Ketenes are useful synthetic building blocks due to their propensity to

undergocycloaddition reactions with several different partners

including alkenes2, aldehydes or ketones3, and imines4 to form a

cyclobutanones, β-lactones, and β-lactams.

Alkenones are very important organic synthesis intermediates due to their ease of undergoing [2 + 2] cycloaddition reactions. They can react with alkenes, aldehydes, and imines to yield cyclobutanones, β-lactones, and β-lactams. Nucleophiles readily add to the carbon of O=C=C, making these reactions very common. Recently, chiral nucleophilic catalysts or chiral auxiliaries have also been applied to achieve enantioselective cycloaddition and addition reactions. Additionally, there have been reports of transition metal-catalyzed C-C bond formation reactions using alkenones, such as Ni-catalyzed [2 + 2 + 2] cycloaddition of diynes with alkenones to form cyclohexadienones; Rh-catalyzed three-component reactions of silane acetylene with two alkenones to obtain 1,3-alkyne carboxylate esters.

There are many methods for synthesizing alkenones: dimerization cleavage of alkenones, pyrolysis of anhydrides, α-diazo ketones undergoingWolff rearrangement and reduction of α-halo acyl halides, etc. However, these methods generally require high temperatures, involve diazo compounds, have limited applications, or require multiple reactions. Due to the tendency of the synthesized alkenones to dimerize and the difficulty in separating by-products, methods for direct synthesis of alkenones via dehalogenation are more practical. This method can synthesize various aryl ortho-substituted, as well as various primary and secondary aryl-alkyl alkenones.

Reaction Examples

A. 4-Methyl-2-(p-tolyl)pentanoic acid (1).

An oven-dried 1-L, one-necked round-bottomed flask fitted with a 4 x 2 cm egg-shaped stir bar is cooled under a stream of nitrogen. p-Tolylacetic acid (Note 1) (17.06 g, 114 mmol, 1 equiv) is added and the flask is sealed with a rubber septum.Tetrahydrofuran (THF) (Note 2) (~700 mL) is added by cannula and the

flask is placed under a nitrogen atmosphere delivered through an 18-gauge

needle. The solution is cooled to 0 °C and stirred vigorously (Note 3). n-

Butyllithium (2.5 M in hexane, 100 mL, 250 mmol, 2.2 equiv) is added

dropwise by cannula (Note 4) (Figure 1). The reaction is maintained at 0 °C

for 90 min, at which point isobutyl bromide (16.0 mL, 148 mmol, 1.3 equiv)

(Note 5) is added via a 30 mL syringe over a period of 15 min, causing the

reaction to turn yellow. The reaction is allowed to warm to room

temperature slowly (Note 6) and stirred overnight (ca. 18 h). The

completion of the reaction is checked by TLC (Note 7). The reaction is

quenched by the addition of water (150 mL), which causes the reaction to

turn from a white-yellow suspension into a clear and biphasic system. The

volatile components are removed by rotary evaporation (35 ºC, 4 mmHg).

The solution is then acidified to pH 1 (Note 8) by addition of concentrated

HCl (~15 mL) over a period of 5 min. The aqueous layer is extracted with

diethyl ether (4 x 150 mL). The combined organic extracts are dried over

MgSO4, filtered, and concentrated by rotary evaporation (30 ºC, 4 mmHg).

The residue is placed under high vacuum with stirring (0.2 mmHg) over

12 h to yield the product as a white solid (23.0 g, >99%) (Notes 9 and 10).

B. 4-Methyl-2-(p-tolyl)pentanoyl chloride (2).

An oven-dried 50-mL round bottomed flask with a 14/20 ground glass joint is fitted with a 1.6 x 0.7 cm egg-shaped magnetic stir bar and Liebig condenser capped with a nitrogen inlet, and the flask is allowed to cool under nitrogen. The condenser is removed and the flask is charged with 1 (12.00 g, 58 mmol, 1 equiv) and thionyl chloride (6.3 mL, 87 mmol, 1.5 equiv) (Note 11). The condenser is replaced and the flask is placed in a pre-heated oil bath set at 90 °C for 1 h. The reaction turns brown and considerable gas evolution is observed

during the first 30 minutes of this period. The reaction is cooled to room

temperature, the condenser is removed, and K2CO3 (~4 g) (Note 12) is

added in a single portion. The mixture is stirred until gas evolution ceases

(~15 min), and placed on a rotary evaporator (40 ºC, 4 mmHg) for 1 h (Note

13). The flask is then fitted with a vacuum distillation head connected to a

multiflask receiving bulb (Figure 2) (Note 14). A single fraction (0.2 mmHg,

130 °C) of 2 (10.28 g, 79%) was obtained (Note 15) as a colorless liquid (Note

16).

