Open access peer-reviewed chapter

The Oxygen-Containing Fused Heterocyclic Compounds

Written By

Hillemane Venkatachalam and Nanjangud Venkatesh Anil Kumar

Submitted: August 14th, 2018 Reviewed: June 13th, 2019 Published: July 12th, 2019

DOI: 10.5772/intechopen.88026

Chapter metrics overview

1,143 Chapter Downloads

View Full Metrics

Abstract

The oxygen-containing heterocycles are an important class of compounds in organic chemistry. These compounds are used as drugs (coumarin and oxazole), solvent (tetrahydrofuran), flavors, and fragrances (lactones). The fusion of aromatic ring to the oxygen-heterocycle will change the electron density; thereby, the physical/chemical/biological properties will alter. Also, the preparation of these fused molecules will require a different strategy/method/reaction condition. The topics covered in this chapter are the general synthetic methods and uses of fused heterocyclic compounds containing oxygen as a heteroatom. The derivatization of the primary scaffold is excluded from this chapter. Some of the fused compounds are coumarin (benzopyrans) and piclozotan (benzoxazepines).

Keywords

  • heterocycles
  • oxygen heteroatom
  • fused molecules
  • coumarin
  • a flavonoid

1. Introduction

The oxygen-containing heterocycles are an important class of compounds in organic chemistry mainly because of their natural abundance and diverse biological functions. Natural and semi-synthetic oxygen heterocyclic compounds such as Taxol [1] (anticancer), Digoxin (CHF treatment), Cyclosporine-A (immunosuppressant) and Lovastatin (hypolipidemic) are well known used as promising therapeutic compounds [2]. Kaur et al. reviewed the oxygen heterocycles wherein saturated and unsaturated compounds are considered. They discussed the classification and chemistry of each of those compounds [1]. Reports are available wherein the synthesis of natural products containing oxygen as heteroatom is reviewed by Cossy and Guérinot [2]. Also, Rowlands and Farley chaptered the book on the anion radicals from oxygen-containing heterocycles [3]. None of these reports target the oxygen-containing heterocyclic compounds where fused rings are taken into consideration.

Advertisement

2. Classification of oxygen heterocycles

The oxygen-containing heterocycles can be classified in several ways like the classification based on (a) the number of oxygen atoms, (b) saturation level, (c) aromaticity or (d) abundance. For the clarity of the concept, the classification based on a number of oxygen atoms is used. The benzene fused furan and pyrans are listed in Figure 1, whereas Figure 2 represents the compounds with two oxygen atoms in the ring system.

Figure 1.

Mono-oxygen containing fused heterocyclic compounds.

Figure 2.

Di-oxygen containing fused heterocyclic compounds.

Advertisement

3. Synthesis of benzofurans

3.1 Mono-substituted benzofurans

3.1.1 Substitution on furan ring

The ortho-hydroxystilbenes are cyclized in 70–90% yield in a metal-free environment using hypervalent iodine and 1 eq. of (diacetoxyiodo) benzene to get 2-substituted benzofurans [4]. The acids are converted to 2,4,6- trichloro-1,3,5-triazine esters, which are subsequently added to toluene, 2-hydroxybenzyl triphenylphosphonium bromide (1 eq.), and NEt3 and irradiated at 110°C for two cycles of 30 min to get the 2-substituted benzofurans having a chiral stereocenter adjacent to the heterocycle in 60–80% yield [5]. Pd-catalyzed cyclisation of 2-chloroaryl alkynes using KOH at 100°C for 8 h resulted in the formation of benzofurans [6]. All three reactions are as shown in Figure 3.

Figure 3.

Preparation of mono-substituted benzofuran.

3.1.2 Substitution on the benzene ring

Also, the substituted 1-allyl-2-allyloxybenzenes cyclizes to give substituted benzofurans by isomerization followed by ring-closure metathesis reaction using 5 mol.% catalyst [7]. The homologous members of benzofurans can be prepared by 0.1 eq. of Ru-catalyzed cycloisomerization of homo- and bis-homopropargylic alcohols in presence of pyridine at 90°C for 1–6 h [8] as shown in Figure 4.

