NROChemistry

Kulinkovich Reaction

Lluis Llorens — Sun, 24 Aug 2025 09:37:58 +0000

The Kulinkovich reaction allows the preparation of cyclopropanol derivatives by the reaction of Grignard reagents with carboxylic esters in the presence of titanium(IV) isopropoxide.

Mechanism

Examples

Reaction mechanism of Kulinkovich reaction

Suggested reaction mechanism:

Dialkylation of the titanium catalyst with two equivalents of ethylmagnesium bromide.
β-hydride elimination gives ethane and titanacyclopropane.
This titanacyclopropane reacts with the carboxylic ester to produce a cyclopropanol derivative.
Addition of ethylmagnesium bromide to the titanium complex delivers the magnesium cyclopropoxide product while regenerating the diethyltitanium intermediate.
Aqueous/acidic workup yields the 1-cyclopropanol product.

For additional details on the chemistry of cyclopropanols, refer to Chem. Rev. 2003, 103, 2597.

Examples and experimental procedures of Kulinkovich reaction

Example 2: Angew. Chem. Int. Ed. 2022, 61, e202115633.

The methyl ester (9.98 mmol, 1.0 equiv) was combined with ClTi(OiPr)3 (0.46 M in THF, 4.8 equiv) under argon. The solution was cooled to 0 ºC, and then EtMgBr (1.0 M in THF, 9.6 equiv) was added dropwise over a 1.5 h period. The solution was left to stir at 0 ºC for another 1 h, and then to room temperature for 30 min. The reaction was quenched by the addition of EtOAc followed by saturated aqueous NH4Cl. The solution was filtered through a Celite pad, followed by EtOAc, and the filtrate was concentrated under reduced pressure and diluted with EtOAc and brine. The organic phase was collected, and the aqueous phase was washed with additional EtOAc. The combined organic phases were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to afford the desired cyclopropanol (86% yield).

Example 1: Angew. Chem. Int. Ed. 2018, 57, 15209.

To a solution of the lactone (4.6 mmol, 1.0 equiv) in THF (16 mL), a solution of ClTi(OiPr)3 (1.0 M in THF, 2.4 equiv) was added at room temperature. The reaction mixture was cooled to 0 ºC, and a solution of EtMgBr (1.0 M in THF, 4.8 equiv) was added dropwise from a syringe over 10 min. After gas evolution ceased, the reaction mixture was warmed to room temperature. The flask was then tightly sealed with a plastic cap and stirred vigorously at room temperature for 36 h. The reaction mixture was diluted with EtOAc and quenched with sat. aq. NH4Cl. Triethylamine was added, and the reaction mixture was stirred for 30 min. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to yield a crude residue, which was purified by flash column chromatography to afford the cyclopropanol product.

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Wolff-Kishner Reduction

Lluis Llorens — Sat, 28 Jun 2025 11:56:04 +0000

The Wolff-Kishner reduction allows the deoxygenation of aldehydes and ketones to hydrocarbons via the corresponding hydrazones under basic conditions and heat.

The reaction is commonly employed to remove a carbonyl group after it has served its synthetic purpose in preceding steps.
The reaction is usually carried out in high boiling solvents (e.g., DGME).
Sterically hindered carbonyl compounds are deoxygenated more slowly.
Since the reaction requires highly basic conditions, it is unsuitable for base-sensitive substrates.

Reaction mechanism of Wolff-Kishner reduction

A suggested mechanism involves the formation of a hydrazone anion by deprotonation of the terminal nitrogen by the base. The rate-determining step is the proton capture at the carbon terminal.

For more details on the reaction mechanism, see: Angew. Chem. Int. Ed. Engl. 1968, 7, 120.

Examples and experimental procedures of Wolff-Kishner reduction

Example 3: Org. Lett. 2023, 25, 4530.

To a solution of KOH (10.6 equiv) and NH2NH2·H2O (5.0 equiv) in ethylene glycol (26 mL), isovanillin (13.1 mmol, 1.0 equiv) was added at room temperature. After the reaction mixture was stirred at 130 ºC for 1 h, the temperature was increased to 190 ºC, and the reaction mixture was stirred at the same temperature for an additional 5 h. After the reaction mixture was cooled to room temperature, the resulting mixture was poured into a mixture of ice and aqueous HCl. The organic materials were extracted with Et2O, dried over anhydrous Na2SO4, and concentrated in vacuo after filtration to give the deoxygenated product, which may be used without further purification.

