This post is about reactions involving the protection of amines in organic chemistry. The post is active and growing, so you can expect more examples to be added over time. Please be sure to come back. The updates will be announced on my instagram account.

Check out the post about protection of alcohols. >>>

Last update 23/03/01.

The benzyl group (Bn) features a benzene ring (C6H6) attached to a methylene group (−CH2−) group. It is removed by hydrogenolysis.

1. For the synthesis of Lascufloxacin.

Benzyl deprotection via hydrogenation.

J. Med. Chem. 2021, 64, 3604.

1. For the synthesis of Aristeromycin.

Boc protection and TFA-promoted amine deprotection.

Org. Lett. 2021, 23, 2863.

1. For the synthesis of A-94964.

Angew. Chem. Int. Ed. 2022, 61, e202200818.

1. For the synthesis of Upadacitinib.

Removal of the carboxybenzoyl group with 10% palladium hydroxide on carbon gave the free amine.

J. Med. Chem. 2021, 64, 3604.

1. For the synthesis of Remimazolam Tosylate. 

DCC-mediated amidation of methyl ester.

J. Med. Chem. 2021, 64, 3604.

1. For the synthesis of Deoxoapodine.

Angew. Chem. Int. Ed. 2022, 61, e202207360.

1. For the synthesis of Deoxoapodine.

Angew. Chem. Int. Ed. 2022, 61, e202207360.

This post is about reactions involving the protection of alcohols in organic chemistry. The post is active and growing, so you can expect more examples to be added over time. Please be sure to come back. The updates will be announced on my instagram account.

Check out the post about protection of amines. >>>

Last update 24/03/27.

The acetyl group (Ac), with the chemical formula −COCH3, contains a methyl group (−CH3) single-bonded to a carbonyl (C=O), making it an acyl group. It is removed by acid or base.

2. For the synthesis of Longiborneol.

Nature Chem. 2022, 14, 450.

1. For the synthesis of Clionastatin A.

J. Am. Chem. Soc. 2021, 143, 13016.

The benzoyl group (Bz), with the formula −COC6H5, is more stable than Ac group. It is also removed by acid or base.

1. For the synthesis of A-94964.

Angew. Chem. Int. Ed. 2022, 61, e202200818.

The benzyl group (Bn) features a benzene ring (C6H6) attached to a methylene group (−CH2−) group. It is removed by hydrogenolysis.

2. For the synthesis of Fusaequisin A.

(1) Monoprotection of the diol. (2) Reductive removal of the benzyl protecting group delivered the diol .

Chem. Eur. J. 2022, 28, e2021035. Open access.

1. For the synthesis of Thebainone A.

Benzyl deprotection via hydrogenation.

Angew. Chem. Int. Ed. 2021, 60, 13507.

Methyl ethers – Cleavage is by TMSI in dichloromethane or acetonitrile or chloroform. An alternative method to cleave methyl ethers is BBr3 in DCM.

4. For the synthesis of (–)-Preussochromone D.

The substrate was alkylated with in-situ-generated difluorocarbene to give the corresponding difluoroether in 95% yield. This rather unusual electron-withdrawing protecting group was chosen to prevent side reactions of electron-rich arenes in the upfollowing oxidative steps. Deprotection of the phenol ether with scandium triflate gave the phenol in 61% yield.

Org. Lett. 2019, 21, 4374.

3. For the synthesis of Cefiderocol.

J. Med. Chem. 2021, 64, 3604.

2. For the synthesis of Dysiherbol A.

Angew. Chem. Int. Ed. 2021, 60, 14915. Open access.

1. For the synthesis of Bauhinoxepin C.

Both of the hydroxyl groups were methylated with dimethyl sulfate in the presence of potassium carbonate to provide dimethoxybenzene.

The methoxy group at the C6 position of the phenol was selectively demethylated with BBr3.

J. Org. Chem. 2021, 86, 1955.

Methoxymethyl ether (MOM) – ROCH2OCH3 – Removed by acid.

