Nitrogen containing compound has drawn much interest in the field of heterocyclic chemistry. The nitrogen containing compounds have considerable biological and pharmacological activites such as antiasthmatic, antimalarial, anti-inflammatory, antiviral, antibacterial, antitumor agents, and anti-HIV. Due to wide activity in medicinal area, various synthetic methods have been developed to prepare nitrogen containing heterocylces. Few interesting protocols are described below.
Dong and co-workers described the first transition metal-catalyzed transformation of conjugated nitroalkenes into indoles. Reaction was carried out using Pd(OAc)2 (2 mol %), phen (4 mol %), CO (1 atm), in DMF at 110 oC and in all the cases yields of the products were found to be excellent (Scheme I.7.1).45
Scheme I.7.1
Balalaie and co-workers reported the procedure for the synthesis of 1,2,3,4-tetra-substituted pyrroles using Iron(III) chloride catalyst from primary amines, dialkyl acetylenedicarboxylates and β-nitrostyrene derivatives. The reaction involves the initial reaction of primary amines with dimethyl acetylenedicarboxylate to form the desired enaminone, then β-nitrostyrene could be activated by FeCl3 and undergo the nucleophilic addition (Scheme I.7.2).46
Scheme I.7.2
Chen et al. described an easy and efficient copper-catalyzed protocol for the synthesis of quinoxalines from o-phenylenediamines and nitroolefins. Reaction was performed in the presence of various substituted nitroalkenes with o-phenylenediamines in ethanol at 110
oC (Scheme I.7.3).47
Scheme I.7.3
Wang and co-workers reported copper acetate-catalyzed [3 + 2] annulation reaction of readily accessible aziridines and nitroalkenes for the synthesis of polysubstituted pyrroles under aerobic condition. The reaction involves a regioselective C–C bond cleavage of aziridines to give an azomethine ylide, which would undergo [3 + 2] cycloaddition with β-nitroalkenes. Reaction was performed using 5 mol % Cu(OAc)2 catalyst in DMSO at 110 oC (Scheme I.7.4).48
Scheme I.7.4
Chen and co-workers reported novel and facile copper-catalyzed [3 + 2] cycloaddition reaction between arylamidines and nitroalkenes for the synthesis of multisubstituted imidazole derivatives using oxygen as an oxidant. Various substituted arylamidines and nitroalkenes treated using 10 mol % CuI catalyst and 20 mol % bipy ligand in DMF at 90
oC (Scheme I.7.5).49
Scheme I.7.5
Lu and co-workers described copper-catalyzed three component synthesis of polysubstituted pyrroles from α-diazoketones, nitroalkenes, and amines under aerobic conditions. The cascade process involves an N-H insertion of carbene, a copper-catalyzed oxidative dehydrogenation of amine, and a [3+2] cycloaddition of azomethine ylide.
Electronic Effect of various electron donating as well as withdrawing groups were studied (Scheme I.7.6).50
Scheme I.7.6
Arigela et al. developed one-pot protocol for the synthesis of indole-based polyheterocycles via a sequential Lewis acid catalyzed intermolecular Michael addition and an intramolecular azide/internal alkyne 1,3-dipolar cycloaddition. Reaction was carried out using 10 mol % Yb(OTf)3 in toluene at 120 oC. Different aromatic/aliphatic 2-alkynyl indoles treated with substituted (E)-1-azido-2-(2-nitrovinyl)benzenes to furnish annulated tetracyclic indolo[2,3-c][1,2,3]triazolo[1,5-a][1]benzazepines in good yields (Scheme I.7.7).51
Scheme I.7.7
Hajra and co-workers reported synthesis of imidazo-[1,2-a]pyridines derivatives from nitro-olefins and 2-aminopyridines using iron (III)-catalyst. Reaction was carried out using 20 mol % catalyst in DMF at 80 oC in DMF. Further, this methodology could be successfully applicable for the synthesis of Zolimidine, a useful drug for the treatment of peptic ulcer (Scheme I.7.8).52
Scheme I.7.8
