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Synthesis of oxygen heterocycles
Tetrahedron Letters Tetrahedron Letters 47 (2006) 1347–1349
Synthesis of oxygen heterocycles A. K. Ganguly,* P. K. Mahata and D. Biswas Stevens Institute of Technology, Hoboken, NJ 07030, USA Received 10 November 2005; revised 6 December 2005; accepted 7 December 2005 Available online 9 January 2006
Abstract—A generalised scheme for the synthesis of flavones, flavonones and chromones involving 3-acyl-c-pyrone intermediates has been developed. Convenient synthesis of other oxygen heterocycles using similar procedure have been outlined. Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Present work
There has been considerable interest1 in recent years in the area of flavonoids, which are known to be kinase inhibitors. They also show activity in apoptosis, which is implicated in cancer chemotherapy. In addition they are known to be antioxidants and also show activity against P-gp 170, a multiple drug resistant gene product. We therefore decided to explore chemistry in this area with an idea of making a library of compounds for biological testing. We decided to synthesise these compounds using Baker–Venkataraman (B–V)2 reaction and during our study we made an unusual observation.3a We observed that Baker–Venkataraman reaction under our experimental condition did not yield the expected c-pyrones instead we obtained 3-acyl-cpyrones.3b
In our present work we have explored this reaction further thus making it possible to prepare a library of flavonoids for biological testing. In addition we have discovered a novel approach for the synthesis of other oxygen heterocycles. In Scheme 2 a brief summary is presented of the acid chlorides used in the above reaction and the products5,6 obtained. It should be noted that excepting in the case of the 3-substituted acid chlorides wherein a single product was isolated in all the other cases both the possible compounds were obtained. We have already reported that the treatment of the phenolic 3-acyl-c-pyrones with aqueous potassium carbonate yield c-pyrones. Thus the combination of the above reactions will provide a library of flavonoids for biological testing.
Thus when compounds 1a–d were treated with aliphatic or aromatic acid chlorides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and pyridine they yielded 3-acyl-c-pyrones. We speculated that the formation 3-acyl-c-pyrones involved the intermediacy of the triketones 2 (Scheme 1).
We also explored whether 3-acyl-c-pyrones could be a source for the preparation of flavonones. Thus we have reduced 11a with sodium borohydride to the trans-dihydro compound 13. The methyl ether 14 obtained from 13 was in turn converted to the oxime 15 by treatment
O R1
OH
Cl
R3
R1
OH O
R3
CH3 R2
O
R1
O
R3
R3 R2
1a R1 = R2 = H; 1b R1 = OH, R2 =H 1c R1 = OCH3, R2 = H; 1d R1 = R2 = OH
O
O
2
Scheme 1. Keywords: Synthesis; Heterocycles. * Corresponding author. Tel.: +1 201 216 5540; fax: +1 201 216 8240; e-mail: [email protected] 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.12.062
R3 R2
O 3
O
1348
A. K. Ganguly et al. / Tetrahedron Letters 47 (2006) 1347–1349 X H3CO
O
H3CO
OH
H3CO
X
O
O
O 5d Y
O
O 4a X = H 4b X = OCH3
10 (65%)
X
6a X = H, Y = Br (35%) 6b X = Br, Y = H (32%) 7a X = H, Y = OCH3 (33%) 7b X = OCH3, Y = H (29%) 8a X = OCH3, Y = NO2 (38%) 8b X = NO2, Y = OCH3 (40%)
O
5e
5a -c
O
H3CO
Y
O O
5a X = Br, Y = Z = H 5b X = OCH3, Y = Z = H 5c X = NO2, Y = Z = H 5d X = Y = H, Z = Br 5e X = Z =H, Y = Br
Z Y
O
9a X = H, Y = Br (40%) 9b X = Br, Y = H (37%)
O
Cl
X HO
Br
X
X
O
HO
O
O O
O
11a X = Y = H 11b X = H, Y = Br 11c X = Br, Y = H
12a X = H 12b X = Br
Y
Scheme 2.
HO
O
H
H3CO
Ph
O
H
H3CO
Ph
O
Ph
H3CO
O
Ph
11a Ph
Ph O 13 (55%)
H
O 14 (75%)
O
H
N OH 15 (45%)
O
O 16 (65%)
Scheme 3.
HO
OH
O
HO
O
HO
O
O CH3
21
O
O
O
O
17 (75%)
OH
18
H
O
Scheme 4.
