Massachusetts Institute of TechnologyOrganic Chemistry 5.511

October 24, 2007Prof. Rick L. Danheiser

Carbanionic Synthons III

Lecture 7

Reading Assignment

Background: Clayden et al. Sections of Chapters 9, 21, and 26

Carey and Sundberg Part B, Chapters 1, 7 (Sections 7.1, 7.2, and 7.3.1), and 8 (Section 8.1) Note: some stereochemical features of this chemistry will not be covered until later units

1. Metalation with base (deprotonation) 2. Oxidative addition (reductive metalation) 3. Halogen-metal exchange 4. Transmetalation 5. Addition to π-bonds 6. Fragmentation and cleavage

Introduction to General Reactivity and Overview ofGeneral Methods for the Generation of Carbanionic Synthons

Unit 2 Outline

An excellent general reference"Organolithiums: Selectivity for Synthesis", Clayden, J. Pergamon, 2002

Henry Gilman1893-1986

Georg Wittig1897-1987

Reviews on Directed Metalation(1) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem. Int. Ed. 2004, 43, 2206(2) "The Directed ortho Metalation Reaction - A Point of Departure for New Synthetic Aromatic Chemistry", Hartung, C. G.; Snieckus, V. In Modern Arene Chemistry, Astruc, D., Ed., Wiley VCH, 2002, pp 330-367

Case Study

Total Synthesis of cis-JasmoneBüchi, G. H.; Wuest, H. J. Org. Chem. 1966, 31, 977McMurry, J. E.; Melton, J. J. Am. Chem. Soc. 1971, 93, 5309

George H. Büchi1921-1998

O

General Reviews on Organozinc Chemistry"Preparation and Applications of Functionalized Organozinc Compounds" Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Organic Reactions 2001, 58, 417-731

"Organozinc Reagents: A Practical Approach" Knochel, P.; Jones, P.; Oxford, 1999

"Polyfunctional Zinc Organometallics for Organic Synthesis" In Handbook of Functionalized Organometallics, Knochel, P., Ed.; Wiley-VCH, Vol. 1, 2005, pp 251-346

General Methods for the Preparation of Organozinc Compounds

Oxidative Addition R-I

Zn, Me3SiClBrCH2CH2Br

THFor

LiNaph, ZnCl2

R-ZnI

Halogen-ZincExchange

Transmetalation

R-I2-5 equiv Et2Zncat CuI or CuCN R2Zn + EtI, Et2Zn (volatile)

RLi or RMgX + ZnBr2 or ZnCl2 R-ZnX

R-BEt2 + 2 equiv Et2Zn, rt (neat) R2Zn + Et3B (volatile)

Generation of Carbanionic Synthons via Addition to π Bonds

Generation of Carbanionic Synthons via Fragmentation and Cleavage

OMet

R

O

e.g. R2CuLi

RMet

O O OLi

H

Li, liq NH3THF, t-BuOH Li

H-Ot-Bu

OSiMe3 OLiMeLi, THF

CH3

NNHSO2Ar

CH3

Li

O NNHSO2

TrsNHNH2HCl, CH3CN

2 equiv s-BuLiTMEDAhexane

Li

Stork: RegiospecificGeneration of Enolates

Shapiro Reaction

50-53%

BuBr

SET SET

CH3

N

Li

N SO2ArLi

CH3

NN Li