Menendez and co-workers described a simple and efficient one-pot three-component synthesis of novel 6-amino-8-aryl-2-methyl/benzyl-7-nitro-1,2,3,4-tetrahydroisoquinoline-5-carbonitriles from the reaction of 1-methyl/benzylpiperidin-4-one with nitroalkenes and malononitrile using morpholine in the presence of ethanol under reflux (Scheme I.7.9).53
Scheme I.7.9
Yao and co-workers reported synthesis of 2-Aryl-3-nitro-1,2-dihydroquinolines from the reaction of β-nitrostyrenes and 2-aminobenzaldehyde using DABCO in benzene under reflux condition. After the formation of 2-Aryl-3-nitro-1,2-dihydroquinolines silica gel
was added in reaction mixture to convert in to 3-nitro-2-substituted-quinolines (Scheme I.7.10).54
Scheme I.7.10
Driver and co-workers described Rh2(II) carboxylates catalyzed a fundamental change in the reactivity of nitrostyrylazide to form 3-nitroindole as the exclusive product, thereby providing a new synthetic method for N-heterocycle formation. Reaction was carried with different substituted starting material using 1 mol % Rhodium carboxylate complexes and 4 Å MS in toluene at 75 oC (Scheme I.7.11).55
Scheme I.7.11
Kumar et al. reported base mediated reaction of α-diazo-β-ketosulfone with nitroalkenes affords sulfonylpyrazoles as single regioisomers in excellent yield in onepot room temperature reaction. Reaction was carried out with different substituted nitroalkenes such as aryl, heteroaryl, styrenyl, alkyl, hydroxymethyl, and hydrazinyl (Scheme I.7.12).56
Scheme I.7.12
Zhou and co-workers described synthesis of optically active 2H-thiopyrano [2,3-b]quinolones derivatives with three contiguous stereocenters using chiral bifunctional squar-amide-catalyzed tandem Michael–Henry reaction between 2-mercaptoquinoline-3-carbaldehydes and nitroolefins. The reactions proceed excellent with to give the title compounds in high yields with high levels of diastereo- and enantioselectivity (up to
>99/1 dr and >99% ee, respectively) (Scheme I.7.13).57
Scheme I.7.13
Yadav and co-workers reported highly enantio- and diastereoselective synthesis of octrahydroquinolines incorporating three contiguous chiral centres from 1,3-cyclohexanedione, nitroalkenes and N-tosyl aldimines. The reaction was carried out using 20 mol % of diphenylprolinol silyl ether catalyst and K2CO3basein 1,4 dioxane solvent at room temperature. The reaction involves diphenylprolinol silyl ether-catalyzed Michael addition of 1,3-cyclohexanedione to nitroalkenes followed by potassium carbonate-promoted aza-Henry reaction with N-tosyl aldimines, intramolecular hemiaminalisation and dehydration reaction in a one-pot operation (Scheme I.7.14).58
Scheme I.7.14
Wang et al. described enantioselective protocol for the synthesis of highly substituted tetracarbazole through hydrogen bonding mediated double Michael addition-aromatization cascade of 2-propenylindoles and nitroolefins. Reaction was performed using 10 mol % catalyst, 10 mol % acetic acid as additive in H2O-saturated CH2Cl2 at -78
°C. The methodology allows an efficient synthesis of diverse and structurally complex tetrahydrocarbazoles in good to excellent enantioselectivities and diastereoselectivities (Scheme I.7.15).59
Scheme I.7.15
Xu and co-workers reported bifunctional thiourea-catalyzed (1) asymmetric Michael addition of oxindoles to nitroolefins for the Synthesis of 2,2-disubstituted oxindoles having adjacent quaternary and tertiary stereocenters in high yields and excellent stereoselectivities. Further, this product was reduced with Zn/HCl in EtOH followed by treatment with AcCl/TEA in CH2Cl2, the desired substituted hexahydropyrrolo[3,2-b]indole was obtained in moderate yields and high enantioselectivity (Scheme I.7.16).60
Scheme I.7.16
I.8. Refrences
1. a) Barrett, A.G.M.; Graboski, G.G. Chem. Rev. 1986, 86, 751;b) Sibi, M.P.; Manyem, S.; Tetrahedron 2000, 56, 8033; c) Barratt, A. G. M. Chem. Soc. Rev. 1991, 20, 95.
