Laurine Gonnard, Amandine Guérinot,* Janine Cossy.*

1

Transition-metal-catalyzedα-alkylationofaminesbyC(sp3)‒Hbondactivation

LaurineGonnard,AmandineGuérinot,*JanineCossy.*LaboratoiredeChimieOrganique,InstituteofChemistry,BiologyandInnovation(CBI)-UMR8231,ESPCIParis,CNRS,PSLResearchUniversity,10rueVauquelin,75231ParisCedex05,France.E-mail:[email protected];[email protected]α-Substitutedaminesarepresent in amyriadofbiologically activenatural and syntheticproducts.Withtheobjectiveofdevelopingatom-economicalreactions,apanelofsyntheticmethodsallowingthedirectfunctionalizationofC(sp3)‒Hbondsadjacenttothenitrogenatomhavebeendeveloped.Thefieldremainsdominatedbythesequenceα-lithiation/additiononanelectrophileeveniftheuseof reactive organolithium reagents is not compatiblewith all functional groups.Over the past tenyears,anincreasinginteresthasbeendevotedtometal-catalyzedC-H-activation,somestudiesbeingspecially dedicated to C(sp3)‒H bond activation. Notably, this approach has been envisioned toperform direct α-functionalization of amines. The aim of this article is to give an overview ofsyntheticmethodsfortransitionmetal-catalyzedα-alkylationofaminesbyC(sp3)‒Hbondactivation.Keywords:amines;α-alkylation;C(sp3)‒Hactivation;transitionmetals;directinggroupIntroduction

Both α-substituted cyclic and acyclic amines are ubiquitous moieties in natural and/orbiologically active compounds. Particularly, α-alkyl cyclic amines are present in a wide array ofnatural alkaloids such as coniine ormorphine. Inspired byNature,medicinal chemists selectedN-heterocyclesasattractive scaffoldsand, in this context,piperidineandpyrrolidine ringsappears inthe top 100 most frequently used rings in drugs listed in the FDA Orange book.1 For example,methylphenidateiscommercializedasconcerta®byJanssenforhyperactivitytroubles.Inaddition,α-alkylacyclicaminesarealsopresentinarangeofdrugssuchasstrattera®(Lilly),whichisusedforthetreatmentofmentaldisorders(Figure1).

Figure1

NH

CH3

Coniine

O

HON

H

HO

Morphine

HN

OMeO

O

NH

Atomoxetine (strattera ®)

2

Notsurprisingly,amyriadofsyntheticmethodshavebeendevelopedtoaccessthesemotifs.Amongthem,onestrategybasedonthedirectfunctionalizationofC(sp3)‒Hbondsadjacenttothenitrogenatomisespeciallyattractive.23Theexistingmethodscouldbedividedintofivemainreactiontypes:(1)oxidationleadingtoiminiumintermediates,(2)α-lithiation,(3)generationofα-amino-radicals,(4)metal-catalyzed carbene insertionand (5)metal-catalyzedC-H functionalization (Scheme1). In thelattercase,aC(sp3)‒Hbondactivation takesplace, the term“C-Hbondactivation”meaning thatasigmaC(sp3)‒MbondisgeneratedinonesinglestepbycleavageofaC(sp3)‒Hbond.4

Scheme1

The C-H activation step can proceed through different mechanisms such as a concertedoxidativeaddition,asigma-bondmetathesisorabase-assistedConcertedMetalation-Deprotonation(CMD).5

Scheme2

Importantly, the C(sp3)‒H bond activation generally requires the presence of a directing

groupforbothreactivityandselectivity issues.6Thedirectinggroupis inmostcasesacoordinatingmoiety such as a nitrogen-containing heteroaromatic, a carbonyl or an unsaturation. More

R1

NR2

R3

H

Alk-Li, diamineR1

NR2

R3

Li

[M] cat. CH-activationR1

NR2

R3

[M]

iminium formation

R1

NR2

R3

α-amino radicalformation

R1

NR2

R3

metal-catalyzed carbene insertion

R4

OR5

N2

R1

NR2

R3

R5R4

O

(1)

(2)

(3) (4)

(5)

[M] +H

R

H

R[M]

H

R[M] [M]

H

R

Concerted oxidative addition

[M]+

H

R

R'

[M]

R' H

R[M]-R + R'-H

σ-Bond metathesis

Carboxylate-assisted concerted metalation-deprotonation

O

OR'

+ H

R

H

R

O

O

R'

[M][M][M]-R +

R' OH

O

3

ephemerally,aC‒halogenbondcanactasadirectinggroup.Inthiscase,anoxidativeadditionofthemetalcatalystintotheC-halogenbondbringsthemetalclosetotheC(sp3)‒Hbond.

Herein, we present a review devoted to the α-alkylation of amines by transitionmetal-catalyzedC(sp3)-Hbondactivation.7Themethodsareclassifiedaccordingtothenatureof(a)themetal catalyst and (b) the nature of the directing group. For eachmethod, details about thesubstratescope,thelimitations,theselectivityand/orthemechanismwillbepresented.8,9,101-Ruthenium-catalyzedα-alkylationofaminesWithapyridinyldirectinggroup

Direct ruthenium-catalyzedalkylationat theC(sp3)‒Hbondalpha to thenitrogenofacyclicamines was first described by Jun et al. in 1998 and was limited to benzylamines.11 When N-benzyl,N-(3-methyl-2-pyridyl)amine1.1(1equiv)wastreatedwithanexcessofhex-1-ene(5equiv)inthepresenceofRu3(CO)12(10mol%)intolueneat130°Cfor6h,thecorrespondinglinearalkylatedproduct1.3wasisolatedin95%yield.TheC3-methylgrouponthepyridinewasthekeyelementasonlytracesofthealkylatedproductwasobservedwhenthemethylgroupwaspresentattheC4-orC6-positionorwasreplacedbyahydrogen.ThepresenceofthemethylgroupatC3slowsdownthefreerotationofthebenzylgrouparoundtheaminegroup,thusfavoringspecialproximitybetweentheC(sp3)‒Hbondandtherutheniumcatalystwhichwasprecoordinatedtothenitrogenatomofthepyridine(Scheme3).

Scheme3

Themethodwasextendedtootherterminalolefins.Whileexcellentyieldwasobtainedwithnon-hindered olefins (1.8, 93%), lower yieldswere observedwith sterically hindered alkenes (1.9,72% and 1.10, 75%). The use of styrene resulted in 70% yield in 1.11 due to a competitivepolymerization(Scheme4).

N NH+

Ph

n-BuRu3(CO)12 (10 mol %)

130 °C, 6 h, toluene(5 equiv)

N NH

Phn-Bu95%1.1 1.2 1.3

H

N NH

PhH[Ru]

4

Scheme4

Surprisingly,whenacyclicinternalolefinswereinvolvedinthisalkylationprocess,onlylinearproductswereformedandnobranchedalkylatedcompoundsweredetected.Theformationof1.3from1.1and3-hexenewouldresultinanisomerizationofasecondaryalkyl-rutheniumcomplextoaprimaryalkyl-rutheniumasalreadydescribedbyBaxteretal. inthecaseofpalladiumandplatinumcomplexes.12 However, when cyclopentene and cyclohexene were utilized, the correspondingproducts1.15and1.16wererespectivelyisolatedin70%and60%yields(Scheme5).

Scheme5

When substrates 1.17 and 1.18, bearing respectively a para-methoxy and a para-trifluoromethyl group on the phenyl ring of the benzylamine, were concurrently engaged in thereaction, products 1.19 and 1.20 were isolated in a 2.3:1 ratio in favor of the para-methoxysubstituted compound (Scheme 6). This result suggested that the reaction was favored in thepresence of an electron-donating group compared to an electron-withdrawing group, probablyduringthealkeneinsertionstep.

Scheme6

Threeyearslater,compound1.22wasisolatedin82%yieldfrom1.1andethylene(10atm)byMuraietal.usingsimilarreactionconditions[Ru3(CO)12(8mol%),iPrOH,140°C].13Inthisarticle,

N NH+

Ph

R1Ru3(CO)12 (10 mol %)

130 °C, 6 h, toluene

(5 equiv)

N NH

PhR1

1.1 1.4-1.7 1.8-1.11

N NH

PhC8H171.8 (93%)

N NH

Pht-Bu1.9 (72%)

N NH

Ph1.10 (75%)

N NH

PhPh1.11 (70%)

H

N NH+

Ph

Ru3(CO)12 (10 mol %)


N NH

Phn-Bu81%1.1 1.12 1.3

N NH+

Ph

Ru3(CO)12 (10 mol %)


N NH

Ph1.1 1.13, n = 1 1.15, n = 1 (70%)

n = 1,2

n = 1,2

1.14, n = 2 1.16, n = 2 (60%)

H

H

N NH+ n-Bu

Ru3(CO)12 (20 mol %)


N NH

n-Bu

1.17 (R = OMe, 1 equiv)

1.2

1.19 (60%)R

N NH

n-Bu

1.20 (26%)OMe CF3

1.18 (R = CF3, 1 equiv) (1.19/1.20 = 2.3:1)

+

H

5

the authors described the first direct ruthenium-catalyzed alkylation of cyclic amines. Whenpyrrolidine 1.23 was submitted to ethylene in the presence of additional CO (1 atm) and of therutheniumcatalyst,thecarbonylatedproductwasnotdetectedbutthedi-alkylatedpyrrolidine1.24was isolated in 92% yield with a 54:46 diastereoisomeric ratio. If the presence of CO was notessential (77% yield in its absence), the authors assumed that it could help to avoid thedecompositionofthecatalyst.Amongthesolventsscreened,iPrOHwasbyfarthesolventofchoice(Scheme7).

