Biologically Active Compounds through Catalysis: Efficient Synthesis ofN-(Heteroarylcarbonyl)-N′-(arylalkyl)piperazines

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  A practical route for the synthesis of new biologically active 5-HT2 A receptor antagonists has been developed. In only three catalytic steps, this class of central nervous system (CNS) active compounds can be synthesized efficiently with high
  Biologically Active Compounds through Catalysis: Efficient Synthesis of   N  -(Heteroarylcarbonyl)-  N  ’ -(arylalkyl)piperazines Kamal Kumar, [a] Dirk Michalik, [a] Ivette Garcia Castro, [a] Annegret Tillack, [a] Alexander Zapf, [a] Michael Arlt, [b] Timo Heinrich, [b] Henning Bˆttcher, [b] andMatthias Beller* [a] Introduction The synthesis of new biologically active molecules is an im-portant element in the development of innovative drugs forhuman and animal disorders. In general, drug developmentis dominated by the use of stoichiometric organic transfor-mations. Although catalytic reactions, such as palladium-cat-alyzed coupling reactions, [1] have in recent years been re-ceiving increasing attention from medicinal chemists, cataly-sis is still somewhat underrated with regard to drug develop-ment. This is rather surprising when one considers the over-all importance of catalysis in chemistry; over 90% of allchemicals produced worldwide are made with the aid of cat-alysis. The reasons for the lesser use of catalytic technolo-gies in drug development are various. Clearly, the commer-cial availability of catalysts and ligands, which is often notguaranteed for new catalysts or novel reactions, plays an im-portant role. [2] Catalytic reactions are also often significantlyinfluenced by small variations in reaction conditions or thesubstrate structure, thus making it difficult for pharmaceuti-cal chemists to use such reactions in a general manner. Opti-mization of catalytic systems is most commonly carried outon comparably simple model systems, so the results ob-tained are often difficult to apply for more complicated leadstructures, often bearing a variety of functional groups. Im-portantly, medicinal chemists also try to avoid the use of air-and water-sensitive organometallic complexes. Nevertheless,catalysis offers a number of possibilities for improved drugdevelopment. Catalytic routes to a desired active compoundare often shorter in terms of reaction steps, providing theproduct in a faster and more economic manner. More im-portantly, catalytic reactions offer unusual modifications of given lead structures, thereby allowing the synthesis of po-tential drugs not easily accessed by stoichiometric organictransformations. In addition, a short catalytic route might bemore easily scaled up than a longer traditional route if larger scale production of a certain molecule is required.To explore the opportunities of homogeneous catalysis fordrug development, we started a program on the synthesis of potentially active amphetamine analogues using catalysis asa tool box. As an interesting target we envisioned the sero-tonin (5-HT)-receptor subtype 2A, for which phenethylpi-perazines (Figure 1) can be strong ligands. [3] Different deriv-atives of this class of compounds are suitable for the treat- [a] Dr. K. Kumar, Dr. D. Michalik, Dr. I. Garcia Castro, Dr. A. Tillack,Dr. A. Zapf, Prof. Dr. M. BellerLeibniz-Institut f¸r Organische Katalyse an der Universit‰t Rostocke.V.Buchbinderstrasse 5±6, 18055 Rostock (Germany)Fax: (   49)381±46693±24E-mail:[b] Dr. M. Arlt, Dr. T. Heinrich, Dr. H. BˆttcherMerck KGaA, Frankfurter Strasse 25064293 Darmstadt (Germany) Abstract:  A practical route for the syn-thesis of new biologically active 5-HT 2A  receptor antagonists has been de-veloped. In only three catalytic steps,this class of central nervous