Figure 4.

Benzene ring substituted benzofuran.

3.2 Di-substituted benzofurans

3.2.1 Substitution on furan and benzene ring of benzofuran

The reaction between 1 eq. of 2-(2-hydroxyphenyl)acetonitriles with 2 eq of aryl boronic acids along with Pd(OAc)2 (5 mol.%), bpy (10 mol.%), TFA (10 eq.), with TFA as solvent heated to 80°C for 36 h resulted in benzofuran derivatives with more than 80% yield [9]. Sonogashira cross-coupling reaction of halide with terminal alkynes followed by cyclization of the resulting 2-alkynylphenols in one-pot method results in benzofuran. The method employs the t-BuOH, PdCl2-(CH3CN)2 (2 mol.%), t-BuOLi (3.6 eq.) and 2-chlorophenol (1 eq.), alkyne (1.5 eq.) were taken in a sealed tube and heated to 110°C for 22 h to get benzofuran [10]. Reaction of N-tosylhydrazones and terminal alkyne in a ligand free environment, using 10 mol.% of CuBr and 3 eq. of Cs2CO3 at 100°C for 4 h resulted in the formation of benzofurans with 38–91% yield [11]. Reductive cyclization of 1-(2-hydroxyphenyl)-propargyl alcohols in presence of Pd(OAc)2 (5 mol.%), t-BuNC (1.2 eq.), Cs2CO3 (1.2 eq.) and MeCN as solvent gives benzofurans [12]. These reaction schemes are as shown in Figure 5.

Figure 5.

Di-substituted benzofurans.

3.2.2 2,3-Substituted benzofuran

Ring closure of 2-haloaromatic ketones (1 eq.) in presence of K3PO4 (1.5 eq.), CuI (10 mol.%) and DMF at 105°C for 12–16 h results in di-substituted benzofurans [13]. The good yield coupled with atom economy was achieved, when o-alkynyl phenyl acetals are cyclized using PtCl2 (2 mol.%), olefin (8 mol.%) in tolene at 30°C [14]. Cyclization of o-iodoanisoles and terminal alkynes under mild conditions using an electrophile (EX like PhSeCl or p-O2NC6H4SCl) (1.5 eq.), DCM at room temperature for 2–6 h yields 2,3-disubstituted benzofurans [15]. These reaction schemes are as shown in Figure 6.

Figure 6.

Preparation of di-substituted benzofuran.

Selective dehydrative C—H alkylation reaction of alkenes with alcohols using [(C6H6)(PCy3)(CO)RuH]BF4, cyclopentene, toluene at 100°C for 6–12 h results in 2,3-substituted benzofurans [16]. O-Arylhydroxylamine hydrochloride (1 eq.) with cyclic or acyclic ketones (1 eq.) in the presence of methanesulfonic acid (2 eq.), THF at 60°C for 2–24 h yields benzofurans in 40–90% yield [17]. Ketones (1 eq.) on treatment with Grignard reagents (3 eq.), benzofurans are formed, in a regioselective manner via [1,2]-aryl migration [18]. These reactions are depicted in Figure 7.

Figure 7.

Substituted benzofurans.

Base-catalyzed, the condensation of o-hydroxyphenones with 1,1-dichloroethylene, gives substituted benzofuran carbaldehydes [19].

Similarly, o-cinnamyl phenols, on oxidative cyclisation, results in 2-benzyl benzofurans [20], while o-alkylphenols, on annulative reaction, gives 3-aminobenzofurans [21] (Figure 8).

Figure 8.

Substituted benzofuran carbaldehydes.

Advertisement

4. Synthesis of benzofuranones

Alkenylphenols and phenyl formate reacts to give benzofuranones [22], while phenylacetic acids undergo cyclisation to give benzofuranones [23] (Figure 9).

Figure 9.

Synthesis of benzofuranones.

