**5. Synthesis**

#### **5.1 Biosynthesis**

There are two general routes for the biosynthesis of phenolic compounds; shikimic acid pathway and the acetic acid pathway [12, 28]. In the shikimic acid pathway (**Figure 35**), hosphoenolpyruvate and erthrose-4-phosphate react in few steps to provide 3-dehydroquinate. Dehydration with shikimate dehydrogenase gives 3-dehydroshikimic acid. Reduction with NADPH gives shikimic acid. 3-Dehydroshikimic acid could lead to gallic acid in several steps. Shikimic acid is then converted into chorismic acid which undergoes Claisen rearrangement to afford prephenic acid. The

*Phenolic Compounds: Classification, Chemistry, and Updated Techniques of Analysis… DOI: http://dx.doi.org/10.5772/intechopen.98958*

**Figure 35.** *Shikimic acid pathway toward phenolic compounds.*

product is then converted in several steps into tyrosine. The amino acid serves as a central point and a crucial precursor for the biosynthesis of various phenolic compounds (**Figure 35**).

Another route toward phenolic compounds, is the phenylpropanoid pathway (**Figure 36**). This route is essentially similar to the shikimic acid pathway until L-phenylalanine stage where the phenylpropanoid pathway takes form. L-Phenylalanine undergoes deamination catalyzed by phenylalanine ammonia lyase (PAL) enzyme to give cinnamic acid. Hydroxylation followed by conversion to the Coenzyme A provides *p*-coumaroyl Coenzyme A. This molecule serves as a central point toward various phenolic compounds.

#### **5.2 Synthesis**

There have been many methods that are used to synthesize phenolic compounds in the laboratory. For instance, phenolic compounds were obtained using

#### **Figure 36.**

*The phenylpropanoid pathway toward phenolic compounds.*

Copper-catalyzed synthesis from 1,3-dicarbonyl compounds employing dimethylsulfoxide (DMSO) as a methylene source (**Figure 37**) [29].

Phenolic compounds have also been obtained using biocatalysis. Thus phenolic compounds were synthesized by lipase-catalyzed synthesis (**Figure 38**) [30].

Various imine phenolic compounds were synthesized starting from 3-aminobenzoic acids as schematically represented below (**Figure 39**) [31].

Various Schiff bases were also accessed from 3-nitroaniline (**Figure 40**) [31].

Other azomethine-based phenolic compounds were prepared from 3-nitroacetophenone (**Figure 41** i) [31].

Sulfonyl amide phenolic compounds were prepared from 3-nitrobenzenesulfonyl chloride (**Figure 41** ii) [31].

Carbohydrate-based polyphenolic compounds were synthesized from 1,5-anhydro-D-glucitol as schematically shown below (**Figure 42**) [32]. Thus maplexin J (R1 = R2 = R3 = OH) and its derivatives were synthesized using this route.

Another example is the synthesis of an analog of tellimagrandin I from benzyl glucoside (**Figure 43**) [32].

**Figure 37.**

*Copper-catalyzed synthesis of phenolic compounds from 1,3-dicarbonyl compounds.*

**Figure 38.**

*Lipase-catalyzed synthesis of phenolic compounds.*

**Figure 39.** *Synthesis of imine phenolic compounds.*

*Phenolic Compounds: Classification, Chemistry, and Updated Techniques of Analysis… DOI: http://dx.doi.org/10.5772/intechopen.98958*

**Figure 40.**

*Synthesis of imine phenolic compounds.*

**Figure 41.** *Synthesis of imine phenolic compounds.*

**Figure 42.**

*Synthesis of maplexin J and its derivatives from 1,5-anhydro-D-glucitol.*

#### **Figure 43.** *Synthesis of tellimagrandin I analog.*

Functionalization and expeditious transformation of phenol derivatives into new functional molecules have been made possible with metal-catalyzed C-H bond functionalization [28, 29]. The C-H activation science has allowed accessing new and further functionalized phenol derivatives in an expedient and efficient manner (**Figure 44**). Thus catalysts based on various transition metals such as Pd, Rh, Ru, Ir, Au and Fe have allowed functionalization of inert C-H bonds in simple phenolic compounds and subsequently their transformation into new functionalized molecules [33, 34].

Recently, 1,3-dipolar cycloaddition (Click chemistry) of cellulose-based azides with alkynes derived from phenolic compounds were transformed into new phenolic compounds-based adducts (**Figure 45**). The new triazole products display some applicable anti UV properties [35].

Simple phenolic compounds such as 4-aminophenol were transformed, *via* Click chemistry between their alkynes and aryl azides, into new triazole-containing isoindoline derivatives (**Figure 46**). The products obtained were of potential biological activities [36].

**Figure 44.** *C-H bond functionalization of phenol derivatives.*

**Figure 45.** *1,3-Dipolr cycloaddition of cellulose-based azides with alkynes obtained from phenolic compounds.*

**Figure 46.** *1,3-Diploar cycloaddition of alkynes obtained from 4-aminphenol with aryl azides.*

**Figure 47.** *1,3-Diploar cycloaddtion of alkynes derived from natural phenolic compounds and aryl azides.*

*Phenolic Compounds: Classification, Chemistry, and Updated Techniques of Analysis… DOI: http://dx.doi.org/10.5772/intechopen.98958*

Natural phenolic compounds were transformed via ther alkyne-derivatives into the corresponding triazole adducts by the click reaction with aryl azides (**Figure 47**). The method demonstrates an example of synthetic elaboration of phenolic compounds into new ones of potential biological functions [37].
