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 of these transformations, highly reactive organolithium, Grignard, or diorganozinc reagents are the nucleophiles of choice. These reactive organometallics, however, are incompatible with many sensitive functional groups, thereby limiting the complexity of both the α,β-unsaturated carbonyl and organometallic reagent, often necessitating the use of protecting groups or alternative strategies in multi-step synthesis.

Monoorganozinc reagents are an attractive class of organometallic reagents which have garnered widespread attention for their mild reactivity and enhanced functional group compatibility^3,4,5,6. In spite of their exceptional functional group tolerance and trivial preparation from organohalides, there are few examples of monoorganozinc reagents in the conjugate addition to  β,β-disubstituted α,β-unsaturated carbonyls to generate quaternary centers^7,8,9. Furthermore, these transformations typically require stoichiometric quantities of toxic cyanocuprate reagents with one report demonstrating minimal catalyst turnover^10,11,12,13. The objective of our study is to establish a simple and practical catalytic method for the conjugate addition of functionalized monoorganozinc reagents to α,β-unsaturated carbonyls to generate all-carbon quaternary centers. Toward this end, we have developed a protocol utilizing N,N-dimethylacetamide (DMA) as a solvent with chlorotrimethylsilane (TMSCl) as a Lewis acid which enables a “one-pot” copper catalyzed (20 mol %) conjugate addition of functionalized monoorganozinc reagents to α,β-unsaturated carbonyls to generate a broad scope of all-carbon quaternary centers in high yield¹⁴.

The utilization of DMA as a solvent has several notable advantages over methods reported in the literature. DMA improves the efficiency of zinc insertion into organohalides which obviates the requirement for expensive and hygroscopic additives such as LiCl employed in ethereal solvent systems¹⁵. This also expands the scope of direct zinc insertion from sensitive, often commercially unavailable organoiodides to more stable and widely accessible organobromides¹⁶. The protocol detailed herein generates alkyl monoorganozinc reagents (2) from diverse organobromides, which are used in situ in the formation of a reactive cuprate complex that engages cyclic α,β-unsaturated ketones in a conjugate addition reaction (Figure 1). DMA also enables the reaction to proceed with cheaper and less toxic copper sources such as CuBr·DMS, eliminating stoichiometric toxic waste generated with CuCN utilized in other reports^10,11,12,13. Our standard reaction conditions provide access to a broad scope of β-quaternary ketones (5) with both five-, six-, and seven-membered ring conjugate acceptors obtained via the hydrolysis of an intermediate silyl enol ether (4). The intermediate silyl enol ether was observed to be moderately stable and could be isolated in excellent yield utilizing a modified workup procedure.

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, 2.5 equiv), DMA (6.0 mL), and I₂ (126.9 mg, 0.500 mmol, 0.10 equiv) to a flame-dried 50 mL Schlenk reaction flask containing a stir bar under argon. Stir the suspension at ambient temperature until the brownish-orange color completely dissipates to a gray suspension.
   CAUTION: DMA is flammable, acutely toxic, and a mild irritant.
2. Add ethyl 4-bromobutyrate (6; 1.43 mL, 10.0 mmol, 2.0 equiv) to the gray suspension. Immerse the flask in an 80 °C oil bath with vigorous stirring until consumption of the organobromide is observed by gas chromatography (GC) analysis.
   CAUTION: Ethyl 4-bromobutyrate is flammable and a mild irritant.
   1. Briefly dip a disposable glass Pasteur pipet into the reaction mixture, remove from the flask and rinse the aliquot with ca. 0.5 mL of diethyl ether (Et₂O) into a 2 mL vial containing ca. 0.5 mL of saturated NH₄Cl. Vigorously shake the vial and analyze the organic layer by GC.
      NOTE: Reaction progress is determined by comparing the disappearance of the organobromide peak to the appearance of the protonated organozinc reagent, which typically has a shorter retention time.
      CAUTION: Et₂O is flammable and acutely toxic.
3. Cool the monoorganozinc reagent to ambient temperature. The remainder of this conjugate addition protocol can be paused at this stage for several hours to overnight under inert atmosphere with minimal impact on the yield of the conjugate addition product.

