Polyphosphoric Acid in Organic Synthesis

Polyphosphoric acid (PPA), a powerful dehydrating agent, has been widely used to perform several important organic reactions and thus has played an important role in the synthesis of organic compounds and natural products. The present micro review describes briefly the use of PPA (i) in the cyclization of acids on the aromatic ring (ii) in acetylation and isopropylation on the aromatic ring, (iii)hydrolysis of esters, (iv) cleavage of epoxides and (v) synthesis of heterocyclic compounds


Introduction
The commercially available PPA is hygroscopic, highly viscous, clear, colorless, or light amber liquid.The acid is neither soluble nor reacts with nonpolar organic solvents such as toluene or hexane.PPA is prepared by mixing phosphoric acid (85% , d 1.7 g mL-1) with phosphorous pentoxide (P 2 O 5 ) followed by heating at 200 o C for 30 min.Due to high viscosity PPA is difficult to pour and stir at room temperature but is much easier to work with a temperature above 60 o C. The addition of solvents, such as xylene, simplifies the difficult workup usually associated with PPA.Ice is normally used during the work-up to moderate the exothermic reaction that occurs with water.The commercially available PPA contains 82-85 % P 2 O 5 .The powerful dehydrating properties, low nucleophilicity and moderate acidity explain the reasons for the wide applications of PPA in organic synthesis.

Cyclization of Acids
Several acids on the aromatic ring have been cyclized with PPA to obtain cyclic ketones and some of these ketones have been utilized for the synthesis of natural products.Some examples are given below.
The acid 1 in Scheme 1, obtained by Friedel-Crafts alkylation of p-xylene with 5-chlorovaleric acid in presence of aluminum chloride, on cyclization with PPA yields the cyclic ketone 2 (Banerjee etal. 2002) which on heating with 2,4pentanediol and p-toluenesulfonic acid (Vuligonda etal.1996)yields the alkene 3. The transformation of the alkene 3 to the reported benzsuberone 4 (Ho & Lin, 1999) is achieved in four steps respectively: acetylation [manganese (III) acetate dihydrate], alkaline hydrolysis (NaOH, MeOH), catalytic hydrogenation (H 2 , PtO 2 ) and oxidation with Jones reagent (Bowers etal., 1953).The Wittig reaction of 4 with ethoxy carbonyl methylenetriphenylphosphorene in the presence of a catalytic quantity of benzoic acid in toluene gives the ester 5.The ester is not obtained in good yield with cinnamic acid.Scheme 1. Synthesis of tavacpallescenicine by cyclization of aromatic acid 1 Oxidative cyclization of the ester 5 with selenium dioxide in acetic acid furnishes butenolide 6 whose transformation to tavacpallescencine 7 has already been accomplished by heating with DIBAL in THF (Ho & Lin, 1999).
PPA cyclization of the acid has also been used for the synthesis of sesquiterpene lacinilene C methyl ether 14 (McCormick etal., 1978).The synthetic route is depicted in Scheme 2.

