in general , the reaction of nucleophilic alkyl or aryl metal compounds with c = n groups yields the corresponding calkylated or arylated products.1 nevertheless , a number of cases are known in which this  normal  regioselectivity is suppressed in favor of an azaphilic addition (  umpolung).2 ,  3 an early example of this unexpected addition mode was reported by kagan and fiaud in 1971 for the reaction of grignard reagents with iminoesters,4a and since then has been expanded into a viable route to amino esters.4 ,  5 additionally , imino groups in special electronic environments , such as cyclopentadieneimines , have been found to follow similar reactive patterns.6 
  the observed azaphilic regioselectivity has been attributed , among other things , to the potentially chelating coordination of a lewis acidic metal cation ( mg for grignard reagents ) by the substrate ; this results in a conformation that favors naddition as well as polarization of the c = n bond due to the electronwithdrawing properties of the adjacent functional group ( in iminoesters ) . another qualitative rationale refers to the similarity of this structural motif in iminoesters to the wellknown nucleophilic addition to vinylogous systems . unfortunately , there is limited insight into this pattern of reactivity available from studies focusing on the underlying organometallic chemistry , experimental mechanistic work , or computational modeling . herein , we demonstrate how the polarization and orientation of metalcoordinated ketimides may influence the regiochemistry of grignard additions to cn multiple bonds . the focal point in the assembly is tetravalent titanium , which effects the fixation and orientation of the substrates , and thus controls the relative approach of key reagents.7 ,  8 the presence of additional functional groups that act as ligating units may significantly alter the preferred coordination mode of the ketimide and , as will be demonstrated , the observed pattern of reactivity ( figure  1 ) . ketimide compounds have been generated in situ by the group of de  meijere and others through the reaction of grignard reagents with various nitriles , including heterocyclic derivatives ( 3 and 4pyridine , 2thiophene , 2furancarbonitrile , etc . ) to yield the corresponding trityl amine products.9 the starting point for our study was the observation that the reaction of 2pyridine carbonitrile with aryl grignard reagents under the same conditions as those described by de  meijere et  al . , and subsequent hydrolytic workup gave narylated amines , and thus , the products of azaphilic addition ( scheme  1 ) . we hypothesized that this unexpected regioselectivity was due to chelation control by the pyridyl ring , which generated reactive intermediates coordinated to the metal center that , in turn , could act as key species in metalcomplexinduced , multicomponent onepot reactions . the critical role played by the nheterocyclic ring within the substrate for this reactive pattern was supported by control reactions ( see the supporting information ) as well as the isolation of a series of other naryl benzhydryl amines by the same titaniummediated route ( table  1 ) . the publisher did not receive permission from the copyright owner to include this object in this version of this product . please refer either to the publisher 's own online version of this product or the printed product where one exists . significantly , we were able to separate the carbo and azaphilic arylation steps , and thus , selectively introduce different aryl substituents , by choosing the order in which the two equivalents of grignard reagent were added ( table  2 ) : the first equivalent of grignard reagent cleanly added to the nitrile carbon , whereas the second addition only took place in the presence of [ ti(oipr)4 ] and occurred at the nitrogen atom . the reaction is not limited to grignard reagents nor to the presence of magnesium salts , since the corresponding lithium compounds are equally applicable in this transformation ( compounds 2  j and 2  k ) . the publisher did not receive permission from the copyright owner to include this object in this version of this product . please refer either to the publisher 's own online version of this product or the printed product where one exists . to obtain mechanistic insights into this intriguing transformation , we aimed to isolate crystalline products of the individual reaction steps that might represent or be related to reaction intermediates . first , grignard addition onto the nitrile moiety was investigated for the addition of 4fluorophenylmagnesium bromide to 2pyridine carbonitrile in thf at room temperature . notably , and crucially , for the selectivity of this transformation , the magnesium imide generated in this reaction step is not susceptible to further reaction with excess grignard reagent . a singlecrystal xray structure analysis of the ketimido magnesium compound 3 established the structural details of an octameric aggregate ( figure  2 ) , in which the 2pyridylimido unit acts as a chelating ligand for magnesium.10 
