Synlett 2018; 29(08): 1087-1091
DOI: 10.1055/s-0036-1591898
letter
© Georg Thieme Verlag Stuttgart · New York

An Efficient Microwave-Assisted Propylphosphonic Anhydride (T3P®)-Mediated One-Pot Chromone Synthesis via Enaminones

C. Balakrishna
a  Chemistry Services, GVK Biosciences Pvt. Ltd., Survey Nos:125 (part) & 126, IDA Mallapur, Hyderabad-500076, Telangana, India   Email: [email protected]
b  Department of Chemistry, GITAM University, Visakhapatnam, Rushikonda, Andhrapradesh State, 530045, India
,
Venu Kandula
a  Chemistry Services, GVK Biosciences Pvt. Ltd., Survey Nos:125 (part) & 126, IDA Mallapur, Hyderabad-500076, Telangana, India   Email: [email protected]
,
Ramakrishna Gudipati
a  Chemistry Services, GVK Biosciences Pvt. Ltd., Survey Nos:125 (part) & 126, IDA Mallapur, Hyderabad-500076, Telangana, India   Email: [email protected]
,
Satyanarayana Yennam
a  Chemistry Services, GVK Biosciences Pvt. Ltd., Survey Nos:125 (part) & 126, IDA Mallapur, Hyderabad-500076, Telangana, India   Email: [email protected]
,
P. Uma Devi
b  Department of Chemistry, GITAM University, Visakhapatnam, Rushikonda, Andhrapradesh State, 530045, India
,
Manoranjan Behera*
a  Chemistry Services, GVK Biosciences Pvt. Ltd., Survey Nos:125 (part) & 126, IDA Mallapur, Hyderabad-500076, Telangana, India   Email: [email protected]
› Author Affiliations
We are grateful to GVK Biosciences Pvt. Ltd., for financial support and encouragement.
Further Information

Publication History

Received: 16 November 2017

Accepted after revision: 26 December 2017

Publication Date:
29 January 2018 (online)

 


Abstract

An efficient synthesis of 4H-chromene-4-ones via enamino ketones, with cyclization by using T3P® under microwave heating is described. This is the first report for the synthesis of chromones by using T3P®. Significant features of this method include short reaction times and high-purity products.


#

Propylphosphonic anhydride (T3P®) has been widely used as a water scavenger and as a coupling reagent for the synthesis of amides.[1] It is available as an ethyl acetate solution, and is easy to handle. It has a broad functional-group tolerance and low toxicity, and its use results in easy workup procedures.[2] Because of these features, applications continue to be developed for this reagent.[3] For instance, T3P® has been used in dehydration chemistry that involves the conversion of carboxylic acids and amides into nitriles, as well as in the syntheses of alkenes, isonitriles, and substituted heterocycles.[4] More recently, a convenient microwave-assisted, T3P®-mediated, one-pot pyrazolone synthesis has been reported.[5]

Chromone derivatives have a wide range of biological activities,[6] and they have been shown to be inhibitors of ­tyrosine and protein kinases[7] [8] and to act as antiinflammatory,[9] antiviral,[10] antioxidant,[11] and antihypertensive agents.[10] Compounds containing the chromone moiety are also active as benzodiazepine receptors,[12] and on lipooxygenase and ­cyclooxygenase.[13] In addition, they have been shown to be anticancer agents,[14] and to activate the cystic fibrosis transmembrane conductance regulator.[15] The vast range of biological effects associated with this scaffold has resulted in the chromone ring system being considered as a privileged structure.[16]

In general, chromones are synthesized under acidic or basic conditions.[17] One of the first methods for the synthesis of chromone, introduced by Heywang and Kostanecki, involved the decarboxylation of chromone-2-carboxylic ­acid.[18] The classical 2,3-disubstituted benzopyranone synthesis utilizes acidic conditions, proceeding through an ­intra­molecular condensation of 3-aryl-1-(2-hydroxyphenyl)propane-1,3-dione derivatives. These 1,3-dione ­derivatives are usually obtained through a Bayer–­Venkataraman rearrangement or through a Claisen ester condensation reaction. Most syntheses require acidic conditions in the final step. On the other hand, syntheses utilizing basic conditions require several hours to effect the ring closure, and are far less common than those under acidic conditions.

