3-(2-Pyridyl)coumarins

Article abstract of DOI:10.1007/s10600-005-0197-5

3-(2-Pyridyl)coumarins were prepared by reaction of substituted salicylaldehydes and 2-pyridylacetonitrile. Benzylation, acylation, and aminomethylation of 7-hydroxy-3-(2-pyridyl)coumarin was studied. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-005-0197-5

Chemistry of Natural Compounds, Vol. 41, No. 5, 2005
3-(2-PYRIDYL)COUMARINS
O. V. Khilya, O. V. Shablykina, M. S. Frasinyuk,
V. V. Ishchenko, and V. P. Khilya
UDC 547.814.5
3
-(2-Pyridyl)coumarins were prepared by reaction of substituted salicylaldehydes and 2-pyridylacetonitrile.
Benzylation, acylation, and aminomethylation of 7-hydroxy-3-(2-pyridyl)coumarin was studied.
Key words: 8-aminomethyl-7-hydroxy-3-(2-pyridyl)coumarins, 7-acyloxy-3-(2-pyridyl)coumarins, 7-benzyloxy-3-(2-
pyridyl)coumarins, 3-(2-pyridyl)coumarins.
Compounds with a coumarin ring are widelydistributed throughout the plant kingdom and much less in animals. They
belong to a large group of so-called phenolic compounds, the formation of which is characteristic of all representatives of the
plant kingdom. Therefore, the important role in the life-cycle of plants of these compounds, which contribute toplant protective
reactions and in many instances their pigmentation, cannot be disputed.
As a rule, coumarins in nature occur as glycosides (highest contents in plants of the Umbelliferae, Rutaceae,
Solanaceae, and Fabaceae families). Natural coumarins have been used in medicine (anticoagulants), foods, and fragrances.
Synthetic coumarins and their analogs are used as fluorescent probes and markers for biological research and as antibiotics,
antiallergens, and fungicides in medicine.
We studied the synthesis of coumarins with a pyridine substituent via Knoevenagel condensation of substituted
salicylaldehydes with 2-pyridylacetonitrile [1-8]. The resulting 2-iminocoumarins were converted to coumarins 1-10 by
hydrolysis of the imine (Scheme 1).
N
N
CHO
OH
N
N
+
H
NC
H
R
1
R1
R1
+
O
NH
O
O
1
- 10
1
: R = H; 2: R = 7-OH;3: R = 8-OH;4: R = 7,8-(OH) ; 5: R = 8-OMe;
1 1 1 1 2 1
6
: R = 8-OEt;7: R = 6-NO ; 8: R = 6-Cl; 9: R = 6,8-Cl ; 10: R = 6-Br
1
1
2
1
1
2
1
Scheme 1.
Properties of the synthesized compounds (1-10) and their IR, UV and PMR spectra are given in the Experimental
section.
The most characteristic signal in the PMR spectra of the 3-(2-pyridyl)coumarins is that for the coumarin 4-H, a singlet
at 8.70-8.95 ppm. The signals of the other coumarin protons depend on the nature and position of the substituent in the
coumarin ring whereas the signals for the pyridine protons are practically the same in all compounds 1-10: (3′-H: 8.2-8.5 ppm,
br.d, J = 8 Hz; 4′-H: 7.8-7.9 ppm, br.t, J = 8 Hz; 5′-H: 7.2-7.4 ppm, br.t, 3J = 4.5-6 Hz; 6′-H: 8.7-8.9 ppm, br.d,
3
3
3J = 4.5-6 Hz).
Two planar conformations (I and II) are possible for 3-(2-pyridyl)coumarins. In these, the pyridine and coumarin
systems are conjugated:
Taras Shevchenko Kiev National University, Ukraine, Kiev, 01033, Ukraine, e-mail: shablykina@mail.univ.kiev.ua.
Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 428-431, September-October, 2005. Original article submitted
August 5, 2005.
©
0
009-3130/05/4105-0523 2005 Springer Science+Business Media, Inc.