Example 2: J. Am. Chem. Soc. 2023, 145, 21170.

Example 1: Angew. Chem. Int. Ed. 2021, 60, 14967.

To a stirred solution of the aldehyde (1.1 mmol, 1.0 equiv) and hydrazine monohydrate (20.0 equiv) in diethylene glycol monomethyl ether (DGME, 22 mL), KOH (6.0 equiv) was added at room temperature. The resulting mixture was heated at 110 ºC for 1 h, at 194 ºC for 4 h, and was then cooled to room temperature. The mixture was quenched by the addition of 1.0 M aq. HCl, and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The resulting residue was purified by flash column chromatography to afford the deoxygenated product.

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Swern Oxidation

Lluis Llorens — Sat, 28 Jun 2025 11:48:14 +0000

The Swern oxidation allows the preparation of aldehydes and ketones from primary and secondary alcohols. DMSO reacts vigorously with oxalyl chloride when no solvent is present; it can lead to an explosion.

The most common solvent for this transformation is DCM.
The oxidation is usually conducted at -78 ºC to stabilize the intermediates of the reaction.
Typical procedure: Reaction of DMSO with oxalyl chloride at low temperature followed by the slow addition of the alcohol. Then, the tertiary amine is added to facilitate the decomposition of the alkoxysulfonium salt leading to the desired product.
Similar oxidation reactions include the Corey-Kim oxidation and the Parikh-Doering oxidation.

Reaction mechanism of Swern oxidation

1. Activation of DMSO with oxalyl chloride.

2. Formation of the chlorosulfonium salt.

3. Activation of the alcohol and formation of an alkoxysulfonium salt.

4. Deprotonation and formation of an alkoxysulfonium ylide.

For mechanistic insights into the Swern oxidation and further applications of oxalyl chloride in organic synthesis, see: ChemistrySelect 2019, 4, 6309.

Examples and experimental procedures of Swern oxidation

Example 2: J. Am. Chem. Soc. 2024, 146, 8456.

To a cold (-78 ºC), stirred solution of (COCl)2 (1.2 equiv) in DCM (40 mL) was added DMSO (2.4 equiv) dropwise over 5 min. (caution! CO/CO2 (g) liberated), and the reaction mixture was stirred for 10 min at -78 ºC. After this time, a solution of the alcohol (8.39 mmol, 1.0 equiv) in DCM (10 mL + 2×5 mL rinse) was slowly added via syringe over 10 min, and the reaction mixture was maintained at -78 ºC for a further 20 min. After this time, Et3N (5.0 equiv) was added via syringe, and the reaction mixture was maintained at -78 ºC for a further 10 min. The reaction mixture was then warmed to room temperature and stirred for a further 1 h 30 min. After this time, water was added and aqueous HCl (1 M) was added until the aqueous layer had a pH of ~4 as determined by pH paper. The resulting biphasic mixture was poured into a separatory funnel and the organic layer was separated and washed with H2O and brine. The combined aqueous layers were extracted with Et2O. The combined Et2O and DCM extracts were dried over MgSO4, filtered, and the solvent was removed in vacuo. This process afforded the crude aldehyde, which was immediately used in the subsequent step without further purification.

Example 1: Angew. Chem. Int. Ed. 2020, 59, 13990.

To a solution of oxalyl chloride (1.5 equiv) in DCM (36 mL) was added a solution of dimethylsulfoxide (2.7 equiv) in DCM (15 mL) at -78 ºC over 5 min. After 5 min, a solution of the secondary alcohol (24.0 mmol, 1.0 equiv) in DCM (24 mL) was added dropwise over 5 min. After 30 min at -78 ºC, triethylamine (7.0 equiv) was added dropwise over 10 min. The mixture was allowed to warm-up to room temperature, and water was added. The product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. Purification by flash column chromatography afforded the ketone.

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Reimer-Tiemann Reaction

Lluis Llorens — Sat, 28 Jun 2025 11:38:38 +0000

The Reimer-Tiemann reaction facilitates the formylation of phenols using chloroform and a strong base, typically an aqueous hydroxide solution.