  top : in situ formation of oligomeric mg  ketimido clusters . hydrogen atoms and cocrystallized solvent molecules have been omitted for clarity . the central cube has been highlighted . ketimido fragment , which exposes the imidon atom that acts as a bridging ligating unit to a neighboring magnesium center . the observed reactivity in subsequent transformations indicates at least partial fragmentation of the octamer under the reaction conditions ( figure  2 ) . the subsequent reaction step , transmetalation with the titanium reagent , was studied by reacting 3 with [ ti(oipr)4 ] and [ tibr(oipr)3 ] ( scheme  2 ) . in both cases , in situ h and c  nmr spectroscopy as well as mass spectrometry results indicated the formation of a mixture of molecular species that defied characterization . however , with [ tibr(oipr)3 ] , we isolated a crystalline reaction product that could be characterized , inter alia , by xrd ( figure  3 ) . the product was a ti / mg heterodinuclear complex 4 , in which the ti atom is coordinated by a bromide ligand , two remaining isopropoxido units and two chelating 2pyridylimido units , one of which bridges the titanium and magnesium centers . the coordination sphere of magnesium is completed by a halogenido ligand and a coordinated thf molecule . in situ formation of labile titanium and magnesiumcontaining heterometallic species . hydrogen atoms and cocrystallized solvent molecules have been omitted for clarity . for selected bond lengths and angles , the 2pyridylimides act as bidentate chelates , and thus , feature bent ketimido  metal units . this form of ligation , which is significant for the subsequent transformations discussed below , should be seen in comparison with the large number of structurally characterized ketimides of the early transition metals , most of which adopt nearlinear c = n  metal arrangements.11 
  the following key reaction step of the transformation , leading to the reaction products represented in table  1 and 2 , involves attack of the second grignard reagent and determines whether carbo or azaphilic coupling is favored . given the complex equilibria of aggregates encountered in this type of chemistry , which precludes in situ characterization by spectroscopic means as well as systematic kinetic studies , additional insight had to be drawn from a computational study ( pbe0 calculations ) by employing an appropriately chosen model system ( see the supporting information for computational details ) . in the first stage , the simplest product of transmetalation between 3 and ti(oipr)4 ( or tibr(oipr)3 ) was considered . this complex features three alkoxy ligands ( herein modeled by ome ) and one ketimide n=c(py)(ar ) ( py=2pyridine ; ar = parafluorophenyl ) with either coordination of the pyridine substituent ( acyc ) or lack of pyridine coordination ( a ) . the two optimized geometries are shown in figure  4 and acyc is computed to be more stable than a by g=3  kcal  mol . o bonds ( 1.784 , 1.788 , and 1.802   ) and a significantly shortened ti n distance of 1.865   , which is indicative of some double bond ( i.e. , azavinylidene ) character.12 upon pyridine coordination in acyc , the geometry becomes a trigonal bipyramidal with the apical pyridine unit and a methoxy ligand . n bond is significantly elongated at 1.988   , whereas the n=c distance remains unchanged ( 1.269   , a ; 1.268   , acyc ) . computed structures of the ti complex fragments a and acyc and the ti  mg heterodinuclear model complexes b and bcyc . the optimized geometries are available in a single xyz file ( geom.xyz ) in the supporting information . color code : green = ti , purple = br , orange = mg , yellow = f , red = o , blue = n , dark gray = c , light gray = h . a natural bonding orbital ( nbo ) analysis of the electronic structure of a and acyc highlighted significantly different electronic properties of the n=c bond in a and acyc . the natural localized molecular orbital ( nlmo ) for the  bond between n and c is delocalized on the ti center with overall weights of 2.7 , 57.1 , and 37.1  % on ti , n , and c , respectively . for the same nlmo , the respective weights are 1.9 , 52.2 , and 42.1  % in acyc . this indicates that the n=c bond is more polarized toward c in acyc than in a. therefore , the carbon atom is more electronrich in acyc than that in a , and thus , less prone to attack by a nucleophile . this is also reflected in the natural population analysis ( npa ) charge for c , which is more positive in a than that in acyc ( 0.286 vs. 0.215 ) . in other words , coordination of mg(br)(ar ) ( ar = parafluorophenyl ) to either a or acyc is exergonic by g=7.7 and 17.5  kcal  mol , respectively . the geometries of adducts b and bcyc are shown in figure  4 . in adduct b , the mg cation is bridging between n and one methoxy ligand ( nmg=2.286   and mgo=2.122   ) . the ti nc linkage deviates from linearity in adduct b with tinc=148. the n=c bond is slightly elongated ( 1.284   ) and the nlmo associated with the  bond is more strongly polarized toward n in adduct b than that in the mononuclear reference system a ( 60.1  % n , 34.2  % c , 2.9  % ti ; charge on c in b : 0.334 ) . coordination of mg(br)(ar ) has increased the reactivity of c toward a nucleophile . in bcyc , the mg cation is bridging between n and the apical methoxy ligand ( mgn=2.089   , mgo=2.027   ) . the initial trigonal bipyramidal geometry of acyc is altered upon coordination of mgbr(ar ) to a pseudooctahedral geometry with creation of a tibr interaction ( 2.842   ) ; thus explaining the larger binding energy . as in the case of b , the geometry of bcyc is qualitatively similar to that observed for the isolated hetereobimetallic adduct ( figure  3 ) . the transition state , tsbc ( figure  5 ) , corresponding to the arylation of c in b has been located on the potential energy surface with g 
 = 25.9  kcal  mol . in tsbc , the forming cc bond length is 2.386   , whereas the n=c bond is elongated to 1.333   and the mg ar bond length increases from 2.110   in b to a value of 2.185   in tsbc . the carylation is exergonic with g=12.9  kcal  mol and , in the product of carylation , c ( figure  5 ) , the mg cation is bridging n ( 2.105   ) and one methoxy unit ( 1.976   ) . optimized geometries of the various extrema located along the pathway for direct carylation without ( left ) or with ( right ) pyridine coordination . the optimized geometries are available in a single xyz file ( geom.xyz ) in the supporting information . color code : green = ti , purple = br , orange = mg , yellow = f , red = o , blue = n , dark gray = c , light gray = h . in the transition state tsbccyc ( figure  5 ) , in which pyridine is coordinated to ti , the forming cc bond has an interatomic distance similar to that observed in tsbc ( 2.380   ) . however , the n=c bond is less elongated ( 1.317   ) and the breaking mgar bond is longer ( 2.290   ) in tsbccyc . this is in agreement with a greater reactivity of c toward nucleophilic attack in b than that in bcyc . as a matter of fact , the activation barrier associated with tsbccyc is greater ( g 
 = 30.4  kcal  mol ) than that for tsbc ( g 
 = 25.9  kcal  mol ) . there is thus a significant decrease in the carylation reactivity upon coordination of pyridine . from b or bcyc , no transitionstate structures associated with direct transfer of ar from mg to n could be located on the potential energy surface . however , in both cases , a transitionstate structure associated with ar transfer from mg to ti could be located . in the case of tsbd ( figure  6 ) , when pyridine is not coordinated , the activation barrier is low , g 
 = 8.9  kcal  mol , and the transformation is endergonic , g=6.9  kcal  mol for d relative to b. the product of the reaction , d , features an aromatic ring bridging mg and ti ( mgc=2.247   and tic=2.353   , see figure  6 ) . optimized geometries of the various extrema located along the pathway for narylation without ( top ) or with ( bottom ) pyridine coordination . the optimized geometries are available in a single xyz file ( geom.xyz ) in the supporting information . color code : green = ti , purple = br , orange = mg , yellow = f , red = o , blue = n , dark gray = c , light gray = h . with pyridine coordinated , the activation barrier associated with tsbdcyc is slightly lower ( g 
 = 4.8  kcal  mol ) and the transformation is still endergonic , with dcyc lying at g=2.8  kcal  mol above bcyc . here again , the transferring aromatic ring is bridging mg and ti in the product dcyc ( mgc=2.366   and tic=2.317   , see figure  6 ) . from intermediate d , narylation is effective through tsde with an activation barrier of g 
 = 20.8  kcal  mol and leads to the narylated product e with g=12.0  kcal  mol . in tsde , the migrating aryl group is bridging the ti n bond ( tic=2.190   and nac=1.784   ) and the n=c bond is elongated to 1.342   . the product of the reaction , e , features a ketimine moiety , n(ar)=c(py)(ar ) , in which the ti center interacts both with the nc ( tin=2.081   and tic=2.112   ) and car bonds ( tiar=2.482   ) , whereas the mg cation interacts with n ( 2149   ) and two methoxy groups . interestingly , the energetics associated with the corresponding narylation from dcyc is similar , with tsdecyc lying at g 
