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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
a r t i c l e
i n f o
a b s t r a c t
Article history:
Received 8 November 2011
Revised 9 December 2011
Accepted 12 December 2011
Available online 17 December 2011
A facile protocol for the stereoselective construction of trans-2,3-dihydrobenzofurans and cis-5,6-dihydrofuro[2,3-d]pyrimidines from the reactions of 2,20 -sulfonylbis(1,3-diarylprop-2-en-1-ones) with cyclic
1,3-diketones, viz. cyclohexane-1,3-diones, barbituric acid, and 2-thioxodihydropyrimidine-4,6(1H,5H)dione in the presence of DBU in ethanol is described. This transformation presumably occurs via domino
Michael addition-proton exchange-annulation via intramolecular displacement sequence.
2011 Elsevier Ltd. All rights reserved.
Keywords:
Domino reaction
trans-2,3-Dihydrobenzofurans
Stereoselectivity
2,20 -Sulfonylbis(1,3-diarylprop-2-en-1-ones)
Michael addition
Annulation
Dihydrobenzofurans belong to an important class of heterocycles, widely embedded in many biologically interesting natural
products,1,2 with important biological activities viz. ()-obtusafuran,3 ()-liliol-B,4 ()-kadsurinone,5 and ()-denudatin6 (Fig. 1).
(+)-Conocarpan (1), rst isolated from the wood of Conocarpus
erectus7 exhibits a diverse array of biological activities, including
insecticidal,8 antifungal,9 and antitrypanosomal properties.10 (+)Lithospermic acid,11 an intensively investigated therapeutic target
for the treatment of AIDS, is a potent and nontoxic anti-HIV agent
that inhibits HIV-1 integrase.12 The 2,3-dihydrobenzofurans act as
Me
Me
HO
O
MeO
HO
OMe
OMe
()-Liliflol-B
()-Obtusafuran
Me
MeO
()-Kadsurinone
O
MeO
Me
OMe
OMe
()-Denudatin
OH
(+)-Conocarpan
OH
OH
CO2H
CO2H O
HO
O
OH
(+)-Lithospermic acid
OH
963
Table 1
Synthesis of trans-2,3-dihydrobenzofurans 6 and 7 and cis-5,6-dihydrofuro[2,3d]pyrimidines 8 and 9
O
O
or
HN
NH
1, R = H
2, R = CH 3
Ar
O2
S
Ar'
3, X = O
4, X = S
S. No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
R
R
or
O
6, R = H
7, R =CH3
Ar
Ar
8, X = O
9, X = S
Ar0
Ar
C6H5
p-ClC6H4
p-ClC6H4
p-CH3C6H4
p-CH3C6H4
C6H5
C6H5
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-CH3C6H4
C6H5
C6H5
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-CH3C6H4
p-CH3C6H4
C6H5
C6H5
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-CH3C6H4
Yielda (%)
Product
C6H5
p-FC6H4
p-CH3C6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
C6H5
p-FC6H4
p-ClC6H4
p-CH3C6H4
p-ClC6H4
C6H5
p-ClC6H4
C6H5
p-FC6H4
p-ClC6H4
p-CH3C6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
C6H5
p-FC6H4
p-ClC6H4
p-CH3C6H4
p-ClC6H4
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
9g
Thermalb
MWc
60
63
69
62
71
62
68
65
68
62
60
66
65
52
56
52
66
67
61
56
52
58
53
54
66
62
52
72
65
72
70
74
69
76
70
75
68
67
70
67
60
62
58
73
75
66
62
58
62
64
61
68
68
63
Table 2
Temperature-optimization for the DBU-catalyzed formation of 7d under microwave
irradiation
S. No.
Temp. (C)
Yielda of 7d (%)
