Direct, Catalytic Hydroaminoalkylation of Unactivated ...ccc.chem.pitt.edu/wipf/Current...

Direct, Catalytic Hydroaminoalkylation ofUnactivated Olefins with N-Alkyl Arylamines

S. B. Herzon and J. F. Hartwig, J. Am. Chem. Soc., ASAP DOI: 10.1021/ja0718366

Current Literature - May 12, 2007

NH

MeR

NH

RR'

R''Me

Ta[NMe2]5 (4-8 mol%)

PhMe, 160-165 oC

24-67h

66-95%

R''

R'

Maciej Walczak @ Wipf Group 5/12/2007

Biological Activation of CH Bonds

• Cytochrome P450, a family of over 60 enzymes, participates in a variety of cellular redoxprocesses

• Ability of P450 to transform endogeous and foreign compounds has a tremendous impacton the metabolism of drugs

For recent studies on the metabolism of cyclopropylamines, see:

Cerny, Hanzlik J. Am. Chem. Soc. 2006, 128, 3346

• Many efforts have been focused on developing a catalytic system mimicking activity ofP450. Metals such as Pd(0), Ru(II), Cu(I) are successful candidates for the catalyticactivation of CH bonds.

N NP450

H+, 2e-RR R R

H2O

NH R

O

R+


• Catalytic carbonylation via pyridine-directed activation of pyrrolidine has beenachieved using Rh(I) catalysts

Murai et al. J. Am. Chem. Soc. 2000, 122, 12882Doye Angew. Chem. Int. Ed. 2001, 40, 3351

• Similarly, imines are viable substrates in Ir(I) promoted 3 component coupling withalkynes

Ishii et al. Angew. Chem. Int. Ed. 2001, 40, 2534

Activation of sp3 CH Bonds Adjacent to Nitrogen

N N N N

Et O

[RhCl(CO)2]2 (4 mol%)

CO, H2C=CH2, i-PrOH

160 oC, 60 h, 73%

N

N

N

N

Et

O

RhCl(cod)2 (4 mol%)

CO, H2C=CH2, i-PrOH

160 oC, 60 h, 70%

R

R = H, 40 h, 68% 3-Me, 60 h, 73% 4-Me, 60 h, 73% 5-Me, 40 h, 84% 6-Me, 60 h, 12% 5-CF3, 60 h, 15%

R

R H

O

R' NH2

R''

R N R'

R''[IrCl(cod)]2 (10 mol%)

THF, 60 oC

R, R', R'' = n-Pr, i-Pr, n-Bu, i-Bu, s-Bu, Hex

+ +

45-74%



Aerobic oxidation of alkyl aminesusing RuCl3 has been successfullyapplied to dimethyl aryl amines

ArN

NaCN, RuCl3 (5 mol%)O2, MeOH, AcOH

ArN CN

81-88%

Murahashi et al. J. Am. Chem. Soc. 2003, 125, 15312

Similarly, Li showed that CuBr cancatalyze oxidative coupling of aminesin the presence of TBHP

Li, Li J. Am. Chem. Soc. 2004, 126, 11810Li, Li J. Am. Chem. Soc. 2004, 126, 3672

NAr

NAr

NO2

CuBr (5 mol %)TBHP, rt, 6 h

R

R NO2

+

30-75%

R = H, Me

N

Ar

R

CuBr (5 mol %)

TBHP, 100 oC, 3 h+ N

Ar R

12-82%


A conceptually different approach was applied by Davis - catalytic CH insertion into CH bondsafforded pyrrolidines and piperidines in high chemoslectivities, de’s, and ee’s.

