form of a singlet in the region of 7.56-7.70 ppm (Table 2). On the
basis of the obtained data, the products 4a-h,j-p were assigned the (Z)-configuration.
Heating of compound 4c in methanol with the addition of hydrochloric acid leads to removal of the
protecting group and the release of methyl 3-{[(2-aminoethyl)amino]methylidene}-6-fluoro-4-oxo-3,4-dihydro-
2H-chroman-2-carboxylate (5) with a high yield.
O
O
COOMe
COOMe
HCl
MeOH
.
HCl
F
F
O
O
HN
HN
NHBoc
NH2
4c
5
In the course of the present work, a simple and effective method was developed for the production of
various 3-aminomethylidene-6-fluoro-4-oxo-3,4-dihydro-2H-chroman-2-carboxylates. The interest in these
compounds arises from their potential biological activity and the possibility of using them as accessible highly
reactive starting materials in the synthesis of more complex molecules.
EXPERIMENTAL
1
The H NMR spectra were recorded in DMSO-d6 solutions on a Mercury-400 spectrometer (400 MHz)
with TMS as internal standard. The COSY spectra were measured by the standard procedure with gradient
isolation of the signal. For the 1D gradient NOESY spectra. a mixing period of 200 ms was used. The
measurement temperature was 20°C. The mass spectra were recorded with an Agilent 1100 LC/MSD
chromatographic system (CI, 200 eV). Column chromatography was performed on silica gel (63-200 mesh,
Merck) with a 7:3 mixture of CH2Cl2 and methanol as eluent. The melting points were determined with a Leica
Galen III high-temperature microscope. The reactions and the individuality of the products were monitored by
TLC on Merck 60 F254 plates with the 7:3 CH2Cl2–MeOH solvent system as eluent. Elemental analysis was
performed on a Perkin-Elmer CHN analyzer. The solvents were purified and dried by the normal procedures.
Compound 1 was obtained by analogy with the method described in [10].
949

950

951

Methyl (3Z)-3-[(Dimethylamino)methylidene]-6-fluoro-4-oxo-3,4-dihydro-2H-chroman-2-carboxy-
late (2). To a solution of methyl 6-fluoro-4-oxo-3,4-dihydro-2H-chroman-2-carboxylate (1) (4.48 g, 20 mmol)
in DMF (10 ml), DMF–DMA (4.76 g, 40 mmol) was added. The reaction mixture was heated with stirring at
150°C for 6 h. At the end of the reaction, the solvent was evaporated, and the residue was crystallized from a
methanol–acetone mixture, 1:1. Yield 4.6 g (77%); mp 156-157°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.61 (1Н,
3
s, =CHNMe2); 7.38 (1H, dd, JН–F = 8.0, 4J = 3.0, Н-5); 7.16 (1Н, td, 3JH–F = 8.0, 4J = 3.0, 3J = 8.0, Н-7); 6.95
3
(1Н, dd, JH–F = 4.0, J = 8.0, Н-8); 6.22 (1Н, s, Н-2); 3.61 (3Н, s, СО2СН3); 3.26 (6Н, s, N(CH3)2). Mass
spectrum, m/z (Irel, %): 280 [М+Н]+ (100). Found, %: С 60.11; Н 4.92; N 4.96. C14H14FNO4. Calculated, %:
С 60.21; Н 5.05; N 5.02.
Methyl 3-Aminomethylidene-6-fluoro-4-oxo-3,4-dihydro-2H-chroman-2-carboxylates (4a-p)
(General Method). To a solution of compound 2 (0.27 g, 1 mmol) in dioxane (5 ml), corresponding amine
3a-p (2.5 mmol) was added. The reaction mixture was boiled with stirring for 3-8 h, and the reaction was
monitored by TLC. At the end of the reaction the reaction mixture was evaporated, and the residue was
chromatographed (compounds 4a-i) or crystallized from acetonitrile (compounds 4j-p).
Methyl
(3Z)-3-{[(2-Aminoethyl)amino]methylidene}-6-fluoro-4-oxo-3,4-dihydro-2H-chroman-
2-carboxylate Hydrochloride (5). A solution of compound 4c (0.39 g, 1 mmol) in methanol (10 ml) and conc
HCl (1 ml) was boiled for 2 h. At the end of the reaction, the solvent was evaporated and the residue was
crystallized from 2-propanol. Yield 0.31 g (93%); mp 115-116°C. 1H NMR spectrum, δ, ppm (J, Hz): 9.81 (1H,
3
4
m, NH); 8.61 (1Н, s, =CHN); 8.41 (3Н, m, NH2·HC1); 7.34 (1H, dd, JН–F = 8.0, J = 3.0, Н-5); 7.12 (Н, td,
4
3
3
3JH–F = 8.0, J = 3.0, J = 8.0, Н-7); 6.91 (Н, dd, JH–F = 4.0, J = 8.0, Н-8); 6.16 (1Н, s, Н-2); 3.62 (2Н, m,
CH2CH2NH2); 3.57 (3Н, s, СО2СН3); 2.99 (2Н, m, CH2CH2NH2). Mass spectrum, m/z (Irel, %): 331 [М+Н]+
100. Found, %: С 50.71; Н 4.73; N 8.41. C14H16ClFN204. Calculated, %: С 50.84; Н 4.88; N 8.47.
REFERENCES
1.
2.
Ø. M. Andersen and К. R. Markham, Flavonoids: Chemistry, Biochemistry, and Applications, CRC,
Taylor & Francis, Boca Raton, FL, 2006.
A. R. Katritzky (editor), Comprehensive Heterocyclic Chemistry III, Vol. 6. Six-membered Rings with
One Heteroatom, Ch. 7-9, Elsevier, 2008.
3.
4.
5.
L. Mosti, P. Schenone, and G. Menozzi, J. Heterocycl. Chem., 17, 61 (1980).
P. F. Schuda, С. В. Ebner, and Т. М. Morgan, Tetrahedron Lett, 27, 2567 (1986).
A. H. Bedair, Y. A. Ammar, A. M. El-Agrody, and Y. A. Mohamed, Proc. Indian Natl. Sci. Acad., Part
B, 53, 308 (1987).
6.
M.-C. Bellassoued-Fargeau, B. Graffe, M.-C. Sacquet, and P. Maitte, J. Heterocycl. Chem., 22, 713
(1985).
7.
8.
9.
H. An, S.-J. Eum, M. Koh, S. K. Lee, and S. B. Park, J. Org. Chem., 73, 1752 (2008).
Ch. Wu, H. Zeng, L. Liu, D. Wang, and Y. Chen, Tetrahedron, 67, 1231 (2011).
F. D. King (editor), Medicinal Chemistry: Principles and Practice, Royal Society of Chemistry,
Cambridge, 2002.
10.
E. Ziegler, G Henning, and A. K. Muller, Liebigs Ann. Chem., 1552 (1973).
952