Enaminones (β-acylated enamines) are polyfunctional reagents that have been extensively used as building blocks for the synthesis of heterocycles;[19] they have been used for the preparation of chromone scaffolds, as well as for the construction of their 3-halogenated analogues.[20] Recently, an efficient synthesis of 3-substituted chromones via enaminones was reported.[21] Silver triflate was employed for the activation of the electrophile to react with enaminone. Similarly, 3-benzylated chromones have been prepared through a cyclobenzylation reaction between enaminones and benzyl bromide in the presence of sodium iodide.[22] Compared with the synthesis of 3-substituted chromones, there are few reports on the preparation of 2,3-unsubstituted chromones by using enaminones.[23] For example, ­TMSCl/DMF has been used for the cyclodeamination reaction of enaminone 2a(see Scheme [1]) to form chromone 3a.[24] Engelhart and Aldrich reported that chromone 3a was formed while they were screening various sulfamoylating reagents for the preparation of chromone-3-sulfonamide from enaminone 2a.[25] However, the reported methods ­involve use of harsh reaction conditions and elevated temperatures, so the development of new methods for the synthesis of 2,3-unsubstituted chromones is still required.

In our continuing efforts to develop novel synthetic methods for the synthesis of natural products and derivatives,[26] we needed to synthesize a number of chromone derivatives, and we surmised that T3P® might be used for the cyclization of enaminoacetophenones, suitably substituted with a hydroxy group, to prepare the chromones. Here, we report the synthesis of chromones by using T3P® under ­microwave irradiation. This is the first example of the use of T3P® as a deamination reagent for the synthesis of chromones.

Initially, the enamino ketone 2a was prepared by the ­reaction of 1-(2-hydroxyphenyl)ethanone (1a) with N,N-­dimethylformamide dimethyl acetal [(dimethoxymethyl)di­methylamine, (MeO)2CHNMe2] in refluxing ­toluene (Scheme [1]). Compound 2a was characterized by 1H NMR and LC-MS analyses; in particular, the peak at δ = 8.2 ppm in the 1H NMR spectrum was assigned to the olefinic proton.

Zoom Image
Scheme 1 Preparation of chromones by using T3P®

The conversion of enamino ketone 2a into chromone (4H-chromen-4-one; 3a) in the presence of T3P® was taken as a model reaction. On treating enaminone 2a in the presence of a 50% solution of T3P® in EtOAc (1.0 equiv) at room temperature for 24 hours, we are pleased to find that T3P® mediated the cyclization, resulting in a 25% conversion of 2a into 3a (Table [1], entry 2). Chromone (3a) was characterized by means of IR and 1H and 13C NMR spectroscopy, as well as by elemental analysis. The reaction was allowed to continue at room temperature as no byproducts were formed (as evidenced by LC-MS analysis), but even after 48 hours, there was no increase in product formation (entry 3). We therefore attempted to optimize the reaction by changing the reaction temperature (entries 4–6) and the solvent (entries 6–8), and by using microwave heating (entries 11–14).[27]

Table 1 Screening of Optimal Cyclization Conditions

Entry

Reaction conditionsa

Yieldb (%)

 1

EtOAc, RT, 24 h

 0

 2

T3P® (1.0 equiv), EtOAc, RT, 24 h

25

 3

T3P® (1.0 equiv), EtOAc, RT, 48 h

54

 4

T3P® (1.0 equiv), EtOAc, 100 °C, 16 h

76

 5

T3P® (2.0 equiv), EtOAc, 100 °C, 12 h

85

 6

T3P® (1.0 equiv), DCE, 80 °C, 5 h

60

 7

T3P® (1.0 equiv), toluene, RT, 16 h

30

 8

T3P® (1.0 equiv), DMF, RT, 24 h

35

 9

T3P® (1.0 equiv), 1,4-dioxane, 100 °C, 16 h

78

10

PPA(1.0 equiv), 100 °C, 16 h

74

11

PPA (1.0 equiv), 60 °C, 10 min, MW

63

12

EtOAc, 90 °C, 10 min, MW

 0

13

T3P® (0.2 equiv), EtOAc, 60 °C, 10 min, MW

65

14

T3P® (1.0 equiv), EtOAc, 90 °C, 10 min, MW

92

15

T3P® (2.0 equiv), EtOAc, 90 °C, 10 min, MW

73

a Reaction conditions: 2a (1.0 equiv), solvent (1 mL).

b Isolated yield.