Scheme7

Whenotheralkenes(10equiv),suchasn-hexene,wereinvolvedinthereactionwith1.23,amixtureofmono-anddi-alkylationproducts1.27 and1.27’wasobtainedand theuseofa smalleramountofalkenedidnotallowtheselectiveformationofthemono-alkylatedproducts.Alkeneswithan electron-withdrawing group or alkynes showed no reactivity. The reactionwas then applied toN-pyridylpiperidine1.25leadingtodi-alkylatedpiperidine1.28’in73%yield(dr=60:40).Whenthisalkylation process was attempted with azepane 1.26, both mono-ethylation and di-ethylationproducts 1.29 and 1.29’ were isolated (1.29, 47% and 1.29’, 14%, dr = 52:48), revealing that thereactionismoreselectivetowardthemono-alkylationoflargerrings(Scheme8).

N NH+

Ph

H2C CH2Ru3(CO)12 (8 mol %)

140 °C, 40 h, iPrOH(10 atm)

N NH

Ph82%1.1 1.21 1.22

N

N+

CO (1 atm)Ru3(CO)12 (8 mol %)

140 °C, 20 h, iPrOH(10 atm)

92%

1.21

N

N

1.23 1.24 (dr = 54:46)

H

HHH2C CH2

6

Scheme8

Toexplaintheroleof iPrOH,thedecompositionoftheruthenium-hydrideintermediate1.Atoacarbenecomplex1.Bwiththeformationofdihydrogenwasspeculated.Toavoiddeactivationofthecatalyst,iPrOHcouldactasahydridedonorandregeneratetheactiverutheniumhydridespecies(Scheme9).Thisreversibleprocesshasalreadybeenobservedwithiridiumcomplexes.14

Scheme9

In 2012,whenMaeset al. tried to alkylateN-pyridyl piperidine1.30a using the previouslydescribed conditionsbyMuraietal., the2-alkylatedproduct1.31a and theunexpectedpiperidine1.32wereisolatedinasimilarlow17%yieldand1.30awaspartiallyrecovered(48%)(Scheme10).15

Scheme10

After an extensive optimization, the authors showed that the addition of a carboxylic acid[trans-1,2-Cy(COOH)2(4mol%)] andanalcohol[2,4-dimethyl-3-pentanol(5equiv)]wereessentialto reach high yields in the alkylated products. Under these optimized conditions [(1-hexene (10equiv), Ru3(CO)12 (4mol%), 140 °C, 24h], thedesiredmono-alkylatedpiperidine1.31a (48%)wasformedalongwiththedi-alkylatedproduct1.33a(43%,trans/cis=1:1)(Table1,entry1).OtherC4-substitutedpiperidinesweresuccessfullymono-anddi-alkylated,thereactionbeingcompatiblewith

NPy

CO (1 atm)Ru3(CO)12 (8 mol %)

140 °C, 20 h, iPrOH

1.2, R1 = n-Bu1.21, R1 = H

NPy

1.23, n=11.25, n=21.26, n=3

1.27-1.29,

R1n = 1-3n = 1-3

1.27'-1.29',

1.27, R2 = H (29%)1.27', R2 = n-Hex (53%, dr= 52:48)

NPy

R2n-BuN

1.28' (73%, dr = 60:40)

N R2

R2

R2 = HR2 = n-Hex ou Et

1.29, R2 = H (47%)1.29', R2 = Et (14%, dr= 52:48)

HH NPy =

Py Py

R1

N

N

[Ru] H N

N

[Ru]

-H2

OHO

1.A 1.B

N

OO

+ n-Bu

(10 equiv)

1.2

Ru3(CO)12 (8 mol %)

140 °C, 60 h, iPrOH

1.30a

N

OO

n-Hex N n-Hex+

1.31a 1.32(17%) (17%)

H

τc = 52%Py Py Py

Py = 2-pyridyl

7

ketal,etherandestergroups.However,mixtureofdiastereomerswereobtained(Table1,entries2-3).

entry 1.30 1.31(yield,dr) 1.33(yield,dr)1

2

3

[a]trans/cisratio.

Table1

Theprotocolwasextendedto2-methylpiperidine1.30d(1.35,78%,trans/cis=5:3)and,forthe alkylation of this compound, 3,4,5-trifluorobenzoic acid was chosen. After separation of thediastereomers, the trans-piperidine 1.35 was converted into (±)-solenopsin A, a natural alkaloid(Scheme11).

N+ n-Bu

(10 equiv)

1.2

Ru3(CO)12 (4 mol %)trans-1,2-Cy(CO2H)2 (4 mol %)

2,4-dimethyl-3-pentanol (5 equiv)

140 °C, 24 h

1.30a-1.30c

N n-Hex N n-Hex+

1.31a-1.31c 1.33a-1.33c

R1 R2 R1 R2 R1 R2

n-HexHHPy Py Py

Py = 2-pyridyl

NPy

OO

1.30a 1.31a (48%)

NPy

OO

n-Hex NPy

OO

n-Hexn-Hex

1.33a (48%, 1:1)[a]

NPy

OMe

1.30b

NPy

n-Hex

OMe

1.31b (39%, 1:1)[a]

NPy

n-Hexn-Hex

OMe

1.33b (47%, 4:1:1)

NPy

O OMe

1.30c

NPy

n-Hex

O OMe

1.31c (32%, 1:3)[a]

NPy

n-Hexn-Hex

OMeO

1.33c (53%, 4:1:1)

8

Scheme11

Further studies have been performed to gain a better understanding of the role of bothcarboxylicacidandalcoholduringthealkylationprocess.Kineticprofilesrevealedthatthereactionwasmuchfasterinthepresenceofacarboxylicacidwithnoinductionperiod.Mostimportantly,theacidadditivewasessentialtoreachfullconversionofthestartingmaterialbypreventingthecatalystdeactivation(whichoccursafterapproximately6hintheabsenceofacarboxylicacid).Interestingly,theauthorshaveshownthat,intheabsenceofacidcatalyst,sidereactionssuchasreductionofthealkene and alcohol oxidation to the corresponding ketonewere favored against alkylation. Finally,when2,4-dimethyl-3-pentanolwas omittedor replacedby tert-BuOH, themono-alkylatedproductwas selectively formedalbeitwithpoor yields. Theseobservations led the authors to suggest thatbothtrans-1,2-Cy(COOH)2and2,4-dimethyl-3-pentanolwereinvolvedinthecatalystactivation.

Thus,inthepresenceofacarboxylicacidadditive,thecatalyticcycledepictedinScheme12was proposed by the authors. Intermediate Ru(0) complex 1.C would first be formed by twosuccessive coordinations (carbonyl group of carboxylic acid and hydroxyl group of the alcohol)favored by hydrogen bonding between the two entities. This interactionwould then facilitate theoxidativeadditionoftherutheniumintotheO-Hbondofthealcoholand,afterprotonationofthealcohol,Ru(II)hydridecomplex1.Epossessinga carboxylate ligandwouldbe released.Subsequentalkeneinsertionwouldleadtocomplex1.Fwhichwouldgive,aftercoordinationofamine1.25andC(sp3)‒H bond activation following a CMD mechanism, the complex 1.G and liberation of thecarboxylicacid.Asthelaststep,reductiveeliminationwouldfurnishthemono-alkylatedproduct(orthedi-alkylatedproductafterasecondcycle)andregenerationoftheRu(0)complex.

N+ C9H19

(10 equiv)

1.34

Ru3(CO)12 (8 mol %)3,4,5-trifluorobenzoic acid

(8 mol %)2,4-dimethyl-3-pentanol

(5 equiv)140 °C, 48 h

1.30d

N C9H19

1.35(trans/cis = 5:3)

78%

Separation

N C9H19

trans-1.35

Rh/C (10 mol %)H2 (75 bar)

75 °C, 16 h, iPrOHNH

C9H19

(±)-SolenopsinA65%

H

NPy =

Py Py

Py

9

Scheme12

Another mechanism (Scheme 13) was also reported in the absence of a carboxylic acidadditive. In this case, ruthenium alkoxide 1.H, formed from Ru(0) complex by oxidative addition,wouldbetheactivecatalyst. ItcouldledtothedesiredcompoundthroughamechanismsimilartotheonedescribedinScheme12,butthemajorpathwaywouldinvolveaβ-Heliminationfurnishingthe dihydride ruthenium complex 1.I. After alkene insertion and reductive elimination, thecorrespondingalkanewouldbereleasedaswellastheRu(0)complex.

