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 ☺