system(CNS) active compounds can be syn-thesized efficiently with high diversity.As the initial step, an  anti -Markovni-kov addition of amines to styrenes pro-vides an easy route to  N  -(arylalkyl)pi-perazines, which constitute the corestructure of the active molecules. Here,base-catalyzed hydroamination reac-tions of styrenes with benzylated piper-azine proceeded in high yield even atroom temperature. After catalytic de-benzylation, the free amines were suc-cessfully carbonylated with different ar-omatic and heteroaromatic halides andcarbon monoxide to yield the desiredcompounds in good to excellent yields.The two key reactions, base-catalyzedhydroamination of styrenes and palla-dium-catalyzed aminocarbonylation of haloarenes/heterocycles, showed toler-ance towards various functional groups,thereby demonstrating the potential tosynthesize a wide variety of new deriv-atives of this promising class of phar-maceuticals. Keywords:  amphetamines  ¥ carbonylation  ¥  homogeneouscatalysis  ¥  hydroamination  ¥ palladium ¹ 2004 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim  DOI: 10.1002/chem.200305327  Chem. Eur. J.  2004 ,  10 , 746±757 746 FULL PAPER  ment of a wide variety of dis-eases, such as psychosis, schizo-phrenia, depression, neural dis-orders, memory disorders, Par-kinson×s disease, amyotrophiclateral sclerosis, Alzheimer×sdisease, Huntington×s disease,eating disorders such as nervousbulimia and anorexia, premen-strual syndromes, and for posi-tive influencing of compulsivebehavior (obsessive-compulsivedisorder, OCD). [4] In general, the synthesis of 5-HT 2A  receptor antagonist mole-cules as shown in Figure 1 andsimilar molecules involves more than five reaction steps andthe use of rather expensive raw materials. [3,4] Overall yieldsof the desired products are in the range of   < 30±50%.Clearly, derivatives of this class of molecules can be easilysynthesized if the corresponding (arylethyl)piperazines and(hetero)arylcarboxylic acids are available. Unfortunately,the known routes for the synthesis of (arylethyl)piperazinesinvolve several reaction steps [5] and only a few of the desiredcarboxylic acids of the heterocycles are commercially availa-ble and so have to be synthesized by longer reaction sequen-ces. [6] In the past, pharmacologically interesting  N  -(2-arylethyl)-piperazines [7] were synthesized by treatment either of   N  -benzylpiperazines with  b -haloethylbenzenes or of substitut-ed phenethylamines with  N  , N  -bis( b -chloroethyl)amines. [8] Thus, the described syntheses started with halogenated sub-strates, producing a considerable amount of salt by-products.Also, from a pharmacological point of view, the known syn-theses have some limitations for variation of the overallstructures of these molecules. For example, the diversity of heterocycles in the core structure is limited to commerciallyavailable carboxylic acids. In addition, variations of the eth-ylene spacer unit are not easily achieved.We imagined a shorter and more flexible approach to 5-HT 2A  receptor antagonists based on our expertise in amina-tion reactions of olefins [9] and carbonylation of aryl halidederivatives, [10] as shown in Scheme 1. We recently reportedon the base-catalyzed hydroamination (BCH) of aryl olefinsas a new synthetic route to amphetamines. [11] The presenceof the  N  -(2-arylalkyl)piperazine unit as a core part of 5-HT 2A  receptor antagonists encouraged us to exploit theBCH of substituted styrenes as a first step towards thetarget molecules. The  anti -Markovnikov addition of mono-protected piperazine would provide the core structure forthese molecules in one step. Subsequent deprotection andpalladium-catalyzed carbonylation of the free amines withdifferent aryl or heteroaryl halides should give the desiredproducts in a short and