Advertisement

5. Synthesis of dibenzofurans

Iododiaryl ether cyclizes under mild conditions to yield dibenzofurans [24]. Ortho-diazonium slats of diaryl ethers undergo intramolecular cyclisation, resulting in dibenzofurans [25]. Cross-coupling of 6-diazo-2-cyclohexenones and ortho-haloiodobenzenes gives substituted dibenzofuran [26] (Figure 10).

Figure 10.

Mono substituted dibenzofurans.

Advertisement

6. Synthesis of coumarins

Phenols react with beta-keto esters to give coumarins [27]. If phenolic acetates are used, then, acrylates are used [28]. Aromatic alkynoate undergoes cyclisation with aldehydes to form 3-acyl-4-arylcoumarins [29] (Figure 11).

Figure 11.

Coumarin synthesis using phenol derivatives.

Substituted 2-hydroxybenzaldehydes react with phenylacetic acids resulting in substituted 3-aryl coumarins [30]. With dialkyl acetylenedicarboxylate, 2-hydroxybenzaldehydes gives 4-carboxyalkyl-8-formyl coumarins [31]. 2-Hydroxybenzaldehydes (or 2-hydroxybenzaldehydes) cyclizes with aryl acetic acids to give 3-aryl coumarins (or 3-aryl-4-methyl-coumarins) [32] (Figure 12).

Figure 12.

Coumarin synthesis using benzaldehyde derivatives.

Advertisement

7. Synthesis of isocoumarins

Bromoalkynes reacts with benzoic acid and produces 3-substituted isocoumarins [33]. o-Halobenzoic acids and 1,3-diketones reacts to give 3-substituted isocoumarins [34]. 2-Halobenzoates and ketones react to give the same product [35]. o-Halobenzoic acids add to alkynes resulting in isocoumarin derivatives [36] (Figure 13).

Figure 13.

Synthesis of isocoumarins.

Advertisement

8. Synthesis of flavones and flavonols

8.1 Baker-Venkataraman rearrangement

The chemical reaction between 2-hydroxyacetophenone and acid chloride in the presence of base yields 1,3-diketone which undergo rearrangement and concomitant cyclisation to produce flavone [37]. This reaction is often used to synthesize chromones and flavones (Figure 14).

Figure 14.

Synthesis of flavone (from 1,3-diketone).

8.2 Algar-Flynn-Oyamada synthesis

In this method, chalcone (1,3-diaryl-2-propen-1-one) is produced by condensing 2-hydroxyacetophenone with an aryl aldehyde in alkaline medium (Claisen-Schmidt condensation) followed by oxidative cyclisation of chalcone to get flavone [38] (Figure 15).

Figure 15.

Synthesis of flavone (from chalcone).

A mixture of acetophenone and aromatic aldehyde when exposed to Microwave irradiation, 2-phenyl γ-benzopyrones are obtained [39]. The same compound can be prepared by cyclizing 1,3-diaryl propanediones (Figure 16).

Figure 16.

Preparation of 2-phenyl γ-benzopyrones.

Advertisement

9. Conclusions

In this chapter, the synthesis of fused heterocyclic compounds having oxygen as heteroatom is considered. The care is taken not to consider the reactions, where the reactions of the compounds leading to derivatizations are not included. Benzofurans, benzofuranones, dibenzofurans, coumarins, isocoumarins, chromones, and flavones are the fused heterocyclic compounds considered in this chapter. Also, the reactions are indicative and not the detailed reaction conditions, and appropriate reagents are not included in this chapter.

Advertisement

Conflict of interest

No conflict of interest from both the authors.

