Reactivity and Application of Reactivity and Application of Pyridinium Salts in Organic Synthesis

Elizabeth Cline

February 12 2010February 12, 2010

2ndYear Literature Seminar

Alexanian Lab

Pyridinium SaltsUseful Synthetic Building BlocksUseful Synthetic Building Blocks

NuNu

N NuN

Nu

N N Nu

Nu

Nu

RRsubstitutedpiperidine

substitutedpyridine

NR

NR

Nu

Rsubstituted

dihydropyridine

Ubiquity in Medicinal Compounds

NexiumPlavix

ActosAbilifyAvandia

Risperdal

Aricept

ConcertaActonel

AciphexSingulair

Ubiquity in Nature

Haliclonin ASarain A

Lonijaposide Aj p

Manzamine AKeramaphidin BGeissoschizine

Halicyclamine A

N

N

N

HOO

NH

H

ONH

DL-FebrifugineNH

CHO

Norfluorocurarine (-)-Cephalotaxine Akagerine

Pyridinium Salts in Nature

R1

N

HO

N

N

R2

NH2

2OH

R1=R2=H njaoamine AR1=R2=Me njaoamine BR1=H R2=Me njaoamine C

Reyes, F.; Fernández, R.; Urda, C.; Francesch, A.; Bueno, S.; de Eguilior, C.; Cuevas, C. Tetrahedron 2007, 2432.R. Laville; G. Genta-Jouve; C. Urda; R Fernandez; O. Thomas; F. Reyes; P Amade. Molecules 2009, 4716.

Pyridinium Salts from PyridineElectrophilic reactions on nitrogenElectrophilic reactions on nitrogen

N

X

RX

NR

RX

R NHR NH2

NR

Cl

Zincke Reaction

T. Eicher, S. Hauptmann, The Chemistry of Heterocyles, p 272, New York, 1995.

General Reactivity

Electrophilic at the 2, 4, and 6 positions

Synthetic Challenges•Control of regioselectivity

•Difficult to differentiate t o faces of the p ridinium salt•Difficult to differentiate two faces of the pyridinium salt

General Rules

+0.165

+0.241

Grignards, organolithiumcompounds, heteroatom

nucleophiles Electron deficiency at C-2 and C-4

T. Eicher, S. Hauptmann, The Chemistry of Heterocyles, p 272, New York, 1995.D. M. Stout; A.I. Meyers Chem. Rev. 1982, 82, 223.

General RulesMO DiagramCuprates, carbanions,

enolates, thiols

LUMO

T. Eicher, S. Hauptmann, The Chemistry of Heterocyles, p 272, New York, 1995.D. M. Stout; A.I. Meyers Chem. Rev. 1982, 82, 223.

Application to Total SynthesisSynthesis of GeissoschizineSynthesis of Geissoschizine

TsOH, LiI NN

SPh

NN Br

SPh

,

THF O

CO2Me

O

CO2Me

Geissoschizine

M.L. Bennasar; J.M. Jimenez; B. Vidal; B.A. Sufi; J. Bosch . J. Org. Chem 1999, 64, 9605.

Face-Selective Addition

S. Yamada; C. Morita. J. Am. Chem. Soc. 2002, 124, 8184.

Asymmetric AdditionUse of Chiral N-Acylpyridinium SaltsUse of Chiral N Acylpyridinium Salts

Dihydropyridone

79% yield34% de34% de

88% yield94% de

•TIPS group blocks 2 position allowing

for greater diastereoselectivity

D. Comins, S. Joseph, R Goehring, J. Am. Chem. Soc. 1994, 116, 4719.

Asymmetric AdditionRemoval of the Chiral Auxiliary and Silyl GroupRemoval of the Chiral Auxiliary and Silyl Group

Dihydropyridone

81% – 88% yield

D. Comins, S. Joseph, R Goehring, J. Am. Chem. Soc. 1994, 116, 4719.

Asymmetric AdditionUse of Chiral N Acylpyridinium SaltsUse of Chiral N-Acylpyridinium Salts