2. Monoorganozinc bromide conjugate addition to α,β-unsaturated ketones

1. Cool the organozinc suspension in an ice/H₂O bath for ca. 5 min, and then add CuBr·DMS (205.6 mg, 1.000 mmol, 0.20 equiv) and additional DMA (10.5 mL, 0.30 M overall with respect to unsaturated ketone), and stir the reaction for ca. 10 min.
2. Add TMSCl (1.52 mL, 12.0 mmol, 2.4 equiv) to the cooled suspension, followed by 3-methyl-2-cyclohexenone (13; 567 µL, 5.00 mmol, 1.0 equiv). Remove the cooling bath after ca. 30 min and monitor the reaction until the a,b-unsaturated ketone is consumed by TLC analysis, or up to 24 h.
   NOTE: TLC analysis is performed with silica-coated glass plates and developed with 4:1 hexanes–ethyl acetate. R_f values: unsaturated ketone 13 = 0.15; silyl enol ether 37 = 0.61; ketone product 21 = 0.21. Visualization is achieved by UV-quenching at 254 nm, followed by p-anisaldehyde staining.
   CAUTION: TMSCl is flammable, acutely toxic, a skin irritant, and corrosive. 3-methyl-2-cyclohexenone is flammable and acutely toxic.

3. Extraction work-up and purification

1. Add acetic acid (1.5 mL, ca. 5 equiv) to the completed conjugate addition reaction to hydrolyze the intermediate silyl enol ether into the ketone product. Monitor the progress of hydrolysis in ca. 15 min intervals by TLC analysis using conditions from step 2.2.
   CAUTION: Acetic acid is flammable and corrosive.
   1. In the event that the silyl enol ether remains after 1 h, add tetrabutylammonium fluoride (TBAF; 1 M solution in THF, 0.5–1.0 equiv at a time) to facilitate complete hydrolysis as evident by TLC.
2. Add 1 M HCl (15 mL) to the reaction flask, mix well, and then transfer the reaction contents into a 250 mL separatory funnel. Rinse the flask with Et₂O (20 mL) and H₂O (15 mL), adding the rinses to the separatory funnel. Gently shake the contents of the funnel, venting between each mixing, and allow the layers to separate. Drain the bottom aqueous layer into a 125 mL Erlenmeyer flask, and then drain the organic layer into a separate 250 mL Erlenmeyer flask.
3. Return the aqueous layer to the separatory funnel and extract with four separate portions of Et₂O (4 x 30 mL), adding each organic extraction to the organic-containing Erlenmeyer flask.
4. Add the combined organic extractions to the separatory funnel and sequentially wash with saturated aqueous NaHCO₃ (25 mL), then saturated aqueous NaCl (25 mL). Drain each aqueous washing into the aqueous-containing Erlenmeyer flask, and drain the final organic layer into a dry 250 mL Erlenmeyer flask.
5. Dry the organic layer over MgSO₄ and vacuum filter into a 250 mL round bottom flask using a glass-fritted Buchner funnel. Rinse the solids on the frit with a small portion of additional Et₂O.
6. Concentrate the filtrate under reduced pressure using a rotary evaporator. Place the flask with remaining residue under high vacuum (ca. 75–200 mtorr) for at least 10 min. Analyze a sample of the crude residue by ¹H NMR using CDCl₃.
7. Purify the crude oil by automated flash chromatography using a silica gel (SiO₂) stationary phase with a dry-loaded sample and elute with ethyl acetate in hexanes.
   1. Dry-load the sample by dissolving the crude oil in a minimal amount of Et₂O, and then transfer this solution to a prepacked SiO₂ cartridge (25 g). Apply a reduced pressure to the bottom of the loading column for ca. 5 min to remove the excess solvent.
   2. Elute the sample using a prepacked SiO₂ column (100 g) with a gradient of ethyl acetate in hexanes (5% → 25%), collecting the column effluent in test tubes.
   3. Assay fraction purity using TLC analysis (conditions in Step 2.2). Combine and rinse all fractions containing the desired quaternary ketone into a tared round bottom flask.
8. Concentrate the solution under reduced pressure on a rotary evaporator and remove the final volatiles under high vacuum for at least 30 min. Obtain a final mass of the flask and analyze a sample of the purified product by ¹H NMR using CDCl₃.
   CAUTION: Hexanes and ethyl acetate are flammable. SiO₂ powder is a respiratory irritant.

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