523

N
O
N
R
1
R
1
O
O
O
I
II
Conformation I, as was demonstrated previously for 3-pyridylchromones [9], is much less favorable than II owing to
mutual repulsion of the two electron-rich atoms, the carbonyl oxygen of coumarin and the pyridine nitrogen. An argument in
favor of this conformation is the significant difference in the chemical shifts of the pyridine β-protons in the PMR spectra. The
signal for 3′-H is located at weaker field than that for 5′-H because of the deshielding effect of the carbonyl O atom. The
difference is about 1 ppm. However, the chemical shifts of 3′-H and 5′-H would be practically identical for conformation I and
for structures in which the coumarin and pyridine rings are not coplanar.
Benzylation, acylation, and aminomethylation of 2 was performed in order to study the effect of the pyridine ring on
the chemical behavior of the coumarin system (Scheme 2).
N
O
N
N
O
RCl
K CO
2
3
R COCl
1
Pyridine
RO
O
HO
O
O
R COO
1
O
1
1 - 13
14 - 16
2
X
N
2
CH
2
Dioxane
N
O
HO
O
N
X
1
7 - 19
1
1
1: R = C H CH ; 12: R = 2-FC H CH ; 13: R = 4-FC H CH ; 14: R = Me; 15: R = Ph;
6
5
2
6
4
2
6
4
2
1
1
6: R = Furyl; 17: X = CH ; 18: X = CH CH ; 19: X = O
1
2
2
2
Scheme 2.
Benzylation of 7-hydroxycoumarin in acetone or DMF with potash and a 40% excess of benzylchloride for 8-10 h
formed 11-13.
Compounds 14-16 were synthesized using a two-fold excess of carboxylic acid chlorides and a solution of 2 in pyridine
acetic anhydride was used to prepare acetylcoumarin).
The PMR spectra of the resulting 7-benzyloxy- and 7-acyloxycoumarins exhibited signals for the benzyl and acyl
(
protons. Signals of the coumarin system were shifted to weak field.
The presence of the 7-OH enabled the 8-position of the coumarin to be activated toward electrophilic attack by
aminomethylating agents. Such a reaction is atypical of a pyrone ring without electron-donating substituents. It was impossible
to carry out the aminomethylation of 7-hydroxy-3-(2-pyridyl)coumarin under classical conditions (in acidic medium) because
of protonation of the pyridine N, which significantly deactivates the compound toward electrophilic substitution and removes
the pyridylcoumarin from the reaction medium since it precipitates as the salt. Therefore, the coumarin Mannich bases were
prepared using formaldehyde aminal [1]. The reaction occurred on boiling 2 with a 20% excess of the aminal in absolute
dioxane over 12 h. Compounds 17-19 were synthesized this way. Introducing the aminomethyl substituent in the coumarin
8
-position shifted the signals for 5-H and 6-H (d, J = 8.5 Hz) of 17-19 to strong field in the PMR spectra. A characteristic signal
for 8-CH (s, 4.1-4.2 ppm) also appeared.
2
TheUVabsorption spectra ofthe3-(2-pyridyl)coumarinsexhibiteda long-wavelength maximum at 310-365nm (except
for aminomethyl derivative 18, for which λmax = 400 nm). Its position depended on the nature of the coumarin substituent as
follows. A donor substituent (hydroxyl or O-benzyl) in the coumarin 7-position shifted the absorption maximum to long-
5
24

wavelength to 351-357 nm compared with unsubstituted 1 (332 nm). Substituents in the coumarin 8-position decreased λmax
26 nm, 3; 322, 5 and 6; 310, 9. However, if the molecule contained a 7-OH in addition to an electron-donating substituent
in the 8-position, then the effect of the former was intensified. Thus, the highest λmax was seen for aminomethyl derivative 18
:
3
(400 nm) and the λmax values were also high for the other aminomethyl derivatives and 7,8-dihydroxy-3-(2-pyridyl)coumarin
(
359-365 and 362 nm, respectively).
-1
The IR spectrum of 1 had the coumarin C=O absorption at 1722 cm . Introducing electron-donating substituents,
especially in the coumarin 7-position, decreased the frequency (to 1700 for 2 and 4). The C=O frequency was correspondingly
greater for compounds with electron-accepting substituents [1748 cm-1 for 6,8-dichloro-3-(2-pyridyl)coumarin, 9].
