bio partnering 2006_final

PEPPSI Catalysts and Beyond: Highly Efficient Pd Catalysts for C−C and C−X Bond

Formation

Aaron G. Maestri, Ph.D.Product Manager - CatalysisSigma-Aldrich Corporation

Presented at the BioParterning Meetings, 2006

Seminar Outline

• A concise overview of cross coupling and current art

• Introduce PEPPSI-IPr pre-catalyst

• General interest in sp3- sp3 coupling reactions

• Present proof-of-concept results in Negishi sp3- sp3 couplings

• Demonstrate scope – use in Negishi, Suzuki, Kumada, Heck and

Buchwald-Hartwig aminations

• Present preliminary results in Sonogashira, Hiyama, enolate

arylation, and Stille reactions

• Utility – easy to use? Produce on scale? Storage? Amenable to

larger scale reactions?

• PEPPSI-IPr: conclusions and what’s next

• Introduce an additional Pd cross-coupling catalyst and illustrate

the scope of reactivity

How does PEPPSI reactivity stack up against the best phosphine-based catalyst systems?

• Phosphine Ligands• High expense due to multi- step syntheses• Sensitivity to oxidation• Catalyzed reactions require purification after fouling of the

product; also usually required in excess relative to Pd• Chemistry is more developed relative to NHC ligands• Few phosphine-based catalysts exhibit broad utility*

• N-Heterocyclic Carbene (NHC) Ligands• Current Literature suggests that the carbene is a stronger σ-donor than related phosphines making the metal more basic/nucleophilic• Often generate highly robust, air- and water-stable catalysts• Less stable than the corresponding phosphine - less likely to

dissociate from the metal thus suppressing β-hydride elimination• Relatively unexplored methodology – early results suggest great

things to come

*It should be noted that Pd(PPh3)4 is widely applied in catalysis,however this complex can suffer from poor long-term stability and is now thought to be less (broadly) active than [Pd(0)-NHC systems].

PR

R2

R1PR2

Ar

where R groups are alkyl

R1R

R2 R3

PEPPSI is Readily Activated in situ

N N

PdCl Cl

N

Cl

N

N

Pd(0)L

R2-R2

2R2-M

N

Clthrow-away ligand

R1-X

active catalyst

activation

oxidativeaddition

N

N

PdII

L

R1

X

M = ZnX, MgX, BR2

R2-M

M-X

N

NPdII

R1

L

R2

R1

R2

reductiveelimination

transmetalation

PEPPSI-IPr

n

enhance basicity ofcatalyst

Coordinativelysaturatethe metal

Increase thesteric environmentaround the metal

Introducing the Catalyst

• Introduction to PEPPSITM:Pyridine, Enhanced, Precatalyst,Preparation, Stabilization and Initiation

or PEPPSI

N N

PdCl Cl

N

Cl

PEPPSI-IPr

• Synthesis: base, PdCl2, imidazolium salt, 3-chloropyridine, heat• No glove box, no inert atmosphere, no special handling,no solvent, 3-chloropyridine is distilled off and recycled (kilo-scale)

Alkyl-alkyl couplings. Impossible?

• Initially, efficient alkyl-alkyl couplings were desired• Historically plagued by a variety of issues:

• Lack of a docking site on the halide or pseudohalide for the metal as we see in allylic and sp2 system, which means oxidative addition is more difficult

• The presence of β-hydrogens can allow for deleterious β− hydride elimination processes to occur

• Reductive elimination of the two alkyl pieces can be difficult• Could utilizing NHC based PEPPSI-IPr technology help overcome these

issues?

Br+ BrZn

PEPPSI-IPr (1 mol %)

THF/NMP (2:1), rt

30 min, quantitative

(1) Organ, M. G. Rational catalyst design and its application in sp3-sp3 couplings. Presented at the 230th National Meeting of the American Chemical Society, Washington, DC, 2005; Abstract 308.