Scheme13

Consecutivetothiswork,Maesetal.triedtoexpandtheirmethodtofunctionalizedalkenes

by using methyl vinyl ketone 1.36 (10 equiv) as the alkylating reagent.16 While no conversion of

Ru(0)

R2

R1O Ru(0)

H

H

O

O

R3

R2

R1O

HO

O

R3

Ru(II)H

ORu(II)

H

OR3

ORu(II)

OR3

R4

N

N

Ru(II)

R4

OHR2

R1

HO R3

O

,

1.C

1.D

1.E

1.F

1.G

Oxidative addition

OHR2

R1

R4

Migratory insertion

CMD

N

N

R4Reductiveelimination

N

N

H

1.25

R3 OH

O

Ru(0)

ORu(II)

H

R2R1

HRu(II)

H

Ru(II)H

R4

O

R2 R1

OH

R2 R1

R4

R4

1.H

1.I

1.J

Oxidative addition

β-H elimination

Migratory insertion

Reductiveelimination

10

piperidine 1.25 was observed under the previously optimized conditions, α,β-unsaturated ketone1.37wastotallyconvertedtobutan-2-one(27%)aswellaspolymerizedproducts.Replacingmethylvinyl ketone 1.36 by its dioxolane protected equivalent 1.38 revealed to be the solution (21%conversionof1.25)and,afteranoptimizationofthereactionconditions[1.38(20equiv),Ru3(CO)12(8mol%), 3,4,5-trifluorobenzoic acid (7mol%), 2,4-dimethyl-3-pentanol (40equiv), 140 °C,17h],90%conversionof1.25wasobtainedprovidingthedesiredmono-alkylatedpiperidine1.39andthedi-alkylated piperidine 1.40 in 39% and 35% yields respectively. Once again, the carboxylic acidcatalystwasessentialtocontrolthealkylationprocessbylimitingthealkenereduction(Scheme14).

Scheme14

Thescopeofthemethodwasthenevaluated(Table2).PiperidinessubstitutedatC4ledtoa

mixtureofmono-anddi-alkylatedproducts.Worthyofnote,thereactionconditionsarecompatiblewith the presence of an ester moiety (Table 2, entry 1). For the C3-substituted piperidines, aregioselectivemono-alkylation at the less hinderedα position of the piperidinewas observed and2,5-disubstitutedpiperidines1.41band1.41cwereisolatedin63%and75%yieldsrespectivelyasamixture of diastereoisomers (Table 2, entries 2-3). Bothmethyl and phenyl substituent at the C2positionwerewell tolerated since 2,6-disubstituted piperidines1.41d and1.41e were isolated in84%and82%respectively(Table2,entries4-5).Pseudo-allylicstraincausedbythepresenceofthedirecting group on the nitrogen atomwould push the C2-substituent of the piperidine to an axialposition,andconsequently,thecis-diastereoisomerwas lessstablethanthetrans-diastereoisomer.Asaresult,compounds1.41dand1.41ewereformedasa1:3mixtureofcis/transdiastereoisomers(Table2,entries4-5).Surprisingly,thehypothesisofapotentialevolutionofthecis/transratioovertimethroughanhypotheticalepimerizationprocesswasnotdiscussed.

N+

(10 equiv)



140 °C, 24 h

1.25

O

Me

O

Me

1.36 1.37

N+

(10 equiv)



140 °C, 24 h

1.25

Me

N

1.39 (19%, GC yield)1.38

OOO O

NO OO O

1.40 (2%, GC yield)

N+

(20 equiv)

Ru3(CO)12 (8 mol %)3,4,5-trifluorobenzoic acid (7 mol %)2,4-dimethyl-3-pentanol (40 equiv)

140 °C, 17 h

1.25

Me

N

1.39 (39%)1.38

OOO O

NO OO O

1.40 (35%)

HH

H H

H H

τc = 21%

τc = 90%

τc = 0%

NPy =

Py

Py Py Py

PyPyPy

(mixture of cis and trans isomers)

27%

11

entry 1.30 1.41(yield,cis/trans) 1.42(yield,dr)

1

2

3

4

5

Table2

N-pyridyl pyrrolidines and azepanes were successfully alkylated under the reactionconditions and,onceagain, the greater reactivityof smaller ringsversus larger rings (pyrrolidine>piperidine>azepane)washighlighted(Table3).

NPy

+

(20 equiv)


140 °C, 17 hMe

NPy

1.38

OOO O

NPy O OO O

R1

1.30c-1.30g

R1 R1

1.41a-1.41e 1.42a

H H

Py = 2-pyridyl

N

CO2Me

O O

1.41a (39%, 2:1)Py

NO OO O

1.42a (17%, 4:5:8)

CO2Me

Py

N

F3C

Py1.30e

NO O

1.41b (63%, 1.7:1)

F3C

Py

NO O

1.41c (75%, 2.8:1)

Ph

Py

NO O

1.41d (84%, 1:2.8)

MePy

NO O

1.41e (82%, 1:3.1)

PhPy

N

CO2Me

1.30cPy

N

Ph

Py1.30f

N

1.30d

MePy

N

1.30g

PhPy

12

entry 1.23-1.25 1.43

1.46(yield,cis/trans)

1

2

Table3

Interestingly,achallengingsubstratesuchasthebicyclicamine1.45wascompatiblewiththereactionconditionsfurnishing1.46in47%yield.(Scheme15).

Scheme15

Furthertransformationswerethenrealizedtounderlinethesyntheticutilityofthisalkylationprocess. The pyridine directing group was efficiently removed by using mild reaction conditions(MeOTfthenNaBH4)and, forexample,piperidine1.47was isolatedfrom1.39 in72%overallyield.Thetreatmentof1.39undercatalyticacidicconditionsdeliveredketone1.48 in93%yield(Scheme16).

Scheme16

In order to develop milder conditions for the α-alkylation of amines, Ackermann et al.reportedaruthenium(II)-catalyzedC(sp3)‒Halkylationofpyrrolidines.Thetreatmentofanexcessofpyrrolidine1.23(3equiv)with1-decene(1equiv)inthepresenceof[RuCl2(PPh3)3](5mol%),BINAP(6mol%)andAgOTf(12mol%)ini-BuOHat120°Cfor18hwasfoundtobeeffective.Undertheseconditions,onlythemono-alkylatedpyrrolidine1.49wasformedin73%isolatedyield(Scheme17).17

N+

(20 equiv)


140 °C, 17 hMe

1.38

OO

n = 1 or 3

N

n = 1 or 3

O O N

n = 1 or 3

O OO O

1.23-1.26 1.43a-1.43b 1.44a-1.44b

HH

Py Py Py

Py = 2-pyridyl

NPy

1.23 1.43a (46%)

NPy

OO

1.44a (38%, 3.8:1)

N O OPy

O O

NPy

1.26

N

1.43b (34%)Py O O

1.44b (15%, 2:1)

NPy O OO O

N+

(20 equiv)


140 °C, 17 hMe

1.38

OO

1.45

N

OO

47%1.46

H

Py Py

N

1.39

O O

1/ MeOTf (1.2 equiv)CH3CN, 0 °C to rt

2/ NaBH4 (5 equiv)MeOH, 0 °C to rt

HCl (10 mol %), H2O

60 °C

NH O O1.47

NPy1.48 O

72%

93%

Py

13

Scheme17

The influence of substituents of the pyridine ring on the alkylation process was thenexamined.WhilethepresenceofamethylgroupattheC6-positionwasdetrimentaltothereaction(1.51a,1%),bothelectron-donating(Me,OMe)andelectron-withdrawing(F,CF3)groupsattheC5-,C4- or C3-position delivered the expected mono-alkylated pyrrolidines 1.51b-1.51f (64-94%).Interestingly, treatment of pyrrolidine 1.50g, bearing an isoquinoline as the directing group, alsogavetheexpectedproduct1.51g,albeitinalower67%yield(Scheme18).

