Regio and diastereoselective synthesis of functionalized 2,3-dihydrofuro[3,2-c]coumarins via a one-pot three-component reaction

Article abstract of DOI:10.1016/j.tet.2010.10.023

An efficient and straightforward synthesis of furo[3,2-c]coumarins via the one-pot three-component condensation of aromatic aldehydes, 4-hydroxycoumarin and α-chloroketones in refluxing n-propanol is described. Pyridine or a mixture of AcOH and AcONH₄ was used as a basic catalyst.

Full text of DOI:10.1016/j.tet.2010.10.023

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Tetrahedron 66 (2010) 9493e9496
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regio and diastereoselective synthesis of functionalized 2,3-dihydrofuro[3,2-c]-
coumarins via a one-pot three-component reaction
*
Elisa Altieri, Massimiliano Cordaro, Giovanni Grassi, Francesco Risitano , Angela Scala
ꢀ
Dipartimento di Chimica Organica e Biologica, Universita degli Studi di Messina, Vill. S. Agata, I-98166 Messina, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2010
Received in revised form 23 September 2010
Accepted 11 October 2010
Available online 15 October 2010
An efficient and straightforward synthesis of furo[3,2-c]coumarins via the one-pot three-component
condensation of aromatic aldehydes, 4-hydroxycoumarin and
described. Pyridine or a mixture of AcOH and AcONH4 was used as a basic catalyst.
Ó 2010 Elsevier Ltd. All rights reserved.
a-chloroketones in refluxing n-propanol is
Keywords:
Multicomponent reaction
Cyclization
Diastereoselectivity
4-Hydroxycoumarin
1. Introduction
In contrast, when the reaction was performed in refluxing n-
PrOH, the addition of 1 to arylaldehydes 2aei and 3 afforded
dihydrofurocoumarins 10aei (Scheme 1, path ii) with complete
regio and diastereoselectivity in fair to good yields (47e80%)
(Table 1, method A).10
The exclusive formation of the unexpected derivatives 10
prompted our interest in developing a general route to access this
valuable class of compounds.
First, it was noted that AcOH/AcONH4 mixture acted only as
a basic catalyst, unlike in our previous studies.4 Therefore, our at-
tention turned towards other catalysts to allow for a more efficient
and selective reaction.
Multicomponent reactions (MCRs)1 involving domino processes
are increasingly emerging as a good way of rapidly and efficiently
generating complex molecules with potential biological proper-
ties.2 Our interest in these reactions to synthesize spiro or fused
five- and six-membered bicyclic rings is well documented.3 Re-
cently,4 we have successfully introduced the use of phenacyl
chloride in new MCRs employing aromatic aldehydes as electro-
philes and azol-5-ones as pronucleophiles with AcOH/AcONH4
performing the dual function of catalyst and nitrogen atom
provider.
Herein, we report the extension of this methodology, using
4-hydroxycoumarin
Using pyridine instead of the AcOH/AcONH4 mixture this three-
component condensation satisfactorily proceeded with a signifi-
cant increase in the yield. Thus, 4-hydroxycoumarin 1 was tested
1 as a
methylene active compound.5 4-
Hydroxycoumarin is a recurring structural motif in many natural
products of interest in medicinal chemistry.6
with a large variety of aldehydes 2aek and a-chloroketones 3, 4
and 5 (Scheme 1, path iii). The results are summarized in Table 1
2. Results and discussion
(Method B).11
The structures of new compounds 10e12 were assigned on the
basis of comprehensive spectroscopic analyses and, in the case of
10aed, confirmed by comparison with authentic samples.12
