Transition-Metal Catalyzed Synthesis of Ketoprofen

Reações catalisadas por complexos de metais de transição tais como carbonilação, hidrovinilação e hidrogenação foram empregadas na síntese do ácido α-(3-benzoilfenil)propanóico (Cetoprofeno). Acoplamento do tipo Heck entre 3-bromobenzofenona e etileno conduziu à 3-vinilbenzofenona que na sequência, por carbonilação catalisada por paládio, foi tranformada no α-(3benzoilfenil)propanoato de isopropila com rendimento de 95% e regiosseletividade >99,5%. Hidrólise deste éster conduziu ao Cetoprofeno com 90% de rendimento. Cetoprofeno foi também obtido em duas etapas a partir da 3-vinilbenzofenona via reação de hidrovinilação catalisada por níquel que conduz seletivamente ao 3-(3’-benzoilfenil)-1-buteno (96%), seguido por oxidação desta olefina em ácido. A 3-etenilbenzofenona pôde ser sintetizada a partir da 3-bromobenzofenona via uma reação de acoplamento catalisada por paládio. Este alcino foi carabonilado em presença de paládio conduzindo regiosseletivamente (97%) ao α-(3-benzoilfenil)acrilato de metila. A hidrólise do éster conduz ao ácido α-(3-benzoilfenil)acrílico que foi então hidrogenado enantiosseletivamente ao (S)-Cetoprofeno (95% e.e.) usando um complexo Ru-(S)-BINAP como catalisador.


Introduction
Homogeneous catalysis has been responsible for many major recent developments in synthetic organic chemistry 1,2 .The combined use of organometallic and coordination chemistry has led to a number of new powerful synthetic methods involving the selective formation and/or cleavage of C-C and C-heteroatom bonds.An appropriate choice of central metal and a careful molecular design of coordinated ligands, especially with regard to electronic and steric properties, have resulted in the development of active and selective (chemo-, regio-and enantioselective) catalytic systems.Over the past years we have focused our attention on the synthesis of tran-sition metal complexes 3 , and their application in the selective transformation of organic unsatured substrates [4][5][6][7][8][9][10] .
α-Arylpropionic acids are an important class of nonsteroidal anti-inflammatory agents with a multibillion-dollar market 11 .Among the numerous methodologies 12,13 for the synthesis of this class of drug, metal-catalyzed reactions appear to be of general utility and are very promising in racemic and asymmetric synthesis.In this work we show the application of homogeneous metal-based catalytic systems for the synthesis of Ketoprofen (Scheme 1).Ketoprofen was developed by Rhône-Poulenc 14 and is commercialized in its racemic form in Brazil by Rhodia as Profenid.The synthesis of ketoprofen generally involves a multi-step reaction procedure 12 .Although many asymmetric syntheses for α-arylpropionic acids have been devel-oped, most of them are not amenable to Ketoprofen.In terms of enantioselective catalytic reactions, asymmetric hydrogenation 15 and epoxidation 16 reactions have been used as key steps.The hydrogenation of α-(3-benzoylphenyl) acrylic acid using a chiral rhodium catalyst gave Ketoprofen in moderate enantiomeric excess (up to 69%) 15 .Another catalytic approach made use of a combination of Sharpless epoxidation followed by a stereoselective hydrogenolysis of a benzylic carbon-oxygen bond to establish the stereochemistry 16 .Using this approach, (S)-Ketoprofen was obtained in 98% ee in 11 steps starting from 3-bromoacetophenone.The other asymmetric syntheses described are not catalytic reactions and the stereoselectivity is achieved using a stoichiometric chiral auxiliary.For instance, α-(3-benzoylphenyl)acetic acid was transformed into a chiral imide using oxazolidines as chiral auxiliaries 17 .Thereafter, the chiral imide was alkylated with methyliodide.Racemizing amide cleavage conditions did not afford (S)-Ketoprofen of sufficient enantiomeric purity and a later separation by recrystallisation of diastereoisomers resulting from reaction with (R)methylbenzylamine was necessary in order to obtain (S)-Ketoprofen in 96% ee.Another approach started from racemic Ketoprofen which was transformed into a ketene 18,19 .Diastereoselectivities for the addition of a chiral hydroxyl compound were, after saponication, Ketoprofen up to 71% for the chiral lactate 18 and up to 99% for (R)-pantolactone 19 .Finally, a photochemical rearrangement of α-chloropropiophenones was used to ob-tain α-arylpropionic acids in low optical yield in the case of Ketoprofen (32%) 20 .