Scheme18

Thealkylationof3-methyl-2-(pyrrolidin-1-yl)pyridine1.50busingabroadvarietyofterminalalkeneswasthenexplored,compounds1.53a-1.53hbeingisolatedwithgoodtoexcellentyields(40-90%). Notably, valuable functional groups such as silane, ketone, methoxy or tosylate were welltolerated.Thisalkylationprocessproved tobehighlychemoselectivesincealkenes incorporatingamethoxygroup,atosylateorahalidedeliveredtheexpectedproducts1.53b-1.53d in60-86%yieldandnoundesirednucleophilicsubstitutiononthecarbonbearingaOMe,OTsgrouporaCl,Bratomwasobservedprovidingthat theaproticdichloroethanewasusedas thesolvent.Thereactionalsotoleratedthepresenceofaketone (1.53f)andstyrenederivatives ledto theexpectedpyrrolidines1.53g-1.53hwith65%and73%yieldrespectively(Scheme19).

NPy

1.23

+ n-H17C8

RuCl2(PPh3)3 (5mol %)BINAP (6 mol %)AgOTf (12 mol %)

120 °C, 18 h, iBuOH

1.4(3 equiv) (1 equiv)

NPy73%1.49

H

Py = 2-pyridyl

n-H17C8

N

N

1.50a-1.50g

+


120 °C, 18 h, iBuOH

1.4(3 equiv) (1 equiv)

N

N

1.51a-1.51g

R1

1.51a (1%) 1.51b (94%) 1.51c (72%) 1.51d (64%)

1.51e (73%) 1.51f (76%) 1.51g (67%)

n-H17C8R1

H n-C8H17

N

N

n-C8H17 N

N

n-C8H17 N

N

n-C8H17 N

N

n-C8H17

Me

Me F3C

Me

N

N

n-C8H17 N

N

n-C8H17 N

N

n-C8H17

Me F

14

Scheme19

Alimitationwasencounteredwith2-methylpyrrolidine1.54sincethealkylatedproduct1.55wasformedinalow7%yield(Scheme20).

Scheme20

Some investigations were performed to gain a better insight into the mechanism of thealkylation.Thereactionwasnotinhibitedinthepresenceofaradicalscavenger[TEMPO(3equiv)],indicated that no radical pathway was involved. Moreover, deuterium incorporation studiessuggestedthattheC(sp3)‒Hbondcleavagewasnottheratedeterminingstep.

The removal of the pyridyl directing group was achieved by platinum-catalyzedhydrogenationfollowedbyhydridereduction(1.56,61%)(Scheme21).

Scheme21

In summary, an intensiveworkhasbeenachieved in the fieldofN-pyridyl directedα-alkylationofcyclic amines. The catalytic system based on a [Ru(II)] complex developed by Ackermann et al.

N

N+


120 °C, 18 h, iBuOH

(3 equiv) (1 equiv)1.53a-1.53h

RMe

1.50b

1.53a (86%)[in (CH2)2Cl2]1.53b (62%)

[in (CH2)2Cl2]1.53c (63%)

1.53f (40%)

[in (CH2)2Cl2]1.53d (82%)

[in (CH2)2Cl2]1.53e (60%) 1.53g (73%) 1.53h (65%)

H N

N

RMe

9N

N

SiEt3Me

N

N

OMeMe

9N

N

OTsMe

9N

N

ClMe

9N

N

BrMe

9N

NMe

N

N

PhMe

N

NMe

Me

OBr

1.52

NPy

1.54

+


120 °C, 18 h, iBuOH

1.4 1.55

n-H17C8

7%

H NPy

n-C8H17

1.51b

1/ Pt/C (10 mol %), HCl (1.2 equiv)H2 (1 atm), 24 h, rt, EtOH

2/ NaBH4, 0 °C, MeOH

61% 1.56

N

N

n-C8H17Me

NH

n-C8H17

15

provedparticularly attractive since it allows the selectivemonoalkylationof pyrrolidineswith highyields.Withoutanydirectinggroup

Pyrrolidine1.57was found todirectC(sp3)‒Hbondactivationα to thenitrogen. Indeed, in2004, Yi et al. described a coupling reaction between pyrrolidine 1.57 (1 equiv) and ethylene (6equiv) catalyzedbyRuHCl(CO)(PCy3)2 (5mol%) inTHFat80 °C for24h.18Under theseconditions,cyclicimine1.61awasisolatedinamoderate61%yield(Table4,entry1).Inaddition,thescopeofthe reaction was quite limited. Hindered alkene such as 3,3-dimethyl-1-butene gave amixture ofcyclicimine1.61bandmono-alkylatedpyrrolidine1.62b(29%GCyield,1.61b/1.62b=55:45)(Table4,entry2).If2-methyl-pyrrolidine1.58andeight-memberedcyclicamine1.59gavethedesiredcyclicimines1.61c(84%GCyield)and1.61d(76%GCyield)(Table4,entries3-4),amixtureofboth1.61eand1.62ewasobtainedwhenazepane1.60wasengagedinthereaction(51%,1.61e/1.62e=60:40)(Table 4, entry 5). No rationalization of the difference of reactivity between seven- and eight-memberedringswasproposed.Surprisingly,noconversionwasobservedwithpiperidine.

entry 1.57-1.60 alkene 1.61(+1.62) 1.61/1.62 yield1

100:0

86%[a],61%[b]

2

55:4529%[a]

3

84%[a]

4

76%[a]

5

60:40

87%[a],51%[b]

[a]GCyield.[b]Isolatedyield.

Table4

Withtheseresults inhand,effortshavethenbeenmadetogainabetterunderstandingof

thenatureof rutheniumactivespeciesandapossiblecatalyticcycle,described inScheme22,wasproposed by the authors. Coordination of the nitrogen to the ruthenium center would first form

NH

+24 h, 80 °C,THFR2

RuHCl(CO)(PCy3)2 (5 mol %)

NR2

NH

R2

1.61a-1.61e 1.62b-1.62e

n = 1-4

R1 R1 R1n = 1-4 n = 1-4

H

1.57-1.60

NH1.57

H2C CH2N1.61a

NH1.57

N NH

1.61b 1.62b

NH1.58

H2C CH2N

1.61c

NH

1.59

H2C CH2

N1.61d

NH1.60

H2C CH2

N NH

1.61e 1.62e

16

complex 1.K. A subsequent C(sp3)‒H bond cleavage followed by alkene insertion would generateintermediate 1.M. The formation of ethane during the reaction led the authors to suppose thatcomplex1.Mwould thenundergodehydrogenation followedbyC(sp2)‒H iminebondactivation toproduce rutheniumhydride1.O. After alkene insertion and reductive elimination, cyclic imine1.Qwouldbereleased.Inparticularcases,e.g.hinderedalkenesorlargerings,dehydrogenationfromthedialkylruthenium1.M can be slowdown thus favoring direct reductive elimination to formmono-alkylatedproduct1.R.

Scheme22

2-Iridium-catalyzedα-alkylationofaminesWithapyridinyldirectinggroup

In 2011, Shibata et al. reported the first iridium-catalyzed enantioselective C(sp3)‒Halkylation of acyclic amines with alkenes using a pyridine as a directing group.19,20,21 When2-(ethylamino)pyridine2.1(1equiv)andstyrene(8equiv)werestirredinDMEat75°Cfor48hinthepresence of cationic iridium complex [Ir(cod)2]BF4 (10 mol %) and (S)-TolBINAP (10 mol %), theenantio-enriched amine2.2was isolated in 76%yield andwith goodenantioselectivity (ee = 88%)(Scheme 23).While quinolinewas as effective as pyridine to direct the alkylation, other nitrogen-containing heterocycles (pyrimidine, pyrazine, substituted pyridines) gave lower yields and/orenantiomeric excess (data not shown). It is worth mentioning that these conditions involving aniridiumcatalystaremilderthanthoseusingarutheniumcatalyst.

C-H activation

C-H activation

insertion

Reductiveelimination

RuHCl(CO)(PCy3)2

NH[Ru]

NH

- PCy3

R

NH

[Ru]H

NH

[Ru]

R

N

[Ru] R

N[Ru]H

N[Ru]

RNH

NR

insertion

dehydrogenation

1.K

1.L

1.M

1.N

1.O

1.P

1.Q

NH

R

1.RReductiveelimination

H

H

H

R

17

Scheme23

Two setsof reaction conditions (methodsAandB)differing from theamountof alkene, timeandtemperaturewere then used to alkylate 2-(ethylamino)pyridine2.1 with a variety of alkenes. Theelectronicandstericpropertiesofstyrenederivativesdonotseemtohaveasignificantinfluenceontheyieldnorontheenantiomericexcessofthealkylatedamine2.1(Table5).

Table5

Functionalizedalkenessuchasacrylatederivativesorvinylsilanesalsoreactedwithamine2.1togivetheexpectedproducts2.6a-2.6d. Interestingly,allyltriphenylsilaneaswellas1-phenyl-buta-1,3-dieneweresuitablecouplingpartners(Scheme24).22

Scheme24

The influence of the length of the alkyl chain of the amine partnerwas also investigated.Even if higher time and/or higher temperature were required, alkylation of compounds 2.7a-2.7cproceededsmoothlyinthepresenceofstyrene(2.8a-2.8c,58-69%,73-86%ee)(Table6,entries1-3).However,noconversionofhinderedamines,suchas2.7d,wasobservedunderthesameconditions(Table6,entry4).

