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7.1 Introduction

The isolation and characterization of flavonoids from medicinal and economically relevant plants has been the main focus of research in the Department of Chemistry, University of Botswana since the 1980s. These research endeavors have contributed several novel flavonoid structures and promising biological activities of these isolated compounds [1]. It however became evident that the limited quantities of compounds that are isolated from plants made it difficult to develop them further into useful chemicals.

In an effort to subvert the quantity problem mentioned above, we develop a synthetic method for the preparation of flavanones from the reaction of cinnamic acids and phenols. Flavanones are a class of flavonoids that has attracted our interest because of their presence in the genus Erythrina. The genus Erythrina has been at the centre of our phytochemical work for over a decade [2,3,4]. In this review, our cinnamic acid method for the synthesis of flavanones will be compared to the conventional methods that rely on the reaction of 2-hydroxyacetophenones and benzaldehydes.

At this juncture, it is instructive to draw attention to the fact that our cinnamic acid route for the synthesis of flavanones was inspired by the biosynthetic pathway. Flavanones biosynthesis involves the chalcone synthase(CHS)-catalyzed condensation of three molecules of malonyl-CoA 1 and one molecule of p-coumaroyl-CoA 2 to give the polyketide intermediate 3 that cyclizes and aromatizes to afford chalcone 4. The chalcone is then cyclized to the corresponding flavanone 5 in a reaction catalyzed by the enzyme chalcone isomerase (CHI), as shown in Scheme 7.1 [5].

Scheme 7.1
scheme 1

Biosynthesis of flavanones

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Section 7.2 of this chapter will discuss the authors’ procedure for the synthesis of flavanones via the reaction of cinnamic acid derivatives with phenols. Section 7.3 will review the literature methods for the synthesis of flavanones via the reaction of 2-hydroxyacetophenone derivatives with benzaldehydes and compare the efficiency of these methods to the authors’ procedure.

7.2 Preparation of Flavanones via the Reaction of Cinnamic Acids and Phenols

The preparation of flavanones that involves BF3·OEt2-mediated reaction of cinnamoyl chlorides and phenols was recently reported by our group [6]. The procedure involved conversion of cinnamic acids into the corresponding cinnamoyl chlorides using thionyl chloride, reaction of the cinnamoyl chlorides with phenols in the presence of BF3·OEt2 to give chalcones and finally cyclisation of chalcones in the presence of a base to give the flavanones. For example, the reaction of cinnamic acid 6 with thionyl choride (SOCl2) gave cinnamoyl chloride 7 which was not isolated. Excess SOCl2 was removed under vacuum and cinnamoyl chloride 7 was reacted with resorcinol in the presence of BF3·OEt2 under reflux to give chalcone 8 in 72% yield (Scheme 7.2). Cyclisation of chalcone 8 in the presence of NaOH gave flavanone 9 in overall yield of 68% [6].

Scheme 7.2
scheme 2

Synthesis of flavanone 9 from cinnamic acid 6

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Further reactions involving cinnamoyl chloride 7 and phenols 10, 11 and 12 in the presence of BF3·OEt2 followed by cyclisation using NaOMe instead of KOH gave flavanones 16, 17 and 18 in 49, 57 and 36% yields respectively (Scheme 7.3) [6]. It is important to note that 4-nitrophenol and 3-nitrophenol failed to react with cinnamoyl chloride 7 to give the corresponding chalcones. The nitro group is a strongly electron-withdrawing group that deactivates the aromatic ring against electrophilic substitution reactions, therefore these results were not surprising. However, bromophenol 12, a phenol with a less electron-withdrawing bromo group, reacted with acid chloride 7 to give chalcone intermediate 15 in lower yield of 42%. Cyclisation of chalcone 15 afforded flavanone 18 in 36% overall yield.

Scheme 7.3
scheme 3

Synthesis of flavanones 16–18

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The effects of both electron donating and withdrawing groups attached to the cinnamic acid on the efficiency of the reaction were also investigated. Thus, 3-methoxycinnamic acid 19 was converted to its acid chloride using SOCl2, reacted with resorcinol to give chalcone 24 in 75% yield and then cyclized using KOH to give flavanone 29 in 92% yield (Scheme 7.4) [6]. Interestingly, subjection of 4-methoxycinnamic acid 20 to the same reaction conditions failed to give the corresponding chalcone 25. Similarly, 3-nitrocinnamic acid 21 was converted to chalcone 26 in 66% yield and chalcone 26 was subsequently cyclized in the presence of KOH to afford flavanone 30 in 90% yield. However, attempts to convert 4-nitrocinnamic acid 22 to the corresponding chalcone 27 under the same reaction conditions failed. 4-Chlorocinnamic acid 23, on the other hand was successively converted to its acid chloride and reacted with resorcinol in the presence of BF3·OEt2 to give chalcone 28 in lower yield of 44%. Cyclisation of chalcone 28 afforded flavanone 31 in 93% yield.