Palladium-catalyzed carbonylation of 3-vinylbenzophe-none (3)
The transition metal-catalyzed carbonylation of organic substrates represents a very important process in organic synthesis.Indeed, carbon monoxide can be directly introduced into unsaturated substrates to produce organic molecules such as aldehydes, ketones, esters, amides, and other carbonyl-containing functionalities 25 .Although many transition metal complexes are effective catalysts for carbonylation, palladium complexes are the most widely employed.
In this respect, palladium-catalyzed carbonylation of styrene derivatives in the presence of alcohols (hydroesterification) affords α-arylpropionic esters that are converted into α-arylpropionic acids by hydrolysis.Recently, we demonstrated that palladium-based catalysts associated with a phosphine ligand and immobilized in 1-n-butyl-3-methylimidazoliumtetrafluoroborate are highly efficient for the biphasic regioselective hydroesterification of styrene derivatives under mild conditions 4 .The choice of the phosphine ligand is crucial on the regioselectivity and activity control and the best results were found using (+)-neomenthyldiphenylphosphine [(+)-NMDPP].These conditions were applied to the carbonylation of 3-vinylbenzophenone in homogeneous media (Eq.3).

Nickel-catalyzed hydrovinylation of 3-vinylbenzophenone (3)
The catalytic hydrovinylation of styrene derivatives can be used to produce 3-aryl-1-butenes 26 .These olefins are converted into α-arylpropionic acids by an oxidation reaction 27 .Moreover, they have also been used as monomers for the homopolymerization or copolymerization of olefins.We have shown that a catalytic system composed of [Ni(MeCN) 6 ][BF 4 ] 2 , triphenylphosphine and diethylaluminum chloride is active and regioselective for the hydrovinylation of styrene and alkylstyrenes 7 .However, low activities or inactivity were observed for styrene derivatives containing a Lewis basic group.Further studies have shown that these styrene derivatives can also be hydrovinylated by changing the relative ratios of the three catalyst components 28 .After intensive investigation of the hydrovinylation of 3-vinylbenzophenone we have pinpointed the reaction conditions and procedure which afford 3-(3'-benzoylphenyl)-1-butene ( 5) with both a high regioselectivity and yield (Eq. 4).The carbonylation of 3 dissolved in a mixture isopropanol (4 mL)/cyclohexane (6 mL) proceeds under 10 atm of CO at 70 o C for 20 h using a catalytic system composed of PdCl 2 (PhCN) 2 , (+)-NMDPP, and p-toluenesulfonic acid.Isopropyl α-(3 benzoylphenyl) propionate ( 8) was obtained in high yield (95%) and high regioselectivity (α : β > 99.5 : 0.5).Hydrolysis of the isopropyl ester with aqueous KOH followed by acidification with HCl gave Ketoprofen in 90% yield.
Yield: 80% Regioselectivity: 96% The hydrovinylation reaction was carried out using an Al/Ni ratio = 25 and PPh 3 /Ni ratio = 4 to afford the hydrovinylated product in 80% isolated yield and 96% regioselectivity.It is interesting to note that in this case the addition order is crucial.In fact 3-vinylbenzophenone must be introduced only after the in situ formation of the catalyst (see experimental section).If it is introduced first, as described for the hydrovinylation of styrene 7 , the carbonyl group in 3 can interact with the organoaluminum Lewis acid preventing the formation of the nickel-hydride catalytic species.The observed chemoselectivity is presumably the result of the Ni-H bond reacting faster with the activated C=C bond of 3 than with that of ethylene and/or the higher stability of the η 3 -benzylic-nickel compared with an ethylnickel intermediate.Steric effects of the triphenylphosphine ligand prevent a second styrene molecule from approaching the resulting Ni-C bond, but not the smaller ethylene molecule, and as a result 3 is almost exclusively hydrovinylated as 3-(3'-benzoylphenyl)-1butene (5) and neither oligomerized or polymerized.Ketoprofen was obtained in 65% yield by oxidation of 5 with KMnO 4 /NaIO 4 .