Performing the cyclization under microwave-heating conditions at 90 °C in the presence of T3P® (0.2 equiv) in ethyl acetate for ten minutes afforded a 65% yield of chromone (3a; Table [1], entry 13). When the amount of T3P® was increased to 1.0 equiv, the yield of 3a increased to 92% (­entry 14), but the use of an excess of T3P® under the same conditions led to a decrease in the yield (entry 15). Finally, to confirm that the ring-closing deamination was mediated by T3P®, a control experiment was conducted. As expected, heating compound 2a in EtOAc at 100 °C without T3P® for ten minutes with microwave irradiation resulted in no conversion (entry 12).

After optimizing the reaction conditions for the cyclization of 2a to obtain chromone (3a), we were interested in exploring a one-pot procedure for the synthesis of 3a (Scheme [2]). Compound 1a was treated with (MeO)2CHNMe2 (1.0 equiv) in a microwave vial and heated at 100 °C. After ten minutes, complete conversion of compound 1a was observed by LC-MS analysis. T3P® (1.0 equiv) was then added, and the mixture was heated at 90 °C for ten minutes, leading to the isolation of 3a in 92% yield, a comparable yield with that of the two-step procedure.[28]

Zoom Image
Scheme 2 One-pot synthesis of chromone using T3P®

To prove the generality of this method, the reactions of various aryl and hetaryl acetophenones were examined, and the results are summarized in Table [2]. Higher yields were observed for substrates having electron-donating groups on the aromatic ring (3g, 3h) compared with those with electron-withdrawing groups (3d, 3i). Importantly, previously inaccessible naphthalene analogues and substituted pyrazole analogues were synthesized in good yields (3o, 3p),[29] and the acid-sensitive benzodioxole ring was not affected during the two-step one-pot procedure using T3P®. Acetophenones having bulky substituents (3m, 3o) were also converted into the corresponding chromones in good yields.

Table 2 Synthesis of Substituted Chromones with T3P® under Microwave Irradiation

Entry

Acetophenone

Product

Yield (%)

1

92

2

90

3

80

4

75

5

92

6

70

7

89

8

95

 9

85

10

85

11

91

12

90

13

87

14

90

15

90

16

83

17

87

18

80

19

74

20

80

A one-step synthesis of chromone was also attempted, but when 1-(2-hydroxyphenyl)ethanone (1a) was treated with (MeO)2CHNMe2 in the presence of T3P® in ethyl acetate, and the mixture was heated to 110 °C for 16 hours or subjected to microwave irradiation, no product was formed, as evidenced by LC-MS analysis.

In summary, we have developed a novel, efficient and easily reproducible T3P®-mediated formation of chromones from readily available o-hydroxyacetophenones under ­microwave irradiation. This protocol offers a useful alternative to the strongly acidic conditions that are generally ­required for this conversion. The reaction conditions are simple and sufficiently mild to tolerate various functionalities that can serve as platforms for further functionalization of the chromone products. We believe that this metho­dology will find widespread application in the synthesis of chromone derivatives.


#

Acknowledgements

The help from the analytical department is appreciated. We thank Dr. Sudhir Kumar Singh for his invaluable support and motivation.