Thus, condensation of salicylaldehydes and 2-pyridylacetonitrile is a convenient preparative method for synthesizing
3
-(2-pyridyl)coumarins. The presence of the hydroxyl enabled 7-O-benzyl- and 7-O-acyl derivatives of 7-hydroxy-3-(2-
pyridyl)coumarin to be prepared and the 8-position of the coumarin system to be activated for electrophilic attack by
aminomethylating agents.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Silufol UV-254 plates with elution by
CHCl :CH OH (9:1 and 19:1). PMR spectra were measured on a Varian Mercury 400 instrument in DMSO-d with TMS
3
3
6
internal standard; UV absorption spectra, on a Shimadzu UV-3100; IR spectra, on a Nexus IR-Fourier spectrometer. Elemental
analyses agreed with those calculated.
GeneralMethodforSynthesizing3-(2-Pyridyl)coumarins1-10. Substitutedsalicylaldehyde(0.1mol)and2-pyridyl-
acetonitrile (0.1 mol) were dissolved in the minimal volume of ethanol or isopropanol at 40°C and treated with piperidine
(
0.1 mL). The reaction mixture was held for 1 d at room temperature, treated with H SO (50 mL, 3%) and boiled for 2-12 h
2 4
to hydrolyze the iminocoumarin. When the reaction was finished, the acidic solution was neutralized with aqueous ammonia
until the pH was 7. The solid coumarin was filtered off and washed thoroughly with water.
Crystallization: 1, 3, 9, 10, ethanol; 2, reprecipitation from acidic aqueous solution; 4 and 5, n-butanol; 6, dioxane;
7
and 8, DMF.
-(2-Pyridyl)coumarin (1). Yield 87%, C H NO , mp 139-139.5°C (141-142°C [6]).
3
14
9
2
-1
IR spectrum (KBr, cm ): 1723, 1605, 1579, 1462, 1244, 1109, 1089.
UV spectrum (EtOH, λmax, nm, log ε): 332 (4.199).
3
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 7.34-7.42 (3H, m, H-6, H-8, H-5′), 7.63 (1H, br.t, J = 8, H-7),
6
3
3
7
.82-7.87 (2H, m, H-5, H-4′), 8.32 (1H, br.d, J = 8, H-3′), 8.66 (1H, br.d, J = 4.5, H-6′), 8.87 (1H, s, H-4).
-Hydroxy-3-(2-pyridyl)coumarin (2). Yield 66%, C H NO , mp 255-256°C (254-255°C [2]; 254-260°C [5]).
7
14
9
3
-1
IR spectrum (KBr, cm ): 1702, 1603, 1581, 1487, 1462, 1221.
UV spectrum (EtOH, λmax, nm, log ε): 357 (4.286), 251 (3.898).
4
3
4
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 6.78 (1H, d, J = 1.5, H-8), 6.85 (1H, dd, J = 8, J = 1.5, H-6),
6
3
3
3
3
7
.63 (1H, br.t, J = 5, H-5′), 7.68 (1H, d, J = 8, H-5), 8.18 (1H, br.t, J = 8, H-4′), 8.41 (1H, d, J = 8, H-3′), 8.75 (1H, br.d,
3
J = 5, H-6′), 8.86 (1H, s, H-4), 10.79 (1H, br.s, OH-7).
-Hydroxy-3-(2-pyridyl)coumarin (3). Yield 63%, C H NO , mp 218-219°C.
8
14
9
3
-1
IR spectrum (KBr, cm ): 1714, 1596, 1465, 1243, 1225, 1129, 1080.
UV spectrum (EtOH, λmax, nm, log ε): 326 (4.255), 255 (3.968).
3
4
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 7.10-7.17 (2H, m, H-6, H-7), 7.24 (1H, dd, J = 7.5, J = 1.5,
6
3
3
3
3
H-5), 7.37 (1H, br.t, J = 4, H-5′), 7.85 (1H, br.t, J = 8, H-4′), 8.33 (1H, d, J = 8, H-3′), 8.66 (1H, br.d, J = 5, H-6′), 8.80 (1H,
s, H-4), 10.12 (1H, br.s, OH-8).
7
,8-Dihydroxy-3-(2-pyridyl)coumarin (4). Yield 61%, C H NO , mp 242-243°C.
14 9 4
-1
IR spectrum (KBr, cm ): 1698, 1608, 1592, 1510, 1478, 1465, 1303, 1245, 1218, 1177.