2. a) Brian, P. W.; Grove, J. F.; McGowan, J. C. Nature 1946, 158, 876; b) McGowan, J.
C.; Brian, P. W.; Hemming, H. G. Ann. Appl. Biol. 1948, 35, 25.
3. Boelle, J.; Schneider, R.; Gerardin, P.; Loubinoux, B.; Maienfisch, P.; Rindlisbacher, A. Pestic. Sci. 1998, 54, 304.
Chapuis, J.-C.; Schmidt, J. M. Bioorg. Med. Chem. 2009, 17, 6606.
6. Kaap, S.; Quentin, I.; Tamiru, D.; Shaheen, M.; Eger, K.; Steinfelder, H. J. Biochem.
Pharmacol. 2003, 65, 603.
7. Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583; b) Berner, O.
M.; Enders, L.; Tedeschi, D. Eur. J. Org. Chem. 2002, 1877.
8. a) Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.; Chandrakumar, A. J. Am.
Gramigna, L.; Bernardi, L.; Ricci, A. Organic Process Research and Development 2010, 14, 687.
14. (a) Bauer, H. H.; Urbas, L. The Chemistry of the Nitro and Nitroso Group; Feuer, H., Ed.; Interscience: New York, 1970, part 2, pp 75; (b) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979, 31, 1; (c) Rosini, G. in: Comprehensive Organic Synthesis, vol. 2 (Eds.: C. H. Heathcock, B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991, chapter 1.10, p. 321.
15. Jalal, S.; Sarkar, S.; Bera, K.; Maiti, S.; Jana, U. Eur. J. Org. Chem. 2013, 4823.
16. Maity, S.; Manna,S.; Rana, S.; Naveen,T.; Mallick, A.; Maiti, D. J. Am. Chem. Soc.
2013, 135, 3355.
17. Das, J. P.; Sinha, P.; Roy, S. Org. Lett. 2002, 4, 3055.
18. Friedricha, A.; Brase, S.; O’Connor, S. E. Tetrahedron Lett. 2009, 50, 75.
19. Zhang, M.; Hu, P.; Zhou, J.; Wu, G.; Huang, S.; Su, W. Org. Lett. 2013, 15, 1718.
20. Rosa, M. D.; Soriente, A. Tetrahedron 2010, 66, 2981.
21. Jia, C.; Chen, D.; Zhang, C.; Zhang, Q.; Cao, B.; Zhao, Z. Tetrahedron 2013, 69,
24. Bartoli, G.; Bosco, M.; Giuli, S.; Giuliani, A.; Lucarelli, L.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem. 2005, 70, 1941.
25. Ramachandiran, K.; Karthikeyan, K.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2010, 51, 3006.
26. Wang, J.; Li, H.; Zu, L.; Wang, W. Org. Lett. 2006, 8, 1391.
27. Chen, J.; Geng, Z.-C.; Li, N.; Huang, X. -F.; Pan, F. -F.; Wang, X. -W. J. Org. Chem.
2013, 78, 2362.
28. Azizi, N.; Arynasab, F.; Saidi, M. R. Org. Biomol. Chem. 2006, 4, 4275.
29. Kuo, C.-W.; Wang, C. -C.; Fang, H. -L.; Raju, B. R.; Kavala, V.; Habib, P. M.; Yao,
34. Kumar, T.; Mobin, S. M.; Namboothiri, I. N. N. Tetrahedron 2013, 69, 4964.
35. Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Deng, J. Z.; Nguyen, D. N.; Potteiger, C.
M.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Org. Lett. 2009, 10, 3235.
36. (a) Willenbring, D.; Dean, J. Russian Journal of General Chemistry. 2008, 7231; (b) Koehn, F. E.; Carter, G.T. Nature Reviews-Drug Discovery. 2005, 4, 206.