H3CO
O
H3CO HCHO
OH O O H 20 (35%)
H
H O
H3CO
H3CO
OH
R
O
R
H3CO
R
19a R = C6H5- (45%) 19b R = 2-ClC6H4- (46.5%) 19c R = 3-ClC6H4- (49%) 19d R = 4-ClC6H4- (46%) O
R 19
O
HCHO
OH
O
RCHO
R O
4a
4a
H3CO
H O
O HO
OO H
R H3CO
O R R
O
20 O O HO
O
O
OH O H
Scheme 5.
H
O
A. K. Ganguly et al. / Tetrahedron Letters 47 (2006) 1347–1349
with hydroxylamine hydrochloride/KOH in ethanol. The oxime 15 was converted to the flavonone 16 by reacting with nitrous acid (Scheme 3). To extend further our synthesis of 3-acyl-c-pyrones we treated 21 with carbonyl diimidazole and DBU/pyridine and obtained in good yield the 4-hydroxy coumarin derivative 17, which has been previously synthesised4 using a multistep procedure. 4-Hydroxy coumarins possess important biological activity, for example, warfarin 18 is a well known anticoagulant (Scheme 4). As diketones such as 21 are easily synthesised the above reaction could be extended further to make analogues. Interestingly when the diketone 4a was treated with aromatic aldehydes it gave 19a–d and on treatment with formaldehyde it yielded 20. The possible mechanisms involved in these conversions are summarised in Scheme 5. Using diketones with different substitutions on the phenolic ring and various aromatic and aliphatic aldehydes we are in the process of making a library of compounds. 3. Conclusion Using our modified experimental condition of Baker– Venkataraman reaction we have developed convenient synthetic procedures, which will allow preparation of libraries of compound containing flavones, flavanones, coumarines and other oxygen heterocycles.
Acknowledgements We wish to thank Schering-Plough Research Institute for generous financial assistance and one of us
1349
(P.K.M.) would like to sincerely thank Stevens Institute of Technology for the award of a postdoctoral fellowship. We also wish to thank Dr. B. N. Pramanik of SPRI for providing MS data presented in this letter. References and notes 1. (a) Marchand, L. L. Biomed. Pharmacother. 2002, 56, 296; (b) Sausville, E. A.; Zaharvitz, D.; Gussio, R. Pharmacol. Ther. 1999, 83, 285; (c) Matsui, J.; Kiyokawa, N.; Takenouchi, H.; Taguchi, T. Leukemia Res. 2005, 29, 573; (d) Lee, Y.; Yeo, H.; Liu, S.-H.; Jiang, Z.; Savizky, R. M.; Austin, D. J.; Cheng, Y.-C. J. Med. Chem. 2004, 47, 5555–5566; (e) Middleton, E., Jr.; Kandaswami, C.; Theoharides, T. C. Pharmacol. Rev. 2000, 52, 673– 751. 2. (a) Baker, W. J. Chem. Soc. 1933, 1381; (b) Mahal, H. Si.; Venkataraman, K. J. Chem. Soc. 1934, 1767. 3. (a) Ganguly, A. K.; Kaur, S.; Mahata, P. K.; Biswas, D.; Pramanik, B. N.; Chan, T. M. Tetrahedron Lett. 2005, 46, 4119–4121; (b) Cummings, R. T.; DiZio, J. P.; Krafft, G. A. Tetrahedron Lett. 1988, 29, 69–72. 4. Veres, K.; Jonas, J.; Horeni, A. In Collection of Czechoslovak Chemical Communications; Karlova University: Prague, 1959; 24, pp 3471–3475. 5. NMR and high-resolution mass spectra of all the compounds described in this paper were consistent with the assigned structures. Assignments were further confirmed using HMBC, HSQC and COSY experiments. 6. All compounds described in this letter were crystalline. Crystals were obtained from dichloromethane–hexane or ethylacetate. The melting points of compounds 6a,b, 7a,b, 8a,b, 9a,b, 10, 11a–c, 12a,b, 13–17, 19a–d and 20 were 182–183, 203–204, 158–159, 196–197, 176–177, 196–197, 186–187, 144–146, 166–167, 270–271, 268–269, 287–288, 241–242, 282–283, 220–221, 175–176, 139–140, 62–63, 263– 264, 123–124, 171–172, 112–113, 152–153 and 129–130 °C. Yields are indicated in the parenthesis.
