Synthesis of 4-aminomethyl analogs of daphnetin

Article abstract of DOI:10.1007/s10600-007-0183-1

4-Aminomethyl analogs of the natural coumarin daphnetin were synthesized. The reaction of 4-chloromethyl-coumarins with aliphatic and aromatic amines was studied.

Full text of DOI:10.1007/s10600-007-0183-1

Chemistry of Natural Compounds, Vol. 43, No. 5, 2007
SYNTHESIS OF 4-AMINOMETHYL ANALOGS OF DAPHNETIN
A. V. Levenets, M. S. Frasinyuk, and V. P. Khilya
UDC 547.814.5
4-Aminomethylanalogs ofthenaturalcoumarindaphnetinwere synthesized. Thereactionof4-chloromethyl-
coumarins with aliphatic and aromatic amines was studied.
Key words: esculetin, daphnetin, coumarin, alkylation.
Coumarin derivatives are widely used in medical practice as pharmacological preparations with a broad spectrum of
biological activity [1-3]. Effective methods of developing new bioactive coumarins include chemical modification of natural
coumarins [4] and introduction of new pharmacophores into the coumarin core [5, 6]. It is known that the presence of a group
containing a basic tertiary N atom or amine significantly improves the bioavailability of the compounds [7]. A good example
of this is the capillary protectant folescutol (1), a derivative of the natural coumarin esculetin (2).
OH
HO
O
O
HO
HO
O
O
HO
O
O
HO
N
2
3
1
O
Therefore, it seemed of practical interest to develop synthetic methods for 4-aminomethylcoumarins containing not
only a basic tertiary N atom but also a free N–H group and to prepare aminomethyl derivatives of the natural coumarin
daphnetin (3). For this we proposed alkylation of primary and secondary amines by substituted 4-chloromethylcoumarins.
R
1
R
1
R
1
X
R
2
O
O
R
2
O
O
R
2
O
O
R
5
HN
HN
R
3
R
3
R
3
R
4
R
4
R
4
N
Cl
N
R
5
X
4 - 6, 8
10 - 18
19, 20
4, 10: R2 = OMe, X = O, R1 = R3 = R4 = H; 5, 11: R2 = Me, X = NH, R1 = R3 = R4 = H
6, 12: R1 = R2 = Me, X = N-Ph-4-OMe, R3 = R4 = H; 8, 13: R1 = R2 = OH, X = O, R3 = R4 = H
5, 14: R2 = Me, X = -CH2CH2-, R1 = R3 = R4 = H; 6, 15: R1 = R2 = Me, X = N-COOEt, R3 = R4 = H
5, 16: R2 = Me, X = N-CH2Ph, R1 = R3 = R4 = H; 5, 17: R2 = Me, X = N-CH2-Ph-3′,4′-OCH2O, R1 = R3 = R4 = H
8, 18: R1 = R2 = OH, X = O, 2′,6′-Me , R3 = R4 = H; 5, 19: R2 = Me, R5 = 2′-CH2CH2OH, R1 = R3 = R4 = H
6, 20: R1 = R2 = Me, R5 = 4′,4′-OCH2CH2O, R3 = R4 = H
Starting 4-chloromethylcoumarins were prepared by Pechmann condensation of substituted phenols with 4-chloro-
acetoacetic esters in the presence of conc. H SO [8-11]. Secondary aliphatic amines reacted smoothly with 4-chloro-
2
4
methylcoumarins in high yields (75-90%) in DMF without heating.
Taras Shevchenko Kiev National University, Ukraine, 01033, Kiev, ul. Vladimirskaya 64, fax: 38-(044) 235 12 73,
e-mail: levenets@mail.univ.kiev.ua. Translated from KhimiyaPrirodnykh Soedinenii, No. 5, pp. 434-436, September-October,
2007. Original article submitted February 8, 2007.
0009-3130/07/4305-0529 ©2007 Springer Science+Business Media, Inc.