RMgX Yield (%) deRMgX Yield (%) dePhMgCl 80 94

p-MePhMgBr 75 82p MeOPhMgBr 68 73p-MeOPhMgBr 68 73

MeMgCl 85 91

i-BuMgBr 86 92

c-HexMgBr 83 81

1-hexynylMgCl 74 83

i lM Cl 75 85vinylMgCl 75 85

D. Comins, S. Joseph, R Goehring, J. Am. Chem. Soc. 1994, 116, 4719.

Total Synthesis of (+)-CannabisativineOZ Cl

OMeTIPS

OO

Et Et

OZnCl

1. O

H

N

NH

HC5H11

OH

OHH O

NCO2R*

Cl 2. H3O+ NCO2R*

O

O O

Et

Et

H

85%

NH

NH

(+) C bi i i 85%de > 95%

(+)-Cannabisativine

D. Comins, J. Kuethe, J. Org. Chem. 2004, 69, 5219.

Total Synthesis of (+)-Cannabisativine

D. Comins, J. Kuethe, J. Org. Chem. 2004, 69, 5219.

(+)-Cannabisativine

RegioselectivityUse of Directing GroupUse of Directing Group

RMgX 1:2 Yield (%)MeMgBr >95:5 83

>95:5 862-FurylMgBr >95:5 96

90:10 70

94:6 76

A.B. Charette; M. Grenon; A. Lemire; M. Pourashraf; J. Martel. J. Am. Chem. Soc. 2001, 123, 11829.

StereoselectivityUse of Directing GroupUse of Directing Group

RMgX 1:2 dr Yield (%)MeMgBr >95:5 >95:5 77

Et2Zn >95:5 >95:5 732-FurylMgBr >95:5 >95:5 68y g

A.B. Charette; M. Grenon; A. Lemire; M. Pourashraf; J. Martel. J. Am. Chem. Soc. 2001, 123, 11829.

Total Synthesis of (+)-Lepadin BApplication of Chiral Directing Group

O

NAux M

Application of Chiral Directing Group

BF3-Et2O50°C

OMe

N

NAux

Ph

Me H

OMO OMeO

NBz

Me H5 steps

OBn

(+)-Lepadin B

A.B. Charette. J. Am. Chem. Soc. 2008, 130, 13873.

RegioselectivityUse of PyridiniumYlidesUse of PyridiniumYlides

Ylides have counterion linked directly to the pyridinium ring•Serves as a Lewis base and as a directing groupServes as a Lewis base and as a directing group

Considerations for choosing X:•N-X bond strength – must be easily cleaved

•Directing ability•Directing ability

A.B. Charette; C. Legault. J. Am. Chem. Soc. 2003, 125, 6360.

RegioselectivityUse of PyridiniumYlidesUse of PyridiniumYlides

1. RMgX, CH2Cl2rt, 25 min N

R

NBzN

rt, 25 min

2. NaBH4, MeOHNBz

N

RNBz

N

1 2

RMgX 1:2 Yield (%)MeMgBr >95:5 91EtMgBr >95:5 83t g 95 5 83

n-PrMgCl >95:5 87i-PrMgCl >95:5 81t-BuMgCl 43/57 39 28t BuMgCl 43/57 39, 28BnMgCl 93/7 71

AllylMgBr >95:5 79

A.B. Charette; C. Legault. J. Am. Chem. Soc. 2003, 125, 6360.

Bulky Grignards usually give predominantly 1, 4 addition

Asymmetric HydrogenationUse of PyridiniumYlidesUse of PyridiniumYlides

N

I2 (2 mol%)H2 (400 psi)

Toluene, rt, 6h

NNNBz

P N

O

IrCOD

NNHBz

R R

ArAr BArF

R Yi ld (%) (%)

COD t-Bu

Ar = p-F

R Yield (%) ee (%)2-Me 84 972-nPr 75 952-Bn 97 58

2-CH2OBn 85 762-(CH2)3OBn 88 88

A.B. Charette; C. Legault. J. Am. Chem. Soc. 2005, 127, 8966.

Catalytic EnantioselectiveAddition of TMSCNAddition of TMSCN

OH

SPhO

Additional chiralityon sulfur atomSulfoxide acts as OH

SO

Phligand

Sulfoxide acts as Lewis base to activate

TMSCN98% ee

E. Ichikawa; M. Suzuki; K. Yabu; M. Albert; M. Kanai; M. Shibasaki. J. Am. Chem. Soc. 2004, 126, 11809.

Addition of Terminal AlkynesCopper Catalyzed Addition to 1-Acylpyridinium SaltsCopper Catalyzed Addition to 1 Acylpyridinium Salts