 = 21.0  kcal  mol above dcyc and ecyc lying at g=13.1  kcal  mol below dcyc . the migrating aromatic ring is further away from both ti ( tic=2.463   ) and n ( nc=1.930   ) in tsdecyc compared with tsde . only the n=c bond exhibits a similar lengthening ( 1.344   ) . because of pyridine coordination , the ketimine moiety , n(ar)=c(py)(ar ) , in product ecyc only interacts with ti through the n=c bond ( tin=2.057   and tic=2.272   ) the mg cation is bridging n ( mgn=2.088   ) and one methoxy group . in figure  7 a , a comparison between the pathways for c and narylation when pyridine is not coordinated is shown ( decoord pathway ) . although aromatic ring transfer is intrinsically easier from ti to n than it is from mg to c , the energy needed to transfer the aromatic ring from mg to ti overall destabilizes the narylation pathway . a comparison between the pathways for c and narylation when pyridine is coordinated ( metallacycle pathway ) is shown in figure  7  b . although the product of carylation is preferred thermodynamically , the formation of the narylated product is preferred kinetically . comparison between the pathways for c and narylation without ( a ) and with pyridine coordination ( b ) . gibbs free energy values are expressed in kcal  mol at 333  k relative to b ( path a ) or to bcyc ( path b ) ; bcyc is 12.7  kcal  mol more stable than b. the kinetic preference for the narylation pathway is the result of two cooperative effects . as already explained , pyridine coordination reduces the intrinsic reactivity of c toward direct reaction with a nucleophile . this leads to an increase in the energy of tsbccyc with respect to bcyc , compared with the energy of tsbc with respect to b. in addition , aromatic ring transfer from mg to ti is slightly favored when pyridine is coordinated ( by ca . 4  kcal  mol ; compare tsbdcyc in figure  7  b   with tsbd in figure  7  a ) . consequently , the transition state of the ratedetermining step for the carylation pathway is destabilized , whereas that of the ratedetermining step for narylation is stabilized when pyridine is coordinated . this eventually leads to inversion of the kinetically preferred pathway in favor of narylation when a substituent on the arylated ketimide can coordinate to titanium , as observed experimentally ( table  1 ) . when such coordination is not possible , the expected carylation product will be obtained . in summary , the proposed mechanism of the azaphilic c n coupling has revealed that the initial idea of an umpolung , in which a nucleophile is added onto the more electronegative nitrogen , has to be revised . in fact , in the selectivitydetermining step , the choice is not between n and carylation , but between c and tiarylation ; the latter opens up a reaction pathway that allows further migration to the nitrogen atom . the reaction product for the pathway involving azaphilic coupling , ecyc , represents a local minimum on the free energy hypersurface , and may rearrange to a pyridylligated titanaaziridine complex , fcyc , as depicted in scheme  3 . complex fcyc is computed to be g=7.7  kcal  mol more stable than ecyc . it is therefore reasonable to assume that such a species represents a key intermediate for the subsequent conversions discussed below . gibbs free energy values ( kcal  mol , 333  k ) are expressed relative to bcyc . in recent work by mller , beckhaus and coworkers , aromatic aldimine and ketimine complexes of titanocene were studied to highlight the accessibility and close structural relationship of three and fivemembered titanacycles ( figure  8) . a structurally related example was reported by rosenthal et  al.13b it was rationalized that steric factors determined the preferred coordination mode ( titanaaziridine vs. 1aza2titanacyclopent4ene species).13 
  structurally characterized titanaaziridine and azatitanacyclopentene complexes . a key insight of the computational study described above has been the likely formation of the titanaaziridine species fcyc , which may thus be viewed as a key intermediate for subsequent reaction steps in the multicomponent transformations described herein . the reactivity of metallacyclic aziridines of the group  4 metals has been studied previously by several research groups and has given rise to exciting examples of metalinduced transformations.14 the most common pattern of reactivity involves the coupling of the metalbonded carbon atom with various electrophilic reagents , including aldehydes or alkyl halides . this opened up the possibility of developing the onepot formation of such species into multiplecomponent reactions for synthetic targets , in which quaternary carbon centers with four different substituents would be accessible in a chemoselective way.15 