37. Lu, S. -C.; Zheng, P. -R.; Liu, G. J. Org. Chem. 2012, 77, 7711.
42. Raimondi, W.; Dauzonne, D.; Constantieux, T.; Bonne, D.; Rodriguez, J. Eur. J. Org.
Chem. 2012, 6119.
43. Gao, Y.; Yang, W.; Du, D. -M. Tetrahedron: Asymmetry 2012, 23, 339.
44. Yang, W.; Yang, Y.; Du, D. -M. Org. Lett. 2013, 15, 1190.
53. Balamurugan, K.; Jeyachandran, V.; Perumal, S.; Menendez, J. C. Tetrahedron 2011, 67, 1432.
54. Yan, M. -C.; Tu, Z.; Lin, C.; Ko, S.; Hsu, J.; Yao, C. -F. J. Org. Chem. 2004, 69, 1565.
55. Stokes, B. J.; Liu, S.; Driver, T. G. J. Am. Chem. Soc. 2011, 133, 4702.
56. Kumar, R.; Namboothiri, I. N. N. Org. Lett. 2011, 13, 4016.
57. Wu, L.; Wang, Y.; Song, H.; Tang, L.; Zhou, Z.; Tang, C. Adv. Synth. Catal. 2013, 355, 1053.
58. Rai, A.; Singh, A. K.; Singh, P.; Yadav, L. D. S. Tetrahedron Lett. 2011, 52, 1354.
59. Wang, X. -F.; Chen, J. -R.; Cao, Y. -J.; Cheng, H. -G.; Xiao, W. J. Org. Lett. 2010, 12, 1140.
60. Jin, C. -Y.; Wang, Y.; Liu, Y. -Z.; Shen, C.; Xu, P. -F. J. Org. Chem. 2012, 77, 11307.
Chapter-II
Alcohol Mediated Synthesis of 4-oxo-2-aryl-4H-chromene-3-carboxylate Derivatives from 4-Hydroxycoumarins
II.1. Introduction
Flavones are an important class of oxygen heterocycles belonging to the flavonoid group that occurs in fruits, seeds, vegetables, nuts, and flowers. The most common flavone in the diet is quercetin. It is present in various fruits and vegetables, but the highest concentrations are found in onion. Several natural products that contain this heterocyclic framework, have antiviral, anticancer, anti-inflammatory, and antioxidant properties.1 Some of the flavones shows promising biological activity such as, querceitin (antioxidative and anti-inflammatory activity), chrysin (aromatase inhibitor in vitro), nobiletin (anti-inflammatory), semiglabarin (antifungal) as well as flavones are found to be useful intermediates in the fields of medicinal, pharmaceutical and synthetic chemistry (Figure II.1.1).1-4
Figure II.1.1 Biologically active 4H-chromen-4-one derivatives
In addition to controlling the efficacy of a reaction, the medium used also has a significant role in determining the reaction pathway.2 The polarity of the solvent used in a reaction is a major determinant of the fate of the reaction. The reaction pathway is determined by the stability of a particular transition state that is produced in a specific medium. Thus, the effect of the medium on a chemical transformation is a very important issue in the field of chemistry.2
II.2. Review of literature
Among the members of the flavone family, 4-oxo-4H-chromene-3-carboxylate derivatives are very interesting scaffolds, since they can act both as a Michael acceptor and a 1, 3-diketone, due to the presence of an ester functionality at C-3.3-5 However, concerning the poly-substituted counterparts, the chemistry of 2-alkyl substituted derivatives have been explored much more extensively than the 2-aryl derivatives.4,5 Although many methods are available in the literature that describes the synthesis of 3-carboxylate flavone scaffold, herein, some efficient and attractive protocols are depicted.