529

R
1
R
1
NH
2
R
2
O
O
R
2
O
O
R
5
+
R
3
R
3
R
4
R
4
Cl
NH
5 - 7, 9
R
5
21 - 28
6, 21: R1 = R2 = Me, R5 = 4-OEt, R3 = R4 = H; 5, 22: R2 = Me, R5 = 2,5-COOMe2, R1 = R3 = R4 = H
7, 23: R3 = OH, R2 = Me, R5 = 2-F, R1 = R4 = H; 9, 24: R3 = OH, R2 = Ph, R5 = 3-Cl, R1 = R4 = H
7, 25: R3 = OH, R2 = Me, R5 = 3-OMe, R1 = R4 = H; 7, 26: R3 = OH, R2 = Me, R5 = 4-OEt, R1 = R4 = H
9, 27: R3 = OH, R2 = Ph, R5 = 2-COOMe, R1 = R4 = H; 7, 28: R3 = OH, R2 = Me, R5 = 2,3-Me2, R1 = R4 = H
The presence of free hydroxyls in both 4-chloromethylcoumarins 13 and 18 and amine 19 did not hinder the alkylation
at the N atom. On the other hand, use of a six-fold excess of piperazine enabled monoalkylated 11 with a free secondary amino
group to be produced.
Thesubstituted4-chloromethylcoumarinsturnedout toberather reactivetowardalkylation ofprimaryaromaticamines.
The duration of the reaction and the yield depended directly on the nucleophilicity of the amine. The reaction was carried out
in DMF with prolonged (48 h) heating.
The prepared 4-aminomethyl coumarin derivatives (10-20) were colorless crystalline compounds with low melting
points and were readily soluble in organic solvents. Conversely, 21-28 were high melting and difficultly soluble. The PMR
spectra of 21-28 exhibited a triplet for the secondary amine at 5.5-6.5 ppm. The methylene bound to the amine appeared as a
doublet at 4.4-4.7 ppm.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Sorbfil UV-254 (Russia) and Merck
(Germany) plates. The eluent was CHCl :CH OH (95:5 and 9:1). Melting points were determined on a Kofler block.
3
3
IR spectra were measured on a Nicolet FTIRNexus 475 spectrometer; PMRspectra, on Varian VXR-300 and Mercury400 (300
and 400 MHz, respectively) spectrometers in DMSO-d relative to TMS (internal standard) on the δ-scale. Elemental analyses
6
of all compounds agreed with those calculated.
Sarting 4-chloromethylcoumarins (4-9) were prepared as before [8-11].
General Method for Preparing 10-20. A hot solution ofthe appropriate 4-chloromethylcoumarin (10 mmol) in DMF
(25 mL) was treated with seconary amine (22 mmol) and held for 24 h at room temperature (completion of reaction determined
by TLC). The mixture was poured into cold water (200 mL). The precipitate was filtered off and crystallized from aqueous
alcohol.
7-Methoxy-4-morpholin-4-ylmethylchromen-2-one (10). Yield 78%, C H NO , mp 152-153°C. IR spectrum
15 17
4
(KBr, cm−1): 1719, 1607, 1511, 1459, 1395, 1296, 1239, 1136. PMR spectrum: 2.49 (4H, br.s, H-2′,6′), 3.07 (4H, br.s, H-3′,5′),
3.65 (2H, s, CH -4), 3.85 (3H, s, OMe-7), 6.32 (3H, s, H-3), 6.98 (2H, m, H-6,8), 7.84 (1H, d, J = 8.4, H-5).
2
7-Methyl-4-piperazin-1-ylmethylchromen-2-one (11). Yield70%, C H N O , mp133-134°C. IRspectrum (KBr,
15 18
2 2
cm−1): 3380, 1726, 1676, 1594, 1487, 1355, 1286, 1242. PMRspectrum: 2.39 (m, 9H, piperazine protons), 3.66 (2H, s, CH -4),
2
6.41 (3H, s, H-3), 7.21 (2H, m, H-6,8), 7.79 (1H, d, J = 8.2, H-5).
4-[4-(4-Methoxyphenyl)-piperazin-1-ylmethyl]-7,8-dimethylchromen-2-one (12). Yield 86%, C H N O ,
23 26
2 3
mp 181-182°C. IR spectrum (KBr, cm−1): 1716, 1700, 1626, 1588, 1494, 1392, 1362, 1292, 1232, 1129. PMR spectrum:
2.32 (3H, s, Me-6), 2.37 (3H, s, Me-8), 2.65 (4H, br.s, CH -3′,5′), 3.59 (5H, br.s, –OMe, CH -4), 6.39 (3H, s, H-3), 6.39 (2H,
2
2
d, J = 8.4, Ph-2,6-H), 6.81 (2H, d, J = 8.4, Ph-3,5-H), 7.09 (1H, d, J = 8.4, H-6), 7.61 (1H, d, J = 8.4, H-5).