Scheme 2. Synthesis of sesquiterpene lacinilene C methyl ether
Alkylation of the ketoester 8 with isopropylmagnesium chloride in THF at -15 o C affords pure lactone 9 whose conversion to the acid 10 is achieved by reduction with zinc and acetic acid.
The transformation of the acid 10 to dihydronaphthalene 11 is accomplished in two steps: (i) cyclization with PPA and (ii) treatment of the resulting tetralone with methylmagnesium iodide.Oxidation of 11 with OsO 4 /NMMO.H 2 O in acetone gives a mixture of diols 12 (Cocker & Sainsbury, 1965) which is oxidized (Bowers etal., 1953) to yield a mixture of ketone 13 and lacinilene C methyl ether 14.Treatment of the mixture with dicyanodichlorobenzquinone (DDQ) provides the natural product 14 in 27% yield.
The PPA cyclization has been utilized in the development of a two-step synthesis of 1,2,3,4-tetrahydro-5,8-dimethyl-1tetralone 16 in high yield (Banerjee etal.,2004)whose transformation to sesquiterpene occidol 21 (Mane & Kadam, 1998) has been accomplished without any difficulty and the synthetic route is presented in Scheme 3. Friedel-Crafts alkylation of xylene with chlorobutyric yields acid 15which on cyclization with PPA affords the tetralone 16 in high yield.An alternative approach of the tetralone 16 has also been published (Mane & Kadam, 1998) but the yield is not high compared with the published procedure (Banerjee etal,.2004).The alcohol17, obtained by the metal hydride reduction of tetralone16, is converted to the aldehyde18by Vilsmeier-Hack reagent (Smith, 1954).Metal hydride reduction produces the alcohol 19 which on oxidation with Jones reagent (Bowers etal., 1953) furnishes the acid 20 whose conversion to occidol 21 is achieved in one step by reaction with an excess of methyllithium.Scheme 3. Synthesis of occidol 21 PPA cyclization of acid has been sought (Giarruso & Ireland, 1968) to achieve the synthesis of (±)-desoxypodocarpic acid 27 and (±)13-methoxydesoxypodocarpic acid 28.The synthetic route is depicted in Scheme 4. The hydrindenone 23, prepared from 2-methyl-2-phenylcyclohexanone 22,on oxidation with selenium dioxide yields dione 24 which is convertedto acid 25 in three steps (reduction, hydrogenation, oxidation respectively).The cyclization of the acid 25 with PPA yields 7-keto-desoxy-podocarpic acid 26 which on hydrogenolyis yield desoxypodocarpic acid 27.Nitration of 26 followed by hydrogenation and addition of isoamyl nitrate affords 13-methoxydesoxypodocarpic acid 28.The use of PPA for the cyclization of acids has also been recorded during synthesis of bicarbocyclic sesquiterpene (±)-Emmotin-H 33 (Reddy & Krishna Rao, 1979) as has been described in Scheme 5.The cyclization of the acid 29 with PPA affords ketone 30 in 63% yield.Esterification followed by oxidation with selenium dioxide give the O-quinone 31 which is reduced and acetylated respectively to obtainthe diacetate 32.No yield is reported of this compound.Treatment of the diacetate with excess methylmagnesium bromide followed by air oxidation leads the formation of Emmotin-H 33.

Scheme 5. Synthesis of Emmotin H
The use of PPA cyclization can be observed in the synthesis (Nambudiry & Krishna Rao, 1974) of Pterosin E, a norsesquiterpene isolated by Yoshihara and others (Yoshihara etal., 1971).The synthetic route is exhibited in Scheme 6.
Alkylation of diethylmethylmalonate 34 with 3,5-dimethylbenzyl bromide 35 affords 36 which on chloromethylation yields 37.The crude product is converted to the diacid 38 by hydrolysis with sodium cyanide in dimethylformamide.The cyclization of the acid 38 with polyphosphoric acid (PPA) leads the formation of sesquiterpene Pterosin E 39.It is worthwhile to go through the published works , ( Mason, 2008, Mason etal., 2008, Edwards etal., 2007, Dodd, 2001, Dodd, 1999, Popp & McEwen, 1958) for more examples.We believe that the cyclization of the above mentioned acids can also be attempted with other acids like sulfuric acid.(Banerjee & Cabrera, 2010).

Acylation and Isopropylation on Aromatic Ring with PPA
Acylation reaction is one of the most important reactions which has been frequently used for the synthesis of organic compounds.Several intermolecular acylation reactions carried out with PPA have been reported (Popp & McEwen, 1958;Snyder & Werber, 1950).Acylation of 1,4-dimethyl-6-methoxytetralin 40 (Bachute & Mane, 1991) with acetic acid and PPA leads the formation of 7-acetyl-6-methoxy-1,4-dimethyltetralin 41.Dehydrogenation with DDQ furnishes the naphthalene 42 which is converted to the sesquiterpene Emmotin-G methyl ether 43 (Scheme7) with the Grignard reagent.