UV spectrum (EtOH, λmax, nm, log ε): 362 (4.350), 269 (4.143).
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 6.82 (1H, d, J = 8.5, H-6), 7.13 (1H, d, J = 8.5, H-5), 7.28 (1H,
br.t, J = 6, H-5′), 7.79 (1H, br.t, J = 8, H-4′), 8.31 (1H, d, J = 8, H-3′), 8.60 (1H, br.d, J = 6, H-6′), 8.74 (1H, s, H-4), 9.51
1H, br.s, OH-8), 10.34 (1H, br.s, OH-7).
6
3
3
3
3
(
525

8
-Methoxy-3-(2-pyridyl)coumarin (5). Yield 72%, C H NO , mp 164-165°C.
15 11 3
-1
IR spectrum (KBr, cm ): 1720, 1615, 1590, 1440.
UV spectrum (EtOH, λmax, nm, log ε): 322 (4.322), 253 (4.0).
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 4.00 (3H, s, MeO-8), 7.11 (1H, dd, J = 7, J = 2, H-6), 7.21-7.32
3
4
6
3
3
3
(
3H, m, H-5, H-7, H-5′), 7.79 (1H, br.t, J = 8, H-4′), 8.44 (1H, d, J = 8, H-3′), 8.68 (1H, br.d, J = 4.5, H-6′), 8.76 (1H, s,
H-4).
8
-Ethoxy-3-(2-pyridyl)coumarin (6). Yield 82%, C H NO , mp 162-163°C.
16 13 3
-1
IR spectrum (KBr, cm ): 1721, 1608, 1579, 1472, 1278, 1092.
UV spectrum (EtOH, λmax, nm, log ε): 322 (4.303), 253 (4.004).
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.53 (3H, t, Me-8β), 4.23 (2H, q, CH O-8α), 7.11 (1H, dd,
6
2
3
4
3
3
J = 7, J = 2, H-6), 7.21-7.23 (2H, m, H-5, H-7), 7.31 (1H, br.t, J = 5, H-5′), 7.79 (1H, br.t, J = 8, H-4′), 8.43 (1H, d,
3
3
J = 8, H-3′), 8.68 (1H, br.d, J = 5, H-6′), 8.74 (1H, s, H-4).
6
-Nitro-3-(2-pyridyl)coumarin (7). Yield 79%, C H N O , mp 216-217°C.
14 8 2 4
-1
IR spectrum (KBr, cm ): 1735, 1610, 1523, 1350, 1111, 1096.
UV spectrum (EtOH, λmax, nm, log ε): 322 (4.204), 269 (4.283), 227 (4.127).
3
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 7.40 (1H, br.t, J = 5, H-5′), 7.62 (1H, d, J = 8.5, H-8), 7.88 (1H,
6
3
3
3
br.t, J = 8, H-4′), 8.27 (1H, br.d, J = 8.5, H-7), 8.42 (1H, d, J = 8, H-3′), 8.68 (1H, br.d, J = 5, H-6′), 8.84 (1H, br.s, H-5),
9
.00 (1H, s, H-4).
-Chloro-3-(2-pyridyl)coumarin (8). Yield 73%, C H ClNO , mp 187-188°C.
6
14
7
2
-1
IR spectrum (KBr, cm ): 1727, 1584, 1463, 1437, 1240, 1118, 1067.
UV spectrum (EtOH, λmax, nm, log ε): 341 (4.079), 307 (4.137).
3
4
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 7.35-7.40 (2H, m, H-8, H-5′), 7.71 (1H, dd, J = 8.5, J = 2, H-7),
6
3
4
3
3
7
.87 (1H, br.t, J = 8, H-4′), 8.07 (1H, d, J = 2, H-5), 8.33 (1H, d, J = 8, H-3′), 8.67 (1H, br.d, J = 5, H-6′), 8.54 (1H, s, H-4).
,8-Dichloro-3-(2-pyridyl)coumarin (9). Yield 82%, C H Cl NO , mp 151-151.5°C.
6
1
4
7
2
2
-1
IR spectrum (KBr, cm ): 1748, 1473, 1456, 1439, 1243, 1092, 992.
UV spectrum (EtOH, λmax, nm, log ε): 310 (4.210), 220 (4.465).