N

NH

MePh

[Ir(cod)2]BF4 (10 mol %)(S)-TolBINAP (10 mol %)

75 °C, 48 h, DMEN

NH

Me

Ph

76% 2.2(ee = 88%)

2.1 1.7(8 equiv)

*H

N

NH

MeR


85 °C, 1-3 days, DMEN

NH

Me

R

2.1 2.5a-2.5d 2.6a-2.6d

N

NH

Me

OEtO

*

2.6a(75%, ee = 99%)

N

NH

Me

SiEt3

*

2.6b(87%, ee = 69%)

N

NH

Me

SiPh3

*

2.6c(88%, ee = 87%)

N

NH

Me*

2.6d(84%, ee = 87%)

Ph

(at 95 °C)

(8 equiv)

*H

Alkene2.3 Ar 2.4(yield%) ee(%)2.3a 4-MeO-C6H4 2.4a(76) 872.3b 4-F-C6H4 2.4b(60) 872.3c 3-Br-C6H4 2.4c(83) 902.3d 2-Br-C6H4 2.4d(76) 86

N

NH

MeAr


75 °C, 48 h, DMEN

NH

Me

Ar

2.1 2.3a-2.3d 2.4a-2.4d(8 equiv)

*H

18

entry T(°C) R 2.7 2.8(yield%) ee(%)1 85 CH2CH3 2.7a 2.8a(69) 832 85 (CH2)2CH3 2.7b 2.8b(58) 863 95 (CH2)4CH3 2.7c 2.8c(60) 734 135 CH(CH3)2 2.7d 2.8d(0) -

Table6

Removalof thepyridyl groupof2.4a (87%ee)was then successfully conductedwith goodyield (81%) and without a loss of enantiomeric excess (87% ee) (Scheme 25). At this stage, theabsoluteconfigurationof2.9couldbedeterminedandappearedtobe(S).

Scheme25

Accordingtotheauthors,thestericdifferentiationoccurredduringthecleavageoftheC‒Hbond. The presence of an enantiopure ligand on the metal center induces the enantioselectivitydeliveringa(pro-S)or(pro-R)iridiumhydride.Afteralkeneinsertionandthenreductiveelimination,anopticallyenriched(S)-or(R)-aminecanbeobtained.

Very recently, Nishimura et al. extended the iridium-catalyzed C(sp3)‒H alkylation to3-carbonyl-2-(alkylamino)pyridines2.10a-2.10d.23Themainadvantageofthismethodisbasedonthesignificant decrease in the quantity of alkene (2 equiv instead of 8 equiv in the case of2-aminopyridine) and the absence of external ligand. The conformational rigidity of substrates oftype2.10,duetohydrogenbondingbetweentheoxygenofthecarbonylgroupandtheNHgroup,couldfavortherightconformationleadingtoamorerapidC(sp3)‒Hbondactivation.

The reaction proved quite general. Amyriad of 3-carbonyl-2-(alkylamino)pyridines bearingdifferent amido groups were alkylated in the presence of styrene (2 equiv) under the developedconditions{[IrCl(cod)]2 (10mol%),NaBArF4 (ArF=3,5-(CF3)2C6H3) (10mol%),dichloroethane,80°C,20h}.Notably, thepresenceofaprimaryamideoranesterat theC3positionof thepyridinewasalsocompatible(2.11a-2.11d,88-92%)(Scheme26).

N

NH

RPh


DMEN

NH

R

Ph

2.7a-2.7d 1.7 2.8a-2.8d(8 equiv)

*H

N

NH

Me

Ar

2.4a

*

(ee = 87%)

Ar = 4-OMe-C6H4

1/ aq. HCl (1 M), rt2/ PtO2, H2, 0 °C3/ N2H4, 75 °C

Me

Ar

H2N81% 2.9

(ee = 87%)

(S)

19

Scheme26

Styrenederivatives,simpleterminalalkenesaswellasallylicalcoholsalsoprovedtobegoodpartnersinthealkylationprocess.Notably,theuseofanenynedeliveredthealkylatedproduct2.12din76%yield.Limitationswerereachedwith iso-butylvinyletherandt-butylacrylatesinceamixtureof linear and branched products were formed (2.12e-f and 2.13e-f) (Scheme 27). Moreover,cyclopenteneand1,1-diphenylethylenewerefoundtobeinactive.

Scheme27

RemovalofthepyridinyldirectinggroupwasachievedbyformationofacarbamatefollowedbyN-methylation of the pyridine and subsequent cleavage of the pyridium intermediate.24 Thus,carbamate2.14wasobtainedinthreestepsfrom2.11awithanoverallyieldof61%(Scheme28).

N

O

R

NH Ph

2.10a-2.10d 1.7(2 equiv)

[IrCl(cod)]2 (10 mol %)NaBArF4 (10 mol %)

80 °C, 20 h, (CH2)2Cl2 N

O

R

NH

Ph

N

O

N

NH

Ph

2.11a (88%)

N

O

N

NH

Ph

MeMe

2.11b (89%)

N

O

NH2

NH

Ph

2.11c (90%)

N

O

Ot-Bu

NH

Ph

2.11d (92%)

2.11a-2.11dH

N

O

N

NH

2.10a

R(2 equiv)

[IrCl(cod)]2 (10 mol %)NaBArF4 (10 mol %)

80 °C, 20 h, (CH2)2Cl2 N

O

N

NH

2.12a-2.12fR

N

O

N

NH

Br 2.12a (87%)

N

O

N

NH

n-hexyl

2.12b (75%)

N

O

N

NH

2.12c (82%)

HON

O

N

NH

2.12d (76%)

TBS

N

O

N

NH

O

N

O

N

NH

O

N

O

N

NH

t-BuON

O

N

NH

t-BuOO

O2.12e 2.13e 2.12f 2.13f

(36%, 2.12e/2.13e = 57:43) (41%, 2.12f/2.13f = 83:17)

N

O

N

NH

2.13e-2.13fR

H

20

Scheme28

A classical catalytic cycle (coordination, oxidative addition, alkene insertion and reductiveelimination) was then postulated by the authors. Deuterium-labeling experiments have indicatedthatbothC(sp3)‒Hbondcleavageandalkeneinsertionwerereversiblesteps.Withabenzoxazoledirectinggroup

ThemethodsdevelopedbyShibataandNishimura suffer fromonedrawback since tertiaryaminescouldnotbealkylated.Tocircumventthislimitation,Opatzetal.developednewconditionsto perform racemic iridium-catalyzed C(sp3)‒H alkylation of tertiary amines with alkenes using aBenzOxAzol-2-yl (BOA)moietyasadirectinggroup.25Acyclicamine2.15 (1equiv)wastreatedwithethyl acrylate (8 equiv) in the presence of [Ir(cod)2]BARF (BARF = tetrakis(3,5-trifluoromethylphenyl)borate] (7 mol %) in DME at 85 °C, the mono-alkylated product 2.16 wasisolated in64%yield.Usinghex-1-eneas thecouplingpartneralsodeliveredtheexpectedproduct2.18albeitinamoderate53%yield.Worthyofnote,noconversionwasobservedwiththedimethylanalog2.19(Scheme29).

Scheme29

Themethodwas extended to cyclic secondary amines such as piperidine2.21, whichwastransformedtothemono-alkylatedpiperidines2.22a-2.22dwithmoderateyields(39-57%)(Table7).However,N-benzoxazol-pyrrolidinewasfoundtobetooreactiveandamixtureofmono-,di-andtri-alkylatedproductswasobtained (notshown).TheenhancedreactivityofpyrrolidinescomparedtopiperidinesinC(sp3-H)activationseemstobegeneralandmaybeduetogeometricalfactorsfavoringtheC-Hinsertionofthemetalinthefive-memberedrings.

N

O

N

NH

Ph2.11a

1/ KN(SiMe3)2 then Boc2O2/ MeOTf3/ NaOMe, MeOH NHBoc

Ph2.1461%

NN

O OEt

O

[Ir(cod)2]BARF (7 mol %)

2.5a (8 equiv)2.15

85 °C, DMENBOA

O

OEt

64%2.16

NBOA C4H9[Ir(cod)2]BARF (7 mol %)

2.17 (8 equiv)2.15

140 °C, µW, DMENBOA

C4H953% 2.18

MeNBOA

2.19

OEt

O

[Ir(cod)2]BARF (7 mol %)

2.5a (8 equiv)

140 °C, µW, DME

MeNBOA

O

OEt

2.20

H

H

H

= BOA

21

[Ir] T(°C) 2.22 yield%

[Ir(cod)2]BF4 140°C,μW

57

[Ir(cod)2]BARF 140°C,μW

48

[Ir(cod)2]BARF 140°C,μW

42

[Ir(cod)2]BARF 85°C

39

Table7

Evenifmoderateyieldsweremostlyobtainedduetotheincompleteconversionofpiperidine2.21and/orformationofthedi-alkylatedproduct,thekeyadvantageofthismethodreliesontheuseofabenzoxazol-2-yl(BOA)moiety.Contrarytothe2-pyridylgroup,theBOAdirectinggroupiseasilyintroduced26 and is efficiently removed in a single step.27However, as shown in Scheme30,harshconditionswereemployed.