The proposed mechanism for this one-pot three-component
tandem Knoevenagel cyclocondensation reaction is summarized in
Scheme 2. The initial regiospecific formation of the non-isolated
arylidene derivative 13 is followed by its irreversible capture by
the in situ-generated dipole 14 to give 15. This Michael adduct, in
contrast with our earlier report,8 irreversibly evolves to fused de-
rivatives 10e12 bya regio- and stereocontrolled intramolecular five-
membered ring O-cyclization. The expected trans-stereochemistry
Initially, we performed a preliminary experiment using our
previously reported procedure.4 In refluxing EtOH (Scheme 1, path
i), the addition of 1 to benzaldehyde 2a and phenacyl chloride 3
(1:2:1) in the presence of an excess of AcOH/AcONH4 did not yield
the expected spiro compound 6, but gave instead an already known
and synthetically uninteresting mixture of products including
furocoumarin 7,3a fused aziridine 87 and bisderivative 9.8
* Corresponding author. Fax: þ39 090 393897; e-mail address: frisitano@
unime.it (F. Risitano).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.023

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E. Altieri et al. / Tetrahedron 66 (2010) 9493e9496
Ph
O
O
N
OH
O
Ph
Ph
(ii)
10a-i
RCHO
2
O
6
O
O
O
R1
(i)
1
O
+
R
Ph
Ph
OH
O
R1COCH2Cl
(iii)
O
Ph
H
N
N
10; R1=Ph
11; R1=Me
+
+
2
3; R1=Ph
O
O
O
O
Ph
Ph
4; R1=Me
5; R1=OCH2CH3
9
7
129; R1=O(CH2)2CH3
8
ꢁ
ꢁ
Scheme 1. Reagents and conditions: (i) 2a and 3 in AcOH/AcONH4, EtOH, 4 A molecular sieves, reflux, 2 h; (ii) 2aei and 3 in AcOH/AcONH4, n-PrOH, 4 A molecular sieves, reflux, 3 h;
ꢁ
(iii) 2aek and 3e5 in Pyridine, n-PrOH, 4 A molecular sieves, reflux, 2e6 h.
Table 1
R1
Synthesis of 2,3-dihydrofuro[3,2-c]coumarins
O
16; R1=Ph 37%
17; R1=Me 40%
18; R1=OEt 30%
O
R
10
11
12
(iv)
1
+ 2a + 3-5
(R1¼Ph) yielda
Method Ab Method Bc Method Bc
%
(R1¼Me) yielda
%
(R1¼OC3H7) yielda
Method Bc
%
O
O
ꢁ
Scheme 3. Reaction conditions: (iv) DBU, n-PrOH, 4 A molecular sieves, reflux, 3 h.
a
b
c
d
e
f
g
h
i
C6H5
4-MeC6H4 78
4-MeOC6H4 77
80
95
98
96
95
95
96
96
94
93
67
64
85
85
80
85
These structures were assigned on the basis of analytical and
spectroscopic data and were confirmed by a gHMBCAD experiment
on 16. Surprisingly, these O-alkyl derivatives remain practically
unaltered either in the presence of an aromatic aldehyde or under
the influence of an acid or a base.
4-ClC6H4
74
3-MeC6H4 51
3-MeOC6H4 47
2-MeC6H4 69
2-MeOC6H4 71
2-ClC6H4
C6H5CH2
CH3CH2
75
70
70
65
66
j
k
3. Conclusions
a
b
c
Yield of pure isolated product.
In summary, we have successfully prepared a series of func-
tionalized angularly-fused dihydrofurocoumarins by an efficient
multicomponent domino process. This protocol offers several ad-
vantages including high diastereoselectivity, high product yields
and simple work up procedures. Further examples of the applica-
bility of our synthetic procedures towards cyclic 1,3-dicarbonyl
compounds will be reported in future publications.
ꢁ
AcOH/AcONH4, n-PrOH, 4 A molecular sieves, reflux, 3 h.
ꢁ
Pyridine, n-PrOH, 4 A molecular sieves, reflux, 2e6 h.
of the reaction final step was proved from NOE NMR studies (no
interactions between H2 and H3) and by analysis of vicinal coupling
constants of the two-methine hydrogens. Our results demonstrate
that the reaction conditions are critical for the successful and ex-
clusive formation of dihydrofurocoumarin derivatives in a diaster-
eoselective fashion. Indeed, using method B all the electrophilic
halides 3e5 are converted toylide 14 removing possible competitive
reactions.