The reaction proceeds via electrophilic aromatic substitution with the formed dichlorocarbene. While the regioselectivity is not high, ortho-formyl products are the predominant outcome. Under the original Reimer-Tiemann conditions, pyrroles undergo ring-expansion to produce 3-chloropyridines, a process known as the Ciamician-Dennstedt rearrangement.

The reaction is an electrophilic aromatic substitution that occurs under basic conditions in a protic solvent.
The substrate is dissolved in 10–40% alkali hydroxide, excess chloroform is added, and the biphasic solution is vigorously stirred at elevated temperatures.
When the reaction is conducted in the presence of cyclodextrins, or if the ortho-position is already substituted, the p-formyl product is formed predominantly.
For further details on the Reimer-Tiemann reaction, see: (i) Chem. Rev. 1960, 60, 169. (ii) Wynberg, H. and Meijer, E.W. (2005). The Reimer–Tiemann Reaction. In Organic Reactions, (Ed.). (iii) Org. Biomol. Chem. 2011, 9, 5109. (iv) Synth. Commun. 2011, 41, 3678.

Reaction mechanism of Reimer-Tiemann reaction

1. Chloroform is deprotonated by the base to generate the chloroform carbanion.

2. Alpha-elimination gives dichlorocarbene.

3. Nucleophilic attack by the phenoxide ion leads to a series of intermediates that provide the desired product upon basic hydrolysis.

The 1,2-proton shift appears unlikely according to Hückel and orbital-symmetry calculations. Tritium isotope experiments showed complete transfer of the isotope from tritium oxide to the formyl group. Proton exchange between water and the aldehydic proton is absent under the reaction conditions. Thus, these experiments favor a mechanism involving the formation of a neutral intermediate. For additional details, see J. Org. Chem. 1971, 36, 202.

Examples and experimental procedures of Reimer-Tiemann reactions

Example 1: Org. Lett. 2007, 9, 1367.

A solution of the phenol (30.9 mmol, 1.0 equiv) and sodium hydroxide (8.0 equiv) in ethanol/H2O (100 mL, 2:1) was heated to 70 ºC, chloroform (2.0 equiv) was added over 1 h. The resulting mixture was stirred for 3 h, cooled to room temperature, and evaporated to remove ethanol. The remaining aqueous solution was adjusted to pH 4~5 and extracted with EtOAc. Standard workup and purification procedures gave the desired aldehyde.

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Corey-Bakshi-Shibata Reduction

Lluis Llorens — Sun, 18 May 2025 05:20:22 +0000

The Corey-Bakshi-Shibata (CBS) reduction allows the enantioselective reduction of ketones using oxazaborolidine catalysts; it is also known as the Corey-Itsuno reduction.

Mechanism

Examples

When the oxazaborolidine has a rigid bicyclic structure, high enantiomeric excess can be achieved.
The CBS catalyst presents good air and moisture stability. However, the presence of water in the reaction mixture has been shown to have a significant effect on enantiomeric excesses. Hence, the reduction must be conducted under anhydrous conditions.
This reaction is an effective and powerful method to reduce a wide range of ketones in a stereoselective and chemoselective manner.
The driving force for the face-selective hydride transfer arises from two main factors: (i) activation of the borane reagent through coordination to the Lewis basic nitrogen, and (ii) enhancement of the Lewis acidity of the boron atom in the catalyst, which facilitates coordination to the ketone.
Reductants range from relatively Lewis acidic BH3·THF and BH3·SMe2 complexes to catecholborane to complexes between amines and boranes.

Reaction mechanism of Corey-Bakshi-Shibata reduction

1. Coordination of BH3 (Lewis acid) to the tertiary nitrogen atom (Lewis base) of the CBS catalyst to enhance the Lewis acidity of the boron atom in the catalyst and to activate the BH3 to become a strong hydride donor.
2. The CBS catalyst-borane complex then binds to the ketone at the sterically more accessible lone pair, the lone pair closer to the smaller substituent.
3. Hydride transfer via a six-membered transition state delivers the alkoxyborane and regenerates the catalyst.
4. Final acidic workup yields the desired chiral alcohol.