PEPPSI-IPr Exhibits Broad Utility in C–C and C–X Bond Forming Reactions

N

Suzuki

Buchwald-Hartwig

α−αρψλατιον Σοναγ ασηιρα

Κυµ αδα

Νεγ ισηι

Ο

ΟΕτ

ΝΗ

ΗΝ

ΡΠη

Ο

ΜεΟ

Ν

ΟΟ

Ο

Ο

Η2Ν

Ο2Ν

ΒΟ

Ο

Πιναχολ Σψντηεσισ

ΟΧΗ3

Ηιψαµ α

PEPPSI Results in the Negishi Reaction: sp3-sp3 couplings

Organ, M. G. et al. Chem. Eur. J. 2006, 12, 4749.

N

O

O81 %

86 %

O

OEt

87 %

70 %

TMS

74 %

64 %

O

O

O

CN

CN

CN

THF:NMP (2:1), rt

Cl Br

+

CN

Cl CN

81%BrZn

Catalyst

Pd2(dba)3 (2 mol %), carbene ligand (8 mol %) (4 % catalyst): 8 h, 75% yield

PEPPSITM-IPr (1 mol % catalyst): 30 min, quantitative

Note that the PEPPSITM-IPr catalyst works well with Cl, Br, I, OTs, OMs, and OTf

Negishi Couplings – Extending PEPPSI-IPr Versatility

• sp2 – sp3:

• sp3 – sp2:


83 %X = Br

N

OO

O

O

THF:DMI (2:1), rt, 2 h+

PEPPSITM-IPr (1 mol % catalyst)R X

R2R1R3 ZnBr

R R3

R2R1(1.3 equiv)

98 %X = Cl

N

O

O

F

O

85 %X = Cl

THF:NMP (1:2), rt, 2 h+

PEPPSITM-IPr (1 mol % catalyst)

R3R2

ClZn RR1 X

R3R2

RR1

LiY (3 equiv)(1.3 equiv)

TMS

O

X = Cl, LiCl, 92%

O

X = Br, LiBr, 87%

TMS

X = Cl, LiCl, 89%

OCN

3

X = OTf, LiBr, 87%

Negishi Couplings – Executionof the Full Reaction Scope

• sp2 – sp2:


THF:NMP (2:1), rt, 2 h+

PEPPSITM-IPr (1 mol % catalyst)

R5R4

BrZn R3

(1.6 equiv)

X = Br, THF/NMP (2:1), 96%

R X

R2R1

R5R4

R3R

R2R1

X = Br, THF/NMP (2:1), 90%

NS

N

X = Cl, THF/NMP (1:2), 90%, 16 h, 60 Co

NNC O

X = Cl, THF/NMP (1:2), 95%

O

O

X = Br, THF/NMP (1:1), 96%, 16 h, 60 Co

N N

S

X = Cl, THF/NMP (1:1), 96%

PEPPSI Results in the Suzuki Reaction

R + R1 B(OH)2

(1.1 equiv)

PEPPSI−ΙΠρ (1 µ ολ %)Ρ Ρ 1Ξ

διοξανε, 60 Χ, 2 − 15 ηο

Κ2ΧΟ3

• sp2 – sp2:


R = Cl, 99 %

S

N

NS

S

R = Br, 98%

NC NO2

OH

OH

R = Br, 90%

O

O

O

H

R = Cl, 60%

2.5 equiv of boronicacid, 10 G scale!

R = Br, 97%

F

R = Cl, 79%

N

N

R = Cl, 96%

SO

KOH, K2CO3 (trace)

PEPPSI Results in the Buchwald-Hartwig Amination Reaction

• Alkyl amines readily transformed; anilines not so well

Organ, M. G. et al. manuscript in preparation.