3
4
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 7.41 (1H, br.t, J = 4.5, H-5′), 7.75 (1H, d, J = 2, H-7), 7.87 (1H,
6
3
4
3
3
br.t, J = 8, H-4′), 7.98 (1H, d, J = 2, H-5), 8.30 (1H, d, J = 8, H-3′), 8.68 (1H, br.d, J = 5, H-6′), 8.89 (1H, s, H-4).
-Bromo-3-(2-pyridyl)coumarin (10). Yield 80%, C H BrNO , mp 225°C.
6
14
8
2
-1
IR spectrum (KBr, cm ): 1723, 1462, 1240, 1118, 1080.
UV spectrum (EtOH, λmax, nm, log ε): 340 (4.167), 307 (4.207), 220 (4.517).
3
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 7.38 (1H, br.t, J = 4.5, H-5′), 7.43 (1H, d, J = 8.5, H-8), 7.59
6
3
3
4
4
3
(
1H, dd, J = 8.5, J = 2, H-7), 7.86 (1H, br.t, J = 8, H-4′), 7.94 (1H, d, J = 2, H-5), 8.31 (1H, d, J = 8, H-3′), 8.67 (1H, br.d,
3
J = 5, H-6′), 8.86 (1H, s, H-4).
General Method for Synthesizing 7-Benzyloxy-3-(2-pyridyl)coumarins 11-13. A mixture of 7-hydroxy-3-(2-
pyridyl)coumarin (5 mmol), benzylchloride (7 mmol), and freshly calcined potash (2 g) was boiled in acetone (30 mL) or DMF
10 mL) with stirring for 8-10 h. The solid was filtered off. If acetone was used as solvent, the product was isolated after adding
(
water to the solid and neutralizing the potash; if DMF, by precipitation with water from the mother liquor.
Crystallization: 11, DMF; 12, DMF:isopropanol; 13, isopropanol.
7
-Benzyloxy-3-(2-pyridyl)coumarin (11). Yield 88%, C H NO , mp 160-161°C.
21 15 3
-1
IR spectrum (KBr, cm ): 1710, 1620, 1585, 1510, 1465, 1440.
UV spectrum (EtOH, λmax, nm, log ε): 352 (4.405), 248 (4.021), 206 (4.585).
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 5.13 (2H, s, CH O-7), 7.01 (1H, d, J = 8, H-6), 7.08 (1H, br.s,
3
6
2
3
3
3
H-8), 7.33 (1H, br.t, J = 4, H-5′), 7.31-7.45 (5H, m, Ph-7), 7.76 (1H, d, J = 8, H-5), 7.82 (1H, br.t, J = 8, H-4′), 8.29 (1H,
d, J = 8, H-3′), 8.65 (1H, br.d, J = 4, H-6′), 8.83 (1H, s, H-4).
3
3
7
-(2-Fluorobenzyloxy)-3-(2-pyridyl)coumarin (12). Yield 93%, C H FNO , mp 168-169°C.
21
14
3
-1
IR spectrum (KBr, cm ): 1713, 1612, 1582, 1462, 1238, 1196, 1173, 1127.
UV spectrum (EtOH, λmax, nm, log ε): 351 (4.447), 248 (4.076), 207 (4.614).
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 5.24 (2H, s, CH O-7), 7.00 (1H, dd, J = 8, J = 1.5, H-6), 7.11 (1H,
6
2
3
d, J = 1.5, H-8), 7.16-7.24 [2H, m, H-4″, H-6″ (2-FC H )], 7.41 [1H, m, H-5″ (2-FC H )], 7.32 (1H, br.t, J = 6, H-5′), 7.76 (1H,
6
4
6 4
5
26

3
3
3
3
d, J = 8, H-5), 7.56 [1H, br.t, J = 8, H-3″ (2-FC H )], 7.81 (1H, br.t, J = 8, H-4′), 8.30 (1H, d, J = 8, H-3′), 8.62 (1H, br.d,
6
4
3J = 6, H-6′), 8.83 (1H, s, H-4).
-(4-Fluorobenzyloxy)-3-(2-pyridyl)coumarin (13). Yield 94%, C H FNO , mp 168-169 C.