The reaction involves the Lewis base activation of the reductant and the Lewis acid activation of the electrophilic substrate.
An interesting aspect of the activation of the electrophilic substrate is the enhanced Lewis acid character of the endocyclic boron. This feature is partially responsible for the enhanced rate of the catalytic CBS reduction over the background hydroboration reaction.
The active reductant is the complex between the Lewis basic pyrrolidine nitrogen atom of the CBS catalyst and the stoichiometric borane reductant.

For more details on the reaction mechanism of the CBS reduction, see Angew. Chem. Int. Ed. 2021, 133, 4873 (open access) and Lewis Base Catalysis in Organic Synthesis (2016): 387-456.

A simple four-center dissociation of the borinate ester of the resulting alkoxide or borane-mediated regeneration of the active catalyst–reductant complex are two possibilities when considering BH3 as the stoichiometric reductant.

A third possibility is that the Lewis basic nitrogen atom can complex with the borinate ester of the product to effect a second reduction.

It is possible that all three of these routes occur to different extents, depending on the Lewis basicity of the oxygen residing on the carbonyl substrate and the Lewis acidity of the stoichiometric reductant.

Examples and experimental procedures of Corey-Bakshi-Shibata reduction

Example 2: J. Am. Chem. Soc. 2022, 144, 5253.

To a stirred solution of (S)-Me-CBS-oxazaborolidine (2.01 equiv) in THF (14 mL), BH3·THF (1.0 M in THF, 1.5 equiv) was added dropwise at 0 ºC. After 15 min of stirring at the same temperature, a solution of the substrate (5.28 mmol, 1.0 equiv; azeotropically dried with toluene) in THF (29 mL) was added dropwise at -78 ºC, and the resulting mixture was stirred for 1 h at the same temperature. BH3·THF (1.0 M in THF, 1.5 equiv) was then added dropwise over 1 h at -78 ºC. The mixture was gradually warmed to -40 ºC over 30 min, and stirring was continued for 30 min at the same temperature. The mixture was quenched with sat. aq. NH4Cl and diluted with CHCl3. The resulting mixture was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography to afford the secondary alcohol.

Example 1: Angew. Chem. Int. Ed. 2020, 59, 16475.

A solution of the cyclopentenone (56 mmol, 1.0 equiv) in anhydrous toluene (110 mL) was cooled to -78 ºC. (R)-2-methyl-CBS- oxazaborolidine (1.0 M in toluene, 0.2 equiv) was added, and the reaction mixture was stirred for 5 min at -78 ºC. Then, a solution of catecholborane (1.0 M in THF, 1.8 equiv) was added slowly, and the reaction mixture was stirred for 24 h at -78 ºC before it was quenched with sat. aq. NaHCO3. The resulting mixture was extracted with Et2O, and the combined organic extracts were sequentially washed with 2.0 M NaOH and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford the alcohol.

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Cope Rearrangement

Lluis Llorens — Sat, 17 May 2025 08:01:03 +0000

The Cope rearrangement is the thermal isomerization of a 1,5-diene. It is a pericyclic reaction that belongs to the group of [3,3]-sigmatropic rearrangements. The oxy-Cope variant involves a hydroxyl substituent on an sp3-hybridized carbon of the substrate.

Mechanism

Examples

The Cope rearrangement is reversible since it does not involve any changes in the number or types of bonds. The equilibrium position depends on the relative stability of the starting material and the product. If the product is stabilized through conjugation or features a more highly substituted double bond, the equilibrium will favor product formation.
The reaction is stereospecific and stereoselective and proceeds concertedly via a cyclic chair-like transition state (TS).

Reaction mechanism of Cope rearrangement

The Cope rearrangement proceeds via a chair-like transition state where there is minimal steric interaction between the substituents.

Experimental investigations of the Cope rearrangement of 1,5-hexadiene rule out the dissociative mechanism.

Other possible pathways include a Woodward-Hoffmann allowed concerted σ bond shift occurring in a chair-like TS; or a two-stage process involving a stable 1,4-diyl intermediate.

The conversions of the meso-3,4-dimethyl-1,5-hexadiene and rac-3,4-dimethyl-1,5-hexadiene stereoisomers showed nearly perfect stereospecificity, indicating a chair-like TS.

For more details on the reaction mechanism of the Cope rearrangement, see J. Mol. Struct. THEOCHEM 2001, 573, 81 and Wiley Interdiscip. Rev. Comput. Mol. Sci. 2011, 1, 172.