Scheme30

Witht-butyloxythiocarbonyldirectinggroup

Inspired by the work of Hodgson,28 Yu et al. turned their attention to tert-butoxythiocarbonyl directing group,which can be easily introduced and removed.29 However, this groupproved to be unstable under iridium-catalyzed alkylation conditions. With the more acid-stablementhoxy-thiocarbonyl directing group present in pyrrolidine 2.25, the alkylation proceededsmoothly(80%yield)butwithpoordiastereoselectivity(dr=1.5:1).Moreover,thepiperidineanalogwas not compatible under these conditions. Finally, a good compromise was achieved with thesimpler 3-pentoxythiocarbonyl derivative. When pyrrolidine 2.29 (1 equiv) and ethyl acrylate (8equiv)weretreatedinthepresenceof[Ir(cod)2]OTf(10mol%)indegassedchlorobenzeneat85°Cfor6h,amixtureofthemono-andthedi-alkylatedpyrrolidines2.30aand2.31awasisolatedin68%yield(2.30a/2.31a=1:1.8).

NBOA

R[Ir] (7 mol %)

T °C, DME NBOA

R

2.21 2.22a-2.22d

H

R

CO2EtNBOA

OEt

O

2.22a

Ph NBOA

Ph

2.22b

C4H9 NBOA

C4H9

2.22c

SiMe3 NBOA

SiMe3

2.22d

NBOA

[A] : KOH, ethylene glycol 24 h, 140 °C[B] : LiAlH4 12 h, reflux, THF

NH

[A] [B]

2.23 2.24or

67%82%

22

Scheme31

When styrenes and other simple alkenes were used, amixture ofmono- and di-alkylatedpyrrolidineswasobtained.Incontrast,allylarenes,allylnitrilesorallylsulfonesdeliveredexclusivelythe di-alkylated products. Functional groups present on the alkene partner, such as a nitrile, aketone,asulfoneoraphthalimidewerealsocompatiblewiththereactionconditions(Table8).

alkene 2.30/2.31 yield

2.30b/2.31b(1.2:1) 42%

2.30c/2.31c(1.5:1) 62%

2.30d/2.31d(0:1) 62%

2.30e/2.31e(0:1) 40%

2.30f/2.31f(0:1) 55%

2.30g/2.31g(0:1) 73%

2.30h/2.31h(0:1)

70%

Table8

Theinfluenceofsubstituentsonthepyrrolidinecyclewastheninvestigated.BothC2-andC3-substitutedpyrrolidines2.32aand2.32bdeliveredthecorrespondingproducts2.33aand2.33bwithmoderate to goodyields. Functionalized substrates suchas the spirocyclicpyrrolidine2.32c or theL-prolineethylester2.32dwerethensuccessfullyengagedinthealkylationprocess(2.33c,40%and2.33d, 48%, trans/cis = 6:1). Piperidine 2.32e was also alkylated in the presence of additionalHBF4.Et2O (10mol%), albeitwith a lower yield (2.33e, 30%) (Scheme32).Worthyof note, acyclicsecondaryamineswerenotalkylatedundertheseconditions.

N

O S

[Ir(cod)2]OTf (10 mol %)OEt

O

2.5a (8 equiv)

85 °C, 24 h, DMEN

O S2.25 2.2680%

(dr = 1.5:1)

N

O S


O2.5a (8 equiv)

85 °C, 6 h, PhCl

2.29 2.30a68%

(2.30a/2.31a = 1:1.8)2.31a

H

H

N

O S


O

2.5a (8 equiv)

85 °C, 24 h, DMEN

O S2.27 2.28

H X

OEt

O

OEt

O

N

S

OEt

OR1O

N

S

OEt

OR1O

EtO

O

R1

N

O S

[Ir(cod)2]OTf (10 mol %)R2

(8 equiv)85 °C, 6 h, PhCl

2.29 2.30b-2.30h68%

R1 =

2.31b-3.31h

HN

S

R2

R1O

N

S

R2

R1O

R2

PhC4H9Ph

CN

SO2Ph

O

N

O

O

23

Scheme32

Thesyntheticutilityofthisalkylationprotocolwasenhancedduetotheeasyremovalofthe3-pentoxythiocarbonyl directing group by treatment with TFA at 65 °C. A subsequent one-potprotectionbyaFmocgroupfinallyproducedpyrrolidine2.34in68%(Scheme33).

Scheme33

Withaβ,γ-unsaturatedamidedirectinggroup

An iridium-catalyzed intramolecularoxidativecouplingofalkenesandamides initiatedbyapreliminaryC(sp3)‒Hbondactivationalphatothenitrogenatomwasreportedin2004bySamesandcoworkers.30 In thisparticularcase,adoublebondwasregeneratedat theendof theprocess.Thereactionwascatalyzedusing[Ir(coe)2Cl]2(coe=cyclooctene)(10mol%)withthecarbeneligandIPr[N,N’-bis-(2,6-diisopropylphenyl)-imidazolyl carbene] (2 equiv) in the presence of norbornene (4equiv). Under these conditions, substrate 2.35 was converted to both the 5-exo and the 6-endocyclizationproducts2.36and2.37with66%and17%NMRyieldrespectively.Despitetheadditionofanexcessofhydrogenacceptor (norbornene), the reductionproduct2.38wasalso formed in10%NMRyield(Scheme34)

Scheme34

N

O S

[Ir(cod)2]OTf (10 mol %)R2

(8 equiv)

85 °C, PhCl

2.32a-2.32e 2.33a-2.33e

R1 =

R3n = 1-2

N

R1O S

Me

2.33a (76%, dr = 1.2:1) 2.33b (30%, dr = 1.3:1) 2.33c (40%)

N

R1O S

2.33d (48%, dr = 6:1)

EtO

ON

SR1O

OEt

O

2.33e (30%)HBF4.Et2O (10 mol %) was added

H N

S

R2

R1O

R3n = 1-2

ON

R1O SO

BocHN

N

R1O S

Me

O

CbzN

Ph

2.31g

TFA 75% in H2O, 65 °Cthen Fmoc-OSu, sat. NaHCO3, dioxane

2.34

68%

N

O SOO

NFmoc OO

N

O

[Ir(coe)2Cl]2 (10 mol %)IPr (2 equiv)

norbornene (4 equiv)

150 °C, 13 h, C6H12

N

O

N

O

N

O

2.35 2.36 2.37 2.38*NMR yields (66%)* (17%)* (10%)*

H

24

Thismethodwas then successfully extended to pyrrolidines 2.39a and 2.39b, respectivelysubstitutedbyasilyletherandanestergroup(Scheme35).

Scheme35

When the pre-formed iridium complex 2.41 was heated at 150 °C for 1 h, the expectedproducts2.36and2.37wereobtainedinsatisfyingyields(Scheme36).Thisexperimentalobservationsuggeststhatcomplex2.41wouldplayanactiveroleintheformationofthebicyclicproducts.

Scheme36

As a result, the authors have proposed a catalytic cycle described in Scheme 37. Activeiridiumcomplex2.41wouldfirstbegeneratedfrom[Ir(coe)2Cl]2.Oxidativeadditionfollowedbythealkene insertion via a carbometalation (favored over hydrometalation and β-hydride elimination)would then form the iridium hydride 2.43. A β-H elimination was favored over a reductiveelimination since dihydride iridium complex2.44 was formedwhile satured product2.46 was notobserved. Hydrogenation of the sacrificial norbornene would regenerate the active iridium 2.41,delivering2.45.Subsequentisomerizationofthedoublebondwouldfinallyfurnishproduct2.36.

N

O

[Ir(coe)2Cl]2 (10 mol %)IPr (10 mol %)

norbornene (3-10 equiv)

150 °C, C6H12

2.39a-2.39b

R1

N

O2.40a-2.40b

R1

N

O2.40a (60%)

TBSO

N

O2.40b (46%, ee > 99%)

H

O

BnO

N

O

2.41IrCl

N N ArAr

150 °C, 1 h, C6H12

N

O

N

O

2.36 2.37(63%) (8%)

Ar = 2,6-iPr-C6H3

H

25

Scheme37

WithastyrenyldirectinggroupIn2017,aniridium-catalyzedasymmetriccycloisomerizationofstyrenylanilinesinvolvingaC(sp3)-Hactivationwas reported.31Aftera ligand screening, (S)-DTBM-SEGPHOSwas selected inassociationwith[IrCl(C2H4)2]2andthereactionwascarriedoutintoluene(Scheme38).Thereactiondeliveredawide array of indolines possessing a quaternary center at the C3 position with high degree ofenantiocontrol.Fromamechanisticpointofview,anoxidativeadditionofiridiumintotheC-Hbondof aN-methyl substituent followed by an intramolecular carbometalation on the pendant doublebondandareductiveeliminationwasproposed.