Geahlen and co-workers deveoped a method for the synthesis of flavone-3-carboxylate derivatives by the treatment of 2-hydroxyacetophenone with excess of lithium bis(trimethylsily1)amide followed by dialkylcarbonates gave alkyl 3-(2-hydroxyaryl)-3-oxopropanoate. Further, this intermediate on treatment with magnesium chelate with benzoyl chloride to give desired product (Scheme II.2.1).6
Scheme II.2.1
Hormi and co-workers reported that, when β-Chloroarylidenemalonate treated with phenol in the presence of K2CO3 in DMF solvent to produce β-(ary1oxy)arylidenemalonates intermediate which further on PPA catalyzed intramolecular cyclization to give flavone 3-carboxylate derivative (Scheme II.2.2).7
Scheme II.2.2
Dean and co-workers reported, flavones are first lithiated by using lithium di-isopropylamide in tetrahydrofuran at -78 oC. Later, this intermediate on treatment with 1 eq. of electrophile gave flavone 3-carboxylate derivative (Scheme II.2.3).8
Scheme II.2.3
Lu and co-workers reported an efficient Et3N-mediated reaction of salicylaldehyde with methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate that provides easy access to 4-hydroxy-2-(trifluoromethyl)-4H-chromene derivatives. Various, substituted salicylaldehydes were used and in all the case yields of the products were found to be excellent (Scheme II.2.4).9
Scheme II.2.4
Long and co-workers have described a highly efficient method for the synthesis of 2-substituted-3-carboxy chromone derivatives. The condensation was carried out between halogen-substituted 3-oxo-3-arylpropanoate and acetyl chloride in the presence of K2CO3
and DIPEA in DMF at 0 oC to get intermediate which further, on heating at 110 oC to afford chromone derivatives (Scheme II.2.5).10
Scheme II.2.5
Doi and co-workers reported Lewis base PBu3 catalyzed synthesis of chromone 3-carboxylate derivatives. Initially, starting materials were prepared via Pd(0)-catalyzed carbonylative Sonogashira coupling reaction of iodobenzene and phenylacetylene. Then, Tributylphosphine efficiently induced the tandem acyl transfer-cyclization of carbonates to afford 3-methoxycarbonylflavone derivatives in excellent yields (Scheme II.2.6).11
Scheme II.2.6
In fact, all of the reported methodologies for the synthesis of these esters consist of a multistep process or involve the use of complex mixtures of reagents. As a result, a demand exists for a more straightforward and cost effective procedure for the synthesis of 4H-chromen-4-one moieties.
Our long term goal is directed at exploring the utility of (E)-(2-nitrovinyl)benzenes in organic synthesis.12 In a continuation of our research dealing with nitro olefins, we wish to report, herein on the, unprecedented solvent mediated synthesis of 4-oxo-2-aryl-4H-chromene-3-carboxylates from 4-hydroxycoumarins and β-nitroalkenes.
II.3. Results and discussion
In a recent publication, we reported on the synthesis of a series of oxime, hydroxyiminodihydrofuroquinolinone derivatives, from 4-hydroxy-1-methyl quinolin-2(1H)-one and (E)-(2-nitrovinyl)benzenes, using methanol as the solvent, in the presence of a catalytic amount of diisopropylethylamine.12a We proposed that the conversion occurred via the formation of a Michael adduct. The Michael adduct underwent base mediated C-O bond formation to produce an oxime. However, when we examined the
reactions of 4-hydroxycoumarin (a, Scheme II.3.1) and (E)-(2-nitrovinyl)benzenes (2) at the same conditions, the reaction was sluggish. From these two experimental outcomes, it appeared that the nitrogen heterocycle, 4-hydroxy-1-methylquinolin-2(1H)-one, itself acts as a base and, because of this, the basicity of the medium appears to be an important factor in the formation of an oxime derivative. Taking cues from these observations, we used 2 equiv of diisopropylethylamine to synthesize an oxime derivative (2a’, Scheme II.3.1), from 4-hydroxycoumarin (a) and (E)-(2-nitrovinyl)benzenes derivatives (2). At room temperature, only the corresponding Michael adduct was observed. At this point, with the desired oxime in mind, we carried out the reaction at 70 oC. However, the desired oxime was not formed, but the result was more exciting and interesting than our expectation. 1H and 13C NMR, IR, Mass, and single crystal X-ray analysis data (Figure II.3.1 and supporting information) revealed that the product was methyl 4-oxo-2-p-tolyl-4H- chromene-3-carboxylate (2a), which was formed in 33% yield. The use of 4 equiv of diisopropylethylamine improved the yield to 51%. This finding presents a novel and straightforward route for the preparation of a relatively unexplored member of the flavone family.
