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Senior seminar

New Synthetic Methods for C-C Bond formation

Justin Holiwell

on 16 April 2013

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Transcript of Senior seminar

Diels-Alder reactions with 2-boron substituted dienes Conjugated diene reacts with a double bond compound
Under heat reaction becomes concerted, forming a cyclic molecule
Trifluroborate substituted dienes
Diethanolamine boron ligand Alkylation Reactions Conversion of 1-pentyne to 3-heptyne Alkylation Reactions Conclusion Organometallic Reactions Chemical compounds with carbon bond to transition metals
Coupling reaction
Gilman reagent
Palladium catalyzed
Pd inserted between carbon & halogen
organopalladium compound By Justin Holiwell New Synthetic Methods
Carbon-Carbon Bond formation Olefination (Metahesis) Reactions Organometallic Reactions Diels-Alder Reactions Overview 1. Bruice, P. Y. Organic Chemistry. Boston: Prentice Hall. 2011, 6. Direct Alkylation of Pyridyl Alcohols Palladium-Catalyzed Alkylation Friedel-Crafts acylation/reduction 2. Jeffrey, J.; Sarpong, R. Organic Letters. 2012, 14(21),
5400-5403. 3. Dai, L.; Hou, X.; You, S.; Zhu, X. Organic Letters.2001, 3(2), 149-51. 4. Blore, C.; Bream, R.N.; Gooding, S. J.; Hulcoop, D.G.;
Watson, S.A. Org. Process. Res. Dev. 2012, 16, 2043-2050 When picoline derivative is functionalized, four constitutional isomers are formed 2,3-cycloheptenopyridine
(pyridyl alcohol)
ligands for catalysts & pharmaceuticals Figure 1. Constitutional Isomers of Picoline 2 Initial deprotonation of alcohol
Secondary interaction between the metal and the Nitrogen
Increase basicity Scheme 1. Proposed Chichibabin Alkylation 2 1. 1.Bruice, P. Y. Organic Chemistry. Boston: Prentice Hall. 2011, 6.
5.Wang, L.; Welker, M. E. J. Org. Chem. 2012, 77 (18), 8280-8286 Olefination (Metathesis) Reactions 5. Wang, L.; Welker, M. E. J. Org. Chem. 2012, 77 (18), 8280-8286 Scheme 6. Diels-Alder reaction Table 1. Yield of direct alkylation 2-methyl-1-tetralone (5) reacts with allylic ethyl carbonate reacts w/ligand