7
21
14
3
-
1
IR spectrum (KBr, cm ): 1715, 1616, 1585, 1520, 1472, 1238.
UV spectrum (EtOH, λmax, nm, log ε): 352 (4.438), 248 (4.061), 212 (4.709).
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 5.20 (2H, s, CH O-7), 7.00 (1H, dd, J = 8, J = 2, H-6), 7.09 (1H,
6
2
3
d, J = 2, H-8), 7.15 [2H, m, H-2″, H-6″ (4-FC H )], 7.33 (1H, br.t, J = 5, H-5′), 7.51 [2H, m, H-3″, H-5″ (4-FC H )], 7.77 (1H,
6
4
6 4
3
3
3
3
d, J = 8, H-5), 7.82 (1H, br.t, J = 8, H-4′), 8.30 (1H, d, J = 8, H-3′), 8.64 (1H, br.d, J = 5, H-6′), 8.84 (1H, s, H-4).
General Method for Synthesizing 7-Acyloxy-3-(2-pyridyl)coumarins 14-16. A solution of 7-hydroxy-3-(2-
pyridyl)coumarin (5 mmol) in pyridine (7 mL) was treated with acid chloride (or anhydride) (10 mmol) and heated at ~80°C
for 10-15 min. The reaction mixture was left for 1 d at room temperature and poured onto ice. The 7-acyloxycoumarin was
filtered off.
Crystallization: DMF.
7
-Acetyloxy-3-(2-pyridyl)coumarin (14). Yield 86%, C H NO , mp 172-173°C (177-178°C [2]).
16 11 4
-1
IR spectrum (KBr, cm ): 1764, 1725, 1606, 1581, 1467, 1366, 1190, 1121.
UV spectrum (EtOH, λmax, nm, log ε): 336 (4.294), 207 (4.461).
3
4
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.34 (3H, s, CH COO-7), 7.12 (1H, dd, J = 8, J = 2, H-6), 7.23
6
3
4
3
3
3
3
(
1H, d, J = 2, H-8), 7.36 (1H, br.t, J = 4.5, H-5′), 7.83 (1H, br.t, J = 8, H-4′), 7.89 (1H, d, J = 8, H-5), 8.28 (1H, d, J = 8,
H-3′), 8.64 (1H, br.d, J = 4.5, H-6′), 8.86 (1H, s, H-4).
3
7
-Benzyloxy-3-(2-pyridyl)coumarin (15). Yield 85%, C H NO , mp 168°C.
21 13 4
-1
IR spectrum (KBr, cm ): 1721, 1614, 1577, 1464, 1435, 1273, 1243, 1152, 1128.
UV spectrum (EtOH, λmax, nm, log ε): 336 (4.352), 234 (4.356).
3
4
4
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 7.29 (1H, dd, J = 8.5, J = 2, H-6), 7.41 (1H, d, J = 2, H-8),
6
3
3
3
3
7
7
.38 (1H, br.t, J = 4.5, H-5′), 7.60 [2H, t, J = 8, H-3″, H-5″ (Ph)], 7.73 [1H, t, J = 8, H-4″ (Ph)], 7.86 (1H, br.t, J = 8, H-4′),
.99 (1H, d, J = 8.5, H-5), 8.17 [2H, d, J = 8, H-2″, H-6″ (Ph)], 8.31 (1H, d, J = 8, H-3′), 8.68 (1H, br.d, J = 4.5, H-6′), 8.92
3
3
3
3
(1H, s, H-4).
7
-(2-Furylcarboxy)-3-(2-pyridyl)coumarin (16). Yield 96%, C H NO , mp 182-183°C.
19
11
5
-1
IR spectrum (KBr, cm ): 1736, 1616, 1578, 1562, 1464, 1296, 1242, 1180, 1132, 1085.
UV spectrum (EtOH, λmax, nm, log ε): 336 (4.320), 259 (4.167), 212 (4.367).
3
4
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 6.76 [1H, dd, J = 4, J = 1.5, H-4″ (furyl)], 7.28 (1H, dd,
6
3
3
4
3
4
3
J = 8.5, J = 2, H-6), 7.38 (1H, br.t, J = 4.5, H-5′), 7.40 (1H, d, J = 2, H-8), 7.54 [1H, d, J = 4, H-5″ (furyl], 7.86 (1H, br.t,
J = 8, H-4′), 7.98 (1H, d, J = 8.5, H-5), 8.04 [1H, d, J = 1.5, H-3″ (furyl)], 8.31 (1H, d, J = 8, H-3′), 8.67 (1H, br.d, J = 4.5,
3
4
3
3
H-6′), 8.91 (1H, s, H-4).