4. Experimental section
4.1. General method
Melting points were determined on a Kofler melting apparatus.
IR spectra were recorded in Nujol with a Nicolet Impact 410D
spectrometer. 1H and 13C NMR spectra were obtained on a Bruker
+
2
3-5
Py
1
AMX R300. The chemical shifts (d) and coupling constants (J) are
expressed in parts per million and hertz, respectively. Microanalyses
were carried out on a Carlo Erba EA 1102. Merck Kieselgel 60F254
plates were used for TLC. All solvents and reagents were obtained
from commercial sources and purified before use if necessary.
O
R1
R
O
O
O
N
+
4.2. General procedure for the synthesis of compounds
10, 11, 12
13
14
R1
O
Method A: To a stirred solution of 4-hydroxycoumarin 1 (0.5 g,
3.1 mmol) in n-PrOH (20 mL) containing 4 A molecular sieves and
N
O
ꢁ
10-12
-Py
R
a mixture of AcOH (10 mL) and AcONH4 (1.55 g, 20 mmol) aldehyde 2
(6.2 mmol) and phenacyl chloride 3 (0.48 g, 3.1 mmol) were added.
The mixture was heated at reflux for 3 h. After cooling, the reaction
mixture was filtered to remove molecular sieves and evaporated.
The resulting residue was washed with cool H2O (20 mL) and the
aqueous suspension was then extracted with CHCl3 (3ꢀ30 mL). The
combined organic layers were washed with H2O (20 mL), dried over
anhydrous Na2SO4, filtered and evaporated under reduced pressure.
The residue was crystallized from Et2O/acetone (9:1). Further re-
crystallization from MeOH led to 10aei as white solids.
O
O
15
Scheme 2. Proposed mechanism of 2,3-dihydrofuro[3,2-c]coumarin formation.
For example, with DBU the reaction of 1, 2a and a-chloroketones
3, 4 or 5 stopped (Scheme 3, path iv) at the exclusive formation of
the O-alkyl derivatives 16, 17 or 18, respectively.

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E. Altieri et al. / Tetrahedron 66 (2010) 9493e9496
9495
Method B: As Method A, but using pyridine (0.47 g, 6 mml) in-
stead of AcOH/AcONH4 mixture, derivatives 10aek were isolated.
The use of 4 (0.28 g, 3.1 mmol) or 5 (0.38 g, 3.1 mmol) in place of 3
provided 11 or 12 as white solids.
CHaHbMe, J 13.8, 7.4, 3.8 Hz); 3.83 (1H, ddd, CH, J 6.8, 4.8, 3.8 Hz);
5.92 (1H, d, CH, J 4.8 Hz); 7.28e8.02 (9H, m, CHarom.). 13C NMR
(75 MHz, CDCl3):
d 10.1; 24.8; 44.5; 104.3; 112.1; 116.8; 116.9;
122.8; 122.9; 124.0; 124.1; 128.8; 128.9; 132.5; 133.7; 134.1; 155.0;
159.9; 166.1; 193.3. Anal. Calcd for C20H16O4: C, 74.99; H, 5.03.
Found: C, 75.00; H, 5.05.
4.2.1. Compound 10a. Mp 192e194 ꢁC. (lit.10 193 ꢁC).
4.2.2. Compound 10b. Mp 194e196 ꢁC. (lit.10 192 ꢁC).
4.2.3. Compound 10c. Mp 177e179 ꢁC. (lit.10 180 ꢁC).
4.2.4. Compound 10d. Mp 168e170 ꢁC. (lit.10 170e172 ꢁC).
4.2.12. Compound 11a. Mp 127e128 ꢁC. IR (Nujol): 1734,
1692 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
2.37 (1H, s, COMe); 4.76
(1H, d, CH, J 5.2 Hz); 5.23 (1H, d, CH, J 5.2 Hz); 7.26e7.85 (9H, m,
CHarom.). 13C NMR (75 MHz, CDCl3):
26.1; 48.7; 95.6; 104.8; 111.8;
d
117.0; 122.8; 124.1; 127.1; 127.2; 127.8; 129.0; 129.1; 132.9; 139.5;