Davis et al. J. Am. Chem. Soc. 2003, 125, 64620

RN

BocPd(OAc)2 (10 mol%)

CH2Cl2, 50 oC, 40 h

IOAc

A. PhI(OAc)2 + I2or

B. AgOAc + I2

RN

Boc

OAc

70-96%R = Alkyl, Aryl

N

Boc

R

N

Boc

R

Ar

CO2Me

H

Rh2(S-DOSP)4

Ar CO2Me

N2

+

N

NR O OB

Art-BuCOMe (5 eq)

Ru3(CO)12 (3.3 mol%)

150 oC, 4-19 h+

N

NR Ar

38-78%dr 1:0 to 3:1


Imine-directed coupling of boronic esters wascarried out in the presence of reducing agent(ketone) in good yields amd modest selectivities

Pastine, Gibkov, SamesJ. Am. Chem. Soc. 2006, 128, 14220

Nitrogen protecting groups are commonlyapplied as directing moieties in Pd-promotedCH activations

Yu et al.Org. Lett. 2006, 8, 3387


Lewis, Bergman, Ellman J. Am. Chem. Soc. 2007, 127, 5332


N N

R

R

R

RR

R

+

[RhCl(coe)2]2 (5 mol%)

PCy3 HCl (15 mol%)

THF, 165 oC

ent r y alkene time (h) Yield (%)

1 t-Bu 9 . 5 9 8

2 n-Bu 9 . 5 80 (linear)

14 (branched)

3

9 . 5 9 6

4

1 9 9 1

5

1 9 9 0

6 N

O

O

3 . 5 5 3

7 CO2i-Bu 1 6 5 3

8 CO2i-Bu 1 4 5 7


CH activation in the Hartwig Group

Hartwig et al. Science 2000, 287, 1995Hartwig et al. J. Am. Chem. Soc. 2004, 126, 15443

Hartwig et al. J. Am. Chem. Soc. 2006, 128, 13684

Tsukada, Hartwig J. Am. Chem. Soc. 2005, 127, 5022

(TpMe2)Pt(Me)2H

200 oC, 24 h

86%

+

SiEt3

HSiEt3 HSi3

(TpMe2)Pt(Me)2H

200 oC, 72 h

Bu2Si

80-86%

[Cp*RuCl2]2 (1-2.5 mol%)

RCH3 R B

O

O

B BO

OO

O

Ot-Bu Bpin

t-Bu Bpin

NBpin n-C8F17

Bpin

>90%

70% 94%

80%

OHB

O

Cp*Rh(!4-C6Me6) (5 mol%)

150 oC

- H2+ B

O

O

65%


Zirconaaziridines• Many metal η2-imine complexes of early TM and lanthanides are known

Buchwald et al. J. Am. Chem. Soc. 1989, 111, 4486Cumming et al. Top. Curr. Chem. 2005, 10, 1

• Rate of methane elimination is dependent on nitrogen substitution (“availability of nitrogenlone pair”)

• Unlike η1-complexes, metallaaziridines undergo typical d0 Ti/Zr (IV) reactions - insertion ofmultiple bonds and coupling reactions

H R''

NR' Li

Cp2ZrN

Me

R'

R''Cp2Zr

N

R''

R'LCp2ZrMeX

X = Cl, OTf

- CH4

+ L

L = THF, PPh3

Cp2ZrN

Me

Ph

MeCp2Zr

N

Me

Bu

Pr103 times faster than

Cp2ZrN

Ph

PhTHFR

R

Cp2ZrN

RR

PhPh

XCp2Zr

N

R

PhPh

X R

X = O, NR


Group 5 Metals

• Stoichiometric reactions of η2-complexes withaldehydes and ketones have been described(umpolung)

Roskamp, Pedersen J. Am. Chem. Soc. 1987, 109, 6551

• M(NMe2)5, M = Nb, Ta have been shown to catalyze alkylation of alkene in lowyields

Cleric, Maspero Synthesis 1980, 305Nugent, Ovenall, Holmes Organometallics 1983, 2, 161

HNR R R'

cat., PhMe,

160 or 200 oC+

R = H, Me

R' = H, Me, -Bu

R'

Me

NH

R

R

13-38%

NbCl3(DME) + NPhAr

THF N

Ar

R

(THF)2Cl2Nb

R' R''

O

Ar

NH

R''

HOR'

R R = Bn, allylR', R'' = H, alkyl

Yields: 34-90%


NH

MePhn-hexyl N

H

Ph n-hexyl

Me

catalyst (4 mol%)

