Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

Summary

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic α,β-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

Abstract

The conjugate addition of organometallic reagents to α,β-unsaturated carbonyls represents an important method to generate C–C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild “one-pot” preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic α,β-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

Introduction

The formation of carbon-carbon bonds is arguably the most important and powerful transformation in organic chemistry. The conjugate addition of organometallic reagents to α,β-unsaturated carbonyls comprises one of the most versatile methods for the construction of C-C bonds, especially in the challenging generation of all-carbon quaternary centers^1,2. Despite the central importance of the conjugate addition of organometallic reagents to the formation of quaternary centers, few methodologies address the challenge of incorporating sensitive functional groups in these reactions. Indeed, in the majority ....

Protocol

CAUTION: Consult Material Safety Data Sheets (MSDS) prior to the use of the chemicals in this procedure. Use appropriate personal protective equipment (PPE), including safety glasses, a lab coat, and nitrile or butyl gloves as many of the reagents and solvents are corrosive, toxic, or flammable. Carry out all reactions in a fume hood. It is necessary to flame-dry glassware and use an inert atmosphere (nitrogen or argon) for this protocol. Liquids used in the first two steps of the protocol are syringe transferred.

1. Functionalized monoorganozinc bromide formation¹⁶

1. Add zinc dust (0.8173 g, 12.50 mmol, 2.....

Results

Conjugate addition product ethyl 4-(1-methyl-3-oxocyclohexyl)butanoate (21) was isolated as a clear, colorless oil (1.0372 g, 4.583 mmol, 92% yield) using this efficient one-pot protocol. ¹H and ¹³C NMR spectra are presented in Figure 2 and Figure 3 to confirm the structure and purity. Of specific note in the ¹H spectrum analysis is the presence of a two proton AB quartet at δ 2.1.......

Discussion

The method detailed herein was developed to harness mild functionalized monoorganozinc reagents in a simple and efficient conjugate addition reaction for the synthesis of β-quaternary ketones¹⁴. Excellent yields and significantly improved catalyst efficiencies were observed through the use of the polar, aprotic solvent DMA with TMSCl. Monoorganozinc formation is aided by DMA, facilitating the direct zinc insertion into readily available alkyl bromides to create a broad scope of functionalized.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Ammonium Chloride
Biotage Isolera One Flash Chromatography System	Biotage	ISO-ISW	UV/vis detection (254, 280, 200-400nm)
Chloroform-D, (D, 99.8%)	Cambridge Isotope Laboratories	DLM-7
Copper (I) bromide dimethyl sulfide complex , 99%	Sigma Aldrich	230502	Air and moisture sensitive
Diethyl Ether, anhydrous, 99%	EMD Chemicals	MEX01906	ACS
Ethyl 4-bromobutyrate	Oakwood	139400
Ethyl Acetate, 99.9%	Fisher	E145-500	ACS
Glacial Acetic Acid	Oakwood	O35907	ACS
HCl			1 M aq
Hexanes, 98.5%	EMD Chemicals	HX0299	ACS
HP 6890 Series GC	HP
HP-1 GC Column	Agilent	19091-60312	0.2 mm x 0.33 um, 12 m, 7 inch cage
Iodine
Magnesium Sulfate, anhydrous, 98%	EMD Chemicals	MX0075
Mehtyl enone
N,N-Dimethylacetamide, anhydrous, 99%	Alfa Aesar	A10924	Dried over 3 Åms
Silica gel	VWR	86306-350	60 Å, 40-60 um
Sodium Bicarbonate
Sodium Chloride
Tetra-n-butylammonium fluoride	Oakwood	O43479	1 M in THF
Thin-layer chromatography plates	EMD Milipore	115341	6.5 x 2.2 cm2, 60 g F254 precoated plates (9.5-11.5 um particle size)
Trimethyl silyl chloride, 99%	Sigma Aldrich	386529	Air sensitive
Zinc			Powder, HCl-washed