530

7,8-Dihydroxy-4-morpholin-4-ylmethylchromen-2-one (13). Yield 80%, C H NO , mp146-147°C. IRspectrum
14 15
5
(KBr, cm−1): 3264, 1726, 1698, 1624, 1505, 1442, 1375, 1286, 1102. PMR spectrum: 3.58 (4H, br.s, CH -3′,5′), 3.60 (2H, s,
2
CH -4), 6.25 (3H, s, H-3), 6.81 (1H, d, J = 8.5, H-6), 7.23 (1H, d, J = 8.5, H-5), 9.67 (2H, br.s, OH-7,8).
2
4-Azepan-1-ylmethyl-7-methylchromen-2-one (14). Yield 72%, C H NO , mp 121-122°C. IR spectrum (KBr,
17 21
2
cm−1): 1729, 1634, 1586, 1502, 1454, 1324, 1246, 1124, 1056. PMR spectrum: 2.46 (4H, br.s, CH -3′,5′), 3.60 (2H, s, CH -4),
2
2
6.25 (3H, s, H-3), 6.81 (1H, d, J = 8.4, H-5), 7.84 (1H, d, J = 8.4, H-6), 9.67 (2H, br.s, OH-7,8).
4-(7,8-Dimethyl-2-oxo-2H-chromen-4-ylmethyl)piperazin-1-carboxylic Acid Ethyl Ester (15). Yield 77%,
C H N O , mp 161-162°C. IR spectrum (KBr, cm−1): 1715, 1676, 1654, 1598, 1524, 1468, 1412, 1363, 1265, 1056.
19 24
2 4
PMR spectrum: 1.18 (3H, t, J = 8.2, CH -4′), 4.02 (2H, q, J = 8.2, CH -4′), 2.27 (3H, s, Me-7), 2.35 (3H, s, Me-8), 3.69 (2H,
2
3
s, CH -4), 2.45 (8H, br.s, piperazine protons), 6.42 (3H, s, H-3), 7.16 (1H, d, J = 8.4, H-6), 7.63 (1H, d, J = 8.4, H-5).
2
4-(4-Benzylpiperazin-1-ylmethyl)-7-methylchromen-2-one (16). Yield 75%, C H N O , mp 187-188°C.
22 24
2 2
IR spectrum (KBr, cm−1): 1729, 1676, 1596, 1480, 1376, 1278, 1215, 1168, 1096, 1044. PMR spectrum: 2.40 (11H, br.s, Me-7,
piperazine protons), 3.46 (2H, s, CH -4′), 3.66 (2H, s, CH -4), 6.38 (3H, s H-3), 7.29 (7-H-Ph, m, H-7,8), 7.78 (1H, d, J = 8.4,
2
2
H-5).
4-(4-Benzo[1,3]dioxol-5-ylmethylpiperazin-1-ylmethyl)-7-methylchromen-2-one (17). Yield 82%, C H N O ,
23 24
2 4
mp 161-162°C. IR spectrum (KBr, cm−1): 1715, 1624, 1575, 1515, 1498, 1392, 1305, 1276, 1210, 1148, 1115. PMRspectrum:
2.40 (8H, br.s, piperazine protons), 3.36 (2H, s, CH -4′), 3.65 (2H, s, CH -4), 5.98 (2H, s, OCH O), 6.38 (3H, s, H-3), 6.74 (1H,
2
2
2
d, J = 8.3, H-2′), 6.84 (2H, m, H-5′,6′), 7.19 (1H, dd, J = 8.4, 2.3, H-6), 7.21 (1H, d, J = 2.3, H-8), 7.78 (1H, d, J = 8.4, H-5).
4-(2,6-Dimethylmorpholin-4-ylmethyl)-7,8-dihydroxychromen-2-one (18). Yield88%, C H NO , mp136-137°C.