Supporting Information

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    • 23a Föhlisch B. Chem. Ber. 1971; 104: 348
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    • 26a Ravi Kumar P. Behera M. Raghavulu K. Jaya Shree A. Satyanarayana Y. Tetrahedron Lett. 2012; 53: 4108
    • 26b Ravi Kumar P. Behera M. Sambaiah M. Venu K. Nagaraju P. Jaya Shree A. Satyanarayana Y. J. Amino Acids 2014; 721291
    • 26c Balakrishna C. Nagaraju P. Satyanarayana Y. Uma Devi P. Behera M. Bioorg. Med. Chem. Lett. 2015; 25: 4753
    • 26d Sambaiah M. Raghavulu K. Shiva Kumar K. Satyanarayana Y. Behera M. New J. Chem. 2017; 41: 10020
    • 26e Kandula V. Gudipati R. Chatterjee A. Kaliyaperumala M. Yennam S. Behera M. J. Chem. Sci. 2017; 129: 1233
    • 27a Kappe CO. Angew. Chem. Int. Ed. 2004; 43: 6250
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  • 28 6-(1,3-Benzodioxol-5-yl)-4H-chromen-4-one (3t); Typical Procedure A mixture of acetophenone derivative 1t (100 mg, 0.39 mmol) and (MeO)2CHNMe2 (0.051 mL, 0.39 mmol) was introduced into a 2–5 mL pressure-resistant vial, and the mixture was subjected to microwave irradiation for 10 min at 100 °C. The mixture was then cooled to RT, a 50% solution of T3P® in EtOAc (0.25 mL, 0.39 mmol) was added, and the mixture was irradiated for a further 10 min at 90 °C until the reaction was complete (TLC; 30% EtOAc–PE). The crude mixture was diluted with EtOAc (10 mL) and washed with H2O (5 mL) and brine (4 mL), then dried (­Na2SO4). After filtration and removal of the solvent, the crude product was purified by column chromatography (silica gel, EtOAc–hexane) to give a white solid; yield: 83 mg (80%); mp 177–179 °C. FTIR (KBr): 3072, 1645, 1463, 1305, 1224, 1120, 1024, 921, 821 cm−1. 1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 2.4 Hz, 1 H), 7.87–7.81 (m, 2 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.13–7.12 (m, 2 H), 6.91 (d, J = 8.8 Hz, 1 H), 6.37 (d, J = 6 Hz, 1 H), 6.01 (s, 2 H). 13C NMR (125 MHz, CDCl3): δ = 177.6, 155.6, 155.2, 148.3, 147.5, 138.1, 133.5, 132.3, 124.9, 123.1, 120.8, 118.6, 112.9, 108.7, 107.6, 101.3. MS (EI): m/z (%) = 267 [M + 1]+ (100). HRMS (ESI): m/z [M + H]+ calcd for C16H10O4: 267.0654; found: 267.0657.
    • 29a Xiang H. Zhao Q. Tang Z. Xiao J. Xia P. Wang C. Yang C. Chen C. Yang H. Org. Lett. 2017; 19: 146
    • 29b Hardcastle IR. Cockcroft X. Curtin NJ. Desage El-Murr M. Leahy JJ. J. Stockley M. Golding BT. Rigoreau L. Richardson C. Smith GC. M. Griffin RJ. J. Med. Chem. 2005; 48: 7829