Scheme 9. Friedel-Crafts acylation
In the phenyl substituent series, the rings carrying an electron-donating group (methyl, methoxy) afford the acylated product at p-position in very good yield (82-92%).The absence of o-product may be explained as a steric effect of the electrophilic agent.The selective acylation occurs at the α-position of thiophene, 2-bromo-thiophene, thiophene-2carboxylic acid, and furan whereas pyrrole gives only degradation products and N-phenylprole affords only 5% of the acylated product.The acylation reaction fails if H 3 PO 4 or P 2 O 5 is used instead of polyphosphoric acid.No acylation occurs with malonic acid ester derivatives and cyanoacetic acid.The acylation reaction under this condition also fails with other diacids such as succinic, glutaric, and adipic acids.
The isopropylation of ketone has been achieved with isopropanol in presence of PPA (Wollinsky etal., 1972).The tricyclic ketone 58 on isopropylation with isopropyl alcohol and PPA furnishes a mixture of the ketones 59 and 60in 75% yield.
Wolff-Kishner reduction of the ketone 59 followed by demethylation with HBr produce ferruginol 61.(yield not specified).
The ketone 60 on demethylation and aerialoxidatin respectively affords xanthoperol 62 (yield not reported) which is characterized as its acetate (Scheme 10).
, PPA in isopropanol has been utilized for the isopropylation of 7-methoxy-1-tetralone 63 (Cabrera etal., 2014) .The resulting tetralone 64 (Scheme 11) obtained in 85% yield, is converted to the tetraline 65 by heating with 2,4-pentanediol and a catalytic amount of p-toluenesulfonic acid.Epoxidation of 65 followed by heating with sulfuric acid affords the tetralone 66.The tetralones 64 and 66 are the potential intermediates for the diterpenes miltirone and carnosic acid respectively.

Hydrolysis of Esters into Acids
PPA has been used for the hydrolysis of esters (67-70) into the acids (71-74) respectively (Scheme12) (He etal., 2002).The use of PPA is particularly useful for the hydrolysis of chromone ester 70 to prevent the formation of the products 75 and 76.It is worthwhile to mention that exist many reagents that can be utilized for the hydrolysis of esters into acids in mild condition.The use of PPA for the hydrolysis of esters into acid is hardly observed.

Cleavage of Aliphatic and Aromatic Epoxides
PPA in 30mol % is used as promoter for the cleavage of aliphatic and aromatic epoxides to alkenes in excellent yield under neat condition (Pathe & Ahmed, 2015) at 50 o C. The present method has several advantages such as use of inexpensive reagent, acquisition of the desired product in high yield and the formation of stereoselective product in short reaction time under ecofriendly reaction conditions.The yield of the alkene gets reduced if the solvent is used to perform the reaction.The following epoxides (77-80) have been cleaved to olefins (81-84)in high yield (Scheme 13) by the present method.
Scheme 13.Cleavage of aliphatic and aromatic epoxides The above mentioned procedure has also been utilized for the cleavage of several chalcones epoxides to obtain chalcones.The method has proved useful for the transformation of the following chalcones epoxides, e.Besides PPA, other acids like sulfuric acid has been used frequently to perform the cleavage of epoxides to obtain olefine (Banerjee etal., 2022).