155.2; 159.0; 165.8; 203.3. Anal. Calcd for C19H14O4: C, 74.50; H,
4.61. Found: C, 74.52; H, 4.62.
4.2.5. Compound 10e. Mp 153e155 ꢁC. IR (Nujol): 1718, 1689 cmꢂ1
1H NMR (300 MHz, CDCl3):
2.33 (3H, s, Me); 4.74 (1H, d, CH,
J 4.9 Hz); 6.15 (1H, d, CH, J 4.9 Hz); 7.07e7.91 (13H, m, CHarom.). 13
NMR (75 MHz, CDCl3): 21.4; 49.2; 92.6; 105.3; 112.1; 116.8; 116.9;
.
d
C
4.2.13. Compound 11b. Mp 113e115 ꢁC. IR (Nujol): 1735, 1695 cmꢂ1
1H NMR (300 MHz, CDCl3):
2.29 (3H, s, COMe); 2.32 (3H, s, Me);
4.69 (1H, d, CH, J 5.2 Hz); 5.20 (1H, d, CH, J 5.2 Hz); 7.03e7.82 (8H,
m, CHarom.). 13C NMR (75 MHz, CDCl3):
20.9; 26.0; 48.4; 95.6;
.
d
d
123.1; 124.0; 124.6; 128.0; 128.1; 128.8; 128.9; 129.0; 129.1; 132.8;
133.0; 134.3; 138.9; 139.4; 155.3; 159.2; 166.2; 192.0. Anal. Calcd
for C25H18O4: C, 78.52; H, 4.74. Found: C, 78.50; H, 4.55.
d
104.8; 111.8; 116.9; 122.7; 124.0; 126.9; 127.0; 129.6; 129.7; 132.8;
136.5; 137.4; 155.1; 158.9; 165.7; 203.3. Anal. Calcd for C20H16O4: C,
74.99; H 5.03. Found: C, 75.01; H, 5.06.
4.2.6. Compound 10f. Mp 151e152 ꢁC. IR (Nujol): 1718, 1686 cmꢂ1
1H NMR (300 MHz, CDCl3):
3.80 (3H, s, Me); 4.77 (1H, d, CH,
J 4.9 Hz); 6.17 (1H, d, CH, J 4.9 Hz); 6.82e7.93 (13H, m, CHarom.).
13C NMR (75 MHz, CDCl3):
49.2; 55.2; 92.4; 105.0; 112.0; 113.2;
.
d
4.2.14. Compound 11e. Mp 104e106 ꢁC. IR (Nujol): 1733,1700 cmꢂ1
1H NMR (300 MHz, CDCl3):
2.29 (3H, s, COMe); 2.32 (3H, s, Me);
4.69 (1H, d, CH, J 5.2 Hz); 5.20 (1H, d, CH, J 5.2 Hz); 7.03e7.82 (8H,
m, CHarom.). 13C NMR (75 MHz, CDCl3):
21.1; 25.9; 48.4; 95.4;
.
d
d
113.4; 116.8; 116.9; 119.7; 123.1; 140.1; 128.9; 129.0; 129.1;
130.2; 132.8; 133.0; 134.3; 141.0; 155.3; 159.2; 160.1; 166.3;
192.0. Anal. Calcd for C25H18O5: C, 75.37; H, 4.55. Found: C, 75.45;
H, 4.45.
d
104.6; 111.6; 116.7; 122.6; 123.9; 127.6; 128.4; 128.5; 128.7; 132.7;
138.5; 139.4; 154.9; 158.8; 165.6; 203.4. Anal. Calcd for C20H16O4: C,
74.99; H, 5.03. Found: C, 74.98; H, 5.05.