Examples and experimental procedures of Cope rearrangement

Example 1: J. Am. Chem. Soc. 2019, 141, 3440.

To a solution of the 1,5-dien-3-ol (84.2 mmol, 1.0 equiv) in THF (500 mL), 18-C-6 (1.2 equiv) was added. The round-bottom flask was immersed in an ice bath, and KH (1.2 equiv) was added in one portion. The reaction mixture was stirred for 2 h at the same temperature before it was slowly quenched with MeOH at -78 ºC. The solution was concentrated under vacuum, and the obtained residue was purified by flash column chromatography to afford the unsaturated carbonyl compound as an inseparable mixture of diastereomers.

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Cope Elimination

Lluis Llorens — Sun, 11 May 2025 07:03:39 +0000

The Cope elimination reaction involves the stereoselective syn elimination of tertiary amine oxides, which are typically prepared by the oxidation of tertiary amines with a peroxide.

Mechanism

Examples

The Cope elimination promotes the intramolecular elimination of an alkyl N-oxide to yield an alkene and a hydroxylamine.
Amine oxides are easily prepared by the oxidation of the tertiary amine with a peroxide. Common peroxides include hydrogen peroxide and peroxycarboxylic acids such as m-CPBA.
The Cope elimination is a one-pot reaction. Isolation of the tertiary amine oxide is not required. The amine is mixed with the oxidizing agent and heated.
Typically, a tertiary amine is oxidized to yield a zwitterionic N-oxide, which can then abstract a β proton upon heating at 120–150 °C with solvents typically employed for high-temperature reactions, such as DMF and DMSO.
The reaction is extraordinarily sensitive to solvent effects; million-fold rate increases can be obtained in going from protic to aprotic solvents. Even among aprotic solvents increasing polarity significantly reduces the reaction rate.
N-oxides can undergo spontaneous Cope elimination at room temperature in polar aprotic solvents (see example 1).

Reaction mechanism of Cope elimination

The Cope elimination reaction is concerted and proceeds via a planar five-membered transition state involving the syn hydrogen.

The mechanism features a syn periplanar elimination.

The Cope elimination involves the thermal decomposition of an amine oxide by a five-membered cyclic transition state. J. Org. Chem. 1973, 38, 1742.

For more details, see J. Am. Chem. Soc. 2006, 128, 6141.

Examples and experimental procedures of Cope elimination

Example 1: Angew. Chem. Int. Ed. 2018, 57, 1991.

To a round-bottom flask equipped with a magnetic stir bar, the racemic amine (0.32 mmol, 1.0 equiv) and DCM (3.10 mL) were added. The solution was cooled in a dry ice/acetone bath and stirred at this temperature for 10 min before the addition of m-CPBA (1.0 equiv) as a solution in DCM. The m-CPBA solution was added dropwise to maintain a consistent temperature. Upon completion of the addition, basic alumina, Al2O3, (0.66 g per mmol), was added to the solution and stirred 20 seconds at this temperature before the solution quickly passed through a plug of basic alumina. Concentration and purification of the filtrate via flash column chromatography afforded the racemic alkene.

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Claisen Rearrangement

Lluis Llorens — Sat, 10 May 2025 09:30:46 +0000

The Claisen rearrangement is a pericyclic reaction involving a concerted mechanism with a cyclic transition state. Specifically, it belongs to the group of sigmatropic reactions, where one σ-bond is exchanged for another. In the Claisen rearrangement, a [3,3]-sigmatropic shift occurs, transforming an allyl vinyl ether into an γ,δ-unsaturated carbonyl compound.

Mechanism

Examples

The Claisen rearrangement was originally applied to rearrangements of allyl aryl ethers to afford ortho– and occasionally para-substituted phenols. Afterward it expanded to analogue rearrangements of allyl vinyl ethers into unsaturated carbonyl compounds, which were classified as [3,3]-sigmatropic rearrangements.
The Claisen rearrangement, as in any other [3,3]-sigmatropic rearrangement, takes place under thermodynamic control. This reaction is irreversible toward the formation of the carbonyl compounds due to their higher thermodynamic stability. In some cases, structural features leading to the relief in torsional strain shift the equilibrium toward the retro-Claisen isomer, favoring the transformation of the carbonyl compound into the vinyl ether.
This transformation can be chemo-, regio-, diastereo-, and enantioselective; the reaction can be performed under mild conditions, and affords potentially useful polyfunctionalized molecules.
The most frequently reported Claisen rearrangement is a process that requires high temperatures (see example #1) and proceeds quite slowly at atmospheric pressure.