16 19
5
IR spectrum (KBr, cm−1): 3384, 1715, 1668, 1602, 1564, 1486, 1393, 1356, 1324, 1254, 1156, 1032. PMR spectrum: 1.03,
1.15, 1.76, 2.27, 2.35, 2.75, 3.62, 3.92 (14H, 9m, morpholine protons), 6.41 (3H, s, H-3), 7.15 (1H, d, J = 8.4, H-6), 7.67 (1H,
d, J = 8.4, H-5).
4-[2-(2-Hydroxyethyl)piperidin-1-ylmethyl]-7-methylchromen-2-one (19). Yield68%, C H NO , mp132-133°C.
18 23
3
IR spectrum (KBr, cm−1): 3420, 1720, 1640, 1594, 1508, 1474, 1432, 1365, 1245 1185, 1130. PMR spectrum: 1.60, 2.63, 2.68,
3.42 (13H, 6m, piperidine protons), 2.32 (3H, s, Me-7), 6.46 (3H, s, H-3), 7.16 (1H, dd, J = 8.4, 2.3, H-6), 7.22 (1H, d, J = 2.3,
H-8), 7.80 (1H, d, J = 8.4, H-5).
4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylmethyl)-7,8-dimethylchromen-2-one (20). Yield 70%, C H NO , mp 155-
19 23
4
156°C. IR spectrum (KBr, cm−1): 1722, 1632, 1565, 1496, 1424, 1398, 1342, 1228, 1130. PMR spectrum: 1.63 (4H, br.s,
H-3′,5′), 2.27 (3H, s, Me-7), 2.35 (3H, s, Me-8), 3.68 (2H, s, CH -4), 3.86 (4H, s, OCH CH O), 6.41 (3H, s, H-3), 7.16 (3H,
2
2
2
s, H-6), 7.64 (3H, 5s, H-5).
General Method for Preparing 21-28. A hot solution ofthe appropriate 4-chloromethylcoumarin (10 mmol) in DMF
(25 mL) was treated with amine (22 mmol) and held for 20-48 h at 80-100°C (completion of reaction determined byTLC). The
mixture was cooled and poured into cold water (200 mL). The precipitate was filtered off and crystallized from
isopropanol:DMF.
4-[(4-Ethoxyphenylamino)methyl]-7,8-dimethylchromen-2-one (21). Yield 70%, C H NO , mp 205-207°C.
20 21
3
IR spectrum (KBr, cm−1): 3260, 1726, 1696, 1624, 1576, 1513, 1482, 1415, 1242, 1208, 1174. PMR spectrum: 1.24 (3H, t,
J = 8.2, CH -4′), 3.85 (2H, q, J = 8.2, CH -4′), 2.27 (3H, s, Me-7), 2.36 (3H, s, Me-8), 4.44 (2H, d, J = 6.5, CH -4), 5.92 (1H,
3
2
2
t, J = 6.5, NH), 6.26 (3H, s, H-3), 6.54 (2H, d, J = 8.4, H-2′,6′), 6.68 (2H, d, J = 8.4, H-3′,5′), 7.19 (1H, d, J = 8.4, H-6), 7.63
(1H, d, J = 8.4, H-5).
2-[(7-Methyl-2-oxo-2H-chromen-4-ylmethyl)amino]terephthalic Acid Dimethyl Ester (22). Yield 60%,
C H NO , mp 258-259°C. IR spectrum (KBr, cm−1): 3375, 1715, 1688, 1612, 1575, 1480, 1424, 1350, 1298, 1220, 1170.
21 19
6
PMR spectrum: 2.41 (3H, s, Me-7), 3.82 (6H, 2s, Me -2′,5′), 5.00 (2H, s, CH -4), 6.60 (3H, s, H-3), 7.04 (1H, dd, J = 8.2, 2.2,
2
2
H-6), 7.25 (1H, d, J = 8.2, H-8), 7.27 (1H, d, J = 8.2, H-5), 7.43 (1H, d, J = 2.1, H-6′), 7.71 (1H, dd, J = 8.4, 2.1, H-4′), 7.71
(1H, d, J = 8.4, H-3′).