4.2.7. Compound 10g. Mp 201e202 ꢁC. IR (Nujol): 1724, 1704 cmꢂ1
1H NMR (300 MHz, CDCl3):
2.31 (3H, s, Me); 5.10 (1H, d, CH,
J 5.0 Hz); 6.18 (1H, d, CH, J 5.0 Hz); 7.18e7.90 (13H, m, CHarom.). 13
NMR (75 MHz, CDCl3): 19.6; 44.7; 93.0; 93.2; 106.2; 112.1; 116.8;
.
d
4.2.15. Compound 11g. Mp 157e159 ꢁC. IR (Nujol): 1734,1699 cmꢂ1
1H NMR (300 MHz, CDCl3):
2.36 (3H, s, COMe); 2.54 (3H, s, Me);
5.02 (1H, d, CH, J 4.6 Hz); 5.20 (1H, d, CH, J 4.6 Hz); 7.01e7.85 (8H, m,
CHarom.). 13C NMR (75 MHz, CDCl3):
19.7; 26.1; 44.4; 95.9; 105.9;
.
C
d
d
116.9; 122.9; 123.0; 123.9; 126.8; 126.9; 127.8; 129.0; 130.7; 132.6;
133.2; 134.3; 136.2; 138.2; 155.2; 159.2; 165.8; 192.0. Anal. Calcd
for C25H18O4: C, 78.52; H, 4.74. Found: C, 78.30; H, 4.70.
d
111.9; 117.0; 122.6; 124.1; 126.4; 126.7; 127.5; 130.8; 132.8; 136.0;
137.9; 155.1; 158.8; 165.4; 203.2. Anal. Calcd for C20H16O4: C, 74.99;
H, 5.03. Found: C, 75.02; H, 5.05.
4.2.8. Compound 10h. Mp 150e152 ꢁC. IR (Nujol): 1716, 1690 cmꢂ1
1H NMR (300 MHz, CDCl3):
4.10 (3H, s, Me); 4.81 (1H, d, CH,
J 5.0 Hz); 6.11 (1H, d, CH, J 5.0 Hz); 7.12e7.94 (13H, m, CHarom.). 13
NMR (75 MHz, CDCl3): 44.0; 55.0; 90.7; 90.9; 103.6; 110.8; 112.2;
.
d
4.2.16. Compound 12a. Mp 101e102 ꢁC. IR (Nujol): 1729, 1717 cmꢂ1
1H NMR (300 MHz, CDCl3):
1.34 (3H, t, CH2Me, J 7.0 Hz); 1.70e1.73
.
C
d
d
(2H, m, CH2Me); 4.25e4.27 (2H, m, OCH2); 4.78 (d, CH, J 5.0 Hz);
116.9; 120.8; 120.9; 122.8; 123.0; 123.8; 128.0; 128.6; 128.7; 128.9;
132.5; 134.0; 136.0; 138.0; 155.2; 156.8; 165.0; 192.0. Anal. Calcd
for C25H18O5: C, 75.37; H, 4.55. Found: C, 75.35; H, 4.75.
5.28 (d, CH, J 5.0 Hz); 7.28e7.85 (9H, m, CHarom.). 13C NMR (75 MHz,
CDCl3):
d 13.9; 21.6; 50.2; 62.1; 88.9; 104.4; 111.8; 116.8; 123.0;
124.0; 126.8; 126.9; 127.8; 128.8; 128.9; 132.8; 139.3; 155.1; 159.1;
166.4; 168.5. Anal. Calcd for C21H18O5: C, 71.99; H, 5.18. Found: C,
71.98; H, 5.20.
4.2.9. Compound 10i. Mp 170e173 ꢁC. IR (Nujol): 1726, 1702 cmꢂ1
1H NMR (300 MHz, CDCl3):
5.47 (1H, d, CH, J 5.0 Hz); 6.15 (1H, d,
CH, J 5.0 Hz); 7.23e7.98 (13H, m, CHarom.). 13C NMR (75 MHz, CDCl3):
45.6; 90.9; 104.1; 112.0; 117.0; 123.0; 124.1; 125.1; 127.6; 128.5;
.
d
4.2.17. Compound 12b. Mp 132e133 ꢁC. IR (Nujol): 1730,1718 cmꢂ1
1H NMR (300 MHz, CDCl3):
1.31 (3H, t, CH2Me, J 7.2 Hz); 1.80e1.84
.
d
d
128.6; 128.9; 129.1; 129.3; 130.2; 131.3; 133.0; 133.5; 134.3; 136.7;
155.3; 159.2; 166.7; 191.3. Anal. Calcd for C24H15ClO4: C, 71.56; H,
3.75; Cl, 8.80. Found: C, 71.60; H, 3.70; Cl, 8.82.