Synthesis of oxygen heterocycles A. K. Ganguly,* P. K. Mahata and D. Biswas Stevens Institute of Technology, Hoboken, NJ 07030, USA Received 10 November 2005; revised 6 December 2005; accepted 7 December 2005 Available online 9 January 2006
Abstract—A generalised scheme for the synthesis of flavones, flavonones and chromones involving 3-acyl-c-pyrone intermediates has been developed. Convenient synthesis of other oxygen heterocycles using similar procedure have been outlined. Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Present work
There has been considerable interest1 in recent years in the area of flavonoids, which are known to be kinase inhibitors. They also show activity in apoptosis, which is implicated in cancer chemotherapy. In addition they are known to be antioxidants and also show activity against P-gp 170, a multiple drug resistant gene product. We therefore decided to explore chemistry in this area with an idea of making a library of compounds for biological testing. We decided to synthesise these compounds using Baker–Venkataraman (B–V)2 reaction and during our study we made an unusual observation.3a We observed that Baker–Venkataraman reaction under our experimental condition did not yield the expected c-pyrones instead we obtained 3-acyl-cpyrones.3b
In our present work we have explored this reaction further thus making it possible to prepare a library of flavonoids for biological testing. In addition we have discovered a novel approach for the synthesis of other oxygen heterocycles. In Scheme 2 a brief summary is presented of the acid chlorides used in the above reaction and the products5,6 obtained. It should be noted that excepting in the case of the 3-substituted acid chlorides wherein a single product was isolated in all the other cases both the possible compounds were obtained. We have already reported that the treatment of the phenolic 3-acyl-c-pyrones with aqueous potassium carbonate yield c-pyrones. Thus the combination of the above reactions will provide a library of flavonoids for biological testing.
Thus when compounds 1a–d were treated with aliphatic or aromatic acid chlorides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and pyridine they yielded 3-acyl-c-pyrones. We speculated that the formation 3-acyl-c-pyrones involved the intermediacy of the triketones 2 (Scheme 1).
We also explored whether 3-acyl-c-pyrones could be a source for the preparation of flavonones. Thus we have reduced 11a with sodium borohydride to the trans-dihydro compound 13. The methyl ether 14 obtained from 13 was in turn converted to the oxime 15 by treatment
O R1
OH
Cl
R3
R1
OH O
R3
CH3 R2
O
R1
O
R3
R3 R2
1a R1 = R2 = H; 1b R1 = OH, R2 =H 1c R1 = OCH3, R2 = H; 1d R1 = R2 = OH
O
O
2
Scheme 1. Keywords: Synthesis; Heterocycles. * Corresponding author. Tel.: +1 201 216 5540; fax: +1 201 216 8240; e-mail: [email protected] 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.12.062
R3 R2
O 3
O
1348
A. K. Ganguly et al. / Tetrahedron Letters 47 (2006) 1347–1349 X H3CO
O
H3CO
OH
H3CO
X
O
O
O 5d Y
O
O 4a X = H 4b X = OCH3
10 (65%)
X
6a X = H, Y = Br (35%) 6b X = Br, Y = H (32%) 7a X = H, Y = OCH3 (33%) 7b X = OCH3, Y = H (29%) 8a X = OCH3, Y = NO2 (38%) 8b X = NO2, Y = OCH3 (40%)
O
5e
5a -c
O
H3CO
Y
O O
5a X = Br, Y = Z = H 5b X = OCH3, Y = Z = H 5c X = NO2, Y = Z = H 5d X = Y = H, Z = Br 5e X = Z =H, Y = Br
Z Y
O
9a X = H, Y = Br (40%) 9b X = Br, Y = H (37%)
O
Cl
X HO
Br
X
X
O
HO
O
O O
O
11a X = Y = H 11b X = H, Y = Br 11c X = Br, Y = H
12a X = H 12b X = Br
Y
Scheme 2.
HO
O
H
H3CO
Ph
O
H
H3CO
Ph
O
Ph
H3CO
O
Ph
11a Ph
Ph O 13 (55%)
H
O 14 (75%)
O
H
N OH 15 (45%)
O
O 16 (65%)
Scheme 3.
HO
OH
O
HO
O
HO
O
O CH3
21
O
O
O
O
17 (75%)
OH
18
H
O
Scheme 4.