Reaction mechanism of Claisen rearrangement

The reaction mechanism involves a concerted rearrangement through a chair-like transition state. However, there is no general agreement about the structure of this transition state. Different transition states (synchronic, fragmented, or 1,4-diyl) have been proposed.

For more details, refer to Chem. Rev. 2004, 104, 2939.

In the Claisen rearrangement of an allyl aryl ether, the first [3,3] step affords an ortho dienone which usually enolizes into an o-allylphenol. It is the reaction known as the ortho-Claisen rearrangement.

When the rearrangement takes place on an ortho position bearing a substituent, a second [3,3] rearrangement (Cope rearrangement) takes place followed by enolization.

This reaction, usually called the para Claisen rearrangement, leads to the corresponding p-allylphenol.

The product resulting from the ortho Claisen rearrangement is usually obtained from the reaction, although the para process can compete even when both ortho positions are not occupied.

If the substrate is a chiral molecule due to the presence of a substituent (e.g., iPr) of the allyl vinyl ether, particularly in the case of acyclic molecules, this chirality can be transferred to the 1 and/or 6 positions through a cyclic transition state.

Examples and experimental procedures of Claisen rearrangement

Example 1: J. Am. Chem. Soc. 2021, 143, 4379.

A solution of the allyl vinyl ether (30.5 mmol, 1.0 equiv) in DMF (250 mL) was heated at 140–150 ºC for 18 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with Et2O, and washed with sat. aq. NaHCO3 and water. The combined aqueous layers were further extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography to afford the unsaturated carbonyl product, which was obtained as a single diastereomer.

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Chugaev Elimination

Lluis Llorens — Sun, 20 Apr 2025 13:24:56 +0000

The Chugaev elimination involves the formation of olefins by pyrolysis of the corresponding xanthates derived from β-hydrogen-containing alcohols via syn elimination.

Mechanism

Examples

The Chugaev elimination reaction is analogous to the thermal decomposition of carboxylic esters of alcohols, and of other related derivatives of alcohols, such as carbamates and carbonates. Xanthates typically undergo elimination from 120 to 200 °C, while esters typically require 400 to 500 °C.
The thermolysis of xanthates is a cis-concerted elimination that occurs via a mechanism in two steps, the first one being the rate-limiting step.
The reaction proceeds without the rearrangement of the carbon skeletons under relatively mild conditions.
The clean formation of the alkene (in example 3) is in line with the well-accepted syn-elimination mechanism of the Chugaev elimination, as generation of a cationic intermediate would generate undesired rearrangements.
The Chugaev elimination mainly focuses on secondary xanthates. For more stable primary xanthates, much higher temperatures (>200 °C) are required, and the yields are unsatisfactory. For more details, see Org. Biomol. Chem. 2018, 16, 1659.

Reaction mechanism of Chugaev elimination

The suggested mechanism of the Chugaev elimination involves a two-step process, with an initial rate-determining step via a six-membered cyclic transition state in which the thiocarbonyl sulfur and the ether oxygen participate, followed by a rapid decomposition of the intermediate.

The initial products are the alkene and an unstable dithiocarbonate derivative which subsequently decomposes to carbonyl sulfide and a thiol.

For more details, refer to J. Phys. Org. Chem. 2008, 21, 797.

Examples and experimental procedures of Chugaev elimination

Example 3: J. Am. Chem. Soc. 2023, 145, 24408.

A solution of KHMDS (1.0 M in THF, 1.5 equiv) was added to a solution of the alcohol (0.47 mmol, 1.0 equiv) in THF (18.5 mL) at -78 ºC. The mixture was stirred for 15 minutes at this temperature before a solution of O-phenyl chlorothionoformate (3.0 equiv) in THF (0.5 mL) was added quickly. The mixture was stirred at -78 ºC for 15 min before being quenched by the addition of sat. aq. NaHCO3. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography.