6(i). Synthesis of isoquinoline and xylopinine
The use of PPA has been observed during the synthesis of heterocyclic compounds.The Bischler-Napieralski (BN) reaction is one of the most effective methods (Whaley & Govindachari, 1951) for the preparation of 3,4dihydroisoquinoline derivative and in the synthesis of a variety of isoquinoline derivatives and analogs of pharmacological interest.Venkov and Ivanov (Venkov& Ivanov, 1996) have reported a new method for the synthesis of a variety of isoquinolines which involves the reactions of carboxylic acids or their anhydrides and esters with a variety of amines such as homoveratryamine, 1, 2-diphenylethylamines, N-acyl-2-phenylethylamines in non-aqueous acidic media as polyphosphoric acid (PPA).The reaction with anhydrides proceeds faster than the corresponding carboxylic acids or their ester.It has been observed that the homoveratrylamine 103 reacts with the acid 104 in PPA to yield the isoquinoline 105.
The reaction probably proceeds first with acylation of the activated aromatic ring of the ammonium salt of 103 to 103(i) and then occurs spontaneous cyclization between the carbonyl group and the amine group to form the isoquinoline 105 via the intermediate 103(ii) (Scheme 16).These results have provided a convenient procedure for the synthesis of isoquioline enamides as important intermediates in alkaloid synthesis.This method has been applied for the synthesis of the alkaloid xylopinine 115 in two steps (Scheme 18).The amine 112 is made to react with homoveratric acid 113 in PPA at 80 o C for 5 h to obtain 2,3,10,11-tetramethoxy- PPA suffers from several drawbacks.As 10 to 50 fold excess of acid is generally employed, it is difficult to pour and stir at room temperature, it is necessary to neutralize the reaction mixture very before the product extraction.PPA/SiO 2 has been used as an efficient heterogeneous catalyst for many organic transformations.Recently it has been shown (Manolov etal.,2013) the use of silica-supported polyphosphoric acid in the synthesis of tetrahydroisoquinoline derivatives as depicted in Scheme 19.The amine 116, obtained from the aminoacetaldehyde dimethylacetal and 1,2-dimethoxybenzene, on acetylation with acid chlorides or sulfochlorides affords the amides 117 which on cyclization with PPA/SiO 2 yield substituted isoquinolines 118.The catalyst is recovered quantitativelywithout significant loss of activity The .cyclization is also obtained with MeCOOH:CF 3 COOH (4:1) but the yields are lower, and the reaction times are larger.The catalyst is recovered quantitatively without significant loss of activity.
Scheme20.The intramolecular cyclization of 122 to obtain the oxazepinedione 123

(ii). One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones
Polyphosphoric acid as a catalyst has proved useful for a one-pot synthesis (Zhao etal.,2015)& Govindachari, 1951).The present method is a simple, time saving, and high yielding process.It has been observed that the different moles ratio of the substrate have some effect on the reaction system.When the mole ratio of aldehyde, βketoester, and urea is 1:1:1.5 the yield of DHPMs is highest.The influence of the amount of catalyst on the reaction yield has also been studied.The presence of 0.1 mmol of PPA as a reaction mediator per mmol of reactions provides a higher yield; a higher amount of PPA does not improve the result to a great extent.DHPMS and their derivatives exhibit a wide range of therapeutical and pharmacological properties such as calcium channel blockers, anti-tumor, anti-bacterial and anti-inflammatory behavior (Yang el al., 2021;Yangetal., 2020).

6(iii). Synthesis of Carbonyl Containing Dihydrobenzofurans and Dihydrobenzopyrans
The   Exist methods for the cyclization of carbonyl-containing ortho-allyl and ortho-prenyl phenols with sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, aluminium chloride and zirconium tetrachloride (Yang etal.,2020).However these reported methods suffer several disadvantages such as the formation of unsatisfactory products,

(iv) Synthesis of Coumarins
The formations of 3,4-disubstituted coumarins 151-152 have been reported (yang etal., 2021) on heating the substituted salicylaldehydes 146-148 and acetic anhydrides 149 respectively with PPA Scheme 25.Synthesis of substitued coumarins These coumarins have also been formed by employing well-known reactions eg.Peachman reaction, Knoevenegal condensation, Wittig reaction etc. (Yang etal., 2020).Most of these methods suffer from some drawbacks including limited substrate scope and sometimes necessity of multistep reactions.The method (Yang etal., 2021) promoted by PPA is convenient than the published procedures for the synthesis of coumarins.The reaction performed in EtOH, THF, 1,4dioxane or DMSO does not give the desiredproduct.The optimized reaction condition consists in the use of substituted salicylaldehydes (1 equiv.),acetic anhydride (2 equiv. in DMF) at 145 o C for 3 hr under nitrogen atmosphere.The natural and synthetic products which contain coumarin ring system exhibit diversos bioactivities such asanti-oxidant, antiinflamatory, anti-cancer, anti-tuberculosis, anti-coagulant etc.