2. For the synthesis of Clionastatin A.

J. Am. Chem. Soc. 2021, 143, 13016.

1. For the synthesis of Undulifoline.

Reaction of the readily available 4-(2-hydroxyethyl)cyclohexan-1-one with bromomethyl methyl ether under standard conditions afforded the MOM ether in 94% yield.

Angew. Chem. Int. Ed. 2021, 60, 12392.

p-Methoxybenzyl ether (PMB) – Removed by acid, hydrogenolysis, or oxidation – commonly with DDQ .

4. For the synthesis of Incargranine A.

Angew. Chem. Int. Ed. 2023, e202314308.

3. For the synthesis of Aberrarone.

J. Am. Chem. Soc. 2022, 144, 15475.

2. For the synthesis of Amycolamicin.

J. Am. Chem. Soc. 2022, 144, 5253.

1. For the synthesis of Adociaquinone A.

Chem. Sci. 2021, 12, 4747. Open access.

tert-Butyldiphenylsilyl, also known as TBDPS; Its formula is C16H19Si-. The increased stability towards acidic hydrolysis and nucleophilic species allows for the TBDPS groups in a substrate to be retained while other silyl ethers are removed. The TMS group may easily be removed in the presence of a TBDPS group by reaction with TsOH.

The group is even more resistant to acid hydrolysis than the bulky TIPS. However, in the presence of a fluoride source such as TBAF or TASF, TIPS groups are more stable than TBDPS groups.

It is possible to remove the TBDPS group selectively, leaving a TBDMS group intact, using NaH in HMPA at 0 °C for five minutes.

2. For the synthesis of Aristeromycin.

Org. Lett. 2021, 23, 2863.

1. For the synthesis of Aberrarone.

J. Am. Chem. Soc. 2022, 144, 15475.

tert-Butyldimethylsilyl, also known as TBS or TBDMS. These silyl ethers hydrolyze much more slowly than the trimethylsilyl ethers.

3. For the synthesis of 10-hydroxyacutuminine.

Angew. Chem. Int. Ed. 2022, 61, e202117480.

2. For the synthesis of Annotinolide C.

J. Am. Chem. Soc. 2021, 143, 11951. Open access.

1. For the synthesis of Codonopiloneolignanin A.

Org. Lett. 2021, 23, 5684.

Triethylsilyl ether.

1. For the synthesis of Norzoanthamine.

The primary hydroxyl group was protected as a triethylsilyl ether group (-OTES). The TES group was then selectively removed with pyridinium p-toluenesulfonate (PPTS).

Angew. Chem. Int. Ed. 2021, 60, 12807.

Triisopropylsilyl ether.

In acidic media, the relative resistance is the following: TMS < TES < TBS < TIPS < TBDPS

In basic media, the relative resistance is the following: TMS < TES < TBS~TBDPS < TIPS

1. For the synthesis of Annotinolide C.

J. Am. Chem. Soc. 2021, 143, 11951. Open access.

This post is about reactions involving the use of halogenated products in organic chemistry. The post is active and growing, so you can expect more examples to be added over time. Please be sure to come back. The updates will be announced on my instagram account.

Last update 23/06/08.

Chemical reactions involving the exchange of a halogen atom for an alkyl group.

2. For the synthesis of Elmonin.

Alkylation via Li-halogen exchange.

Org. Lett. 2022, 24, 9361.

1. For the synthesis of Ubrogepant.

Halogen-metal exchange followed by quenching of the arylmagnesium species with DMF and subsequent reduction to provide the alcohol.

J. Med. Chem. 2021, 64, 3604.

Reactions where the alpha position of a carbonyl group gains a halogen atom. 

4. For the synthesis of Asnovolin A.

An iodide handle was installed on the electron-rich vinylogous ester in high yield (84%) using CAN/I2 at 0 °C.

J. Am. Chem. Soc. 2022, 144, 12970.

3. For the synthesis of Phomarol.

The substrate was treated with iodine, TMSN3, and pyridine in dichloromethane to generate the iodide.

CCS Chem. 2021, 3, 348. Open access.

2. For the synthesis of Adociaquinone A.

Angew. Chem. Int. Ed. 2021, 60, 12392.