  initially , we examined the addition of a range of different electrophiles to the reaction mixture prior to hydrolytic workup . upon the addition of an excess of paraformaldehyde , the oxazolidines 5a , b were isolated as the main products , depending on the electronic nature of the naryl substituent ( scheme  4 ) . the oxazolidine is thought to be formed by a mannichtype mechanism from an initial aminoalcohol intermediate . in situ hydrogen atoms in the molecular structure of 5  a have been omitted for clarity ; thermal ellipsoids are shown at the 50  % probability level . subsequently , the reactive potential of the titanaaziridine intermediate towards various alkyl halides was investigated . both allyl and benzyl bromides afforded the corresponding trisubstituted amines ( scheme  5 ) . hydrogen atoms , except for n(1)h have been omitted for clarity ; thermal ellipsoids are shown at the 50  % probability level . remarkably , and in contrast to the reaction involving formaldehyde , which had to be added in the final step of the onepot procedure , the halides were found to be inert under the reaction conditions chosen for the formation of the active titanium species , and therefore , could be added during the initial setup of the reaction , rendering this a true onepot , multicomponent coupling . recently , micalizio and coworkers reported the reaction of in situ generated azatitanacyclopropanes ( generated from imines and the sato reagent16 ) with allylic or allenylic alkoxides to yield homoallylic amines or dienes.17a  d this approach was used , inter alia , for the synthesis of complex natural products . reacting allylic alkoxides with the titanium intermediate , we observed the formation of the corresponding homoallylic amines ( scheme  6 ) . hydrogen atoms , except for n(1)h , have been omitted for clarity ; thermal ellipsoids are shown at the 50  % probability level . a rationale for the observed e selectivity of these transformations based on an empirical model is depicted in the supporting information . again , the allylic alkoxide could be added directly to the reaction mixture and did not interfere with the ti n aryl transfer . using chiral allylic alkoxides as coupling partners , we obtained the corresponding enantioenriched reaction products , albeit with a slight erosion of chirality.18 chirality is thus transferred from an easily accessible chiral allylic alcohol to a metallacycle , thereby creating an enantioenriched quaternary carbon atom . the selectivity observed in this transformation is consistent with an empirical model based on a formal metallorearrangement.17 
  finally , we exchanged the allylic alkoxides for allenylic alkoxides.19 instead of the expected dienecontaining product , the 1,5aminoalkohols 8a and 8b were isolated ( scheme  7 ) . the results of a workup in d2o ( 8ad1 ) suggest a reaction mechanism through 1,2carbometalation of the terminal allene  bond , in contrast to the previously reported formal metallorearrangement . hydrogen atoms , except for n(1)h and o(1)h , have been omitted for clarity ; thermal ellipsoids are shown at the 50  % probability level . we have developed a powerful new multicomponent strategy for the rapid convergent assembly of structural complexity starting from simple nheterocyclic nitriles , grignard reagents , and electrophilic coupling agents . notably , this process relies on inexpensive , readily available starting materials , is highly modular , and yields environmentally benign and easily separable byproducts . the range of products thus accessible comprises valuable nitrogencontaining heterocycles , enantioenriched quaternary carbon centers , and densely functionalized structural motifs of pharmaceutical and biomedical relevance , as exemplified by the class of cholesterylester transfer protein ( cetp ) inhibitors shown in figure  9.20 ,  21 
  cetp inhibitors comprising an naryl tritylamine motif ( ms = mesyl ) . whereas the reaction products described herein are accessible through conventional approaches , namely , nucleophilic addition to diarylimines , these methods require multiple steps and tedious workup procedures.22 the reaction mechanism of the unexpected azaphilic addition of nucleophiles to ketimide titanium complexes was explored by dft methods , which revealed the formal umpolung of a c  n group as the key step toward reactive intermediary metallacycles ( titanaziridines and azatitanacyclopentenes ) . a central role is attributed to the tethered nitrogen donor moiety , which serves as a precoordinating directing group and , in conjunction with an ancillary  system , as an electron reservoir . finally , the reactivity profile of the titanacyclic intermediates was assessed by four mechanistically distinct followup reactions , namely , by insertion reactions with a c = o function , by nucleophilic substitution of halogenated alkanes , by allylic alkoxides featuring a formal metallorearrangement , and by allenic alkoxides resulting in a 1,2carbometalation reaction . notably , these transformations show a high degree of regioselectivity , although the control of absolute stereochemistry in this process remains a challenge . moreover , the stepeconomic concept presented in this work shows the great utility of group  4 metals for mediating challenging c  c and c  n bond formations .