  • References

    • 1a Wissmann H. Kleiner HJ. Angew. Chem. Int. Ed. Engl. 1980; 19: 133
    • 1b Escher R. Bünning P. Angew. Chem. Int. Ed. Engl. 1986; 25: 277
  • 2 Llanes García AL. Synlett 2007; 1328
  • 3 Waghmare AA. Hindupur RM. Pati HN. Rev. J. Chem. 2014; 4: 53
    • 4a Desroses M. Wieckowski K. Stevens M. Odell LR. Tetrahedron Lett. 2011; 52: 4417
    • 4b Augustine JK. Atta AN. Ramappa BK. Boodappa C. Synlett 2009; 3378
    • 4c Ragghavendra GM. Ramesha AB. Revanna CN. Nandeesh KN. Mantelingu K. Rangappa KS. Tetrahedron Lett. 2011; 52: 5571
    • 4d Wen X. El Bakali J. Deprez-Poulain B. Deprez B. Tetrahedron Lett. 2012; 53: 2440
    • 4e Poojari S. Parameswar Naik P. Krishnamurthi G. Tetrahedron Lett. 2012; 53: 4639
    • 4f Jida M. Deprez B. New J. Chem. 2012; 36: 869
  • 5 Desroses M. Jacques-Cordonnier MC. Llona-Minguez S. Jacques S. Koolmeister T. Helleday T. Scobie M. Eur. J. Org. Chem. 2013; 5879
  • 6 Reis J. Gaspar A. Milhazes N. Borges M. J. Med. Chem. 2017; 60: 7941
  • 7 Leahy JJ. J. Golding BT. Griffin RJ. Hardcastle IR. Richardson C. Rigoreau L. Smith GC. M. Bioorg. Med. Chem. Lett. 2004; 14: 6083
  • 8 Griffin RJ. Fontana G. Golding BT. Guiard S. Hardcastle IR. Leahy JJ. J. Martin N. Richardson L. Rigoreau M. Stockley GC. M. Smith C. J. Med. Chem. 2005; 48: 569
  • 9 Kim HP. Son KH. Chang HW. Kang SS. J. Pharmacol. Sci. (Tokyo, Jpn.) 2004; 14: 6083 10.1254/jphs.CRJ04003X
  • 10 Bhat AS. Whetstone JL. Brueggemeier RW. Tetrahedron Lett. 1999; 40: 2469
    • 11a Benett CJ. Caldwell ST. McPhail DB. Morrice PC. Duthie GG. Hartley RC. Bioorg. Med. Chem. 2004; 12: 2079
    • 11b Krishnamachari V. Levin LH. Zhou C. Paré PW. Chem. Res. Toxicol. 2004; 17: 795
  • 12 Marder M. Viola H. Bacigaluppo JA. Colombo MI. Wasowski C. Wolfman C. Medina JH. Rúveda EA. Paladini AC. Biochem. Biophys. Res. Commun. 1998; 249: 481
  • 13 Hoult JR. S. Moroney MA. Payá M. Methods Enzymol. 1994; 234: 443
  • 14 Parmar VS. Bracke ME. Philippe J. Wengel J. Jain SC. Olsen CE. Bisht KS. Sharma NK. Courtens A. Sharma SK. Vennekens K. Van Marck V. Singh SK. Kumar N. Kumar A. Malhothra S. Kumar R. Rajwanshi VK. Jain R. Mareel MM. Bioorg. Med. Chem. 1997; 5: 1609
  • 15 Galietta LJ. Springsteel MF. Eda M. Neidzinsk EJ. By K. Haddadin MJ. Nantz MH. Verkman AS. J. Biol. Chem. 2001; 276: 19723
    • 16a Horton DA. Bourne GT. Smythe ML. Chem. Rev. 2003; 103: 893
    • 16b Gaspar A. Matos JM. Garrideo J. Uriarte E. Borges F. Chem. Rev. 2014; 114: 4960
  • 17 Rangappa SK. Srinivasa B. Pai RK. Balakrishna RG. Eur. J. Med. Chem. 2014; 78: 340
  • 18 Li N.-G. Shi Z.-H. Tang Y.-P. Ma H.-Y. Yang J.-P. Li B.-Q. Wang Z.-J. Song S.-L. Duan J.-A. J. Heterocycl. Chem. 2010; 47: 785
    • 19a Elassar A.-ZA. Ei-Khair AA. Tetrahedron 2003; 59: 8463
    • 19b Riyadh SM. Abdelhamid IA. Al-Matar HM. Hilmy NM. Elnagdi MH. Heterocycles 2008; 75: 1849
    • 20a Gammill RB. Synthesis 1979; 901
    • 20b Biegasiewicz KF. St Denis JD. Carrol VM. Priefer R. Tetrahedron Lett. 2010; 51: 4408
    • 20c Ravi Kumar P. Balakrishna C. Murali B. Gudipati R. Hota PK. Chaudhary AB. Jaya Shree A. Yennam S. Behera M. J. Chem. Sci. 2016; 128: 441
  • 21 Joussot J. Schoenfelder A. Larquetoux L. Nicolas M. Suffet J. Blond G. Synthesis 2016; 48: 3364