1. For the synthesis of Esaxerenone.

J. Med. Chem. 2021, 64, 3604.

Reactions involving the fluorine atom.

4. For the synthesis of Alpelisib.

Subjecting the picoline analog to Ruppert’s reagent (TMSCF3) in the presence of sodium acetate followed by hydrolytic silyl group removal provided the tertiary alcohol.

J. Med. Chem. 2021, 64, 3604.

3. For the synthesis of Ubrogepant.

Trifluoroethylation was effected under strongly basic conditions to obtain the desired monoalkylated product.

J. Med. Chem. 2021, 64, 3604.

2. For the synthesis of Lascufloxacin.

Treatment with perfluoro-1-octanesulfonyl fluoride, POSF, delivered the chiral fluoride with inversion of stereochemistry.

J. Med. Chem. 2021, 64, 3604.

1. For the synthesis of Bauhinoxepin C.

This compound was fluorinated with Selectfluor to give 4-fluoro-2-methylresorcinol.

J. Org. Chem. 2021, 86, 1955.

13. For the synthesis of Amphidinolide C2.

J. Org. Chem. 2022, 87, 1110.

12. For the synthesis of Relugolix.

Radical bromination conditions gave the benzyl bromide.

J. Med. Chem. 2021, 64, 3604.

11. For the synthesis of 10-hydroxyacutuminine.

Angew. Chem. Int. Ed. 2022, 61, e202117480.

10. For the synthesis of Erdafitinib.

Chlorination of 6-bromoquinozaline.

J. Med. Chem. 2021, 64, 3604.

9. For the synthesis of Darolutamide.

The pyrazole was lithiated at C-5 and quenched with bromine to yield bromopyrazole.

J. Med. Chem. 2021, 64, 3604.

8. For the synthesis of Siponimod.

Bromination with DBMH, an alternative to NBS.

J. Med. Chem. 2021, 64, 3604.

7. For the synthesis of Trifarotene.

J. Med. Chem. 2021, 64, 3604.

6. For the synthesis of Cefiderocol.

J. Med. Chem. 2021, 64, 3604.

5. For the synthesis of Spiroindimicin A.

Chem. Sci. 2021, 12, 10388. Open access.

4. For the synthesis of Russujaponol F.

Monoiodination using iodine and Selectfluor.

J. Am. Chem. Soc. 2021, 143, 687.

3. For the synthesis of Peniciketal A.

J. Am. Chem. Soc. 2021, 143, 1740.

2. For the synthesis of Lynamicin A.

Chem. Sci. 2021, 12, 13756. Open access.

1. For the synthesis of Codonopiloneolignanin A.

 Bromination of the benzene ring with NBS.

Org. Lett. 2021, 23, 5684.

6. For the synthesis of Bempedoic acid.

The substrate was reacted with 0.5 equivalents of toluenesulfonylmethyl isocyande under basic conditions to facilitate a double alkylation reaction of the iodide to obtain the isonitrile. The isonitrile was then subjected to acidic conditions in isopropyl acetate and pH adjustment to uncover the masked carbonyl group.

J. Med. Chem. 2022, 65, 9607.

5. For the synthesis of Remogliflozin Etabonate.

Chlorination of the benzyl alcohol moiety.

J. Med. Chem. 2021, 64, 3604.

4. For the synthesis of Ubrogepant.

Conversion to the iodide via a Finkelstein reaction.

J. Med. Chem. 2021, 64, 3604.

3. For the synthesis of Voxelotor.

Treatment with thionyl chloride in dichloromethane provided pyridinyl chloride.

J. Med. Chem. 2021, 64, 3604.

2. For the synthesis of Ambiguine G.

Appel Reaction.

J. Am. Chem. Soc. 2021, 143, 10872. Open access.

1. For the synthesis of Alpneumine H.

Appel Reaction. 

Chem. Sci. 2021, 12, 4747. Open access.