[Ir(coe)2Cl]2

N

O

2.41IrCl

IPr

N

O

IrH IPr

Cl

2.42

N

O2.43

Ir(Cl)IPr

H

N

O2.44

IrH2(Cl)IPr

Norbornadiène

N

O2.45

N

O2.36 Oxidative addition

Alkene insertionβ-H elimination

Isomerisation

reductive elimination

N

O2.46

Not observed

IPr

H

26

Scheme38

WithanureadirectinggroupNishimuraandco-workersreportedaniridium-catalyzedalkylationofN-methylureaswithterminalolefinsoperatingthroughaC(sp3)-Hactivationprocess.32Thecatalyticsystemwascomposedofthehydroxoiridium complex [Ir(OH)(cod)2] and of the biphosphine ligand 1,2-bis(diisopropylphosphino)benzene (dippbz). A variety of alkene could be involved in the reactiondeliveringthealkylatedureaswithexcellentyields.ThereactionrequiredthepresenceofaN-Hontheureaallowingtheformationofatransientamido-iridiumcomplex2.51priortotheC-Hactivationstepwasproposed(Scheme39).

Scheme39

3-Rhodium-catalyzedα-alkylationofamines33Withconjugateddienesasdirectinggroups

NMe

Me

Ar

[IrCl(C2H4)2]2 (3 mol %)(S)-DTBM-SEGPHOS (6 mol %)

110 °C, 24 h, tolueneR

NMe

MeAr

R

NMe

Me

F3C

NMe

Me

(pin)B

NMe

Me

NMe

NMe

MePhMeO

NMe

MePh

NMe

MePh

F

Me

2.47a-2.47f 2.48a-2.48f

2.48a (82%, 97% ee) 2.48b (89%, 97% ee) 2.48c (93%, 97% ee)

2.48d (83%, 98% ee) 2.48e (83%, 96% ee) 2.48f (82%, 97% ee)

NH

O

NMe

Ph PhR

+

[Ir(OH)(cod)]2 (5 mol % Ir)dippbz (5 mol %)

70 °C, 20 h, 1,4-dioxaneNH

O

NPh Ph

R

NH

O

NPh Ph

Ph

NH

O

NPh Ph

n-Hex

NH

O

NPh Ph

SiEt3

NH

O

NPh Ph

PO(OEt)2

2.49 2.50a-2.50d

2.50a 2.50b 2.50c 2.50d

N

O

NPh Ph

[Ir] Me2.51

27

In 2010, a rhodium-catalyzed intramolecular alkylation of amines of type 3.1 at the allylic

C(sp3)‒Hbondadjacenttothenitrogenatomwasreportedtoformadiversityofpyrrolidines.34,35Thealkylation of substrate 3.1a was catalyzed by [RhCl(PPh3)3] (10 mol %) and AgSbF6 (10 mol %) indichloroethane(65°C)andthecorrespondingsubstitutedpyrrolidine3.2awasisolatedin90%yieldasasinglediastereomer(Table9,entry1).Amethylsubstituentattheinternalpositionofthealkenewastolerated(3.2b,81%)(Table9,entry2).Substrate3.1c,bearingaphenylgroupattheconjugateddienemoiety,smoothlyreactedtodeliverthe2,3-disubstitutedpyrrolidine3.2c ingoodyield(64%)andgooddiastereoselectivity(dr=7:1)(Table9,entry3).Polysubstitutedpyrrolidines3.2dand3.2ewerealsosynthesized(Table9,entries4-5).

entry 3.1 3.2 yield,dr1

3.1a

3.2a

90%,>20:1

2

3.1b

3.2b

81%,>20:1

3

3.1c

3.2c

64%,7:1

4

3.1d

3.2d

59%,15:1

5

3.1e

3.2e

76%,8:1

Table9

A DFT study of the mechanism revealed that the chemoselective allylic C(sp3)‒H bond

activationofsubstrate3.1awouldbedirectedbytheconjugateddieneviathepreliminaryformationofrhodium(I)complex3.A.AfterallylicC‒Hactivation,insertionoftheinnerenepartofthedienebyhydrorhodation would produce the bis-allylic rhodium complex 3.C. Subsequent reductive

NTs

Me

R5

R1

R2

R3

[RhCl(PPh3)3] (10 mol %)AgSbF6 (10 mol %)

65-80 °C, (CH2)2Cl2

3.1a-3.1e 3.2a-3.2e

NTs

R5

R3R1

R2

R4

MeNTs

NTs

Me

Me

MeNTs Me

NTs

Me

Me

Me

PhNTs Me

NTs

Me

Ph

BuNTs Me

Ph NTs

Me

Bu

Ph

BuNTs Me

MeMe N

Ts

Me

Bu

MeMe

28

eliminationwouldallowthecyclization,formingaproduct-rhodiumcomplex.Afteraligandexchangewith the starting material, the cis-divinyl cyclized product 3.2a would be delivered with highdiastereoselectivity(Scheme40).

Scheme40

Oneyearlater,anasymmetricversionofthistransformationwasdeveloped.36Anextensive

screeningofchiralligandsrevealedthatdiphosphinesweredetrimentaltothereactionwhereastheuse of easily accessible phosphoramidites gave encouraging results in regard with both yield andenantioselectivity.Thebestresultwasfinallyachievedusing[Rh(coe)2Cl]2(5mol%)withchiralligandL1*(25mol%)inthepresenceofAgOTf(12mol%)inDME.Undertheseconditions,substrate3.1awasconvertedtopyrrolidine3.2ain90%yieldwith90%enantiomericexcess(dr>19:1).Worthyofnote,avarietyofenantio-enriched2,3-divinylpyrrolidineswasalsoefficientlysynthesized(datanotshown).37

Scheme41

Withapyridyldirectinggroup

[RhCl(PPh3)3]

AgSbF6

[Rh]

NTs

Me

[Rh]Me

allylic CH activation

alkene insertion

NTs

Me

Me

reductive eliminationand exchange

3.1a

3.A

3.B3.C

3.1a

3.2a

Ln

Ln

NTs

Me

H

NTs

Me

H

[Rh] Ln

NTs

Me

H

NTs

Me

H

NTs

Me

Me

3.1a

[Rh(coe)2Cl]2 (5 mol %)AgOTf (12 mol %)L1* (25 mol %)

70 °C, DME

3.2a (dr > 19:1, ee = 90%)90%

OOP NEt2

L1*

MeNTs

29

More recently, Schnürch and co-workers developed a rhodium-catalyzed alkylation of benzylicamines using either alkyl bromides or alkenes. The mechanism of the reaction using olefins wasparticularly investigatedandtheauthorsshowthataC(sp2)-Hactivationofan insitu formed iminewastakingplaceinsteadofadirectC(sp3)-Hactivationatthebenzylicposition(Scheme42).

Scheme42

ConclusionSince the pioneeringwork reported by Junet al. in 1998, an extensivework has been realized todevelop metal-catalyzed α-alkylation of amine through C(sp3)-H bond activation. Ruthenium andiridiumcatalystsclearlydominatethefield,allowingtheα-alkylationofbothcyclicandacyclicamineswithalkenesaspartners.Ingeneral,thesereactionsrequiredadirectinggrouponthenitrogenatomand the pyridyl group is themost frequently used. The scope of the developedmethods is broadbothintermofamineandalkenediversity.However,severalchallengesstillneedtobeaddressed.First, the alkylation reactions generally necessitate high temperatures, which could not be alwayscompatiblewithfunctionalizedmoleculesandthedevelopmentofmilderconditionsisstilldesirable.Pyrrolidinesareparticularlyreactiveunderthevariousreportedalkylationconditionsandmixtureofmono-anddialkylatedproductsareoftenobserved.Onthecontrary, largerN-heterocyclessuchaspiperidines and azepanes revealed often reluctant in the alkylation reactions. Examples ofα-alkylationof amines in the absenceof anydirecting groupare scarce and, to increase the atomeconomyof theprocess, theuseof tracelessdirectinggroupcouldbe interesting.Finally,only fewasymmetric α-alkylation of amines through C-H activation have been reported so far and thedevelopmentofarobustandgeneralenantioselectivereactionwouldhaveahighsyntheticvalue.38

N

NH

Ph

H n-Bu

[RhCl(cod)]2 (5 mol %)K2CO3 (3 equiv)