  • 22 Lin Y.-F. Fong C. Peng W.-L. Tang K.-C. Liang Y.-E. Li W.-T. J. Org. Chem. 2017; 82: 10855
    • 23a Föhlisch B. Chem. Ber. 1971; 104: 348
    • 23b Pleier A.-K. Glas H. Grosche M. Sirsch P. Thiel WR. Synthesis 2001; 55
    • 23c Khoobi M. Alipour M. Zarei S. Jafarpour F. Shafiee A. Chem. Commun. 2012; 48: 2985
  • 24 Iaroshenko VO. Mkrtchyan S. Gevorgyan A. Miliutina M. Villinger A. Volochnyuk D. Sosnovskikh VY. Langer P. Org. Biomol. Chem. 2012; 10: 890
  • 25 Engelhart CA. Aldrich CC. J. Org. Chem. 2013; 78: 7470
    • 26a Ravi Kumar P. Behera M. Raghavulu K. Jaya Shree A. Satyanarayana Y. Tetrahedron Lett. 2012; 53: 4108
    • 26b Ravi Kumar P. Behera M. Sambaiah M. Venu K. Nagaraju P. Jaya Shree A. Satyanarayana Y. J. Amino Acids 2014; 721291
    • 26c Balakrishna C. Nagaraju P. Satyanarayana Y. Uma Devi P. Behera M. Bioorg. Med. Chem. Lett. 2015; 25: 4753
    • 26d Sambaiah M. Raghavulu K. Shiva Kumar K. Satyanarayana Y. Behera M. New J. Chem. 2017; 41: 10020
    • 26e Kandula V. Gudipati R. Chatterjee A. Kaliyaperumala M. Yennam S. Behera M. J. Chem. Sci. 2017; 129: 1233
    • 27a Kappe CO. Angew. Chem. Int. Ed. 2004; 43: 6250
    • 27b Dai W.-M. Shi J. Comb. Chem. High Throughput Screening 2007; 10: 837
    • 27c Kappe CO. Dallinger D. Mol. Diversity 2009; 13: 71
  • 28 6-(1,3-Benzodioxol-5-yl)-4H-chromen-4-one (3t); Typical Procedure A mixture of acetophenone derivative 1t (100 mg, 0.39 mmol) and (MeO)2CHNMe2 (0.051 mL, 0.39 mmol) was introduced into a 2–5 mL pressure-resistant vial, and the mixture was subjected to microwave irradiation for 10 min at 100 °C. The mixture was then cooled to RT, a 50% solution of T3P® in EtOAc (0.25 mL, 0.39 mmol) was added, and the mixture was irradiated for a further 10 min at 90 °C until the reaction was complete (TLC; 30% EtOAc–PE). The crude mixture was diluted with EtOAc (10 mL) and washed with H2O (5 mL) and brine (4 mL), then dried (­Na2SO4). After filtration and removal of the solvent, the crude product was purified by column chromatography (silica gel, EtOAc–hexane) to give a white solid; yield: 83 mg (80%); mp 177–179 °C. FTIR (KBr): 3072, 1645, 1463, 1305, 1224, 1120, 1024, 921, 821 cm−1. 1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 2.4 Hz, 1 H), 7.87–7.81 (m, 2 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.13–7.12 (m, 2 H), 6.91 (d, J = 8.8 Hz, 1 H), 6.37 (d, J = 6 Hz, 1 H), 6.01 (s, 2 H). 13C NMR (125 MHz, CDCl3): δ = 177.6, 155.6, 155.2, 148.3, 147.5, 138.1, 133.5, 132.3, 124.9, 123.1, 120.8, 118.6, 112.9, 108.7, 107.6, 101.3. MS (EI): m/z (%) = 267 [M + 1]+ (100). HRMS (ESI): m/z [M + H]+ calcd for C16H10O4: 267.0654; found: 267.0657.
    • 29a Xiang H. Zhao Q. Tang Z. Xiao J. Xia P. Wang C. Yang C. Chen C. Yang H. Org. Lett. 2017; 19: 146
    • 29b Hardcastle IR. Cockcroft X. Curtin NJ. Desage El-Murr M. Leahy JJ. J. Stockley M. Golding BT. Rigoreau L. Richardson C. Smith GC. M. Griffin RJ. J. Med. Chem. 2005; 48: 7829

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Scheme 1 Preparation of chromones by using T3P®
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Scheme 2 One-pot synthesis of chromone using T3P®