efficient synthetic route (Scheme 1). Results and Discussion The first reaction step in the planned sequence is a catalytichydroamination [12] of substituted styrenes with a monopro-tected piperazine derivative. This reaction is 100% atom-economic and much more elegant than the sometimes trou-blesome nucleophilic substitution of   b -(haloethyl)benzenes.While base-catalyzed hydroamination of aliphatic olefins didnot proceed to any significant extent, the activating aryl sub-stituent makes styrenes more suitable substrates for this re-action. [13] Pre-catalysts used for this reaction include metallicsodium, CsOH, and alkali metal amides, which can beformed in situ from  n BuLi, Na 2 Np, or KO t  Bu. In general,primary and secondary amines add to styrene to form thecorresponding secondary and tertiary amine products attemperatures  > 100   C. Figure 1. Target molecules and possible variations.Scheme 1. Catalytic route to biologically active amphetamine analogues. Chem. Eur. J.  2004 ,  10 , 746±757  ¹ 2004 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim  747746±757  Initially we attempted the reaction between styrene andmono- N  - tert  -butoxycarbonyl-protected (Boc-protected) pi-perazine ( 2a ), due to the easy cleavage of the Boc group af-terwards. In the presence of catalytic amounts of   n BuLi,however, only low yields ( < 5%) of   N  -Boc- N  ’ -2-phenethyl-piperazine were obtained. As shown in Scheme 2, the use of NaH as pre-catalyst gave a better yield of   3  (22%). How-ever, no further improvement in the product yield could beobtained with styrene or substituted styrenes such as 4-chloro- and 3-(trifluoromethyl)styrene, despite significantvariations in the reaction conditions (temperature: roomtemperature up to 120   C; catalyst: 5±20 mol%; amine/olefin ratio 2:1 to 1:2).To avoid side reactions of the Boc protecting group,which is not stable under the basic conditions at high tem-perature, we used  N  -benzylpiperazine for the hydroamina-tion reaction. Here, use of a catalytic amount (0.1 equiv) of  n BuLi in THF was effective, yielding  N  -benzyl- N  ’ -phene-thylpiperazine ( 4a ) in 94% yield (Table 1, entry 1). In addi-tion, different substituted styrenes with electron-donatingand -withdrawing functionalities–such as 3- and 4-chloro-styrene, 3- and 4-methylstyrene, 4-methoxystyrene, 2- and 3-bromostyrene, and 3-(trifluoromethyl)styrene–were suc-cessfully hydroaminated to the substituted  N  -benzyl- N  ’ -(2-arylethyl)piperazines ( 4a ±  j ) (Table 1, entries 1±15).Typically we applied 0.1 equivalents of base pre-catalystat 65±120   C, although in some cases better yields of the de-sired products were obtained in the presence of 0.2 equiva-lents of base.To speed up synthesis, we considered automation a prom-ising approach. Automated and parallel synthesis andscreenings of reaction parameters have become valuablemethods in drug development. [14,15] Sample preparation (ad-dition of reactant stock solutions), reaction processing (heat-ing, mixing), and workup (cooling, dilution, analysis) stepswere performed in an ACT-Vantage system. We used 12-and 48-well reactors and several modules providing theliquid handling. In these reactions a GC/MS system wasused for analysis of the products. Both the automated andthe manual synthesis of the  N  -(2-arylethyl)piperazines ( 4 )gave similar yields.With the exceptions of 2- and 3-bromostyrene and 4-fluo-rostyrene (Table 1, entries 8±10, 13, 15), all other startingmaterials gave the corresponding products in sufficient tovery good yields (60±95%). In some cases a difference be-tween the degree of conversion and the isolated productyield was observed. Here, base-catalyzed oligomerizationand polymerization of the olefin had mainly occurred. Be-cause of its expected pharmacological properties, we