References

  1. 1. Kaur P, Arora R, Gill NS. Review on oxygen heterocycles. Indo American Journal of Pharmaceutical Research. 2013;3(11):18
  2. 2. Cossy J, Guérinot A. Natural products containing oxygen heterocycles—Synthetic advances between 1990 and 2015. Advances in Heterocyclic Chemistry. 2016;119:107-142
  3. 3. Rowlands CC, Farley RD. 15.3.1 Oxygen Containing Heterocycles, vol. 26E1. 2008. pp. 308-315
  4. 4. Singh FV, Wirth T. Hypervalent iodine mediated oxidative cyclization of o-hydroxystilbenes into benzo- and naphthofurans. Synthesis. 2012;44(08):1171-1177
  5. 5. De Luca L, Giacomelli G, Nieddu G. A facile approach to the synthesis of chiral 2-substituted benzofurans. The Journal of Organic Chemistry. 2007;72(10):3955-3957
  6. 6. Anderson KW et al. The selective reaction of aryl halides with KOH: Synthesis of phenols, aromatic ethers, and benzofurans. Journal of the American Chemical Society. 2006;128(33):10694-10695
  7. 7. van Otterlo WAL et al. An isomerization-ring-closing metathesis strategy for the synthesis of substituted benzofurans. Tetrahedron. 2005;61(32):7746-7755
  8. 8. Varela-Fernández A et al. Cycloisomerization of aromatic homo- and bis-homopropargylic alcohols via catalytic Ru vinylidenes: Formation of benzofurans and isochromenes. Organic Letters. 2009;11(22):5350-5353
  9. 9. Wang X et al. Palladium-catalyzed reaction of arylboronic acids with aliphatic nitriles: Synthesis of alkyl aryl ketones and 2-arylbenzofurans. Synthesis. 2013;45(16):2241-2244
  10. 10. Wang J-R, Manabe K. Hydroxyterphenylphoshine−palladium catalyst for benzo[b]furan synthesis from 2-chlorophenols. Bifunctional ligand strategy for cross-coupling of chloroarenes. The Journal of Organic Chemistry. 2010;75(15):5340-5342
  11. 11. Zhou L et al. CuBr-catalyzed coupling of N-tosylhydrazones and terminal alkynes: Synthesis of benzofurans and indoles. Organic Letters. 2011;13(5):968-971
  12. 12. Rajesh M et al. Pd-catalyzed isocyanide assisted reductive cyclization of 1-(2-hydroxyphenyl)-propargyl alcohols for 2-alkyl/benzyl benzofurans and their useful oxidative derivatization. The Journal of Organic Chemistry. 2015;80(24):12311-12320
  13. 13. Chen C-Y, Dormer PG. Synthesis of benzo[b]furans via CuI-catalyzed ring closure. The Journal of Organic Chemistry. 2005;70(17):6964-6967
  14. 14. Nakamura I, Mizushima Y, Yamamoto Y. Synthesis of 2,3-disubstituted benzofurans by platinum−olefin-catalyzed carboalkoxylation of o-alkynylphenyl acetals. Journal of the American Chemical Society. 2005;127(43):15022-15023
  15. 15. Yue D, Yao T, Larock RC. Synthesis of 2,3-disubstituted benzo[b]furans by the palladium-catalyzed coupling of o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization. The Journal of Organic Chemistry. 2005;70(25):10292-10296
  16. 16. Lee D-H, Kwon K-H, Yi CS. Dehydrative C–H alkylation and alkenylation of phenols with alcohols: Expedient synthesis for substituted phenols and benzofurans. Journal of the American Chemical Society. 2012;134(17):7325-7328
  17. 17. Contiero F et al. Direct preparation of benzofurans from O-arylhydroxylamines. Synlett. 2009;2009(18):3003-3006
  18. 18. Pei T et al. Controlled synthesis of 2- and 3-substituted benzo[b]furans. Organic Letters. 2010;12(21):4972-4975
  19. 19. Schevenels F, Markó IE. Efficient and connective assembly of highly functionalized benzofurans using o-hydroxyphenones and dichloroethylene. Organic Letters. 2012;14(5):1298-1301
  20. 20. Rehan M et al. Synthesis of functionalized benzo[b]furans via oxidative cyclization of o-cinnamyl phenols. The Journal of Organic Chemistry. 2017;82(7):3411-3424