In this context, recently, Balalaie and co-workers disclosed that the treatment of 4-hydroxycoumarin with (E)-(2-nitrovinyl)benzenes in acetonitrile, in the presence of ammonium acetate, resulted in the formation of the (3E)-3-[amino(aryl)methylidene) chromane-2,4-dione derivative (Scheme II.3.1).13 However, in our case, when methanol was used as solvent instead of acetonitrile, a flavone derivative was produced as the major product. Hence, these results explain the effect of the medium in chemical transformations in a more comprehensive fashion.
Scheme II.3.1. Reaction of 4-hydroxycoumarin and (E)-1-methyl-4-(2-nitrovinyl)benzene
Figure II.3.1. X-ray Crystal structure of 2a (ORTEP diagram)
This exciting experimental outcome prompted us to determine the optimal conditions for the conversion. To pursue this goal, we first ran the reaction using different bases (Table II.3.1). No product was obtained with diethylamine (entry 3), piperidine (entry 7) and amberlyst A-25, a basic ion exchange resin (entry 8). However, the use of ammonium acetate (entry 4), DABCO (entry 5), NaHCO3 (entry 6) and DBU (entry 11) resulted in the formation of an inseparable mixture. On the other hand, bases like DIPEA (entry 1), pyridine (entry 2), TEA (entry 9), KF (entry 10), and N,N-dimethyl cyclohexyl amine (entry 12) were found to be more effective. Among them, TEA was found to be superior to the other bases used. When the reaction was carried out at room temperature, only the Michael adduct was formed and no evidence of the desired product was observed.
However, at 70 °C the desired product (2a) was obtained in good yield and the yield was not improved when the reaction was conducted at higher temperatures. Hence, the substrate scope was explored by carrying out the reaction at 70 oC with TEA as the base.
The scope of the methodology was examined, first, by treating 4-hydroxycoumarin with a series of β-nitroalkene derivatives. To accomplish this, we used several o-, m-, p- as well as unsubstituted (E)-(2-nitrovinyl)benzenes, containing both electron donating and withdrawing groups (Table II.3.2). We also tested a variety of 4-hydroxycoumarin derivatives (Scheme II.3.2) and alcohols (Table II.3.3) to elaborate the chemistry further.
In the case of 4-hydroxycoumarin, the yields of the desired products were found to be dependent on the electronic nature of the substituents on the phenyl moiety of (E)-(2-nitrovinyl)benzene (Table II.3.2). With the unsubstituted (E)-(2-(E)-(2-nitrovinyl)benzene the expected product was obtained in 72% yield (Table II.3.2, entry 1). The desired products were obtained in moderate to good yields when electron donating groups were present on the phenyl ring (entries 2-7).
Table II.3.1. Effect of different bases
a All reactions were performed on a 2 mmol scale. b Yield refers to the isolated yield of the purified compound. c No product was observed. d An inseparable mixture was formed.
However, the introduction of an electron withdrawing group (such as a nitro group), resulted in a lower product yield (entry 10). Halide substituted (E)-(2-nitrovinyl)benzenes (entries 8 and 9) also produced lower product yields than the (E)-(2-nitrovinyl)benzenes with methoxy, methyl, ethyl, and amine functionalities, presumably, the electron withdrawing inductive effect of the halide functionality makes the phenyl ring electron deficient. The effect of steric factors on product yields was quite interesting. When more sterically hindered (E)-(2-nitrovinyl)benzenes were used, the yields were improved. The presence of an o-substituent resulted in good to excellent yields of the desired products ((Table II.3.2, entries 11 and 12). (E)-(nitrovinyl)benzenes, derived from 2-napthaldehyde, produced the expected product in good yield (entry 13). However, a low product yield was obtained in the case of (E)-2-(2-nitrovinyl)thiophene (entry 14). With other heterocyclic nitroalkenes, like pyridine, pyrrole, indole and furan, we did not
observe the desired product and an inseparable mixture of products were obtained in all the cases.