wereespecially interested in the corresponding  N  -(4-fluorophene-thyl)piperazine ( 4e ), and so we studied this reaction inmore detail. Increasing the amount of   n BuLi to 0.2 equivcould not enhance the yield of this product (Table 1,entry 9). However, when the amine was used in excess(olefin to amine in 1:3 ratio),  4e  was obtained in 57% yield(Table 1, entry 10). Surprisingly, even better yields of   4e (87%) were observed when the reaction was performed inthe presence of 0.2 equiv of base pre-catalyst at room tem-perature (Table 2, entry 5). This is one of the few examplesof efficient olefin hydroamination at room temperature. [16] Because of the success of the lower reaction temperature weperformed a number of further experiments at room tem-perature. As demonstrated in Table 2, in most cases similaror even better yields were achieved.In addition to the reactions shown in Table 2, 1,2-dihydro-naphthalene ( 5 ) and allylbenzene ( 7 ) were also successfullyhydroaminated with  N  -benzylpiperazine and the use of 0.2 equivalents of pre-catalyst in THF solution at room tem-perature. Previous studies had revealed that it is possible toisomerize allylbenzene to give  b -methylstyrene under the re-action conditions required for base-catalyzed hydroamina-tion. [17] The reaction therefore generates branched ampheta-mine derivatives, which considerably broadens the structuraldiversity of our synthetic route. Here, hydroamination of al-lylbenzene proceeded regioselectively ( > 99%) to yield  N  -benzyl- N  ’ -(2-phenylpropyl)piperazine ( 8 ) in good yield(88%; Scheme 3).The next step in our reaction sequence was the deprotec-tion of the  N  -benzyl- N  ’ -(2-arylethyl)piperazines. Debenzyla-tion was performed with 10 mol% of Pearlman×s catalyst(Pd(OH) 2 , 20 wt% on carbon) under hydrogen atmosphere Scheme 2. Base-catalyzed hydroamination of aryl olefins with  N  -Boc-pi-perazine.Table 1. Base-catalyzed hydroamination of aryl olefins at high tempera-ture. [a] Entry R Olefin/  n BuLi  T   Conv. [b] Productamine [mol%] [   C] [%] (Yield [c] [%])1 H 1:1 10 120 94  4a  (94)2 [d] 4-Cl 1:1 10 65 92  4b  (38)3 4-Cl 1:1 20 120 92  4b  (65)4 [d] 4-Me 1:1 10 65 91  4c  (75)5 4-Me 1:1 20 120 98  4c  (95)6 [d] 4-OMe 1:1 10 65 98  4d  (71)7 4-OMe 1:1 20 120 96  4d  (92)8 [d] 4-F 1:1 10 65 28  4e  (15)9 [e] 4-F 1:1 20 70 50  4e  (11)10 4-F 1:3 20 120 66  4e  (57)11 3-Cl 1.5:1 10 120 96  4 f   (88)12 [d] 3-Me 1:1 10 65 91  4 g  (75)13 [d] 3-Br 1:1 10 65 89  4h  (40)14 3-CF 3  1:1 10 120 80  4i  (60)15 [d] 2-Br 1:1 10 65 90  4j  (30)[a] Reaction conditions:  2  (2.2 mmol), olefin in THF (5 mL) in a pressuretube. [b] Determined by GC with hexadecane as internal standard (basedon  2 ). [c] Yield of isolated product. [d] Automated parallel synthesis.[e] 48 h. ¹ 2004 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim  Chem. Eur. J.  2004 ,  10 , 746±757 748 FULL PAPER  M. Beller et al.  in the presence of 10 mol% Et 3 N at 40   C. [18] On smallscales (2±4 mmol), deprotection proceeded with excellentyields ( > 99%) under 1 bar of hydrogen in 7 h. On largerscales ( > 9 mmol; Table 3, entry 5), however, reactions hadto be run for 15 h under 10 bar of H 2  to obtain completecleavage of the benzyl group. After filtration of the reactionmixture over celite and evaporation of the solvent the ana-lytically pure free amines were obtained ( 9a ± f  , Table 3).Next, we studied the aminocarbonylation of aromatic hal-ides with  N  -benzylpiperazine as a model system closely re-sembling  9 . On the basis of our recently reported alkoxycar-bonylation of   N  -heteroaryl chlorides [19] we used 1 mol% of Pd(PhCN) 2 Cl 2  in the presence of 3 mol% 1,1 ’ -bis(diphenyl-phosphino)ferrocene (dppf) as catalyst system. 