N

10 mol% CuI, L 10 mol%

i-Pr2NPr-n CH2Cl2 -78°CR

NNCO2Me

i Pr2NPr n, CH2Cl2, 78 C NCO2Me R

Bis(oxazoline)

R Yield (%) ee (%)CO2CH3 74 95CO Bn 81 86CO2Bn 81 86COCH3 69 93

COCH2CH3 65 99CO(CH ) CH 70 91Increasing Decrease in CO(CH2)3CH3 70 91CO(CH2)4CH3 68 90CO(CH2)3OBn 70 77

Ph 75 1

Increasing steric bulk

Decrease in enantioselectivity

Carbonyl Ph 75 1(CH2)3CH3 63 11

Carbonyl necessary to get enantiocontrol

Z. Sun; S. Yu; Z. Zing; D. Ma. J. Am. Chem. Soc. 2007, 129, 9301.

Catalytic Enantioselective AdditionAddition of Dialkylzinc ReagentsAddition of Dialkylzinc Reagents

First example of catalytic enantioselective addition of organometallic reagents

Phosphoramidite

R Yield (%) ee (%)Et 69 95Bu 63 93

CH2CH2Ph 50 97iPr 65 56

M. A. Fernandez-Ibanez; B. Macia; M. G. Pizzuti; A. J. Minnaard; B. L. Feringa; Angew. Chem. Int. Ed. 2009, 48, 9339

Pyridine N-OxidesSynthesis of trans-2,3-Substituted Piperidinesy , p

Prior knowledge

R1MgX

Addition of Grignard and Addition of Grignard results

NR1OH

RT

Pyridine N-Oxides are gsubsequent addition of electrophilein ring-opening dienal oximes both nucleophilic and

electrophilic

H. Andersson; M. Gustafsson; D. Bostrom; R. Olsson; F. Almqvist. Angew. Chem. Int. Ed. 2009, 48, 3288

Pyridine N-OxidesSynthesis of trans-2 3-Substituted PiperidinesSynthesis of trans 2,3 Substituted Piperidines

N-Oxide E+ Yield (%) R Yield (%)( )

81

e d (%)

72

MgCl

80

71

76

60

F

MgCl

96

60

H. Andersson; M. Gustafsson; D. Bostrom; R. Olsson; F. Almqvist. Angew. Chem. Int. Ed. 2009, 48, 3288

Heterobiaryl CompoundsGlGleevec

Crestor

Amythiamicin D

NO

N

bVesicare

HN

Etorcoxib

O

OO

FPaxil CRSodium channel inhibitor

Tyrosine kinase inhibitor

Arylation of PyridineAryl pyridines usually prepared by:Aryl pyridines usually prepared by:

• Cross-coupling (i.e. Suzuki, Stille or Negishi reaction) from pyridyl halides or triflates

• Nucleophilic addition of arylmetallic reagents to pyridine N-oxide compounds followed by rearomatization

Drawbacks:Must use stoichiometric amounts of organometallic reagents

2 pyridyl organometallics are unstable and difficult to make2-pyridyl organometallics are unstable and difficult to make

Andersson, H.; Almqvist, F.; Olsson, R. Org. Lett.2007, 9, 1335.A.B. Charette; A. Larivee; J. Mousseau. J. Am. Chem. Soc. 2008, 130, 52.

Arylation of PyridinePalladium Catalyzed Direct Arylation of Pyridine N-Oxidesy y y

RPd/C, HCOONH4MeOH, rt

84% - 88% N

Commercially available, I i d b h t bl

NRActivated

C-H bond

Inexpensive, and bench stableN-Oxide Aryl-Br Yield (%)

95

N-Oxide Aryl-Br Yield (%)

80Br OMe

97 78

74

76

Br

CO2Me

Br

76CF3

L. Campeau; R. Rousseaux; K. Fagnou. J. Am. Chem. Soc. 2005, 127, 18020.

Catalytic Reaction Pathway

Oxidative Addition

Reductive Elimination

ConcertedMetalation/Deprotonation

H. A. Chiong; Q. Pham; O. Daugulis. J. Am. Chem. Soc. 2007 129 9879.

Arylation of PyridineUse of PyridiniumYlidesUse of PyridiniumYlides

Pd(OAc)2 (5 mol%)P(tBu)3 (15 mol%)K2CO3 (3 equiv)Ylide (1 5 equiv)

Activated C-H bond

Ylide (1.5 equiv)Aryl-Br (1 equiv)

M.S. 3 Åtoluene 125°C

Aryl-Br Yield (%) Aryl-Br Yield (%)80 76Br

NC

77 53

NC

86 50

76 83Br

O

N

N

Br

O

OMe

A.B. Charette; A. Larivee; J. Mousseau. J. Am. Chem. Soc. 2008, 130, 52.