Ar + NH

R1

R2

N

R1

R2

Ar

N

O

X

81%, Cl

70%, Br

HN

NH

65%, Cl

N

Me

S

73%, 20h, Br

NH

82%, 20h, Cl

PEPPSITM-IPr (2 mol %)

DME, KOtBu, 50 C, 2 ho

O

O

O

NOO

O

O

O

N

N

O

N 3

3

75%, Cl, 60 C, 24 ho

58%, Br, 60 C, 24 ho71%, Br

Extending PEPPSI Reactivity in the Buchwald-Hartwig Amination Reaction

• Aryl chlorides only• All reactions complete at room temperature

Organ, M. G. et al. manuscript in preparation.

Ar + NH

R1

R2

N

R1

R2

Ar

N

Cl

90%


DME, KOtBu, rt, 24 h

H

N OF3C

92%

NN N

O

92% 83%78%

N

NN

H Ph

60%

N

OCH3

N

O

OCH387%

N

F3C

N

O

H

59%

N

NPh

SO

46%89%

t-Bu

N

H

Ph

Kumada-Tamao-Corriu Coupling

Ph

NN N

OH

X = Cl, 82%, NaH,1.3 equiv Grignard

N

S

S

X = Cl, 85% X = Cl, 80%

N

N

X = Cl, 63%

S

X = Br, 99%

N

OO

t-Bu X = Br, 77%

NN

N

OO

t-Bu X = Br, 83%

OEt

OEt3

X = Cl, 90%, 24 h

3

TMS

X = Cl, 70%, 24 h

R + MgBrR1XPEPPSITM-IPr (2 mol %)

Grignard in THF, 16 - 24 h1.6 equivTHF:DME (2:1), rt

R R1

• Coupling works well at room temperature

Organ, M. G. et al. Chem. Eur. J. 2006, Accepted.

Kumada-Tamao-Corriu Coupling:Exploiting PEPPSI’s High Activity

85%

PEPPSITM-SIPr (2 mol %)

Grignard in THF, rt, 16 h

1.6 equiv

LiCl (3.2 equiv)

NN

NN

BrMgBr +

• First room temperature tetra ortho substituted

cross coupling reported of any kind

62%

PEPPSITM-SIPr (2 mol %)THF, rt, 16 h

S ClBrMg

S

Br

S ClS

MgBr

S

S

• Sequential Coupling Chemistry

Organ, M. G. et al. Chem. Eur. J. 2006, Accepted.

PEPPSI Competition Experiment

Catalys t (2 mol %),THF, 24 h

+

MgBr

NN

Cl

Ph

NN

Ph

(PPh3)4Pd(40)

PCy3(41)

PCy2iPri-Pr

iPr

PCy2OMeMeO

PEPPSi-IPr(1)

(42) (43)

(Pd2dba3 was us ed as the Pd s ourcewith lig ands 41, 42, and 43)

• PEPPSI-IPr is very reactive relative to other known strong catalysts in the literature

Heck-Amination Sequence - PEPPSIExhibits Robust Microwave Behavior

R Br

NH

R

R = Et, 95% (81%)R = Me, 92% (72%)R = Ph, 85% (68%)

H2N

Br

H2N

Br

Cl

H2N

Br

F

H2N

Br

H2N

Br

NH

R

R = Et, 92% (72%)R = Me, 92% (85%)R = Ph, 94% (82%)

NH

R

R = Et, 92% (72%)R = Me, 98% (82%)R = Ph, 90% (70%)

NH

FR

R = Et, 85% (76%)R = Me, 84% (73%)R = Ph, 88% (78%)

NH

ClR

R = Et, 79% (70%)R = Me, 76% (62%)R = Ph, 82% (69%)

1.5 eq

RC: Pd-coated capillary, PEPPSI (5%), tBuONa, toluene, 215 oC, P = 75 psi, FR = 10 µΛ/µ ιν.

• Yields > 75%, small library of 20 indoles prepared

Sonagashira Coupling – is PEPPSI Versatile?