2-Bromo-naphthalene and various haloheteroarenes were carbonylat-ed in excellent yields at 10±25 bar of CO pressure in tolueneat 130   C (Table 4). When the CO pressure was reduced,some quantities of directly aminated products were ob-served in the reaction mixture.Chloropyridines (Table 4, entries 2 and 3) and 1-chloroiso-quinoline (Table 4, entry 4) yielded exclusively the amino-carbonylated product. 2,5-Dichloropyridine (Table 4,entry 3) reacted with  N  -benzylpiperazine selectively at the2-position. Interestingly, 5-bromoindole (Table 4, entry 6)gave the corresponding 5-piperazinylcarbonylindole in > 99% yield.  To the best of our knowledge, this is one of therare examples of a palladium-catalyzed coupling reaction in-volving unprotected haloindoles.  Clearly, this is an efficientroute to this class of molecules, which otherwise need pro-tection and deprotection steps for their synthesis. It is inter-esting to note that compounds  10a ± f  , apart from beingmodels for 5-HT 2A  receptor antagonists, are also interestingbuilding blocks for other drugs containing piperazinyl moiet-ies.Finally, we performed the carbonylation of different halo-pyridines, halo(iso)quinolines, and haloindoles with  N  -(2-ar-ylethyl)piperazines  9 . Because of the biological activity ex-pected of the products, most of the reactions were per-formed with  N  -[2-(4-fluorophenyl)ethyl]piperazine and  N  -(2-phenethyl)piperazine. Selected experiments are shown inTable 5.All tested heteroaryl halides and 4-(trifluoromethyl)bro-mobenzene gave the desired product in practical, often very Scheme 3. Base-catalyzed hydroamination of 1,2-dihydronaphthalene andbase-catalyzed isomerization/hydroamination of allylbenzene at roomtemperature.Table 3. Debenzylation of   N  -benzyl- N  ’ -(2-arylethyl)piperazines.Entry R 1 R 2 Time [h] Conv. [%] Product (yield [a] [%])1 [b] H H 7.0 100  9a  (95)2 [b] 3-Me H 7.0 100  9b  ( > 99)4 [b] 4-Me H 7.0 100  9c  ( > 99)5 [c] 4-OMe H 15.0 100  9d  (98)6 [b] 4-F H 7.0 100  9e  (95)7 [b] H Me 6.5 100  9 f   (86)[a] Yield of isolated product. [b] 1.0±3.0 mmol scale reactions, 2±4 bar H 2 . [c] 9.0 mmol scale reaction, 10 bar H 2 .Table 2. Base-catalyzed hydroamination reactions of aryl olefins at roomtemperature. [a] Entry R Olefin/ Conv. [b] Productamine [%] (Yield [c] [%])1 H 2:1 82  4a  (80)2 4-Cl 2:1 99  4b  (60)3 4-Me 2:1 99  4c  (96)4 4-OMe 2:1 100  4d  (99)5 4-F 2:1 98  4e  (87)6 3-Cl 2:1 94  4 f   (85)7 3-Me 2:1 80  4 g  (47)8 3-Br 2:1 90  4h  (41)9 3-CF 3  2:1 78  4i  (69)10 2-Br 1:1 88  4j  (59)11  [d] 2:1 96  4k  (94)12 4-Ph 2:1 98  4l  (98)[a] Reaction conditions:  2  (2.2 mmol), olefin in THF (5 mL) in a pressuretube. [b] Determined by GC with hexadecane as internal standard (basedon  2 ). [c] Yield of isolated product. [d] 2-Vinylnaphthalene was used. Chem. Eur. J.  2004 ,  10 , 746±757  ¹ 2004 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim  749Synthesis of   N  -(Heteroarylcarbonyl)- N  ’ -(arylalkyl)piperazines 746±757  good, yields. However, in contrast to the model system weobserved competitive amination of the heteroaryl halide insome carbonylation reactions (especially of 1-chloroisoqui-noline). As in the model system, 4-bromo- and 5-bromoin-dole reacted well with amines to yield the carbonylated ad-ducts exclusively, with no amination products observed. Ingeneral,  N  -(2-arylalkyl)piperazines with an ethylene bridgereacted with higher yields than the corresponding deriva-tives with a propylene bridge.It is important to note that a significant number of thesynthesized compounds showed strong binding to the 5-HT 2A  receptor. In particular,  11g  and  11h  (Table 5; en-tries 7, 8) proved to be very potent ligands. In binding ex-periments,  11g  showed a sub-nanomolar and  11h  a single-digit nanomolar affinity, respectively. [20] Conclusion A short and practical route to biologically