C. 4-Methyl-2-(p-tolyl)pent-1-en-1-one (3).

All glassware is oven dried. A 300-mL schlenk tube with a 2.5 cm wide valve and 24/40 joint is fitted with a 3.2 x 1.6 cm egg-shaped stir bar and a rubber septum (Note 17). The flask is purged (0.4 mmHg) and backfilled with dry nitrogen through an 18 G needle three times as it is allowed to cool to room temperature. Compound 2 is then added via 20 mL syringe (10.8 g, 48 mmol, 1 equiv), followed by diethyl ether (150 mL) via 50 mL syringe. The solution is stirred (Note 18) and dimethylethylamine (20.7 mL, 192 mmol, 4 equiv) (Note 19) is added

via multiple uses of a 20 mL syringe, and the reaction begins to turn yellow

and a white precipitate begins to form in the yellow solution (Figure 3, left).

The valve on the schlenk flask is closed and the reaction is stirred for 72 h.

The reaction is then filtered as follows (Figure 3, right): a 1-necked (24/40)

500 mL round-bottomed flask with a sidearm with a ground-glass stopcock

(stopcock A) is placed under a stream of argon through tube A, and fitted

with a 100-mL schlenk filter with a sidearm with a ground-glass stopcock

(stopcock B) and 14/20 female ground glass joint. A tube is connected to the

schlenk line and to the filter’s sidearm at stopcock B. The septum is

removed from the reaction vessel and the vessel placed on top of the

filtration apparatus. Stopcock A is closed, and the filter apparatus is purged

by applying a vacuum (0.5 mmHg) via stopcock B and backfilling with

argon three times. With stopcock A closed, the tube attached to the lower

stopcock (tube A) is placed under vacuum. The reaction vessel’s valve is

then opened slowly. When ~3 cm of reaction mixture has collected above

the frit, vacuum is gently applied to the flask by quickly opening and

closing stopcock A. If the level of reaction mixture approaches stopcock B,

the schlenk flask’s valve is closed temporarily to prevent the reaction

mixture from entering tube B. When all of the liquids have entered the

collection flask, stopcock B is closed, and the solvent and excess amine are

removed under high vacuum. The collection flask is placed in a warm water

bath (~30 °C) to expedite the concentration, which takes ~30 minutes.

Stopcock A is closed, and the apparatus backfilled with argon through

stopcock B. The tube attached to stopcock A is backfilled with argon and

removed from the apparatus, a rubber septum is placed over the end of the

sidearm, and tube A is fitted with a luer-lock connector and a 1.5” 18 gauge

needle. A 50-mL round-bottomed flask with a 14/20 ground glass joint is

fitted with a rubber septum, which is pierced with the needle on tube A. A

cannula is placed between the 50-mL flask and the septum on sidearm A

(Figure 4). The flask, cannula, and end of the sidearm are purged

(0.6 mmHg) and backfilled with argon three times. Stopcock A is then

opened and the crude ketene is transferred to the round-bottomed flask.

The flask is backfilled with argon and the cannula removed. The septum is

removed from the 50-mL flask and the flask is immediately attached to a

vacuum distillation apparatus equipped with a multiflask collector (Figure

5) with tared receiving flasks. The distillation apparatus is then purged

(0.5 mmHg) and backfilled with argon three times. The ketene is then

distilled in one fraction (0.15 mmHg, 120 °C) (Note 20). Upon completion of

the distillation, the apparatus is refilled with argon. The receiving flask is

removed, and is quickly equipped with a septum. Compound 3 is obtained

as a yellow liquid (6.30 g, 70%) (Notes 20, 21, and 22).

This article is compiled from: Org. Synth. 2017, 94, 1-15

DOI: 10.15227/orgsyn.094.0001