Arylation of PyridineFunctionalization of 2-Substituted PyridiniumYlides

1. MeMgBrCH2Cl2 NMe

2. O2, TFACH2Cl2

45%, two steps

NNO

N

Me

Reductive Cleavage of N-N Bond

A.B. Charette; A. Larivee; J. Mousseau. J. Am. Chem. Soc. 2008, 130, 52.

Arylation of PyridineCompetition Experiments and Attempted DiarylationCompetition Experiments and Attempted Diarylation

S L i Strong Lewis Base

A.B. Charette; A. Larivee; J. Mousseau. J. Am. Chem. Soc. 2008, 130, 52.

Zincke ReactionReaction of Pyridinium Salts with Primary AminesReaction of Pyridinium Salts with Primary Amines

W. Cheng; M. J. Kurth. Org Prep and Procedures. 2002, 34, 585.

Zincke AldehydeReaction of Pyridinium Salts with Secondary Amines

AN

XR2NHRNH2

Reaction of Pyridinium Salts with Secondary Amines

NR

OA-NH2 +R +A-NH2

NR X

2

A. M. Kearney; C. D. Vanderwal. Angew. Chem. Int. Ed. 2006, 45, 780

Efficient Access to Core of Strychnos Alkaloidsof Strychnos AlkaloidsA Short Synthesis of Norfluorocurarine

Two Challenges:

tetracyclic core

Indoles are known to be poor dienophilesMost aminodienes are electron rich and would be poorly reactive

electron-deficient C atom at R1

Tryptamine derived Zincke aldehyde

D. B. Martin; C. Vanderwal. J. Am. Chem. Soc. 2009, 131, 3472.

Efficient Access to Core of Strychnos Alkaloidsof Strychnos AlkaloidsA Short Synthesis of Norfluorocurarine

HO 1. MsCl then LiBr NH SiMe3

NDNP

ClN

SiMe3

N

NH2SiMe3

2.NH

DNP

then NaOH67% N

H

SiMe3

CHO

NH

75%, 2 steps

Norfluorocurarine

D. B. Martin; C. Vanderwal. J. Am. Chem. Soc. 2009, 131, 3472.

Ring Opening of Pyridinium Salts

A. M. Kearney; C. D. Vanderwal. Angew. Chem. Int. Ed. 2006, 45, 780

Photochemistry of Pyridinium Salts

No yield reported• Late 1960s y p

Excited using standard UV-light sources

Unreactive to light used to promote the

• 1980s

light sources promote the process

U. Yoon, S. Quillen, P. Mariano, R. Swanson, J. Stavinoha, E. Bay. J. Am. Chem. Soc., . 1983, 105, 1204.L. Kaplan, J. Pavlik, K. Wilzbach. J. Am. Chem. Soc. 1972, 94, 3283.

Photochemistry of Pyridinium SaltsSynthesis of Aminocyclopentene DerivativesSynthesis of Aminocyclopentene Derivatives

Unsymmetrical Aminocyclopentenes

T h OTreatment with Organo-cuprates

R’CuLi(MgX) Yield (%)Me2CuLi 40Bu2CuLi 39

(vinyl)2CuMgBr 45

C. S. Penkett; I. D. Simpson. Tettrahedron Letters. 2001, 42, 1179.J. Zou; P. S. Mariano. Photochem. Photobiol. Sci. 2008, 7, 393.

Formal Synthesis of (-)-CephalotaxineApplication of Photocyclization of Pyridinium SaltsApplication of Photocyclization of Pyridinium Salts

Heck Reaction

(-)-Cephalotaxine Yoshida Tietze Intermediate

1. H2, Pd/C2. 6N HCl

OO

O

3.O

O

CH2COCl

I

NRO

R=HpTsCl83% 3 steps

I

R=pTs85%

83%, 3 stepsYoshida TietzeIntermediate

Z. Zhao; P. S. Mariano. Tetrahedron.2006, 62, 7268.

ConclusionsPyridinium salts are easily accessed and versatile precursors to nitrogen containing heterocycles