interesting am-phetamine analogues has been developed with catalysis as atool box. In three catalytic steps, different 5-HT 2A  receptorantagonists have been synthesized in good to excellentyields. The developed strategyis an interesting alternative toprevious routes to this class of compounds and can be used tosynthesize new active agents,which may otherwise be diffi-cult to access. As the first reac-tion step, base-catalyzed hydro-amination of styrenes with  N  -benzylpiperazine provides thecore structure of the desiredcompounds. Interestingly, hy-droamination proceeds smooth-ly even at room temperature,thus minimizing side reactionsof reactive substituents. Subse-quent removal of the benzylgroup and palladium-catalyzedaminocarbonylation of differenthaloarenes with the free (arylal-kyl)piperazines gives the de-sired target molecules in goodoverall yields. Experimental Section General : Starting materials were usedas received from commercial suppliers.THF was dried over sodium. Toluene(over molecular sieves) was used as re-ceived from Fluka. Hydroaminationreactions were performed in threadedACE pressure tubes, and in a parallelACT-Vantage synthesizer, with 12-and 48-well ARES reactors, respec-tively. For aminocarbonylation reac-tions, two types of autoclaves–160 mL (with magnetic stirring) and 25 mL (with electromechanical stir-ring)–were used.NMR spectra were recorded on a Bruker ARX 400 instrument. Chemicalshifts ( d ) are given in ppm and were referenced to residual solvent(CDCl 3 ) as internal standard in the case of   13 C NMR spectra and to tetra-methylsilane as external standard in the case of   1 H NMR spectra. EImass spectra were recorded on an AMD 402 spectrometer (70 eV, AMDIntectra GmbH) and high-resolution mass spectra were recorded on anAMD 402/3 spectrometer (70 eV, AMD Intectra GmbH). IR spectrawere recorded on a Nicolet Magna 550. GC was performed on a HewlettPackard HP 6890 chromatograph with a 30 m HP5 column.Melting points are uncorrected, and no attempts were made to crystallizethe molecules, which resist crystallization after purification. General procedure for NaH-catalyzed hydroamination of styrene with  N  -Boc-piperazine :  N  -Boc-piperazine (413 mg, 2.22 mmol) in THF (4 mL)was added slowly to a suspension of NaH (60% in mineral oil, 22.2 mg,0.55 mmol) in THF (3 mL), in a dry threaded tube. This was followed byaddition of styrene (0.5 mL, 4.44 mmol) and the mixture was stirred at120   C. After 45 h the reaction mixture was allowed to come to rt. andquenched with methanol (1 mL). The solvent was removed undervacuum. The hydroamination product ( 3 ) was purified by column chro-matography with AcOEt/hexane 4:1 as eluent.  N  -Boc-  N  ’ -(2-phenethyl)piperazine (3) : White amorphous solid;  R  f   =  0.50(AcOEt/hexane 4:1);  1 H NMR (400 MHz, CDCl 3 , 25   C, TMS):  d  = 7.36±7.28 (m, 2H; 9-H), 7.27±7.20 (m, 3H; 8-H, 10-H), 3.53 (t,  3  J  (H,H) =  4.8 Hz, 4H; 2-H), 2.85 (m, 2H; 5-H), 2.52 (m, 2H; 6-H), 2.53 (t, 3  J  (H,H)  =  4.8 Hz, 4H; 3-H), 1.34 (s, 9H;  t  Bu) ppm;  13 C NMRTable 4. Aminocarbonylation of (hetero)aromatic halides with  N  -benzylpiperazine. [a] Entry (Hetero)Aryl-X Time [h] pCO [bar] Conv. [b] [%] Product (yield [b] [%])1 20 10 100  10a  (96)2 20 25 100  10b  (99)3 20 10 100  10c  (95)4 20 25 100  10d  (99)5 20 25 100  10e  (85)6 20 25 100  10 f   ( > 99)[a] Reaction conditions: (Hetero)aryl-X (1.2 equiv),  N  -benzylpiperazine (2±3 mmol), Et 3 N (1.2 equiv),[Pd(PhCN) 2 Cl 2 ] (1 mol%), dppf (3 mol%), toluene (10 mL), 130   C in an autoclave (25 mL). [b] Determinedby GC with hexadecane as internal standard. ¹ 2004 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim  Chem. Eur. J.  2004 ,  10 , 746±757 750 FULL PAPER  M. Beller et al.
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