1
2
3
100
120
140
45
35
25
42
48
75
Ar
Table 3
Base-screen for the synthesis of trans-2,3-dihydrobenzofurans 7d
S. No.
1
2
3
4
5
Ar'
a
N
H
O
N
H
Ar'
HN
Ar
1
1
1
1
1
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
Ar'
1,3-Diketone
Ar'
HN
6, R = H
7, R =CH3
DBU
Ar'
Base
K2CO3
Et3N
t-BuOK
NaOEt
DBU
Reaction time
Yield (%)
a
MW (min)
Thermal (h)
MW
Thermala
25
25
25
25
25
7
6
8
4
5
36
38
39
68
75
32
35
35
63
68
Ar
8, X = O
9, X = S
964
Cl
2.16, d; 2.24, d
193.5
(J = 16.2 Hz)
51.0
Hb O
Ha
H
H3 C
5.82, d, J = 4.2 Hz
H
34.3
1.15, s, 6H
O
H3C
28.3, 28.9
91.4
O
Ha
Hb
O
H
H3 C 5
4H
3a
H3C 6
7a
H
7
4.37, d, J = 4.2 Hz
48.4 Cl
3 H
O
O 2
1
2.51, d; 2.62, d
(J = 17.7 Hz)
37.6
CH3
CH3
yield of the product, 69 (5875%) in a shorter time than the thermal method (5271%) under the conditions employed. It is pertinent to note that ve compounds belonging to series 6 and 7,
viz. 6a, 6d, 7a, 7b, and 7c obtained in the present work have been
previously reported and their yields in the present method [6a
(72%), 6d (70%), 7a (69%), 7b (76%), and 7c (70%)] are either comparable to or higher than that reported in the literature methods
R1
SO2
B:
O
Ar
1, R = H
2, R = CH3
Ar
O O
R
5
R
O
SO2R
ArOC
O-
COAr
O
Ar
annulation
R =
SO2R1
11'
11
H
H
10
OAr
O Ar
proton
exchange
O 2 S R1
Ar'
O Ar'
Michael
addition
-R1 -SO2
Ar'
O
O
Ar'
Ar'
O
O
R
R
R
O
6, R = H
7, R =CH3
Ar
O
6', R = H
7', R =CH3
Ar
965
H
N
H
SO2 R1
H
X
N
O- H O
H
N
B:
X
C Ar
Ar'
O
SO2R1
ArOC
H
O-
HN
O
3, X = O
4, X = S
O
HN
O
N
H
Ar'
Ar'
HN
X
Ar
X
O
Ar'
X
Ar
N
H
Ar
8, X = O
9, X = S
8', X = O
9', X = S
966
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
1995, 51, 1310313159; (e) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341
5378; (f) Bur, S. K.; Padwa, A. Adv. Heterocycl. Chem. 2007, 94, 1105; (g)
Pellissier, H. Tetrahedron 2006, 62, 16191665; (h) Pellis-sier, H. Tetrahedron
2006, 62, 21432173; (i) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem., Int. Ed. 2006, 45, 71347186; (j) Lieby-Muller, F.; Simon, C.;
Constantieux, T.; Rodriguez, J. QSAR Comb. Sci. 2006, 25, 432438.
(a) Prasanna, P.; Balamurugan, K.; Perumal, S.; Menndez, J. C. Green Chem.
2011, 13, 21232129; (b) Michael Rajesh, S.; Devi Bala, B.; Perumal, S.;
Menndez, J. C. Green Chem. 2011, 13, 32483254; (c) Indumathi, S.; Perumal,
S.; Menndez, J. C. J. Org. Chem. 2010, 75, 472475.
General procedure for the synthesis of 6-9: Conventional method: A mixture of
2,20 -sulfonylbis(1,3-diarylprop-2-en-1-ones) 5 (1 mmol), cyclic 1,3-diketones
14 (1 mmol) and DBU (0.5 mmol) in ethanol (20 mL) was heated under reux
at 80 C for 4 h. After completion of the reaction (TLC), the reaction mixture
was concentrated under vacuum and the residue subjected to ash column
chromatography using petroleum etherethyl acetate mixture [4:1 (v/v)] as
eluent to obtain pure 69. Microwave irradiation: A mixture of 2,20 sulfonylbis(1,3-diarylprop-2-en-1-ones) 5 (1 mmol), cyclic 1,3-diketones 14
(1 mmol) and DBU (0.5 mmol) in ethanol (5 ml) was taken in a 10 ml quartz
vial which was sealed and subjected to microwave irradiation in a Biotage
focused microwave oven at 140 C, 50 W, 5 bar pressure and maximum
absorption level. After about 4 min, the temperature reached 140 C, and
remained constant thereafter. After 25 min the vial was gas jet cooled to room
temperature (5 min), and the product after work-up was puried as done for
the thermal reaction. Spectroscopic data for a representative compound in
each series, 69 are given below.
trans-3-(4-Chlorophenyl)-2-(4-methylbenzoyl)-2,3,6,7-tetrahydrobenzofuran4(5H)-one (6e): Isolated as white solid. Yield: 74%; mp = 106109 C; IR (KBr):
1230, 1405 cm1 (CO), 1637, 1691 cm1 (C@O); 1H NMR (300 MHz, CDCl3) dH:
1.962.00 (m, 2H, H-6), 2.19 (t, 2H, J = 7.2 Hz, H-7), 2.29 (s, 3H, CH3), 2.57 (t,
2H, J = 5.7 Hz, H-5), 4.29 (d, 1H, J = 4.8 Hz, H-3), 5.69 (d, 1H, J = 4.8 Hz, H-2),
7.06 (d, 2H, J = 8.1 Hz, Ar-H), 7.13 (d, 2H, J = 8.1 Hz, Ar-H), 7.19 (d, 2H,
J = 8.4 Hz, Ar-H), 7.59 (d, 2H, J = 8.4 Hz, Ar-H). 13C NMR (75 MHz, CDCl3) dC:
21.4, 21.5, 23.6, 36.4, 48.0, 90.9, 115.8, 128.5, 128.7, 128.8, 129.4, 130.4, 132.9,
139.5, 145.1, 177.3, 191.9, 193.9. Anal. Calcd for C22H19ClO3: C, 72.03; H, 5.22%.
