Ruthenium NHC Catalyzed Highly Asymmetric Hydrogenation of

Asymmetric Hydrogenation

DOI:10.1002/anie.201107811

Ruthenium NHC Catalyzed Highly Asymmetric Hydrogenation of Benzofurans**

Nuria Ortega,Slawomir Urban,Bernhard Beiring,and Frank Glorius*

Asymmetric hydrogenation of aromatic and heteroaromatic compounds is one of the most straightforward ways for the synthesis of saturated or partially saturated cyclic molecules,which are present in many biologically active compounds.[1]Starting from the pioneering work of Murata and co-workers in 1987,[2]who obtained enantiomeric excess in the hydro-genation of 2-methylquinoxaline,impressive advances have been made in the asymmetric hydrogenation of certain heterocycles.Mostly N-heterocycles,such as quinolines,[3]quinoxalines,[2,4]and indoles,[5]were successfully hydrogen-ated to the corresponding tetrahydroquinolines,tetrahydro-quinoxalines,and indolines with more than 90%ee by using homogeneous transition-metal catalysts or Br?nsted acid organocatalysts.However,despite the effort put into this area in the last years,some valuable classes of substrates,especially (non-N)heterocycles,such as furans,thiophenes,benzofur-ans,and benzothiophenes,are much less explored and still constitute a challenge for the field of asymmetric hydro-genation.Therefore,new efficient and highly enantioselective methodologies that permit access to the corresponding reduced analogues are highly desirable.

There are numerous reports on the synthesis of 2,3-dihydrobenzofurans.[6]However,even though hydrogenation seems to be the most direct route for their synthesis,arguably,it is more difficult compared to the hydrogenation of many other heteroaromatic compounds.[7]Often partial decompo-sition of the furan ring to 2-ethylcyclohexanol and b -cyclo-hexylethyl alcohol is observed.[6,8]Regarding the asymmetric hydrogenation of benzofurans,to date only two reports can be found:In 2003,Baiker and co-workers used a combination of Pd/Al 2O 3with cinchonidine derivatives to obtain reduced 2-benzofuran carboxylic acid in very low yield and only 50%ee .[9]In the field of homogeneous catalysis,Pfaltz and co-workers applied pyridine phosphinite iridium complexes obtaining a few 2,3-dihydrobenzofurans with excellent ee val-ues (Scheme 1).[10]However,longer reaction times were needed and only three of these substrates were described.Herein we report an efficient,high yielding,highly regio-and enantioselective hydrogenation of substituted benzofurans proceeding under mild conditions.

Recently,we have reported a new method for the enantioselective hydrogenation of the aromatic carbocyclic ring of substituted quinoxalines by using a chiral ruthenium N-heterocyclic carbene [11](NHC)complex.[12]This report was the first example of a catalytic asymmetric hydrogenation of the carbocyclic ring of aromatic compounds.In addition,the choice of the NHC allowed a switch between the selective hydrogenation of either the carbocyclic (using the NHC ICy)or the heterocyclic ring (using the NHC SIPr).However,even though the structure and mode of action of the catalysts are not yet known,we decided to explore the reactivity of this new catalytic system for other challenging substrates.To our surprise,when we applied our Ru catalyst formed from ICy for the hydrogenation of benzofuran,we selectively reduced the heterocyclic ring,exclusively obtaining the corresponding 2,3-dihydrobenzofuran (Scheme

2).

Scheme 1.Asymmetric hydrogenation of

benzofurans.

Scheme 2.Switching between carbocycle and heterocycle b0f0398dbb4cf7ec4bfed008plete regioselectivity (>99:1)and quantitative yield was obtained in each case.

[*]Dr.N.Ortega,S.Urban,B.Beiring,Prof.Dr.F.Glorius Westf?lische Wilhelms-Universit?t Münster Organisch-Chemisches Institut

Corrensstrasse 40,48149Münster (Germany)E-mail:glorius@uni-muenster.de

Homepage:http://www.uni-muenster.de/Chemie.oc/glorius/

index.htm [**]Generous financial support by the Deutsche Forschungsgemein-schaft (SFB 858)is gratefully acknowledged.The research of F.G.has been supported by the Alfried Krupp Prize for Young University Teachers of the Alfried Krupp von Bohlen und Halbach Foundation.We also thank BASF (Prof.Dr.Klaus Ditrich)for the donation of precious chiral amines (Ch i Pros).NHC =N-heterocyclic

carbene.

Supporting information for this article is available on the WWW under b0f0398dbb4cf7ec4bfed008/10.1002/anie.201107811.