(v). Synthesis of Benzofuro [2,3-b] and 6H-Indolo [2,3-b]Quinoline Cores
Several indoles (153-155)can be made to react with 1-methoxy-2-(2-nitrovinyl)-benzene (156-158) using PPA at 80-110 o C (Aksenov etal., 2021) to yield benzofuro[2,3-b]quinolines.In Scheme 26, the reaction of indoles (153-155) with only nitrovinyl benzene 156 has been discussed.To the resulting complex is added pyridine and heated at 320 o C to yield benzofuro [2,3-b] quinolines 159A-159C (Scheme 26).Although the method does not provide good yield, it allows all synthetic operations to be carried out in a single operation instead of multiple step sequence.Similarly many other benzofuro quinolines have been obtained by the reaction of the indoles (153-155) with nitrovinyl benzene (154 and 156).A-C) Scheme 27.Synthesis of norcryptolepine and neocryptolepine The mentioned method has also been applied for the synthesis of the indolealkaloid neocryptolepine 163.The synthetic route is described in Scheme 27.A mixture of the indole 160 and the nitrostyrene 161, if heated with PPA at 110-130 o C and Sn foil (3 equiv) followed by further heating for 2 hr at 180 o C, yields norcryptolepine 162 which on methylation affords neocryptolepine 163.
In conclusion a novel approach has been developed for the synthesis of benzofuro [2,3-b]quinolines and 6H-indole [2,3b]quinolines by PPA assisted cyclization.This unusual process involves the alkylation of indoles with nitroalkenes, subsequent rearrangement into 3-aryl-2-quinolines and annulation of five-membered ring (furan or pyrrole) to give the teracyclic core.The transformation is quite efficient if one considers the number of steps performed in a single step.In addition it offers an alternative to the known multi-step process.

(vii ). Synthesis of Benzonaphtho Naphthyridines
The use of PPA has been recorded (Prabhaetal., 2021) during the synthesis of benzonaphtho naphthyridines from 2,4dichloroquinolines.The synthetic route is depicted in Scheme 29.

6(x) Synthesis of 2-arylquinolines
The importance of quinoline derivatives in the development of new pharmaceuticals is well known.Several alkaloides contain the quinoline fragment and most of these structures exhibit varied biological activity.Many approaches have been developed for the synthesis of quinoline ring.It has been observed (Grishin etal., 2022

Conclusion
It can be observed that PPA has been utilized to achieve many important organic reactions.PPA has been widely used for the cyclization of acids to obtain the cyclic ketones and some of them have been utilized for the synthesis of natural products like tavacpallescenicine, sesquiterpene lacinilene C methyl ether, desoxypodocarpic acid, emmotin H, Pterosin E and many others.The acylation and isopropylation promoted by PPA proved useful in the synthesis of emmotin G methyl ether, potential intermediates for diterpene ferruginol, xanthoperol, miltirone and carnosic acid.The hydrolysis of esters into acids and cleavage of epoxides (chalcone epoxides, nitrostyrene epoxides, nitrochromene epoxides) have been easily carried out with PPA.The carbonyl containing O-allyl phenols and O-prenyl phenols have been cyclized with PPA to yield dihydrobenzofurans and dihydrobenzopyrans.The importance of PPA has been recorded during the synthesis of several substituted coumarins, benzofuro quinoline, pyrroloquinoxalines and benzo naphtho naphyridines.It also been shown for the first time the possibility of performing the reaction the of direct electrophilic acylamination of arenes with nitroalkenes in PPA together with acylation as a one-pot synthesis.o-Acetylacetanilides generated in situ undergo a series of cascade the formation of 2-(2-acylaminoary) quinolines., D. A., Arutyunov, N. A., Gasanova, A. Z., Aksenov, N. A., Aksenov, A. V., Lower, C., & Rubin, M. (2021).

Scheme16.
Scheme16.Preparation of isoquinoline by the Bischler-Napieralski (BN) reaction in presence of PPA The acylation of the aromatic ring of homoveratrylamine 106 with carboxylic acid 107 in PPA leads to the formation of enamines of isoquinoline 109 (a-d) via the adduct 108 (Scheme 17).The 1 H NMR spectra clearly shows that 109 is obtained as a mixture of E and Z isomers.Reduction with NaBH 4 in MeOH affords the corresponding tetrahydroisoquinolines 110(unspecific yield) while the oxidation with KMnO 4 in CHCl 3 in the presence of 18-crown-6 gives dihydroisoquinolones 111(unreprted yield).