Methods have been developed to achieve asymmetric and regioselective addition

Arylation has been accomplished via C-H activation

Ring-opening Zincke aldehydes are proven to be useful synthetic building blocks

Irradiation of pyridinium salts with UV in presence of base gives unique bicyclic aziridine compounds

AcknowledgementsProfessor Erik Alexanian

lAlexanian GroupKayla BloomeAndy BrusoeyValerie SchmidtBen GiglioJustin Goodwin

Thermal Rearrangement f Zi k Ald h dof Zincke Aldehydes

E to Z 6

NRR

OR2

N

HO

RR

R2N

HR

R6 [1,5]-H

ORR1

HR1

ROH

R1R2

Pericyclic Cascade Reactions

NCHO

Me200°C N

OM

N

O

[3,3]

Me Me

200°C rearrangement

N

OMe

O

N

Me

CopeDiels-Alder

N

OMe

N

Me

H

O

Major 60%Expected Product

Minor 15%

Polycyclic Lactam Cascade Products

OHOH OH OHPh

N

H

N Bn N Bn

H

N Bn

HHO

73% 52% 65% 76%

N

O

Bn

H

N

OH

N

O

Bn

H

N

O

Bn

H

73% 52% 65% 76%

N Bn N

H

N Bn

HO

NH

Ts61% (2:1 mixture

of products)82% (mixture

diastereomers)76% 30%

of products) )

Salts of AlkylpyridinesHydrogens of 2 and 4 substituted alkyl side chains are acidicHydrogens of 2- and 4- substituted alkyl side chains are acidic

EE+

NR X

RegioselectivitySynthesis of 4 substituted PyridinesSynthesis of 4-substituted Pyridines

R1 R2 Yi ld (%) 1 2R1 R2 Yield (%) 1 : 22,6-di-t-Bu-4-Me-C6H2 Me 43 49 : 51

Et Me 55 46 : 54Et Et 70 8 : 92

Et i-Pr 73 0 : 100

K. Akiba; H. Matsuoka; M. Wada. Tetrahedron Lett. 1981, 22, 4093.

Pyridinium SaltsWhere They Come From And Why They Are Important.Where They Come From And Why They Are Important.

This slide is going to be taken out and split up into two slides

Pyridine derivatives are ubiquitous in nature

Nitrogen containing heterocycles are

important pharmacophores

RegioselectivitySynthesis 4 substituted PyridinesSynthesis 4-substituted Pyridines

O O

N

P(OiPr)2H1. BuLi

2. RX N

P(OiPr)2R

OEtO OEtO

RX Yield (%)RX Yield (%)MeI 74EtBr 76

All lB 70AllylBr 70n-BuBr 78

BnBr 87

K. Akiba; H. Matsuoka; M. Wada. Tetrahedron Lett. 1981, 22, 4093.

Arylation of Pyridine

Substrate Yield (%)

78

57

58

70

76

No additiond tproduct

No reaction

Pyridine N oxide Pyridine N-oxide Both more nucleophilic and more electrophilic than pyridine

Negatively charged oxygen can release electrons to stablise an intermediate from electrophilic attackPositively charged ring nitrogen can act as an electron sink to Positively charged ring nitrogen can act as an electron sink to encourage nucleophilic addition

N AcylPyridinium SaltsN-AcylPyridinium SaltsSomething about acyl pyridinium ions are more stable –dihydropyridines produced are more stable due to nitrogen being an amide

Synthesis of (+)-NordextrorphanApplication of the Zincke ReactionApplication of the Zincke Reaction

Why Are They Useful?

4Nu Nu

NR

2

Nu-

NR

NR

Nu

reduction

NR

NuNR

substituted substituteddihydropyridine piperidine

Nu

oxidation

R = alkylaryl

Nu = hydrideorganometallic compound

N N Nuoxidation

substitutedpyridine

arylacyl

organometallic compoundcarbanioncyanide ionheteroatom centered

J. A. Joule; K. Mills. Heterocyclic Chemistry, Malden, MA, 2000.

Total Synthesis of (+)-Cannabisativine

NH

C5H11

OH

H O

NH

NHOH

H O

(+)-Cannabisativine

DIOXALANONEWords in all caps in red are notes to

D. Comins, J. Kuethe, J. Org. Chem. 2004, 69, 5219.

Words in all caps in red are notes to myself so I can remember how to name these compounds ☺