(2H, m, CH2Me); 2.33 (3H, s, Me); 4.33e4.37 (2H, m, OCH2); 4.74
(1H, d, CH, J 5.0 Hz); 5.25 (1H, d, CH, J 5.0 Hz); 7.17e7.85 (8H, m,
CHarom.). 13C NMR (75 MHz, CDCl3):
d 14.1; 21.0; 21.2; 50.1; 62.2;
89.2; 104.7; 12.0; 116.9; 123.1; 124.1; 126.8; 126.9; 129.7; 129.8;
132.8; 136.5; 137.7; 155.2; 159.2; 166.4; 168.7. Anal. Calcd for
C22H20O5: C, 72.51; H, 5.53. Found: C, 72.52; H, 5.55.
4.2.10. Compound 10j. Mp 182e184 ꢁC. IR (Nujol): 1720, 1689 cmꢂ1
1H NMR (300 MHz, CDCl3):
2.84 (1H, dd, CHaHbPh, J 13.9, 10.3 Hz);
3.55 (1H, dd, CHaHbPh, J 13.9, 3.8 Hz); 3.90 (1H, ddd, CH, J 13.9, 3.8,
3.4 Hz); 6.02 (1H, d, CH, J 3.4 Hz); 7.21e7.77 (14H, m, CHarom.). 13
NMR (75 MHz, CDCl3): 38.1; 45.8; 87.4; 87.6; 104.6; 112.1; 116.8;
.
d
C
4.2.18. Compound 12e. Mp 100e101 ꢁC. IR (Nujol): 1755,
d
1719 cmꢂ1 1H NMR (300 MHz, CDCl3):
. d 1.35 (3H, t, CH2Me, J
122.9; 124.0; 127.0; 128.4; 128.6; 128.9; 129.0; 129.5; 129.6; 132.6;
132.7; 133.7; 137.4; 155.0; 158.9; 159.9; 166.7; 192.6. Anal. Calcd for
C25H18O4: C, 78.52; H, 4.74. Found: C 78.55; H 4.70.
7.1 Hz); 1.75e1.79 (2H, m, CH2Me); 2.33 (3H, s, Me); 4.32e4.36
(2H, m, OCH2); 4.73 (1H, d, CH, J 4.6 Hz); 5.27 (1H, d, CH, J 4.6 Hz);
7.07e7.85 (8H, m, CHarom.). 13C NMR (75 MHz, CDCl3):
d 14.1; 21.4;
21.6; 50.3; 62.2; 89.2; 104.7; 112.0; 117.0; 123.1; 124.1; 124.2;
127.7; 128.8; 129.0; 132.9; 138.8; 139.4; 155.3; 159.2; 166.4; 168.7.
Anal. Calcd for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.53; H,
5.56.
4.2.11. Compound 10k. Mp 124e126 ꢁC. IR (Nujol): 1718,
1704 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
1.02 (3H, t, Me, J 7.4 Hz);
1.96 (1H, sex, CHaHbMe, J 13.8, 7.4, 3.8 Hz); 2.06 (1H, sex,

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E. Altieri et al. / Tetrahedron 66 (2010) 9493e9496
4.2.19. Compound 12g. Mp 137e138 ꢁC. IR (Nujol): 1752,
Supplementary data
1720 cmꢂ1 1H NMR (300 MHz, CDCl3):
. d 1.32 (3H, t, CH2Me,
J 7.0 Hz); 1.72e1.76 (2H, m, CH2Me); 2.23 (3H, s, Me); 4.20e4.24
(2H, m, OCH2); 5.00 (1H, d, CH, J 4.4 Hz); 5.23 (1H, d, CH, J 4.4 Hz);
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.10.023.