PhMe, 160-165 oC

+

% yield entry

catalyst precursor 1.3 h 5.1 h 24 h

1 Ta[NMe2]5 3 2 6 0 9 6

2 Ta[NEt2]5 2 3 4 1 6 6

3 Nb[NMe2]5 2 0 2 9 3 5

4 Cp2Zr[NMe2]2 0 . 6 1 . 2 3

5 Zr[NMe2]4 0 0 0 . 1

6 none 0 0 0

Title Paper -Experiment Design and Initial Studies

(Me2N)3MNMe2

NMe2

- HNMe2(Me2N)3M

N

Me

HNMe2product

R

(Me2N)3MN

Me

R


Title Paper - Reaction Scope

NH

n-hexyl

Me

Me

Me

NH

n-hexyl

Me

t-Bu

t-Bu

NH

n-hexyl

Me

F

FNH

n-hexyl

Me

MeO

NH

n-hexyl

Me

F

NH

Me

n-hexyl

NH

Me

88%dr 1:1

88%

93%

84%90%

78%72%(single diastereomer)

NH

Ph n-hexyl

Me88%

NH

Ph

Me

Ph

77%

NH

Ph n-pentyl

Me

76%Me

NH

Ph

Me71%

NH

Ph TMS

Me66%

NH

Ph

96%dr 3:1

NH

Ph SiPhMe2

Me

NH

PhSiPhMe2

and

50% 28%

Typically, high selectivity was observedalthough some olefins give a mixture of linearand branched isomers

Only aromatic rings with m- and p-substituents were shown to undergohydroaminoalkylation


• Exchange of aromatic protons occurs most likely faster than the insertion reaction

• Ligand exchange

Title Paper - Mechanistic Proposal

NH

CD3Phn-hexyl

NH

n-hexyl

Me

Ta[NMe2]5 (4 mol%)

PhMe, 160-165 oC

+

46%45%

12%27%

at 25% conversion: 15% D in ortho position

[Ta]

N MeArene activation via

N

Me

Me

HN

Me

Me

[Me2N]4TaN

Me

Me

[Me2N]3Ta

2

Ta[NMe2]5 +

5.0 eq

PhMe-d8

dodecane,

80 oC, 24 h+

37% 39%

with 25 eq of toluidine, 1:1 ratio


Reactivity of Tantalum Complexes• Primary amines form imido complexes with tantalum

Nugent, Harlow J. Chem. Soc. Chem. Comm. 1978, 579,

• Neutral Ta complexes have been shown to catalyze hydroamination reactions ofanilines and alkynes

Anderson, Arnold, Bergman Org. Lett. 2004, 6, 2519

Ph

PhH2NPh

5 mol% [Ta]

C6D5Cl, 135 oC+

Ph

NPh

PhPh

HNPh

Ph

3:1

ent r y alkene time (h) yield (%)

1 Bn3Ta=NCMe3 3 0 >95

2 [BnTa=NCMe3]+ 8 >95

3 Np3Ta=CMe3 1 2 >95

4 (Et2N)3Ta=NCMe3 3 0 >95

5 Ta(NMe2)5 3 0 >95

6 Cl3Ta=NCMe3 3 0 NR

Ta(NMe2)5 + t-BuNH2 (NMe2)3Ta=Nt-Bu + 2 NHMe2


• Catalytic hydroaminoalkylation of alkenes using Ta proceeded in high yields andappreciable selectivities

• Although electronic properties of amine control the selectivity, typical directinggroups (e.g. pyridyl, iminoyl, carbamoyl) are not necessary

What needs to be done– Improve reaction conditions and scope– More mechanistic data is needed to explain the selectivity as well as reactivity

of Ta complexes

Summary and Future Prospective


Direct, Catalytic Hydroaminoalkylation of Unactivated ...ccc.chem.pitt.edu/wipf/Current...

Documents

Transcript of Direct, Catalytic Hydroaminoalkylation of Unactivated ...ccc.chem.pitt.edu/wipf/Current...