• 1° Alkyl Centers:

• 2° Alkyl Centers:


CuI (4 mol %), 16 h, 50 C

DMF/DME (3:2), CsCO3 (1.5 equiv)

Br +R H

nHex

R

nHex

o

nHexO

O

85%

nHex

97%

nHex

Cl

92%

nHex

NC

90%


CuI (10 mol %), 18 h, 60 CDMF/DME (1.8:1), CsCO3 (1.5 equiv)

Br+R

H

nHexnHex

o

nHex

87%

nHex

85%

CH3(CH2)7NH (0.2 equiv)

R1

R

R1

N

O

O

Enolate Arylation – Extending PEPPSI Utility Under Mild Conditions

X = Cl, 94% X = Br, 91%X = Cl, 79%;X = Br, 84%

Ar +

(1.2 equiv)

PEPPSI−ΙΠρ (2 µ ολ %)Ξ

ΝαΟτΒυ, τολυενε , ρτ, 12 ηΗ

Ο

Ρ 1

Ρ

Ο

Ρ 1

Ρ

Αρ

Ο Ο Ο Ο

Ξ = Χλ, 2 εθυιϖΑρ−Ξ, 39%

Ο Ο

Ξ = Χλ, 58% Ξ = Βρ, 51%

Ο

Ξ = Βρ, 88%

Ο

Ξ = Χλ, 57%;Ξ = Βρ, 2 εθυιϖΑρ−Ξ, 51%

Hiyama Coupling

• Note that the reaction of silanol and their respectiveSodium salts are efficiently promoted in this reaction.

• The Silanoates are available as a convenient solid that can be stored and dispensed directly into the reaction

90%

PEPPSI−ΙΠρ (3 µ ολ %)

ΝαΗ (1 ε θυιϖ)τολυε νε , 60 Χ, 12 η

Βρ ΣιΗ3ΧΟΟΗ

+

ΟΧΗ3

ο

What About Scale-up??

+

2 mol % PEPPSI-IPrDME, NaOtBu, 1h, 60 oCN

Cl H N N CH3N

N N CH3

• Buchwald-Hartwig on Scale

• Work Up • 1) filter thru Celite, 2) extract into acid, 3) titrate until basic 4) back extract into ether, 5) dry and remove solvent

26.5 G!

OHOH

CH3

CH3

CH3

CH3

10 G!

• Suzuki on Scale

OH

10 G!

• Kumada on Scale

Pd(AmPhos)2Cl2: A Highly Efficient, Air-StableCatalyst for the Heteroaryl Suzuki Reaction

Pd

ClCl

PP

NMe2Me2N

Ar X (HO)2B+Rn

ArRn

1.2 equivK2CO3 (2 equiv), toluene/H2O (5:1), 100 C, 12 h

1 mol %

o

89 - 99%

Aldrich #: 678740

N

R = Cl, 92%

CF3

H2N

N

R = Cl, 98%, 2 mol % cat,

H2NN

N

R = Cl, 95%

O

S

NN

R = Cl, 89%, anhyd toluene

O

COOMe

NN

O

O

R = Cl, 97%

S

R = Cl, 96%

O

NN

R = Br, 93%, K3PO4 (base)

F

NN

R = Br, 95%, K3PO4 (base)

Conclusions

• Extremely stable to air and moisture• Commercialized on kilo scale• Improved or comparable activity to known Pd

catalysts (Buchwald, Nolan)• High performance in various reaction paradigms• Many reactions occur at room temperature• No need for additional ligands → one-component catalyst• Competitive pricing (per mole basis vs. Pd(PPh3)4 )• Preliminary data also suggests that PEPPSITM is effective in couplings

that historically prove challenging for Pd catalysis, i.e., the coupling of nitrogen and sulfur-containing compounds

• Three results illustrated that PEPPSITM-catalyzed reactions scale well• PEPPSITM behaves well in microwave conditions, while many Pd

catalysts do not

Innovative PEPPSI website including ordering information:

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to your discovery and process design. Visit www.sigma-aldrich.com/peppsi