This post is about reduction reactions in organic chemistry. These are reactions that change the oxidation state of the atoms on the substrate. Thus, reduction occurs when the oxidation number of an atom becomes smaller. The scope of this post is limited to the reduction of the carbon atom. The post is active and growing, so you can expect more examples to be added over time. Please be sure to come back. The updates will be announced on my instagram account.

Last update 23/12/16.

Chemical reactions involving the removal of oxygen atoms from a molecule.

5. For the synthesis of Ambiguine G.

The hydroxyl group was removed under ionic hydrogenation conditions (BF3·OEt2 and Et3SiH), forming a single diastereomer.

J. Am. Chem. Soc. 2021, 143, 10872. Open access.

4. For the synthesis of Aberrarone.

Barton-McCombie reaction: The hydroxy-functional group in an organic compound is replaced by a hydrogen atom to give an alkyl group. The alcohol is first transformed into a thioxoester that is then exposed to n-Bu3SnH and AIBN in refluxing toluene.

J. Am. Chem. Soc. 2022, 144, 15475.

3. For the synthesis of Sotagliflozin.

Triethylsilyl hydride reduction of the ketone.

J. Med. Chem. 2021, 64, 3604.

2. For the synthesis of Pexidartinib.

The alcohol was reduced with triethylsilane. Subsequent treatment with TFA removed both Boc protecting groups to afford the aminopyridine.

J. Med. Chem. 2021, 64, 3604.

1. For the synthesis of Cephanolide A.

A Barton-McCombie deoxygenation reaction.

J. Am. Chem. Soc. 2021, 143, 2710.

Reactions where an alkyne or alkene is reduced to the corresponding alkene or alkane.

8. For the synthesis of Calyciphylline R.

The 1,1-disubstituted alkene in the substrate was diastereoselectively hydrogenated (dr = 5:1) under Li’s conditions.

 J. Am. Chem. Soc. 2022, 144, 16042.

7. For the synthesis of Longiborneol.

This is an interesting example of a vinyl sulfonate being used as a radical acceptor in metal-hydride hydrogen atom transfer, MHAT, chemistry.
Subjecting the substrate to optimized Fe-HAT conditions, which required buffering agents, smoothly effected cyclization in a remarkable 85% yield. Presumably, this reaction occurs by H-atom transfer from an iron hydride to the terminal position of the western alkene of the substrate, generating a tertiary radical that adds into the vinyl phenyl sulfonate, leading to a homolytic cleavage of the S–O bond to give the ketone.

Nature Chem. 2022, 14, 450.

6. For the synthesis of Asnovolin A.

Stereoselective metal hydride atom transfer, MHAT, reduction to install an axial methyl group under Baran’s conditions [Fe(acac)3, PhSiH3, EtOH]. In initial experiments, hydrogenation (H2, Pd/C) resulted in full recovery of starting material. Alternatively, MHAT hydrogenation of alkenes pioneered by Shenvi and co-workers has been widely applied in natural product synthesis to afford thermodynamically stable products. This is a rare example of production of the thermodynamically less stable axial methyl group through 1,6-MHAT, where an initially formed tertiary radical abstracts a spatially proximal hydrogen atom through an interesting chair-to-boat conformational change under Curtin−Hammett conditions.

J. Am. Chem. Soc. 2022, 144, 12970.

5. For the synthesis of Chimonanthine.

Hydrogenation using Zn and AcOH.

Chem. Commun. 2022, 58, 3929.

4. For the synthesis of Amphidinolide C2.

Hydrogenation using Lindlar’s catalyst. The Lindlar catalyst is a heterogeneous catalyst that is used for the selective hydrogenation of alkynes to alkenes, allowing the selective hydrogenation of triple bonds to cis-double bonds.

J. Org. Chem. 2022, 87, 1110.

3. For the synthesis of Drupacine.

Hydrogenation using Adam’s catalyst.

Angew. Chem. Int. Ed. 2021, 60, 12060.

2. For the synthesis of Cephanolide A.

Hydrogenation and susbsequent epimerization. An epimerization is a process in which there is a change in the configuration of only one chiral center. As a result, a diastereomer is formed. In this case, the methyl group resulting from hydrogenation epimerizes after being exposed to DBU. 