  21. 21. Hirano K, Satoh T, Miura M. Copper-catalyzed annulative amination of ortho-alkynylphenols with hydroxylamines: Synthesis of 3-aminobenzofurans by umpolung amination strategy. Organic Letters. 2011;13(9):2395-2397
  22. 22. Wang H et al. A palladium-catalyzed regioselective hydroesterification of alkenylphenols to lactones with phenyl formate as CO source. Organic Letters. 2014;16(1):186-189
  23. 23. Cheng X-F et al. Pd(II)-catalyzed enantioselective C—H activation/C—O bond formation: Synthesis of chiral benzofuranones. Journal of the American Chemical Society. 2013;135(4):1236-1239
  24. 24. Panda N, Mattan I, Nayak DK. Synthesis of dibenzofurans via C—H activation of o-iodo diaryl ethers. The Journal of Organic Chemistry. 2015;80(13):6590-6597
  25. 25. Du Z et al. Synthesis of dibenzofurans by palladium-catalysed tandem denitrification/C—H activation. Synlett. 2011;2011(20):3023-3025
  26. 26. Zhao H et al. A one-pot synthesis of dibenzofurans from 6-diazo-2-cyclohexenones. Organic Letters. 2015;17(23):5744-5747
  27. 27. Potdar MK, Mohile SS, Salunkhe MM. Coumarin syntheses via Pechmann condensation in Lewis acidic chloroaluminate ionic liquid. Tetrahedron Letters. 2001;42(52):9285-9287
  28. 28. Gadakh SK, Dey S, Sudalai A. Rh-catalyzed synthesis of coumarin derivatives from phenolic acetates and acrylates via C—H bond activation. The Journal of Organic Chemistry. 2015;80(22):11544-11550
  29. 29. Mi X et al. Preparation of 3-acyl-4-arylcoumarins via metal-free tandem oxidative acylation/cyclization between alkynoates with aldehydes. The Journal of Organic Chemistry. 2014;80(1):148-155
  30. 30. Sashidhara K et al. Efficient and general synthesis of 3-aryl coumarins using cyanuric chloride. Synlett. 2012;23(04):611-621
  31. 31. Majumdar K et al. Aromatic electrophilic substitution vs. intramolecular Wittig reaction: Vinyltriphenylphosphonium salt mediated synthesis of 4-carboxyalkyl-8-formyl coumarins. Synlett. 2011;2011(05):694-698
  32. 32. Phakhodee W et al. Ph3P/I2-mediated synthesis of 3-aryl-substituted and 3,4-disubstituted coumarins. Synlett. 2017;28(07):825-830
  33. 33. Jiang G et al. Palladium-catalyzed sequential nucleophilic addition/oxidative annulation of bromoalkynes with benzoic acids to construct functionalized isocoumarins. Organic Letters. 2017;19(17):4440-4443
  34. 34. Cai S, Wang F, Xi C. Assembly of 3-substituted Isocoumarins via a CuI-catalyzed domino coupling/addition/deacylation process. The Journal of Organic Chemistry. 2012;77(5):2331-2336
  35. 35. Casnati A et al. Pd-catalyzed/iodide-promoted α-arylation of ketones for the regioselective synthesis of isocoumarins. The Journal of Organic Chemistry. 2017;82(15):8296-8303
  36. 36. Guo X-X. Synthesis of isocoumarin derivatives by copper-catalyzed addition of o-halobenzoic acids to active internal alkynes. The Journal of Organic Chemistry. 2013;78(4):1660-1664
  37. 37. Baker W. 322. Molecular rearrangement of some o-acyloxyacetophenones and the mechanism of the production of 3-acylchromones. Journal of the Chemical Society (Resumed). 1933:1381-1389
  38. 38. Algar J, Flynn JP. A new method for the synthesis of flavonols. Proceedings of the Royal Irish Academy. Section B: Biological, Geological, and Chemical Science. 1934;42:1-8
  39. 39. Fridén-Saxin M et al. Synthesis of 2-alkyl-substituted chromone derivatives using microwave irradiation. The Journal of Organic Chemistry. 2009;74(7):2755-2759

Written By

Hillemane Venkatachalam and Nanjangud Venkatesh Anil Kumar

Submitted: August 14th, 2018 Reviewed: June 13th, 2019 Published: July 12th, 2019