A solution of the thiocarbonate O-ester (0.42 mmol, 1.0 equiv) in Ph2O (16 mL, freshly degassed under 3×10 min vacuum-argon cycles) was stirred at 220 ºC for 3 h. After cooling to room temperature, THF (32 mL) was added, the mixture was cooled to 0 ºC followed by the dropwise addition of TBAF (1.0 M in THF, 3.0 equiv). After 2 h at 0 ºC the reaction mixture was poured into sat. aq. NH4Cl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography to afford the alkene.

Example 2: J. Am. Chem. Soc. 2022, 144, 18823.

To a stirred solution of the alcohol (2.33 mmol, 1.0 equiv) in THF (30 mL) at 0 ºC was added sodium hydride (NaH, 60% dispersion in mineral oil, 25.0 equiv) over 10 minutes, the reaction mixture was stirred for 1 h at 0 ºC, carbon disulfide (CS2, 35.0 equiv) was added to the mixture. Then the reaction mixture was warmed to 25 ºC and stirred for 2 h. Then, iodomethane (MeI, 40.0 equiv) was added to the mixture, and the resultant mixture was stirred for 12 h at 25 ºC. The reaction mixture was then carefully poured into sat. aq. NH4Cl with crushed ice, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was passed through a short silica gel column. The eluate was concentrated to give the xanthate, which was used without further purification. The xanthate was dissolved in chlorobenzene (PhCl, 30 mL), the stirred solution was heated at 148 ºC to reflux for 5 h. Then the mixture was cooled down to 25 ºC, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography to give the alkene.

Example 1: J. Am. Chem. Soc. 2020, 142, 4592.

To a stirred solution of the alcohol (50 μmol, 1.0 equiv) and CS2 (4.0 equiv) in THF (5 mL) at 0 ºC, NaH (60% dispersion in mineral oil, 4.0 equiv) was added. The resulting mixture was stirred at room temperature for 5 h before MeI (4.0 equiv) was added. The reaction mixture was stirred for an additional 10 min before it was quenched with NH4Cl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford the crude product.

A stirred solution of the xanthate (crude product obtained above) in o-DCB (5 mL) was warmed to 150 oC and stirred for 20 h before it was cooled to room temperature. Then, MeOH (5 mL) and p-TsOH·H2O (2.0 equiv) were added. The resulting mixture was warmed to 30 ºC and stirred for 36 h before it was diluted with EtOAc and quenched with NaHCO3. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. Flash column chromatography afforded the desired alkene.

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Chan-Lam Coupling

Lluis Llorens — Fri, 11 Apr 2025 07:10:09 +0000

The Chan-Lam coupling is the cross-coupling reaction between an aryl boronic acid and an amine or alcohol to generate the corresponding secondary aryl amine or ether.

Mechanism

Examples

In contrast to other cross-coupling reactions, the Chan-Lam reaction is unique in that it couples two nucleophiles: an aryl organoboron compound and an amine (see example 2) or alcohol (see example 1 and example 3).
Typical substrates: phenols, amines, anilines, amides, imides, ureas, carbamates, sulfonamides, sulfoximes, and NH-heterocycles (see example 4).
Cu source: Cu(OAc)₂, Cu(OTf)₂, Cu(OPiv)₂, Cu(acac)₂, Cu(TFA)₂, CuBr₂, CuCl₂, CuSO₄, CuFAP, [Cu(DMAP)₄I]I, [Cu(OH)·TMEDA]₂Cl_2, Cu(MeCN)₄PF₆, CuCl, Cu₂O, Cu₂S.
Oxidant: O₂(air), O₂, pyridine N-oxide, TEMPO, (t-BuO)₂.
Base: Et₃N, (i-Pr)₂NEt, pyridine, 4-methylpyridine, 2,6-lutidine, K₂CO₃, K₃PO₄, KOt-Bu, N-methylpiperidine, n-Bu₄NOH, NaOSiMe₃, none.
Solvents used: CH₂Cl₂, MeCN, EtOAc, MeOH, EtOH, 1,4-dioxane, NMP, THF, DMF, PhMe, DMSO, H₂O, t-BuOH.
Temperature range: rt to 100 °C.
For synthetic applications of the Chan-Lam coupling, see: Mol Divers 2019, 23, 215 and Adv. Synth. Catal. 2020, 362, 3311.