4-[(2-Fluorophenylamino)methyl]-6-hydroxy-7-methylchromen-2-one (23). Yield 56%, C H FNO , mp 231-
17 14
3
232°C. IR spectrum (KBr, cm−1): 3256, 1714, 1688, 1612, 1556, 1480, 1424, 1342, 1296, 1232, 1160. PMR spectrum: 2.46
(3H, s, Me-7), 4.49 (2H, br.s, CH -4), 6.12 (3H, s, H-3), 6.20 (1H, br.s, NH), 7.14 (1H, s, H-5), 7.22 (1H, s, H-8), 6.58 (1H, d,
2
J = 8.2, H-6′), 6.61 (1H, d, J = 8.2, H-5′), 6.93 (1H, t, J = 7.8, H-4′), 7.09 (1H, dd, J = 7.8, 12, H-3′), 9.75 (1H, s, OH-6).
4-[(3-Chlorophenylamino)methyl]-6-hydroxy-7-phenylchromen-2-one (24). Yield 60%, C H ClNO , mp 248-
22 16
3
249°C. IR spectrum (KBr, cm−1): 3416, 1724, 1684, 1610, 1532, 1462, 1390, 1282, 1198, 1100. PMR spectrum: 4.51 (2H,
531

br.s, CH -4), 6.27 (3H, s, NH), 7.47 (5H, m, Ph-7), 7.37 (1H, s, H-8), 7.30 (1H, s, H-5), 7.19 (1H, t, J = 8.1, H-2′), 9.99 (1H,
2
s, OH-6).
6-Hydroxy-4-[(3-methoxyphenylamino)methyl]-7-methylchromen-2-one (25). Yield 75%, C H NO , mp 215-
18 17
4
216°C. IR spectrum (KBr, cm−1): 3321, 3115, 1725, 1674, 1565, 1521, 1441, 1324, 1210, 1168, 1112. PMR spectrum: 2.23
(3H, s, Me-7), 3.65 (3H, s, OMe-3′), 4.41 (2H, br.s, CH -4), 6.20 (4H, m, H-3,2′,4′,6′), 6.27 (1H, br.s, NH), 6.99 (1H, t, J = 8.1,
2
H-5′), 7.13 (1H, s, H-8), 7.21 (1H, s, H-5), 9.72 (1H, s, OH-6).
4-[(4-Ethoxyphenylamino)methyl]-6-hydroxy-7-methylchromen-2-one (26). Yield 80%, C H NO , mp 225-
19 19
4
226°C. IR spectrum (KBr, cm−1): 3390, 3320, 1712, 1640, 1556, 1492, 1432, 1375, 1284, 1182, 1090. PMR spectrum: 1.35
(3H, t, J = 8.2, CH -4′), 4.07 (2H, q, J = 8.2, CH -4′), 2.24 (3H, s, Me-7), 7.06 (2H, d, J = 9.0, H-3′,5′), 7.22 (3H, s, H-3), 8.46
3
2
(1H, s, H-5), 8.80 (1H, s, H-8), 9.72 (1H, s, OH-6).
2-[(6-Hydroxy-2-oxo-7-phenyl-2H-chromen-4-ylmethyl)amino]benzoic Acid Methyl Ester (27). Yield 71%,
C H NO , mp 198-199°C. IR spectrum (KBr, cm−1): 3336, 3212, 1719, 1670, 1572, 1424, 1394, 1324, 1262, 1124, 1102.
24 19
5
PMR spectrum: 3.85 (3H, s, Me-2′), 4.75 (2H, br.s, CH -4), 6.13 (1H, s, H-3), 6.69 (2H, m, H-4′,5′), 7.40 (5H, m, Ph-6), 8.16
2
(1H, t, J = 6, NH), 10.05 (1H, s, OH-6).
4-[(2,3-Dimethylphenylamino)methyl]-6-hydroxy-7-methylchromen-2-one (28). Yield79%, C H NO , mp205-
19 19
3
207°C. IR spectrum (KBr, cm−1): 3212, 1708, 1620, 1560, 1475, 1432, 1226, 1162, 1032. PMR spectrum: 2.20 (9H, 3s, Me-7,
Me-2′,3′-), 4.48 (2H, br.s, CH -4), 5.58 (1H, t, J = 5.4, NH), 6.10 (3H, s, H-3), 6.19 (1H, d, J = 7.8, H-6′), 6.48 (1H, d, J = 7.5,
2
H-4′), 6.83 (1H, t, J = 7.5, H-5′), 7.18 (1H, s, H-5), 7.21 (1H, s, H-8), 9.75 (1H, s, OH-6).
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