150 °C, 2 h, tolueneN

NH

Ph

n-Bu

1.1 1.366%

N

N Ph

[Rh]H

30

1 a) Taylor RD,MacCossM, Lawson ADG. J.Med. Chem. 2014;57:5845-5859. b)McGrath NA, BrichacekM,NjardarsonJT.J.Chem.Educ.2010;87:1348-1349.2 (a) Mitchell EA, Peschiulli A, Lefevre N, Meerpoel L, Maes BUW. Chem. Eur. J. 2012;18:10092-10142; (b)CamposKR.Chem.Soc.Rev.2007;36:1069-1084.3ForsomerecentgeneralreviewsonC(sp3)-Hactivation,see:a)ChuJCK,RovisT.Angew.Chem.Int.Ed.2018;57:62-101.b)KarimovRR,HartwigJF.Angew.Chem. Int.Ed.2018;57:4234-4241.c)XuY,DongG.Chem.Sci.2018;9:1424-1432.d)Saint-DenisTG,ZhuRY,ChenG,WuQF,YuJQ.Science2018;359:inpress.4LabingerJA,BercawJE.Nature2002;417:507-514.5ForgeneralreviewsconcerningC-Hactivationmechanisms,see:a)BalcellsD,ClotE,EisensteinO.Chem.Rev.2010;110:749-823.b)AckermannL.Chem.Rev.2011;111:1315-1345.c)DaviesDL,MacgregorSA,McMullinCL.Chem.Rev.2017;117:8649-8709.6Forageneralreviewondirectinggroupsincatalysis,seeRousseauG,BreitB.Angew.Chem.Int.Ed.2011;50:2450-2494.7 For a general reviewdevoted to the functionalizationbymetal-catalyzedC(sp3)‒Hbond activation, see (a)JazzarR,HitceJ,RenaudatA,Sofack-KreutzerJ,BaudoinO.Chem.Eur.J.2010;16:2654-2672;Forageneralreviewdevotedtothemetal-catalyzedarylationofnonactivatedC(sp3)‒Hbonds,see(b)BaudoinO.Chem.Soc.Rev.2011;40:4902-4911.8Forageneralreviewonmetal-catalyzedC-Halkylationusingalkenes,seeDongZ,RenZ,ThompsonSJ,XuY,DongG.Chem.Rev.2017;117:9333-9403.9AlkylationattheC(sp3)‒HbondadjacenttonitrogenatomofamideswhosethecarbonyldoesnotassisttheC(sp3)‒H bond cleavagewill not be reviewed. For an example, see Pedroni J, Boghi,M, Saget T, Cramer N.Angew.Chem.Int.Ed.2014;53:9064-9067.10 Early-transition-metal-catalyzed hydroaminoalkylation reactions have been the purpose of several properand recent reviewsandwill notbediscussedhere, see ref.8and: (a)RykenSA, Schafer LL.Acc.Chem.Res.2015;48:2576-2586;(b)ChongE,GarciaP,SchaferLL.Synthesis2014;46:2884-2896;(c)EisenbergerP,SchaferLL.PureAppl.Chem.2010;82:1503-1515;(d)RoeskyPW.Angew.Chem.Int.Ed.2009;48:4892-4894.11JunCH.Chem.Commun.1998;1405-1406.12RegerDL,GarzaDG,BaxterJC.Organometallics1990;9:873-874.13ChataniN,AsaumiT,YorimitsuS,IkedaT,KakiuchiF,MuraiS.J.Am.Chem.Soc.2001;123:10935-1094114LeeDH,ChenJ,FallerJW,CrabtreeRH.Chem.Commun.2001;213-214.15 Bergman SD, Storr TE, Prokopcová H, Aelvoet K, Diels G, Meerpoel L, Maes BUW. Chem. Eur. J.2012;18:10393-10398.16KulagoAA,VanSteijvoortBF,MitchellEA,MeerpoelL,MaesBUW.Adv.Synth.Catal.2014;356:1610-1618.17SchinkelM,WangL,BielefeldK,AckermannL.Org.Lett.2014;16:1876-1879.18YiCS,YunSY.Organometallics2004;23:5392-5395.19PanS,EndoK,ShibataT.Org.Lett.2011;13:4692-4695.20C(sp3)‒Hbondcleavageof2-(ethylamino)pyridinebyusinganiridiumcomplexwasalreadyreportedintheliterature. In this case, stoichiometric iridium-carbene complexes were obtained but no furtherfunctionalizationwasexplored, see ref.14and (a)ClotE,Chen J, LeeDH,SungSY,AppelhansLN,Faller JW,Crabtree RH. J. Am. Chem. Soc. 2004;126:8795-8804; (b) Li X, Appelhans LN, Faller JW, Crabtree RH.Organometallics2004;23:3378-3387.21ThismethodwasthenappliedtotheenantioselectivealkylationattheC(sp3)‒Hbondalphatonitrogenoflactams,seeTaharaY,MichinoM,ItoM,KanyivaKS,ShibataT.Chem.Commun.2015;51:16660-16663.22PanS,MatsuoY,EndoK,ShibataT.Tetrahedron2012;68:9009-9015.23NagaiM,NagamotoM,NishimuraT,YorimitsuH.Chem.Lett.2017;46:1176–1178.24JanaCK,GrimmeS,StuderA.Chem.Eur.J.2009;15:9078-9084.25LahmG,OpatzT.Org.Lett.2014;16:4201-4203.26 Formation by nucleophilic substitution between an amine and 2-chlorobenzoxazole in the presence ofHünig’sbase,see(a)GimHJ,CheonYJ,RyuJH,JeonR.Bioorg.Med.Chem.Lett.2011;21:3057-3061.Formationby metal-free oxidative coupling of an amine with benzoxazole in the presence of Bu4NI and tert-butylhydroperoxide, see (b) Froehr T, Sindlinger CP, Kloeckner U, Finkbeiner P, Nachtsheim BJ. Org. Lett.2011;13:3754-3757;(c)KloecknerU,WeckenmannNM,NachtsheimBJ.Synlett2012;97-100.27Treatmentof(benzoxazol-2-yl)-1,2,3,4-tetrahydroisoquinolinewithKOHinethyleneglycolat140°CorwithLiAlH4 in refluxing THF delivered the expected 1,2,3,4-tetrahydroisoquinoline in 67% and 82% yield

31

respectively.However,inthepresenceofmono-alkylatedsubstrates,moderateyieldwasobtainedorharsherconditionswereused.Moreover,noexamplewasreportedinthepresenceofsecondaryamines.28 (a) Hodgson DM, Kloesges J. Angew. Chem. Int. Ed. 2010;49:2900-2903; (b) Hodgson DM, Mortimer CL,McKennaJM.Org.Lett.2015;17:330-333.29TranAT,YuJQ.Angew.Chem.Int.Ed.2017;56:10530-10534.30DeBoefB,PastineSJ,SamesD.J.Am.Chem.Soc.2004;126:6556-6557.31TorigoeT,OhmuraT,SuginomeM.Angew.Chem.Int.Ed.2017;56:14272-14276.32YamauchiD,NishimuraT,YorimitsuH.Angew.Chem.Int.Ed.2017;56:7200-7204.33 Rhodium-catalyzed alkylation of benzylic amineswith alkenes or alkyl bromideswas reported in 2015 bySchnürchandcoworkers.However,mechanistic andkinetic studies revealed that thealkylationoccurredviaC(sp2)‒Hbondactivationthankstotheformationofanimineintermediate.AsnonerhodiumintermediateoftypeC(sp3)‒[Rh]‒Hisformedduringtheallprocess,thisworkwillnotbedetailedinthisreview,see(a)PolliceR, Dastbaravardeh N, Marquise N, Mihovilovic MD, Schnürch M. ACS Catal. 2015;5:587-595; (b) Pollice R,SchnürchM. J. Org. Chem. 2015;80;8268-8274; For a similar observation, see Jo EA, Lee JH, Jun CH.Chem.Commun.2008;5779-5781.34LiQ,YuZX.J.Am.Chem.Soc.2010;132:4542-4543.35ForaDFTstudyofthemechanism,seeLiQ,YuZX.Organometallics2012;31:5185-5195.36LiQ,YuZX.Angew.Chem.Int.Ed.2011;50:2144-2147.37 One of these products was used as a chiral ligand in rhodium-catalyzed enantioselective conjugatedadditions,seeLiQ,DongZ,YuZX.Org.Lett.2011;13:1122-1125.38Apalladium-catalyzedenantioselectiveC-Hα-functionalizationofaminesincludingoneexampleofalkylationhasbeenrecentlyreported,see:JainP,VermaP,XiaG,YuJQ.Nat.Chem.2017;9:140-144.

Documents

Laurine Gonnard, Amandine Guérinot,* Janine Cossy.*