The utility of the Chan-Lam amination is often hampered by significant problems with by-product formation. Some by-products include the oxidation product, the protodeboronation product, or the homocoupling of the organoboron component.

The Chan-Lam coupling can be viewed as a combination of the Suzuki coupling, which involves the aryl boronic component, and the Buchwald-Hartwig reaction, which involves the amine component. Unlike these reactions, which are catalyzed by palladium, the Chan-Lam coupling typically uses a catalytic or stoichiometric amount of copper, and the reaction can be conducted in air and at room temperature. It also bears resemblance to the Ullmann-type reaction, a copper-catalyzed nucleophilic aromatic substitution between nucleophiles such as amines and aryl halides. However, Ullmann-type couplings often require harsh conditions, such as high temperatures or strong bases.

Reaction mechanism of Chan-Lam coupling

A suggested general mechanism of the Chan-Lam coupling is presented:

1. Transmetalation of the organoboron compound, here a boronic acid, delivers a Cu(II) complex.
2. Disproportionation using a second Cu(II) delivers the key Cu(III) complex.
3. Reductive elimination forges the C–N bond, liberating the product and a Cu(I) species.
4. Oxidative turnover of Cu(I) to Cu(II) using a terminal oxidant, most commonly O2, completes the catalytic cycle.

For mechanistic aspects of the Chan-Lam coupling, see: Tetrahedron 2012, 68, 7735, J. Am. Chem. Soc. 2017, 139, 4769, and Chem. Rev. 2019, 119, 12491.

Examples and experimental procedures of Chan-Lam coupling

Example 4: Chem. Eur. J. 2020, 26, 7678.

A mixture of the aryl boronic ester (0.955 mmol, 1.0 equiv), 3-isopropyl-1H-pyrazole (2.5 quiv), B(OH)3 (2.0 equiv), Cu(OAc)2 (1.0 equiv) and 3 Å molecular sieves (300 mg) in acetonitrile (3 mL) was stirred at 70 ºC for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through Celite and washed with sat. aq. NaHCO3. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The organics were combined and washed with sat. aq. NaHCO3, water, and brine. The organic phase was dried over MgSO4 and concentrated in vacuo, giving a crude product that was purified by flash column chromatography.

Example 3: Org. Lett. 2020, 22, 2022.

To a stirred solution of the boronic ester (10.9 mmol, 1.0 equiv) in DCM/MeOH (109 mL, 1:1) at room temperature, 4Å molecular sieves (activated, 6.0 g), Cu(OAc)2 (1.0 equiv), and DMAP (2.0 equiv) were added. The resulting mixture was stirred for 8 h before it was filtered through a pad of silica gel, eluted with EtOAc, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford the coupled product.

Example 2: New J. Chem. 2020, 44, 308.

A 25 mL dry two-necked round bottom flask equipped with a magnetic stirrer and a guard tube containing calcium chloride was charged with 2-aminopyridine (1.0 mmol, 1.0 equiv), p-tolylboronic acid (2.0 equiv), DIPEA (3.0 equiv) and Cu(OAc)2 (1.0 equiv) in anhydrous DMSO (3 mL) with molecular sieves (200 mg). The mixture was heated at 120 ºC for 24 h. An aqueous solution of ammonium hydroxide was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by flash column chromatography.

Example 1: J. Org. Chem. 2018, 83, 3417.

To a 5 mL scintillation vial equipped with a Teflon-coated magnetic stir bar were added the phenol (0.3 mmol, 1.0 equiv), cyclopropyl potassium trifluoroborate (3.0 equiv), Cu(OAc)2 (10 mol%), 1,10-phenanthroline (10 mol%), and K2CO3 (2.0 equiv). The vial was charged with toluene (0.5 mL) and water (0.15 mL) and sealed with a septum cap. (Caution! Because the reaction involves heating an organic solvent under O2, a blast shield should be used at all times, particularly in large-scale experiments. After the indicated reaction time, the reaction vessel should be allowed to cool to room temperature behind the blast shield prior to workup.) The septum was pierced with a 21G needle connected to an O2 balloon. The septum cap was partially unscrewed to purge the vial for 5 seconds and then resealed by tightening the cap. The reaction was stirred under O2 (balloon) at 70 ºC for 12 h, after which it was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then purified by flash column chromatography.

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