Scheme 7.4
scheme 4

Synthesis of flavanones 29–31

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The logical explanation for the similar effect of 4-OMe and 4-NO2 groups is that BF3·OEt2 coordinates with the oxygen atom of the methoxy group and turns it into an electron-withdrawing group. The effect is less pronounced for 3-OMe and 3-NO2 substituted cinnamic acid substrates because of lack of conjugation between the substituents and the acid carbonyl group.

To the best of the knowledge of the authors, this is the only method in the literature for the synthesis of flavanones from cinnamic acids. Flavanones were prepared in three steps in overall yields of 36–69%.

7.3 Preparation of Flavanones via the Reaction of 2-Hydroxyacetophenones and Benzaldehydes

Unlike the preparation of flavanones from the reaction of cinnamic acids and phenols described above, the synthesis of flavanones through the reaction of 2-hydroxyacetophenones and benzaldehydes has been reported extensively in the literature. The synthesis of flavanones through this route can be achieved either by a one-step process or a two-step procedure. Zhou and co-workers achieved the one-step synthesis of flavanones 37–40 in 54–68% yields from acetophenone 32 and benzaldehydes 33–36 in the presence of catalytic amount of pyrrolidine and BF3·OEt2 (Scheme 7.5) [7]. The benzaldehydes 34, 35 and 36 with electron-withdrawing groups afforded the corresponding flavanones in lower yields when compared to the benzaldehyde 33. This procedure afforded flavanones with electron-withdrawing groups on ring B in better yields that the authors’ procedure described in Sect. 7.2.

Scheme 7.5
scheme 5

One-step synthesis of flavanones 37–40 from 32

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A one-step Julia-Kocienski olefination reaction was used by Kumar and co-workers in the synthesis of an array of flavanones. The reaction involved the refluxing of sulphone 41 with benzaldehydes 33, 42, 43 and 44 in the presence of the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give flavanones 45, 46, 47 and 48 respectively in 40–68% yields (Scheme 7.6) [8]. Benzaldehyde 43 with an unprotected hydroxyl group gave the flavanone with the lowest yield. It is important to note that the authors’ procedure discussed in Sect. 7.2 tolerated free hydroxyl groups and afforded the corresponding flavanones in better yields.

Scheme 7.6
scheme 6

One-step synthesis of flavanones 45–48

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In their one-step approach to flavanones 50 and 51, Mahalle and Khaty relied on the reaction of diketone 49 with benzaldehydes 33 and 42 respectively in the presence of the base piperidine [9]. Thus, flavanones 50 and 51 were prepared in 75% yields by the condensation of diketone 49 with benzaldehydes 33 and 42 respectively in ethanol for two hours in the presence of catalytic amount of piperidine (Scheme 7.7). The products were purified by recrystallization and were afforded in slightly better yields than those achieved in the authors’ procedure discussed in Sect. 7.2.

Scheme 7.7
scheme 7

One-step synthesis of flavanones 50 and 51

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Albogami and co-workers have described the use of microwave irradiation in the one-step synthesis of flavanones. Their procedure involved reactions of acetophenones 52–54 with benzaldehyde 33 to give the corresponding flavanones 56–58 in 81–88% yield. Further reactions of 4-chlorobenzaldehyde 55 and acetophenones 52 and 53 afforded the corresponding flavanones 59 and 60 in 92 and 88% yield respectively (Scheme 7.8) [10]. This method showed an excellent tolerance of different functional groups on both the acetophenone and benzaldehyde reagents and gave yields of the flavanone that were considerably higher that those achieved by the authors’ procedure discussed in Sect. 7.2.

Scheme 7.8
scheme 8

Microwave mediated one-step synthesis of flavanones 56–60

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It is important to note that the yields of the majority of the one step-procedures discussed above were not significantly different from those achieved in the authors’ three-step procedure discussed in Sect. 7.2. The exceptions that gave significantly higher yields of the flavanones are the reactions catalyzed by an organic base and the one performed under microwave irradiation.

In addition to the one-step procedures discussed above, flavanones have been prepared via two-step procedures involving the reaction of 2-hydroxyacetophenones and benzaldehydes to give chalcones followed by cyclisation of the chalcones. The expedient synthesis of flavanone 64 for example was achieved by the condensation of 2-hydroxyacetophenone 61 and benzaldehyde 62 in the presence of KOH in ethanol to give chalcone 63 that was subsequently cyclized in the presence of sodium acetate (NaOAc) under reflux, Scheme 7.9 [11]. The overall percentage yield of this reaction was 39% and was significantly lower than that of the authors’ three-step procedure discussed in Sect. 7.2.

