The Pharma Innovation Journal 2019; 8(5): 580-595 ISSN (E): 2277- 7695 ISSN (P): 2349-8242 NAAS Rating: 5.03 Cinnamic acid derivatives: An ERA TPI 2019; 8(5): 580-595 © 2019 TPI www.thepharmajournal.com Nitish Kumar and Amrita Parle Received: 25-03-2019 Accepted: 29-04-2019 Abstract Nitish Kumar Cinnamic acid and its derivatives are a class of unsaturated compounds containing carboxyl group. Department of Pharmaceutical Cinnamic acids are present almost in all green plants even though in minute quantities. They are obtained Chemistry, Delhi Institute of from natural sources and some are synthesized chemically as well as enzymatically. Cinnamic acid and Pharmaceutical Sciences and its derivatives possess pharmacological actions like: anti-oxidant, antiviral, anti-diabetic, CNS Research, New Delhi, India depressant, hepatoprotective etc. Currently they are attaining considerable importance for their anti- microbial activity. Current marketed preparations containing cinnamic acid as core moiety and ongoing Amrita Parle clinical trials of cinnamic acid derivatives are also included in this review. Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Keywords: Cinnamic acid, antimicrobial, anti-diabetic, marketed preparations, clinical trials Research, New Delhi, India Introduction Cinnamic acid is an unsaturated carboxylic acid having formula C6H5CHCHCOOH. Properties of cinnamic acid are described in Table 1. Table 1: Properties of cinnamic acid. S. No. Cinnamic Acid 1. Physical state Crystalline Compound 2. Colour White 3. Odour Honey like Odour 4. Solubility Slightly soluble in water, and freely soluble in many organic solvents [1]. 5. Melting Point 133oC 6. Boling Point 300oC 7. Acidity[pKa] 4.44 Geometric It exists as both a cis and a trans isomer [2] in which trans isomer is more 8. Isomerism common [Figure 1]. H H O H OH H O H rans-cinnamic acid cis-cinnamic acid Fig 1: Structure of cinnamic acid Sources of cinnamic acid and its derivatives Cinnamic acid and its derivatives are found in natural sources or can be synthesized in laboratory. Natural sources Cinnamic acid is present almost in all green plants even though in minute quantities [3]. The term cinnamic is derived from the spice cinnamon [Cinnamomum zeylanicum] [4]. Cinnamic acid is found in free form or as an ester, amide, alcohol or aldehydic derivative. They are Correspondence [5] Nitish Kumar obtained from oil of Cinnamon, balsam of Peru, balsam of Tolu, Storax and Benzoin . Some Department of Pharmaceutical other plants like coffee beans, tea, mate, cocoa, apples and pears, berries, citrus, grape, Chemistry, Delhi Institute of brassicas vegetables, spinach, beetroot, artichoke, potato, tomato, celery, faba beans, and Pharmaceutical Sciences and cereals also contain cinnamic acid and/or its derivatives [6]. Research, New Delhi, India ~ 580 ~ The Pharma Innovation Journal In biological chemistry, Cinnamic acid is a key intermediate [anthocyanins for pigmentation, flavonoids protect against in biosynthetic pathways such as shikimate and phenyl- UV photodamage] [7, 8]. propanoid pathway in green plants, algae, fungi, and even in Since ancient times they are used for flavouring the food some prokaryotes and leads to the formation of secondary preparations. Medicinally it is used as stimulant, carminative, metabolites such as lignin, isoflavonoids, flavonoids, antiseptic and insecticide [9]. Cinnamic acid derivatives found anthocyanins, coumarin etc. These secondary metabolites play in plants, their structure, source and pharmacological actions significant roles in physiological change in plants are depicted in Table 2. Table 2: Cinnamic acid derivatives found in plants. Cinnamic acid S. No. Structure Source Pharmalogical activity Reference derivative Cinnamic Esters O HO Anti-diabetic activity Solanum [10] 1. Methyl caffeate OCH3 against streptozotocin . torvum Swartz. induced diabetic rats HO O H3CO Ethyl 3,4,5- OCH2CH3 2. trimethoxy Piper longum Anti-inflammatory [11]. cinnamate H3CO OCH3 Cinnamic amide O O H3CO N 3. Piplartine Piper longum Anticancer [12]. H3CO OCH3 Cinnamic alcohol OH Cinnamomum Perfumes, tonics and 4. Cinnamyl alcohol [13]. species other hair grooming aid H3CO OH 5. Coniferyl alcohol Gum Benzoin fungal growth inhibitor [14]. HO H3CO OH Bio- synthesized via Anti-inflammatory and 6. Sinapyl alcohol [15]. HO pheyl- anti-nociceptive effects propanoid OCH3 Cinnamic aldehyde O Flavouring agent, [16]. Attenuates pressure Oil of [17] 7. Cinnamaldehyde H overload-induced cardiac . Cinnamon hypertrophy, Anti-diabetic. [18]. O HO Piper 8. Caffeic aldehyde H antitubercular [19]. taiwanense, HO Synthesis of cinnamic acid and its derivatives cinnamic acid and its derivatives. Different synthetic methods used for preparation of cinnamic Condensation of an aromatic aldehyde and acid anhydride acid and its derivatives are: takes place in this reaction, in the presence of an alkali salt [Sodium acetate] of the acid, which acts as a base catalyst and 1. Perkin reaction gives α, β-unsaturated aromatic acid [20]. Perkin reaction is not Perkin reaction is an organic reaction named after William possible with simple aliphatic aldehyde or aromatic ketones. Henry Perkin. It is a primary method for the synthesis of ~ 581 ~ The Pharma Innovation Journal Scheme 1a produce cinnamic acids [25]. It is simple and eco-friendly In presence of anhydrous sodium acetate, benzaldehyde and procedure for the synthesis of cinnamic acid. Excellent yield acetic anhydride is condensed to form cinnamic acid [21]. and high purity of product are obtained. Aldehyde leads to the formation of unwanted side product like alcohols in presence of bases which is main disadvantage COOH TBAB, K2CO3, H2O of this method. R CH2(COOH)2 R MW, 900 W R' COOH CHO NaOAc R' O (CH3CO)2O Ar aldehyde or ketones cinnamic acid derivative Benzaldehyde Cinnamic acid R/R' = H/H; 4-OMe/H; 4-NO2/H; 3-Br/H; 2, 4-Cl/H; 4- OH/H; H/CH3; 4-Br/CH3; 4-NO2/CH3 Scheme 1b Benzaldehyde converts into cinnamic acid via perkin reaction Scheme 2c in presence of acetic anhydride and biodegradable deep Under mild condition, aqueous extract of Acacia concinna eutectic solvent [DES] based on choline chloride and urea, in pods catalyze the condensation of Meldrum’s acid with 4 hours at 30±2oC. The yield obtained is 92% yield [22]. aromatic aldehyde to yield cinnamic acids via Knoevenagel condensation [26]. Excellent yield[95%], eco-friendly, easy O O availability of catalyst and simple reaction procedure are the advantages of this method. H OH (CH3CO)2O , DES O aqueous extract 30 2oC of CHO O Acacia concinna COOH pods Benzaldehyde Cinnamic acid 60oC O H 2. Knoevenagel condensation O The Knoevenagel condensation reaction is an organic reaction developed by Emil Knoevenagel. Malonic acid undergoes 3. Phosphorous oxychloride method knoevenagel condensation with almost every type of aldehyde Scheme 3a and very reactive ketones. Methylenemalonic acids are Aromatic aldehydeis condensed with N-aroylglycine by usually obtained, if condensation [with malonic acid] is heating in phosphorusoxychloride leads to 4- performed in ethanolic ammonia below 70⁰C. If, however, benzylideneoxazol-5-one derivative in high yield. On basic solvents like pyridine and piperidine [Doebner hydrolysis of 4-benzylideneoxazol-5-one derivative, α- modification] are used in place of ethanolic ammonia, benzoylaminocinnamic acid is formed [27]. This procedure is decarboxylation normally takes place and acrylic or cinnamic somewhat lengthy and energy consuming. [23] acid is formed . O O CHO Scheme 2a H2C C OH POCl3 Aryl aldehyde reacts with malonic acid under microwave heat N O HN C C H irradiation in presence of polyphosphate ester which acts as 6 5 catalyst and reaction mediator gives cinnamic acid and its O derivatives as the product [24]. There is advantage of this method over Perkin reaction is that electron donor substituent like 2, 6-dimethylbenzaldehyde can be used for synthesis of cinnamic acid. Long reaction time is disadvantage of this method. hydrolysis R CHO COOH O O MW, PPE CH2(COOH)2 OH HN R Benzeldehyde Cinnamic acid α-benzoylaminocinnamic acids R = 4-Br; 3, 4-di [OMe]; 4-OH; 4-NO2; 2, 5-di [OMe]; OMe; 4-Me; 3-Cl; H. 4. From benzal chloride Scheme4a Scheme 2b Benzal chloride and anhydrous acetate is heated at 180° to Aromatic aldehye or ketone and malonic acid undergo 200° C for 10 hours to get the desired product cinnamic acid Knoevenagel condensation in presence of tetra butyl [28]. This procedure is also being used for commercial ammoniumbromide [TBAB] and potassium carbonate preparations. Benzal chloride used in this reaction is cheaper [K2CO3] under microwave irradiation in presence of water to than benzaldehyde. ~ 582 ~ The Pharma Innovation Journal Cl O products can be obtained in aqueous solution at ambient O O temperature using this method [31]. It is also well accepted Cl OH method for commercial preparations. (n) MO CH 3 (m-n) M1O CH3 X Benzal chloride Wherein I RT, 4.5 h . M and M1 are the same or different and are alkali metals. X . M and N are integers from 0-3. PdCl2, Na2CO3, TBAB, H2O R1 R2 R1 R2 5. Under ultrasonication method R Scheme 5a R Arylpropene is used to synthesize cinnamaldehyde[trans] by R = H, OMe, Cl, Br, NHCOMe, or NO using DDQ [2, 3-Dichloro-5, 6-dicyno-1, 4-benzoquinone] 2 R1= I, CHO, H and few drops of acetic acid [29]. Economical substrates, 100% R2= I or H [E]-selectivity of cinnamaldehyde and atom economy are X = CO Me, COOH, CN or Ph merits of this process. 2 O Scheme 6c Diatomite-supported palladium nanoparticles have been prepared by following way DDQ(3.1 equiv.), acetic acid H Ultrasonic condition SnCl H O H PdCl 2 2 2 4 Diatomite-supported Pd R Diatomite R CF COOH PVP Cinnamaldehyde 3 6. Heck coupling reaction Prepared Pd-nanoparticle is used in the reaction of aryl halide When Aryl halide is coupled with alkene in presence of a base and methyl acrylate which gives cinnamic acid derivatives as and palladium as catalyst, the reaction is referred as Heck product in presence of a solvent NMP [N-Methyl pyrolidine] [32] coupling reaction.