Found: C, 72.16; H, 5.31%.
trans-3-(4-Chlorophenyl)-6,6-dimethyl-2-(4-methylbenzoyl)-2,3,6,7-tetrahydrobenzofuran-4(5H)-one (7g): Isolated as white solid. Yield: 70%; mp = 173
176 C; IR (KBr): 1222, 1400 cm1 (CO), 1639, 1697 cm1 (C@O); 1H NMR
(300 MHz, CDCl3) dH: 1.15 (s, 6H, 2CH3), 2.16 (d, 1H, J = 16.2 Hz, H-5), 2.24 (d,
1H, J = 16.2 Hz, H-5), 2.42 (s, 3H, CH3), 2.51 (d, 1H, J = 17.7 Hz, H-7), 2.62 (d, 1H,
J = 17.7 Hz, H-7), 4.37 (d, 1H, J = 4.2 Hz, H-3), 5.82 (d, 1H, J = 4.2 Hz, H-2), 7.17
(d, 2H, J = 8.1 Hz, Ar-H), 7.21 (d, 2H, J = 7.8 Hz, Ar-H), 7.32 (d, 2H, J = 7.8 Hz, ArH), 7.70 (d, 2H, J = 8.1 Hz, Ar-H). 13C NMR (75 MHz, CDCl3) dC: 21.8, 28.3, 29.0,
34.3, 37.6, 48.4, 51.0, 91.4, 114.8, 128.7, 129.0, 129.2, 129.6, 130.6, 133.3,
139.8, 145.4, 176.5, 192.1, 193.5. Anal. Calcd for C24H23ClO3: C, 73.00; H, 5.87%.
Found: C, 72.92; H, 5.80%.
cis-6-(4-Chlorobenzoyl)-5-(4-chlorophenyl)-5,6-dihydrofuro[2,3-d]pyrimidine2,4(1H,3H)-dione (8e): Isolated as white solid. Yield: 73%; mp = 224226 C; IR
(KBr): 1282, 1367 cm1 (CO), 1716, 1768 cm1 (C@O) 3484, 3558 cm1 (NH);
1
H NMR (300 MHz, DMSO-d6) dH: 4.72 (d, 1H, J = 12.0 Hz, H-5), 6.91 (d, 1H,
J = 12.0 Hz, H-6), 7.06 (d, 2H, J = 7.5 Hz, Ar-H), 7.35(d, 2H, J = 7.5 Hz, Ar-H), 7.66
(d, 2H, J = 8.7 Hz, Ar-H), 8.12 (d, 2H, J = 8.7 Hz, Ar-H). 13C NMR (75 MHz, DMSOd6) dC: 48.8, 58.0, 64.8, 128.7 (2C), 128.8, 130.5, 131.9, 133.1, 134.4, 139.8,
147.4, 169.7, 170.4, 185.7. Anal. Calcd for C19H12Cl2N2O4: C, 56.60; H, 3.00; N,
6.95%. Found: C, 56.52; H, 3.09; N, 6.83%.
cis-5-(4-Chlorophenyl)-6-(4-methylbenzoyl)-2-thioxo-2,3,5,6-tetrahydrofuro[2,3-d]pyrimidin-4(1H)-one (9g): Isolated as white solid. Yield: 63%; mp
>300 C; IR (KBr): 1189 cm1 (C@S), 1284, 1311 cm1 (CO), 1664,
1643 cm1 (C@O), 3222, 3328 cm1 (NH); 1H NMR (300 MHz, DMSO-d6) dH:
2.38 (s, 3H, CH3), 4.73 (d, 1H, J = 12.0 Hz, H-5), 6.86 (d, 1H, J = 12.0 Hz, H-6),
7.03 (br s, 2H, Ar-H), 7.32 (br s, 2H, Ar-H), 7.39 (d, 2H, J = 7.8 Hz, Ar-H), 7.98 (d,
2H, J = 7.8 Hz, Ar-H). 13C NMR (75 MHz, DMSO-d6) dC: 20.8, 49.0, 58.4, 64.3,
128.8, 128.9 (2C), 129.3, 132.0, 133.1, 133.5, 145.6, 167.9, 168.2, 176.3, 185.8.
Anal. Calcd for C20H15ClN2O3S: C, 60.22; H, 3.79; N, 7.02%. Found: C, 60.34; H,
3.86; N, 7.14%.
Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 33253355.
(a) Ye, Y.; Wang, L.; Fan, R. J. Org. Chem. 2010, 75, 17601763; (b) Maiti, S.;
Perumal, P. T.; Menendez, J. C. Tetrahedron 2010, 66, 95129518.
Ceylan, M.; Fndk, E. Synth. Commun. 2008, 38, 10701077.
Crystallographic data (excluding structure factors) for compound 7g in this
letter have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 789575. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
Vinosha, B. M.; Renuga, S.; Gnanadeebam, M.; Perumal, S.; Lycka, A. Synth.
Commun. 2009, 39, 27762788.