.Angewandte Communications

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Interestingly,using the substituted 2-phenyl benzofuran (1a )as model substrate,hydrogenation resulted in the formation of the corresponding racemic 2,3-dihydrobenzo-furan 2a in quantitative yield and with complete regioselec-tivity.Encouraged by these preliminary results,we tested to see if our previously developed chiral ruthenium NHC complex,formed from the imidazolium salt 3a (for formula,see Table 1),could induce enantioselectivity in the hydro-genation of substituted benzofurans.[13]When we submitted 1a to the hydrogenation process at 60bar of H 2and 808C,starting material was recovered,probably because of the decomposition of the catalyst (Table 1,entry 1).Intriguingly,upon decreasing the temperature to 408C,full conversion into the desired product 2a was obtained.Moreover,the enantio-meric ratio reached surprisingly good 96:4.Furthermore,it was possible to perform the reaction at even lower temper-ature (258C)and lower hydrogen pressure (10bar),resulting in a reproducible slight increase of the enantiomeric ratio to 97:3(Table 1,entry 4).Solvent screening revealed that non-polar,aprotic solvents,such as n -hexane and toluene,were best suited for this reaction,and the use of n -hexane gave an increase of the enantiomeric ratio to excellent 99:1(Table 1,entry 5).Modifying the NHC derived from 3a by using its unsaturated derivative 3b ,led to similar results in conversion and regioselectivity,but a slight decrease of enantiomeric ratio of the product 2a (Table 1,entry 3).Having established the optimized reaction conditions,we tested a variety of substituted benzofurans to probe the versatility of our catalytic system (Table 2).Interestingly,the reactivity of the 2-phenyl-substituted benzofurans changes significantly with the electronic properties of the substituents:When the phenyl ring contains electron-withdrawing groups,such as fluorine (1g )or trifluoromethyl (1f )in a para position,the reaction proceeds smoothly at 10bar of hydro-gen pressure and at room temperature,with full conversion and very good enantiomeric ratio.However,when the phenyl ring bears electron-donating substituents,such as a methoxy group (1e ),low conversion to the desired product was observed.Fortunately,with 1e ,full conversion was achieved when the reaction was carried out at 60bar of hydrogen and 408C,maintaining an excellent enantiomeric ratio of 99:1.We also studied the effect of the substitution pattern of the 2-phenyl ring on the reactivity.The reaction worked nicely for the 2-(p-tolyl)(1d )and 2-(m-tolyl)benzofuran (1c )with full

conversion and enantiomeric ratio of 99:1,but in the case of 2-(o-tolyl)benzofuran (1b )the reactivity dropped,resulting in only 73%yield of isolated product,and 96:4enantiomeric ratio.To our knowledge,this is the first report of highly asymmetric hydrogenations of aryl-substituted benzofurans.In the case of alkyl-substituted benzofurans,the reaction proceeds with perfect conversion and high enantioselectivity Table 1:Optimization of the reaction conditions for the asymmetric hydrogenation of 2-phenyl benzofuran 1a .

[a]

Entry NHC·HX Solvent T [8C]p (H 2)[bar]Yield [b][%] e.r.[c]13a toluene 8060n.d.n.d.23a toluene 4060>9996:433b toluene 4060>9994:643a toluene 2510>9997:353a hexane 2510>9999:1[a]General conditions:[Ru(cod)(2-methylallyl)2](0.015mmol),KO t Bu (0.045mmol)and 3a or 3b (0.03mmol)were stirred at 708C in the shown solvent (2mL)for 12h,after which it was added to 1a (0.30mmol),and hydrogenation was performed under conditions shown in each case for 16h.The optimized conditions are shown in italics.[b]Yields given are of isolated product.[c]E.r.was determined by HPLC on a chiral stationary phase;n.d.=not detected.Table 2:Scope of the asymmetric hydrogenation of benzofurans 1a –q .

[a][a][Ru(cod)(2-methylallyl)2](0.015mmol),3a (0.03mmol),KO t Bu

(0.045mmol),n -hexane (2mL)were stirred at 708C for 12h,after which

it was added to substrate 1a –q (0.3mmol).Hydrogenation was performed at 10bar H 2,258C,16h.Yields given are of isolated product.

Enantiomeric ratio was determined by HPLC on a chiral stationary phase.The stereochemistry of the 2-alkyl and aryl-substituted products was assigned in analogy to 2h and corsifuran A,respectively.[b]Reaction was performed at 60bar H 2,408C,16h.[c]The absolute configuration of 2h was determined by comparison of optical rotation data with the literature value (see the Supporting Information).In addition,we succeeded in synthesizing corsifuran A,[15]a 2-aryl substituted 2,3-dihydrobenzofuran,

with this new hydrogenation method,again allowing the comparison of optical rotation with the literature data.[d]Run with 0.5mol %catalyst.