H3CO
O
H3CO HCHO
OH O O H 20 (35%)
H
H O
H3CO
H3CO
OH
R
O
R
H3CO
R
19a R = C6H5- (45%) 19b R = 2-ClC6H4- (46.5%) 19c R = 3-ClC6H4- (49%) 19d R = 4-ClC6H4- (46%) O
R 19
O
HCHO
OH
O
RCHO
R O
4a
4a
H3CO
H O
O HO
OO H
R H3CO
O R R
O
20 O O HO
O
O
OH O H
Scheme 5.
H
O
A. K. Ganguly et al. / Tetrahedron Letters 47 (2006) 1347–1349
with hydroxylamine hydrochloride/KOH in ethanol. The oxime 15 was converted to the flavonone 16 by reacting with nitrous acid (Scheme 3). To extend further our synthesis of 3-acyl-c-pyrones we treated 21 with carbonyl diimidazole and DBU/pyridine and obtained in good yield the 4-hydroxy coumarin derivative 17, which has been previously synthesised4 using a multistep procedure. 4-Hydroxy coumarins possess important biological activity, for example, warfarin 18 is a well known anticoagulant (Scheme 4). As diketones such as 21 are easily synthesised the above reaction could be extended further to make analogues. Interestingly when the diketone 4a was treated with aromatic aldehydes it gave 19a–d and on treatment with formaldehyde it yielded 20. The possible mechanisms involved in these conversions are summarised in Scheme 5. Using diketones with different substitutions on the phenolic ring and various aromatic and aliphatic aldehydes we are in the process of making a library of compounds. 3. Conclusion Using our modified experimental condition of Baker– Venkataraman reaction we have developed convenient synthetic procedures, which will allow preparation of libraries of compound containing flavones, flavanones, coumarines and other oxygen heterocycles.
Acknowledgements We wish to thank Schering-Plough Research Institute for generous financial assistance and one of us
1349
(P.K.M.) would like to sincerely thank Stevens Institute of Technology for the award of a postdoctoral fellowship. We also wish to thank Dr. B. N. Pramanik of SPRI for providing MS data presented in this letter. References and notes 1. (a) Marchand, L. L. Biomed. Pharmacother. 2002, 56, 296; (b) Sausville, E. A.; Zaharvitz, D.; Gussio, R. Pharmacol. Ther. 1999, 83, 285; (c) Matsui, J.; Kiyokawa, N.; Takenouchi, H.; Taguchi, T. Leukemia Res. 2005, 29, 573; (d) Lee, Y.; Yeo, H.; Liu, S.-H.; Jiang, Z.; Savizky, R. M.; Austin, D. J.; Cheng, Y.-C. J. Med. Chem. 2004, 47, 5555–5566; (e) Middleton, E., Jr.; Kandaswami, C.; Theoharides, T. C. Pharmacol. Rev. 2000, 52, 673– 751. 2. (a) Baker, W. J. Chem. Soc. 1933, 1381; (b) Mahal, H. Si.; Venkataraman, K. J. Chem. Soc. 1934, 1767. 3. (a) Ganguly, A. K.; Kaur, S.; Mahata, P. K.; Biswas, D.; Pramanik, B. N.; Chan, T. M. Tetrahedron Lett. 2005, 46, 4119–4121; (b) Cummings, R. T.; DiZio, J. P.; Krafft, G. A. Tetrahedron Lett. 1988, 29, 69–72. 4. Veres, K.; Jonas, J.; Horeni, A. In Collection of Czechoslovak Chemical Communications; Karlova University: Prague, 1959; 24, pp 3471–3475. 5. NMR and high-resolution mass spectra of all the compounds described in this paper were consistent with the assigned structures. Assignments were further confirmed using HMBC, HSQC and COSY experiments. 6. All compounds described in this letter were crystalline. Crystals were obtained from dichloromethane–hexane or ethylacetate. The melting points of compounds 6a,b, 7a,b, 8a,b, 9a,b, 10, 11a–c, 12a,b, 13–17, 19a–d and 20 were 182–183, 203–204, 158–159, 196–197, 176–177, 196–197, 186–187, 144–146, 166–167, 270–271, 268–269, 287–288, 241–242, 282–283, 220–221, 175–176, 139–140, 62–63, 263– 264, 123–124, 171–172, 112–113, 152–153 and 129–130 °C. Yields are indicated in the parenthesis.