General Method for Synthesizing 8-Aminomethyl-7-hydroxy-3-(2-pyridyl)coumarins 17-19. 7-Hydroxy-3-(2-
pyridyl)coumarin (5 mmol) and formaldehyde aminal (6 mmol) were boiled in absolute dioxane (25 mL) for 12 h. The resulting
solution was evaporated to dryness in a rotary evaporator. The solid was crystallized from hexane:toluene.
7
-Hydroxy-8-(piperidinomethyl)-3-(2-pyridyl)coumarin (17). Yield 66%, C H N O , mp 165-165.5°C.
20 20 2 3
-1
IR spectrum (KBr, cm ): 1720, 1614, 1565, 1506, 1463, 1306, 1230, 1132, 1063.
UV spectrum (EtOH, λmax, nm, log ε): 365 (4.301), 265 (4.201).
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.69 [6H, m, CH -3″, CH -4″, CH -5″ (piperidyl)], 2.26 [2H, m,
6
2
2
2
3
CH -2″ (piperidyl)], 3.04 [2H, m, CH -6″ (piperidyl)], 4.07 (2H, s, CH -8), 6.77 (1H, d, J = 8.5, H-6), 7.24 (1H, br.t,
2
2
2
3
3
3
3
3
J = 5, H-5′), 7.42 (1H, d, J = 8.5, H-5), 7.76 (1H, br.t, J = 8, H-4′), 8.38 (1H, d, J = 8, H-3′), 8.65 (1H, br.d, J = 5, H-6′),
.69 (1H, s, H-4), 9.91 (1H, br.s, OH-7).
-Hydroxy-8-(azepanomethyl)-3-(2-pyridyl)coumarin (18). Yield 72%, C H N O , mp 105-106°C.
8
7
21 22 2 3
-1
IR spectrum (KBr, cm ): 1719, 1604, 1580, 1478, 1462.
UV spectrum (EtOH, λmax, nm, log ε): 400 (4.393), 266 (4.0), 212 (4.602).
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.67 [4H, m, CH -4″, CH -5″ (azepinyl)], 1.74 [4H, m, CH -3″,
6
2
2
2
3
CH -6″ (azepinyl)], 2.84 [4H, m, CH -2″, CH -7″ (azepinyl)], 4.18 (2H, s, CH -8), 6.77 (1H, d, J = 8.5, H-6), 7.23 (1H, br.t,
2
2
2
2
3
3
3
3
3
J = 5, H-5′), 7.43 (1H, d, J = 8.5, H-5), 7.76 (1H, br.t, J = 8, H-4′), 8.36 (1H, d, J = 8, H-3′), 8.64 (1H, br.d, J = 5, H-6′),
.68 (1H, s, H-4), 11.83 (1H, br.s, OH-7).
8
527

7
-Hydroxy-8-(morpholinomethyl)-3-(2-pyridyl)coumarin (19). Yield 71%, C H N O , mp 181-182°C.
19 18 2 4
-1
IR spectrum (KBr, cm ): 1717, 1604, 1581, 1463, 1267, 1114.
UV spectrum (EtOH, λmax, nm, log ε): 359 (4.344), 252 (3.949).
PMR spectrum (400MHz, DMSO-d , δ, ppm, J/Hz): 2.69 [4H, m, CH -3″, CH -5″ (morpholyl)], 3.80 [4H, m, CH -2″,
6
2
2
2
3
3
3
CH -6″ (morpholyl)], 4.12 (2H, s, CH -8), 6.81 (1H, d, J = 8.5, H-6), 7.24 (1H, br.t, J = 4.5, H-5′), 7.47 (1H, d, J = 8.5, H-5),
.78 (1H, br.t, J = 8, H-4′), 8.37 (1H, d, J = 8, H-3′), 8.65 (1H, br.d, J = 4.5, H-6′), 8.70 (1H, s, H-4).
2
2
3
3
3
7
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