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for many primary and secondary alkyl chains(1h–k).We noticed that the enantiomeric ratio decreased slightly when the length or substitution of the chain was increased,while maintaining perfect conversion into the desired product. Surprisingly,the reaction even works with the2-(tert-butyl)-benzofuran(1l)albeit with lower conversion and ee value. The reaction also gave the desired product for2-benzyl benzofuran(1m)with an e.r.of92:8.Changing the position of the substituent to position3(1o)led to a slight drop in enantioselectivity(93:7)compared to the regioisomer1h,but maintains perfect regioselectivity and conversion.By com-parison of the optical rotation data of2h,the absolute configuration could be assigned to be R(see Table2).

We also studied the influence of the substitution on the carbocyclic ring of the benzofuran.When6-(tert-butyl)-2-phenylbenzofuran(1n)was submitted to hydrogenation conditions,the corresponding2,3-dihydrobenzofuran2n was obtained with no change on the enantiomeric ratio or reactivity compared to the analogue2a.Moreover,we studied the influence of the presence of other aromatic rings.When2-(benzofuran-2-yl)pyridine(1p)was submitted to hydrogenation conditions,the corresponding2,3-dihydro-benzofuran derivative(2p)was obtained smoothly without any observed hydrogenation of the pyridine,but with a considerable drop in the enantiomeric ratio compared to the phenyl analogue1a.The basis for this deterioration might be the ability of1p to form a bidentate chelate.To test this hypothesis,we used the regioisomeric3-(benzofuran-2-yl)pyr-idine(1q),which led to the exclusive formation of2,3-dihydrobenzofuran with excellent99:1enantiomeric ratio.

To explore the kinetic behavior of this hydrogenation process we chose2-methyl benzofuran(1h)as model substrate.First,we discovered that a significantly reduced catalyst loading of0.5mol%was sufficient for full conversion into2h,providing a turnover number(TON)of200(Table2). Using0.5mol%of catalyst the reaction was stopped after certain times.To our surprise,the reaction was already complete after2h.However,when we reduced the reaction time to1h all of the starting material was recovered unchanged.[14]A closer inspection showed that most of the substrate was converted into2-methyl-2,3-dihydrobenzofuran between70and80min,showing a turnover frequency(TOF) of1092hà1.An induction period of1h seems to be required to form the catalytically active species.Once formed,this species provides most of the turnover within10min,demon-strating a high efficiency of the catalyst.

In conclusion,we have successfully applied a chiral ruthenium NHC complex in the high-yielding,regioselective, and highly asymmetric hydrogenation of substituted benzo-furans.Notably,the catalyst shows very high TOF and good TON.We also present a very simple and straightforward method for the asymmetric synthesis of valuable2,3-dihy-drobenzofuranes.Further studies focusing on catalyst char-acterization,mechanistic aspects of this reaction and hydro-genation of other challenging substrates are ongoing.

Experimental Section

General procedure:In a glove box,to a flame-dried screw-capped tube equipped with magnetic stir bar was added the[Ru(cod)(2-methylallyl)2](4.8mg,0.015mmol;cod=cyclooctadiene),imidazo-lium salt3a(14.1mg,0.03mmol),and dry KO t Bu(5.0mg, 0.045mmol).The mixture was suspended in hexane(2mL)and stirred at708C for12h.Then the mixture was transferred under argon to a glass vial containing benzofuran1a–q(0.3mmol)and a magnetic stirring bar.The glass vial was placed in a150mL stainless-steel reactor.The autoclave was pressurized with hydrogen gas (10bar or60bar)and depressurized three times before the indicated reaction pressure was set.The reaction mixture was stirred at258C or 408C for16h.After the autoclave was carefully depressurized,the crude mixture was filtered through a plug of silica using a pentane/ EtOAc mixture(9:1),yielding analytically pure compounds2a–q. The enantiomeric ratio of all compounds was determined by HPLC on a chiral stationary phase.

Received:November6,2011

Published online:January3,2012

.Keywords:2,3-dihydrobenzofuran·asymmetric hydrogenation·heterocycles·N-heterocyclic carbenes·ruthenium

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[13]The catalyst was pre-formed before the hydrogenation reaction:

[Ru(cod)(2-methylallyl)2],KO t Bu,and the imidazolium salt(3a

or3b)were stirred at708C for12h in hexane,after which it was

added to1a and hydrogenation was performed under conditions

shown in Table1.

[14]Yields given are determined by NMR spectroscopy.For more

details,see the Supporting Information.

[15]The synthesis of corsifuran A will be reported in due course.

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