ja710451s

Site-Selective sp2and Benzylic sp3Palladium-Catalyzed Direct Arylation

Louis-Charles Campeau,Derek J.Schipper,and Keith Fagnou*

Center for Catalysis Research and Inno V ation,Uni V ersity of Ottawa,Department of Chemistry,10Marie Curie,

Ottawa,Ontario,Canada K1N6N5

Received November19,2007;E-mail:keith.fagnou@uottawa.ca

Metal-catalyzed transformations at C-H bonds are emerging as

valuable tools in organic synthesis.1A particularly appealing aspect

of this chemistry is the potential to introduce multiple new

functional groups at precise locations.Current practices,however,

are usually limited to single site reactivity,ascribable to the

challenges associated with achieving a high yielding reaction at

even just one position.Toward the goal of multisite selectivity,

important seminal advances have been made with heteroaromatic

substrates at sp2positions.2As a greater appreciation of the reaction

possibilities for C-H bond cleavage/functionalization is gained,

particularly for reactions exhibiting orthogonal reactivity,the goal

of site selective direct functionalization should increasingly become

within reach.

Herein,we describe site selective arylation reactions of both sp2

and benzylic sp3sites3,4on azine and diazine N-oxide substrates

and illustrate that this reactivity can be performed both divergently

and sequentially.The products have demonstrated importance in

medicinal chemistry and the new reactivity represents an attractive alternative to other routes to this class of molecule.5To realize this goal,the need to properly establish the metal to ligand ratio was uncovered in sp2arylation,and a complete reinvestigation of all reaction parameters was required for sp3arylation.From these studies,the choice of base emerged as a pivotal component for site selectivity,pointing to its intimate involvement in the mech-anism of direct arylation.

We have described the use of N-oxides in direct arylation reactions as a means of avoiding the use of problematic organo-metallics in the formation of biaryl molecules.6Ongoing studies revealed that lower yields were encountered with substrates bearing methyl substituents adjacent to the N-oxide moiety.This prompted a re-evaluation of the sp2arylation conditions during which superior yields and selectivities were observed when using a1:1Pd(OAc)2 to P t Bu3stoichiometry compared to a1:3ratio(Table1,entries1 and2).Pertinent to the chemistry that follows,the selection of the base is crucial,with carbonates providing the optimal outcomes. Under these conditions,no other products are detected in1H NMR analysis of the crude reaction mixture.High yields of the azine/ diazine biaryl compounds can also be achieved as illustrated by entries1to4of Table2.

The challenges associated with these substrates lead us to question whether competing palladacycle formation(such as6) might be responsible for the challenging reactivity.7A corollary to this hypothesis is that intermediates such as6might also enable sp3arylation under appropriate conditions.8Toward this goal,every aspect of the reaction was reinvestigated.A promising lead involved the combination of2with1.5equiv of1,2.5mol%Pd2(dba)3,6 mol%S-Phos,and1.05equiv of NaO t Bu in toluene at70°C, which provides31%conversion to a4.3:1mixture of4and5(Table 1,entry3).

While increasing the amount of N-oxide improves selectivity (entry4),we also found that use of3equiv of NaOtBu also increased conversion and selectivity for4with2equiv of N-oxide (entry5).A survey of other ligands revealed that X-Phos provides 4exclusively,albeit with only41%conversion(entry6).We were gratified to find that employing X-Phos and microwave heating at 110°C provides an89%isolated yield of4with no drop in selectivity(entry8).With these conditions,1mol%palladium and1.5equiv of1can be used to provide4in84%isolated yield (entry9).Importantly,no products arising from arylation at the sp2position are detected by1H NMR analysis of the crude reaction mixture,indicating that a complete in V ersion in catalyst selecti V ity can be achie V ed.These results underline the eminent tunability of palladium in organic chemistry and its excellent responsiveness to changing reaction conditions.

A variety of substitution patterns,including ortho,meta,and para,can be employed(Table2).Although di-ortho substitution is tolerated,we found that replacing X-Phos with S-Phos led to Table1.Optimization of Picoline N-Oxide sp3-Arylation

a

a Conditions:substrates,Pd,ligand and base dissolved in PhMe and heated in an oil bath or microwave reactor.1H NMR yield of the major product.

b Isolated yield of the major product.

c Using1mol%Pd.

Scheme1.sp2/sp3Arylation in Heterocycle

Functionalization

Published on Web02/23/2008

32669J.AM.CHEM.SOC.2008,130,3266-326710.1021/ja710451s CCC:$40.75?2008American Chemical Society

superior yields (entries 7,8).Other alkyl groups can also be arylated where use of the corresponding alkyl organometallic may be problematic due to -hydride elimination at the alkylpalladium intermediate (entries 14,15).

This methodology has been validated in both divergent sp 2/sp 3arylation and in sequential sp 2/sp 3arylation which should be useful for the rapid derivatization of heterocyclic compounds (Scheme 1).Furthermore,the N -oxide moiety can be used to introduce a wide range of other functional groups or easily de-oxygenated under mild conditions if desired.9,10Consequently,these reactions should be useful for the derivatization of heterocyclic compounds in medicinal chemistry.Finally,the ability of palladium to selectively react at both sp 2and sp 3centers under different reaction conditions

should prompt its evaluation for similar selectivity switches with other substrates and reaction classes.

Acknowledgment.We thank NSERC,the University of Ottawa,the Research Corporation,Boehringer Ingelheim (Laval),Merck Frosst Canada,Merck Inc.,and Astra Zeneca Montreal are thanked for support of this work.

Supporting Information Available:Experimental procedures and spectroscopic characterization of all new products.This material is available free of charge via the Internet at https://www.wendangku.net/doc/2d6588287.html,.References

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(7)Reaction of 4-picoline N -oxide under Conditions B yields only sp 2arylation

in 21%yield

(8)Niwa,T.;Yorimitsu,H.;Oshima,https://www.wendangku.net/doc/2d6588287.html,.Lett.2007,9,2373.(9)For example,see ref 6a,b and references therein.

(10)See Supporting Information for examples of product deoxygenation.

JA710451S

Table 2.Scope of Picoline N -Oxide sp 2/sp 3-Arylation

a

a

Conditions A:N -oxide (2equiv),aryl halide (1equiv),Pd(OAc)2(5mol %),P t Bu 3HBF 4(5mol %),K 2CO 3(1.5equiv)dissolved in toluene and heated to 110°C.Conditions B:N -oxide (1.5equiv),aryl halide (1equiv),Pd 2dba 3(2.5mol %),X-Phos (5mol %)and NaO t Bu (3equiv)dissolved in PhMe and heated in a microwave reactor at 110°C for 45min.b Isolated yield.c Using 1.1equiv of N -oxide.d Using Ru-Phos (10mol %).e Using S-Phos (10mol %)and 3equiv of the N -oxide.

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