Scheme 7.9
scheme 9

Synthesis of flavanone 64 in two steps

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A similar two-step procedure was used by Rao and co-workers in the preparation of the protected derivative of a prenylated flavanone isolated from Dalea boliviana. Condensation of 2-hydroxyacetophenone 65 and benzaldehyde 66 in the presence of KOH gave chalcone 67 that was cyclized in the presence of NaOAc under reflux to give flavanone 68 in overall yield of 38% (Scheme 7.10) [12]. The prenyl units did not significantly affect the yield of the reaction when compared to the reaction summarized in Scheme 7.9.

Scheme 7.10
scheme 10

Synthesis of flavanone 68 in two steps

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A third approach to flavanones in two steps by Mardjan and co-workers involved condensation of 2-hydroxyacetophenone 69 with benzaldehydes 42 and 70 to give the corresponding chalcones 71 and 72 in 81 and 71% yield respectively. Cyclisation of chalcones 71 and 72 in the presence of NaOAc gave the corresponding flavanones 73 and 74 in overall yields of 54 and 42% respectively (Scheme 7.11) [13]. The presence of the acid group in the 2-acetophenone reagent is suspected to be responsible for the increase in the overall yield of this procedure. The overall yields are comparable to those achieved by the authors’ procedure discussed in Sect. 7.2.

Scheme 7.11
scheme 11

Synthesis of flavanones 73 and 74 in two steps

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In another approach to the chalcone intermediate, Ketabforoosh and co-workers used NaOH instead of KOH as the base in the condensation of 2-hydroxyacetophenone and aldehydes as illustrated in Scheme 7.12. Reactions of 2-hydroxyacetophenone 61 and benzaldehydes 70, 75 and 76 gave chalcone intermediates 77, 78 and 79 respectively [14]. It is worth noting that the reaction that involved the chloro-substituted benzaldehyde 76 gave the corresponding intermediate 79 in a very poor yield of 36%. Subsequent cyclisation of the chalcone intermediates 77–79 afforded the corresponding flavanones 80–82 in overall yields of 57, 54 and 10% respectively.

Scheme 7.12
scheme 12

Synthesis of flavanones 80–82 in two steps

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Bhasker and co-workers have reported the piperidine-mediated condensation of 2-hydroxyacetophenone 83 and benzaldehyde 42 in the synthesis of chalcone intermediate 84 that was subsequently cyclized in the presence of NaOAc to give flavanone 85 in overall yield of 49% (Scheme 7.13) [15].

Scheme 7.13
scheme 13

Synthesis of flavanone 85 in two steps

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An interesting two-step procedure was reported by Lee and co-workers and it involved the lithium diisopropylamide (LDA)-mediated condensation of 2-hydroxyacetophenones 53, 61 and 86 and benzaldehydes 22, 33 and 42 in THF to give an array of 3-hydroxyketone intermediates that were subsequently cyclized to give flavanones [16]. The condensation of benzaldehyde 33 and 2-hydroxyacetophenones 53, 61 and 86 under these conditions afforded the corresponding 3-hydroxyketone intermediates 89, 87 and 88 respectively. Cyclisation of intermediates 87, 88 and 89 by treating them with triphenylphosphine/diethyl azodicarboxylate (Ph3P/DEAD) in CH2Cl2 at 0 °C afforded the corresponding flavanones 45, 92 and 57 in overall yields of 63–69%, as shown in Scheme 7.14. In a parallel sequence of reactions, 2-hydroxyacetophenone 61 underwent condensation reactions with benzaldehydes 22 and 42 to give the corresponding hydroxyketone intermediates that were cyclised to afford flavanones 93 and 46 respectively.

Scheme 7.14
scheme 14

Synthesis of flavanones 45, 46, 57, 92 and 93

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In general, the two-step procedures involving the reaction of 2-hydroxyacetophenones or its derivatives and benzaldehydes afforded the flavanones in comparable yields to those achieved in the authors’ three-step procedure for the synthesis of flavanones from cinnamic acids described in Sect. 7.2.

7.4 Conclusion

A comparative review of the synthesis of flavanones via the reaction of cinnamic acids and phenols and via the reaction of 2-hydroxyacetophenones and benzaldehydes was achieved. Both methods afforded the flavanones in yields that were not in general significantly different. The two methods are highly complementary. Flavanones that are not accessed through one method are easily prepared using the other procedure.