6.99e7.85 (8H, m, CHarom.). 13C NMR (75 MHz, CDCl3):
d 14.1; 19.7;
21.2; 46.2; 62.2; 89.2; 104.8; 114.0; 117.0; 123.0; 124.1; 126.2;
126.8; 127.8; 130.9; 132.8; 138.8; 139.4; 155.3; 159.2; 166.4; 168.7.
Anal. Calcd for C22H20O5: C, 72.51; H, 5.53. Found: C, 72.52; H, 5.54.
References and notes
1. For reviewes, see: (a) Ho, T. L. Tandem Organic Reactions; Wiley: New York, NY,
1992; (b) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137e166; (c)
Tietze, L. F. Chem. Rev. 1996, 96, 115e136; (d) Domling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168e3210; (e) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem.dEur. J. 2000, 6, 3321e3329.
€
4.3. General procedure for the synthesis of compounds
16, 17, 18
ꢀ
ꢀ
2. (a) Rieger, D.; Lotz, S. D.; Kernbach, U.; Andre, C.; Bertran-Nadal, J.; Fehlammer,
To a stirred solution of 4-hydroxycoumarin 1 (0.5 g, 3.1 mmol) in
n-PrOH (20 mL), containing 4 A molecular sieves and an excess of
DBU (0.56 g, 3.7 mmol), benzaldehyde 2a (0.66 g, 6.2 mmol) and a-
W. P. J. Organomet. Chem. 1995, 491, 135e152; (b) Armstrong, R. W.; Combs, A.
P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123e131;
(c) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449e472; (d)
Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366e374.
ꢁ
chloroketones 3, 4 or 5 (3.1 mmol) were added. The resulting
mixture was heated at reflux for 3 h. After cooling, the reaction
products 16, 17 and 18, respectively, were collected for filtration.
Recrystallization from MeOH led to colourless needles. Benzalde-
hyde 2a was recovered unaltered.
3. (a) Risitano, F.; Grassi, G.; Foti, F. J. Heterocycl. Chem. 2001, 38, 1083e1089; (b)
Risitano, F.; Grassi, G.; Foti, F.; Biliardo, C. Tetrahedron Lett. 2001, 42,
3503e3505; (c) Risitano, F.; Grassi, G.; Foti, F.; Nicolo, F.; Condello, M. Tetra-
ꢀ
hedron 2002, 58, 191e195; (d) Risitano, F.; Grassi, G.; Foti, F.; Romeo, R. Synthesis
ꢀ
2002, 116e120; (e) Grassi, G.; Risitano, F.; Foti, F.; Cordaro, M.; Bruno, G.; Nicolo,
F. Chem. Commun. 2003, 1868e1869.
4. Altieri, E.; Cordaro, M.; Grassi, G.; Risitano, F.; Scala, A. Synlett 2010, 14,
2106e2108.
4.3.1. Compound 16. Mp 190e192 ꢁC. IR (Nujol): 1701, 1713 cmꢂ1
1H NMR (300 MHz, CDCl3):
5.48 (2H, s, OCH2), 5.59 (1H, s, CH),
7.26e7.99 (9H, m, CHarom.). 13C NMR (75 MHz, CDCl3):
70.4; 91.3;
115.0; 116.7; 123.8; 124.0; 127.8; 127.9; 129.0; 129.1; 132.6; 134.0;
134.4; 153.3; 162.4; 164.9; 184.4. Anal. Calcd for C17H12O4: C, 72.85;
H, 4.32. Found: C, 72.75; H, 4.30.
.
5. Risitano F. Grassi G. Cordaro M. Liotta C. Moraci S. Abstracts of Papers, 3rd In-
ternational Conference on Multi-Component Reactions and Related Chemistry;
RSC-Advancing the Chemical Sciences: Amsterdam, The Netherlands, July
9e13, 2006.
d
d
6. (a) Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins, Occurrence,
Chemistry, and Biochemistry; Wiley: New York, NY, 1982; 13; (b) Gunatilaka, A.