Table II.3.2. Reaction of 4-hydroxycoumarin with different nitroalkene derivatives
aYields refer to isolated and purified compounds. Parentheses indicate the yield calculated by 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as an internal standard. bAll reactions were performed on a 2 mmol scale.
Continued………
aYields refer to isolated and purified compound. Parentheses indicate the yield calculated by 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as the internal standard. bAll reactions were performed on a 2 mmol scale.
Next, to explore the diversity of our protocol further, we treated halo (1b, Scheme II.3.2) and methyl (1c, Scheme II.3.2) substituted 4-hydroxycoumarin derivatives with
(E)-1-methyl-4-(2-nitrovinyl)benzene. Presumably, due to the electron donating inductive effect of the methyl functionality, the latter produced a higher product yield (1c) than the former (1b). The presence of strong electron withdrawing group, like 4-hydroxy-nitro-2H-chromen-2-one, the desired product (1d) was obtained in poor yield. However, with 6-(dimethylamino)-4-hydroxy-2H-chromen-2-one, the expected flavone derivative (1e) was obtained in good yield.
aYields refer to isolated and purified compound. Parentheses indicate the yield calculated by 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as the internal standard. b All reactions were performed on a 2 mmol scale.
Scheme II.3.2. Reaction of substituted 4-hydroxycoumarin and (E)-1-methyl- 4-(2-nitrovinyl) benzene
After studying the different reactions of (E)-(2-nitrovinyl)benzenes and 4-hydroxycoumarins, we focused our attention on determining the effect of the medium used in the reaction (Table II.3.3). To pursue this goal, the reaction of (E)-1-methyl-4-(2-nitrovinyl)benzene and 4-hydroxycoumarin were performed in different alcoholic media.
We observed that, the presence of a sp2 carbon α to the C-O bond resulted in a higher yield of the flavone derivative than bulkier sp3 counterparts. Hence, benzyl alcohol (entry 3, Table II.3.3) and allylic alcohol (entry 4) were more productive than ethanol (entry 1), n-propyl alcohol (entry 2), and ethylene glycol (entry 5). The low yields of the desired products with thiophene methanol (entry 6) and furfuryl alcohol (entry 7) is probably due to the instability of the sulfur and oxygen heterocycles at the high temperature used.
Table II.3.3. Reaction in different alcoholic medium
aYields refer to isolated and purified compounds. Parentheses indicate the yield calculated by 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as the internal standard. b All reactions were performed on a 2 mmol scale.
To further explore the effect of medium, we used methylamine and ethylmercaptan as solvents (Scheme II.3.3). In these cases, no expected product (2b and 2c) was obtained.
However, compounds 2d and 2e were formed as the primary amine and the thio nucleophiles underwent a faster Michael addition with (E)-(2-nitrovinyl)benzene than the C-nucleophile, 4-hydroxycoumarin, in the presence of a base. However, with less activated nitrogen containing nucleophiles, like aniline and N-methylaniline, a complex mixture of products was obtained.
Scheme II.3.3. Reaction in non-alcoholic medium
To study the efficacy of other Michael acceptors in this transformation, we used cinnamylnitrile (i, Scheme II.3.4) and cinnamyl gemdicarboxylate (ii). However, no Michael adduct was formed and only the starting materials were recovered.
Scheme II.3.4. The use of different Michael acceptors
The phenomenon could be explained by considering the role of the methoxide ion in the reaction, which is formed from the solvent methanol in the presence of a base (Scheme II.3.5). The initially formed Michael adduct (A) is either attacked by a methoxide ion to form intermediate B via C-O bond cleavage (Pathway a, Scheme II.3.5), or, the elimination of nitromethane occurs, accompanied by the formation of intermediate M
The phenomenon could be explained by considering the role of the methoxide ion in the reaction, which is formed from the solvent methanol in the presence of a base (Scheme II.3.5). The initially formed Michael adduct (A) is either attacked by a methoxide ion to form intermediate B via C-O bond cleavage (Pathway a, Scheme II.3.5), or, the elimination of nitromethane occurs, accompanied by the formation of intermediate M