Solvent effected the percent yield (dimethoxyethane or tetrohydrofuran) Ferrocene derivatives as ligands
bis-N-[2-(diphenylphosphino) ferrocenylcarbonyl]-diaminocyclohexane Figure 2. Ferrocene ligand derivative conformations 2 Scheme 2. Palladium-catalyzed Asymmetric Alkylation equation 3 Table 2. Reaction conditions for alkylation 3 Basic alkylation of hexamethyleneimine along with 3-phenoxyppropyl bromide 1877 Charles Friedel and James Crafts
Allows placement of an acyl or alkyl group Scheme 3. Basic Friedel-Crafts Acylation 1 AlCl and DCM provided 99% yield to attach 4-chlorobutyrl Scheme 4. Friedel-Crafts acylation/reduction reaction 1. Bruice, P. Y. Organic Chemistry. Boston: Prentice Hall. 2011, 6. 4H-benzo[d][1,3] oxazin-4-ones Optimal yield was 91%
Ag O & Cu(OAc) also used
Mizoroki-Heck alternative
Inexpensive benign materials 8.XiaoJie, S.; ZhongQuan, L. Chin. Sci. Bull. 2012, 57(19), 2335-2337 1. Bruice, P. Y. Organic Chemistry. Boston: Prentice Hall. 2011, 6. 2 2 Scheme 7. Pd-catalyzed olefination 6.Cheng, C.; Gandeepan, P. J. Am. Chem. Soc.
2012, 134, 5738-5741 7.Chen, P.; Liu, G.; Liu, Q. ACS Catal. 2013, 3, 178-181 Figure 3. 4H-benzo[d][1,3] oxazin-4-ones Triple bond cleavage >200kcal/mol
C-C triple bond cleavage utilizing metal catalyst Scheme 8. Proposed palladium catalyzed formation carbon centered nucleophiles
benzylic alcohols Alkene double bound is broken and rejoined
Transitional metal catalyst
Grubbs catalyst 1. Bruice, P. Y. Organic Chemistry. Boston: Prentice Hall. 2011, 6. Scheme 10. Metathesis mechanism with Grubbs catalyst Wittig Reaction Types of olefination reactions Wittig Reaction (X=PR )
Julia Olefination (X=SO R)
Peterson Olefination (X=SiR ) 3 2 3 Georg Wittig & Geiser in 1953
Three step synthesis
Metal catalyst can create a "one-pot" C-C bond formation 9.Shen, Y. Acc. Chem. Res. 1998, 31(9),
584-592 Scheme 11. "One-Pot" Wittig reaction mechanism Table 4. Carboxylic derivatives (X) and their respective percent yields Julia Olefination McMurry Coupling Olefination drawbacks reaction between tosylhydrazone and alkenylboronic acid
conditions necessary to produce only one isomer Phosphine mediated
olefination & reductive coupling complex multiple step synthesis
original: elimination of an ester, homolytic cleavage, transformation into a trans olefin 10.Wang, Z. Comprehensive Organic Name Reactions
and Reagents. 2010, 1576-1582 Scheme 12. Orignal Julia Olefination One-step mechanism using hetorocyclic sulfones
reversible addition of carbanion to a carbonyl
Closed transition state Scheme 13. Modified Julia olefination (Julia-Kocienski) Low valent titanium
Cross McMurry coupling
two carbonyl compounds 11.Duan, X.; L, J.; Zeng, J.; Shang, Z. J. Org.
Chem. 2006, 71, 9873-9876 Scheme 14. General titanium McMurry Reaction Wittig: low steroselectivity, harsh byproduct, minimal reactivity
Peterson: separation of diastereomeric intermediates
Julia: cumbersome, low selectivity 12.Kartrizky, A. R.; Li, Jianqing. J. Org. Chem.
1997, 62 (2), 238–239 N-allylbenzotriazoles or N-benzylbenzotriazoles undergo lithiation
React with aldehydes or ketones
Treated with low-valent titanium Scheme 16. Stereoselective olefination of carbonyl compounds Iridium Olefination Diazo compounds to form aldehydes
Olefination of 3-phenylpropanal 13.Ladjel, C.; Lebel, H. Organometallics, 2008, 27 (11),
2676–2678 14.Perez-Aguilar, M. C.; Valdes, C. Angew. Chem. Int.
Ed. 2012, 51, 5953-5957 Scheme 18. Olefination of tosylhydrazone with alkenylboranic acid Method A: Potassium Carbonate (2 eq.), cesium fluoride (2 eq.), in 1,4-dioxane at 110 C
Method B: 1 to 1 mixture of 1,4-dioxane/MeOH
Method C: Microwave heating creates a trisubstituted conjugated diene
y-benzyl allenoate, various allenes, and phosphine catalysts Scheme 19. Phosphine-mediated olefination reaction 15.He, Z.; Ma, R.; Xu, S.; Wang, Z.; Zeng, S.; Zhou, L. Organic Letters, 2009,
11(15), 3498-3501 Scheme 20. Proposed mechanism for olefniaton Asymmetric allylic alkylation Create asymetric quatinary carbon centers w/enantioselectivity Azocine:
Used as glucosidase inhibitors (anti-diabetic drugs)
Reduced the impact of carbohydrates on blood sugar Reducing cumbersome reactions (Julia)
Increase in selectivity (Ferrocene)
Some mechanisms are not completely understood (Chichibabin, triple bond)
Future innovations
Diabetic medication
laxatives Laxatives (Dantron, Aloe emodin)
antidepressants Reacted w/Grignard reagets, primary sulfamide compounds etc.
products were tested for inhibitory effects on 2 strains of bacillus Pd catalyzed oxidative olefination of arenes Acetylide ion Electrophile generation 3 Thank you for your time!! X-OH: oxone or
NFS/H O/Pd 2 I II III histamine antagonist drugs
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