Palladium-catalyzed carbonylation of 3-ethynylbenzo-phenone (4)
Recently we described a simple method for the synthesis of chiral α-arylacrylic esters by the carbonylation of arylacetylenes in the presence of chiral alcohols catalyzed by palladium complexes under mild conditions with high yields 5 .Two regioisomers can be obtained (α and βarylacrylic esters) and the regioselectivity depends on the phosphine ligand used.The selective carbonylation of 4 was performed using a catalytic system composed of Pd(dba) 2 , PPh 3 and p-toluenesulfonic acid (Eq.5).In the presence of methanol and operating under mild conditions (10 atm, 100 o C, 2 h), this catalytic system affords the methyl α-(3-benzoylphenyl)acrylate (9) in a very good yield (93%) and with high regioselectivity (α : β = 97 : 3).Hydrolysis of the methyl ester 9 with aqueous KOH followed by acidification with HCl gave the α-(3-benzoylphenyl) acrylic acid (6) in almost quantitative yield.metric hydrogenation reaction 11 .Recently, we have shown that the asymmetric hydrogenation of α-arylacrylic acids can be performed in presence of in situ or preformed Ru-BINAP catalyst precursors immobilized in an ionic liquid phase 6 .In comparison with the homogeneous reaction, similar or slightly increased optical yields were obtained.It is interesting to note that no significant effect of the hydrogen pressure was observed.At the end of the reaction the hydrogenated product can be separated by simple decantation and the ionic catalyst solution can be recycled without significant changes in activity and selectivity.
We performed the hydrogenation of α-(3-benzoylphenyl) acrylic acid (6) in homogeneous media using the commercially available [RuCl 2 -(S)-BINAP] 2 .Et 3 N as catalyst (Eq.6).The reaction was carried out in methanol at room temperature giving Ketoprofen in good yield.Although Ru-BINAP complexes have also been used in the hydrogenation of ketones 30 , only hydrogenation of the C=C bond was observed under the conditions employed.On the other hand, the optical yields of the hydrogenation products depended on the reaction conditions.Under the conditions studied the optical yield in (S)-Ketoprofen improved from 43 to 70% upon increasing the hydrogen pressure from 30 to 70 atm.In addition, an increase in the optical yield of (S)-Ketoprofen was observed due to the lowering of the temperature and the addition of an organic base.When the reaction was carried out at -5 o C and using triethylamine (NEt 3 /substrate = 1) as a base promoter, (S)-Ketoprofen was obtained in 95% ee.Compared with the literature [12][13][14][15][16][17][18][19][20] , these results are a significant improvement in terms of the enantioselective synthesis of (S)-Ketoprofen.It is worthwhile to mention that the racemic catalytic carbonylation and hydrovinylation reactions described herein should be transposable into an asymmetric variant if a suitable chiral catalyst is found and this work is in progress.

Ruthenium catalyzed asymmetric hydrogenation of α-(3-benzoylphenyl)acrylic acid (6)
The anti-inflammatory activity of α-arylpropionic acids resides in the (S)-isomers but, with the exception of Naproxen where the (R)-isomer is a liver toxin, they are currently administered as racemates.However, in recent years the use of enantiomerically pure drugs has become almost mandatory not only to achieve enhanced specificity of drug action but to avert the possible toxicity and undesirable load on metabolism by the other enantiomer 29 .
(S)-Ketoprofen was obtained in moderate optical yield (up to 67%) by asymmetric hydrogenation of α-(3benzoylphenyl)acrylic acid using a rhodium homogeneous catalyst and (-)-DIOP as a chiral phosphine ligand 15 .A significant advance in chiral synthesis involves asymmetric hydrogenation reactions of α,β-unsaturated acids catalyzed by Ru-BINAP complexes 30 .Noyori has demonstrated that the complex [(S)-BINAP]Ru(OAc) 2 catalyzes the hydrogenation of α-(6-methoxy-2-naphtyl)acrylic acid to (S)-Naproxen in 92% chemical yield and with an enantiomeric purity of 97% 31 .Despite the relatively high pressure required (135-150 atm) for the reaction that may present a practical limitation, Monsanto patented an industrial process for the synthesis of (S)-Naproxen where the key-step is this asym-

Conclusions
In this work, metal-catalyzed processes such as the Heck reaction, carbonylation, hydrovinylation and asymmetric hydrogenation were applied for the synthesis of an α-arylpropionic acid (Ketoprofen) by different pathways.In each ) ) reaction, through the suitable choice of transition metal complex, ligand and experimental conditions, we have found an active catalytic system that operates under mild conditions with high selectivity.

General experimental procedures
Catalytic reactions were performed under argon by standard manipulation of air-sensitive compounds.NMR spectra were recorded on a Varian VXR-200 or Varian XL 300.Infrared spectra were recorded on a Bomem B-102 spectrometer.Mass spectra were recorded on a GC/MS Shimadzu QP-5050 (EI, 70eV).Optical rotation values were recorded on a Perkin Elmer 341 polarimeter at 20 o C.

Oxidation of 3-(3'-benzoylphenyl)-1-butene (5)
To a solution of 5 (90 mg, 0.38 mmol) in 10 mL of BuOH and 20 mL of water, KMnO 4 (185 mg, 1.17 mmol), NaIO 4 (1.46 g, 6.86 mmol) and K 2 CO 3 (366 mg, 2.64 mmol) were added.The pH of the solution was adjusted to 8 with 3 mol L - 1 aq NaOH and then the reaction mixture was stirred at room temperature for 3 h.After this time the pH of the mixture was adjusted to 1 with concentrated HCl and NaHSO 3 was added to reduce the MnO 2 .The mixture was washed with ether and the ethereal layer was extracted with 3 mol L -1 aqueous NaOH.The aqueous layer was acidified with concentrated HCl and then extracted with ether.The organic layer was dried over MgSO 4 , filtered and the volatiles were removed under reduced pressure, yielding α-(3-benzoylphenyl)propionic acid (Ketoprofen) as a colorless oil (63.2 mg, 65%).