A. L.; Kingston, D. G. I.; Wijeratne, E. M. K.; Bandara, B. M. R.; Hofmann, G. A.;
Johnson, R. K. J. Nat. Prod. 1994, 57, 518e520; (c) O’Kennedy, R.; Thornes, R. D.
Coumarins: Biology, Applications and Mode of Action; Wiley: Chichester, 1997;
(d) Takeuchi, Y.; Xie, L.; Cosentino, L. M.; Lee, K. H. Bioorg. Med. Chem. Lett. 1997,
7, 2573e2578; (e) Zhao, H.; Neamati, N.; Hong, H.; Mazumder, A.; Wang, S.;
Sunder, S.; Milne, G. W. A.; Pommier, Y.; Burke, T. R., Jr. J. Med. Chem. 1997, 40,
242e449; (f) Magiatis, P.; Melliou, E.; Skaltsounis, A.; Mitaku, S.; Leonce, S.;
Renard, P.; Pierre, A.; Alassi, G. J. Nat. Prod. 1998, 61, 982e986; (g) Asomaning,
W. A.; Otoo, E.; Akoto, O.; Oppong, I. V.; Addae-Mensah, I.; Waibel, R.; Achen-
bach, H. Phytochemistry 1999, 51, 937e941.
4.3.2. Compound 17. Mp 173e175 ꢁC. IR (Nujol): 1699, 1710 cmꢂ1
1H NMR (300 MHz, CDCl3):
2.36 (3H, s, COMe), 4.75 (2H, s, OCH2),
5.55 (1H, s, CH), 7.29e7.93 (4H, m, CHarom.). 13C NMR (75 MHz,
CDCl3): 26.5; 72.5; 91.2; 115.0; 116.7; 123.0; 124.0; 132.7; 153.2;
.
d
d
162.2; 164.4; 200.8. Anal. Calcd for C12H10O4: C, 66.05; H, 4.62.
Found: C, 66.25; H, 4.49.
7. (a) Risitano, F.; Grassi, G.; Foti, F.; Moraci, S. Synlett 2005, 1633e1635; (b) Bruno,
G.; Rotondo, A.; Nicolo, F.; Risitano, F.; Grassi, G.; Foti, F. Helv. Chim. Acta 2006,
89, 190e200.
ꢀ
4.3.3. Compound 18. Mp 86e88 ꢁC. IR (Nujol): 1712, 1745 cmꢂ1. 1H
ꢀ
8. Risitano, F.; Grassi, G.; Bruno, G.; Nicolo, F. Liebigs Ann. 1997, 441e445.
NMR (300 MHz, CDCl3):
(2H, m, CH2Me, J 7.45, 6.85 Hz), 4.20 (2H, t, CH2CH2Me, J 6.85 Hz),
4.77 (2H, s, OCH2), 5.57 (1H, s, CH), 7.26e7.92 (4H, m, CHarom.). 13
NMR (75 MHz, CDCl3): 10.1; 21.7; 65.2; 67.4; 91.0; 115.1; 116.7;
d 0.95 (3H, t, CH2Me, J 7.45 Hz), 1.70e1.74
9. Performing the reaction with 5 (R1¼OCH2CH3) in n-PrOH, an unavoidable
transesterification led to exclusive formation of 12 (R1¼OCH2CH2CH3).
10. Under these conditions, no reaction occurred with aliphatic aldehydes 2j, k or
C
with aliphatic a-halogen ketones 4 and 5.
11. Our one-pot procedure is more convenient with respect to Ref.12 in terms of
yield and reaction time.
d
123.2; 123.9; 132.7; 153.2; 162.3; 164.6; 166.4. Anal. Calcd for
C14H14O5: C, 64.12; H, 5.38. Found: C, 64.10; H, 5.33.
12. Wang, Q. F.; Hou, H.; Hui, L.; Yan, C. C. J. Org. Chem. 2009, 74, 7403e7406.