- Direct Synthesis of Enamides via Electrophilic Activation of Amides
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A novel, one-step N-dehydrogenation of amides to enamides is reported. This reaction employs the unlikely combination of LiHMDS and triflic anhydride, which serves as both the electrophilic activator and the oxidant, and is characterized by its simple setup and broad substrate scope. The synthetic utility of the formed enamides was readily demonstrated in a range of downstream transformations.
- Berger, Martin,Kaiser, Daniel,Maulide, Nuno,Spie?, Philipp
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supporting information
p. 10524 - 10529
(2021/07/28)
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- Late-Stage β-C(sp3)-H Deuteration of Carboxylic Acids
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Carboxylic acids are highly abundant in bioactive molecules. In this study, we describe the late-stage β-C(sp3)-H deuteration of free carboxylic acids. On the basis of the finding that C-H activation with our catalysts is reversible, the de-deuteration process was first optimized. The resulting method uses ethylenediamine-based ligands and can be used to achieve the desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks and enables the functionalization of nonactivated methylene β-C(sp3)-H bonds for the first time.
- Mal, Sourjya,Uttry, Alexander,Van Gemmeren, Manuel
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supporting information
p. 10895 - 10901
(2021/08/03)
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- Palladium-Catalyzed Nondirected Late-Stage C-H Deuteration of Arenes
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We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labeling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, among other applications, will prove useful as a tool in drug development processes and for mechanistic studies.
- Farizyan, Mirxan,Mondal, Arup,Mal, Sourjya,Deufel, Fritz,Van Gemmeren, Manuel
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supporting information
p. 16370 - 16376
(2021/10/21)
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- Observation of 1,3-diketones formation in the reaction of bulky acyl chlorides with methyllithium
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The formation of 1,3-diketones was observed in the reactions of bulky acyl chlorides with methyllithium. The reaction products depend on the steric hindrance around the carbonyl group of the acyl chloride and the electronic effect of the group(s) linked to the carbonyl. When the steric hindrance around the carbonyl group of the acyl chloride is big enough, the 1,3-diketone is the only product. In the case of the moderate hindrance around the carbonyl group of the acyl chloride, a moderate yield of 1,3-diketone is obtained and some tertiary alcohol is generated. When there is no steric hindrance around the carbonyl group of the acyl chloride, the tertiary alcohol is the only product. When the steric hindrance around the carbonyl group is moderate and an electron-donating group is connected to the carbonyl of the acyl chloride, all three products-ketone, 1,3-diketone and tertiary alcohol-can be isolated from the reaction mixture after long reaction times.
- Zhang, Jian,Yang, Nianfa,Yang, Liwen
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body text
p. 6415 - 6423
(2012/09/08)
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- Dipole-Stabilized Carbanions: The α' Lithiation of Piperidides
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The α' lithiations and subsequent electrophilic substitutions of two series of piperidides are reported.In the cases of 2,4,6-triisopropylbenzopiperidide (5) and 4-tert-butyl-2,4,6-triisopropylbenzopiperidide (6) lithiations and electrophilic substitutions give α'-substituted products, as shown in Table I, which cannot be cleaved. 2,2-Diethylbutanopiperidide (19), 4-phenyl-2,2-diethylbutanopiperidide (20), and N,N-diethyl-2,2-diethylbutanamide (18) undergo α' lithiation and electrophilic substitution as shown in Table II to give products that can be cleaved to the substituted amines.This sequence thus provides the (α-lithioalkyl)alkylamine synthetic equivalent from secondary amines.The addition of the α'-lithiated piperidides from 20 to aldehydes is shown to provide equatorial substitution with erythro and threo isomers of the amido alcohol 31 produced in a 1:1 ratio.Exclusive conversion to an equatorial threo amino ester 36t is observed on treatment with strong acid.All four possible equatorial-axial and erythro-threo isomers of the amino alcohol 34 can be obtained by appropriate manipulations.The formation of the equatorially substituted products from 6 and 20 and of syn products from N,N-diethyl-2,4,6-triisopropylbenzamide (4) is noted to be consistent with oxygen-lithium complexation and dipole stabilization as important factors in α' lithiation.
- Beak, Peter,Zajdel, William J.
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p. 1010 - 1018
(2007/10/02)
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- Dipole-Stabilized Carbanions from Thioesters. Secondary α'-Lithio Carbamates and Tertiary α'-Lithio Thioesters
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The formation of 5 and 17, synthetic equivalents of the α-lithioalkylthio and α-lithiodialkylthio functions, respectively, by deprotonations of the corresponding carbamate 4 and thioester 16 are reported.The reactions of these formally dipole-stabilized carbanions with a variety of electrophiles and their use in synthese of 2,3-substituted thiiranes are demonstrated.The rearrangement of 17 to an α-thiol ketone is shown to be intramolecular by a double labeling experiment.Potentially chiral or conformationally isomeric α'-lithio thioesters are found to be racemized and equilibrated.Formations of secondary α'-lithio thioesters in medium chain, β'-dimethylamino, and allyl systems are reported while β'-alkoxy groups are shown to eliminate to give vinyl thio esters which undergo further metalation.The kinetic acidity of a methyl thioester is shown to be comparable to a propenyl thioester and greater then an ethyl thioester.
- Beak, Peter,Becker, Peter D.
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p. 3855 - 3861
(2007/10/02)
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- Dipole-Stabilized Carbanions from Esters: α-Oxo Lithiations of 2,6-Substituted Benzoates of Primary Alcohols
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The synthetic utility of dipole-stabilized carbanions from esters is illustrated by the preparations, α-oxo lithiations, electrophilic substitutions, and cleavages of the 2,4,6-triisopropylbenzoates and the 2,6-bis(dimethylamino)-3,5-diisopropylbenzoates of primary alcohols, 2 and 3, respectively.Typical electrophiles used in this methodology include primary alkyl halides, aldehydes, ketones, trimethylsilyl chloride, and tri-n-butyltin chloride.Cleavages of the substituted esters of 2 are accomplished with lithium aluminum hydride while hydrolyses of derivatives of3 can be achieved under acidic conditions.The 2,6-substitutions of 2 and 3 are considered to enforce orthogonality of the carbonyl group and the phenyl ring and thereby to inhibit addition to the carbonyl by the organolithium base used for the metalation by placing the substituents in the trajectory for nucleophilic addition along the LUMO of the carbonyl.The acidic hydrolysis of 3 under conditions where 2 is stable is attributed to protonation of the dimethylamino group which provides subsequent assistance for nucleophilic addition.These metalations provide the key steps in the preparation of secondary α-lithio alcohol synthetic equivalents from primary alcohols.Lithiation of 1'-methylbenzyl 2,4,6-triisopropylbenzoate proceeds α to oxygen as expected, but attempts to prepare analogous unactivated tertiary α-lithio esters were unsuccessful.The lithiation of 2'-methoxyethyl 2,4,6-triisopropylbenzoate is followed by elimination of methoxide and α-oxo metalation of the resulting vinyl ester.Lithiation of allyl 2,4,6-triisopropylbenzoate provides 1-(2,4,6-triisopropylphenyl)-1,2-butanedione by rearrangement.
- Beak, Peter,Carter, Linda G.
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p. 2363 - 2373
(2007/10/02)
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