Scheme 19 .
Scheme 19.Synthesis of tetrahydroisoquinoline PPA has been utilized for the construction of a new tricyclic ring system containing 1,5-benzooxazepine fused with an imidazolone ring(Stainisheva etal., 2017).The synthetic details are given below (Scheme 20).The transformation of benzoxazolone derivative 119 to the imidazolone derivative 120 is achieved two steps (alkylation with chloroacetate and treatment with methylamine in n-propanol).Alkylation of 120 with ethylbromoacetate affords 121 which on alkaline hydrolysis yields acid 122 in quantitative yield.The intramolecular cyclization of 122 with PPA furnishes oxazepinedione 123.Many oxazepinediones have been prepared by changing the substituents eg: R 2 = Cl, R 1 =Cl, N-Bz etc.
of 3,4-dihydropyrimidin-2(1H)-one (DHPMS) 130-133 in good yield by grinding a mixture of aromatic aldehydes 124-127, ethylacetoacetate 128 (R= Et, Me) and urea 129 under solvent-free condition (Scheme 21).The reactions are carried out at room temperature.Many DHPMS have been prepared by using different aldehydes.Scheme 21 shows the synthesis of some DHPMS by using different aldehydes and different esters.Many important procedures are known for the synthesis of DHPMs(Whaley carbonyl containing O-allyl phenols and O-prenyl phenols undergo cyclization activated by PPA to yield dihydrobenzofurans and dihydrobenzopyrans respectively (Yang et al., 2021).Dihydrobenzofuran and dihydrobenzopyran systems are found in a variety of biologically active compounds and exhibit significant biological activities such as antigen toxic, antiproliferative, anticancer etc.The optimized reaction condition consists in heating the O-allyland O-prenyl phenols (1 equivalent), and PPA (5 equivalent) in DMF at 130 o C for 10 hr under a normal atmosphere.In some cases the reaction conditions are changed.The allyl phenols 134-136 undergo cyclization with PPA providing dihydrobenzofurans 137-139 respectively (Scheme 22).The possible mechanism of the cyclization is depicted in Scheme 23.
Scheme 22. Cyclization of O-allyl phenols 134-136 to dihydrobenzofurans 137-139 respectively time.The optimized condition exists in the use of carbonyl product (1 equivalent), PPA (5 equivalent) in dimethylformamide at 130 o C for 10 hr under a normal atmosphere.
Scheme 14. Cleavage of several chalcones epoxides to obtain chalcones Scheme 15.Deoxygenation of various nitrostyrene epoxides, and nitrochromene epoxides chalcones By similar procedure the naphthyridines 211 and 212 can be prepared.No angular naphthyridine is obtained.The cyclization carried out without benzoic acid affords no desired result.The benzoic acid can be replaced by p-toluic acid.The reaction time should be significantly reliant on benzoic acid substituent.The presence of a methyl group at para position of the phenyl ring aids reaction rate and increases product yield significantly.The utility of PPA as catalyst has been recorded in relation to the synthesis(Ersan etal., 2020)of naphthyl-substituted benzimidazole under microwave irradiation and conventional synthetic methods.These compounds show antimicrobial activity.In order to develop the synthesis of benzimidazole derivative, a mixture of the diamine 213, naphthalene carboxylic acid 214and PPA is stirred and irradiated (100-150 W) to obtain the naphthalene substituted benzimidazole 215.Similarly the diamines (216-219) are mixed with hydroxy diacid 220 in presence of PPA and irradiated to obtain the naphthalene substituted imidazoles (221-224) respectively (Scheme 31).
Scheme 31.Synthesis ofbenzimidazoles with naphthalene moiety compoundsThe condensation carried out by conventional heating affords low yield and requires more time.The structures of the products have been established on the basis of spectral data.The compounds also have been screened for their antimicrobial activity.