J. Am. Chem. Soc. 2021, 143, 2710.

1. For the synthesis of Adociaquinone A.

Birch reduction: the 1,4-reduction of aromatic rings to the corresponding unconjugated cyclohexadienes and heterocycles by alkali metals (Na, Li, K) dissolved in liquid ammonia in the presence of alcohol.

Angew. Chem. Int. Ed. 2021, 60, 12392.

10. For the synthesis of Incargranine A.

A chemoselective iridium-catalyzed reduction of an amide to produce a silylated hemiaminal (employing a modified Vaska’s complex (IrCl(CO)(PPh3)2) and 1,1,3,3-tetramethyldisiloxane (TMDS)). Upon acid treatment, the silylated hemiaminal undergoes elimination to generate the corresponding iminium ion, to which the pendant alcohol adds, yielding a cyclic hemiaminal. The desired reactivity is accomplished by directly treating the reaction mixture with dry hydrochloric acid in 1,4-dioxane. This single step achieves two critical objectives: deprotection of the tri-n-butylsilyl (TBS) group and initiation of a retro-oxa-Mannich/oxa-Michael/Mannich cascade, along with concurrent p-methoxybenzyl (PMB) deprotection.

Angew. Chem. Int. Ed. 2023, e202314308.

9. For the synthesis of Amphidinolide F.

The high syn selectivity could be explained by the bulkiness of the silane reagent in a Felkin−Ahn type model, with Ph3SiH being noticeably superior to Et3SiH.

J. Org. Chem. 2022, 87, 1110.

8. For the synthesis of Calyciphylline R.

Selective amide reduction conditions using Vaska’s complex (IrCl(CO)(PPh3)2). This is typical Darron Dixon chemistry in which Vaska‘s catalyst hydrosilylates the amide to the hemiaminal, which can be further functionalized. In this case, it is simply reduced with STAB to give the amine.

 J. Am. Chem. Soc. 2022, 144, 16042.

7. For the synthesis of Lascufloxacin.

Reduction of the amide to the corresponding amine with borane.

J. Med. Chem. 2021, 64, 3604.

6. For the synthesis of Drupacine.

Reduction of the lactam moiety.

Angew. Chem. Int. Ed. 2021, 60, 12060.

5. For the synthesis of Peniciketal A.

J. Am. Chem. Soc. 2021, 143, 1740.

4. For the synthesis of Bathymdiolamide A.

J. Org. Chem. 2021, 86, 1868.

3. For the synthesis of Clionastatin A.

Corey-Bakshi-Shibata reduction: the chemical reaction in which an achiral ketone is enantioselectively reduced to produce the corresponding chiral alcohol by the influence of the CBS oxazaborolidine catalyst. 

J. Am. Chem. Soc. 2021, 143, 13016.

2. For the synthesis of Peyssonnoside A.

Luche reduction. The luche reduction is the selective organic reduction of α,β-unsaturated ketones to allylic alcohols with sodium borohydride (NaBH4) and lanthanide chlorides, mainly cerium(III) chloride (CeCl3), in methanol or ethanol.

J. Am. Chem. Soc. 2021, 143, 14083. Open access.

1. For the synthesis of Altemicidin.

J. Am. Chem. Soc. 2021, 143, 7935.

4. For the synthesis of Quizartinib Dihydrochloride.

Reduction of the nitro group to generate aniline.

J. Med. Chem. 2021, 64, 3604.

3. For the synthesis of Mirogabalin besylate.

Reduction of the nitro group with Fe.

J. Med. Chem. 2021, 64, 3604.

2. For the synthesis of Spiroindimicin A.

Reduction of the nitro group with Zn.

Chem. Sci. 2021, 12, 10388. Open access.

1. For the synthesis of Bauhinoxepin C.

The nitro group and the double bond of the oxepine were both reduced with hydrogenation to provide the amine.

J. Org. Chem. 2021, 86, 1955.

2. For the synthesis of 10,22-Dioxokopsane.

Reduction of the nitrile to the corresponding amine and condensation with the ketone.

Angew. Chem. Int. Ed. 2022, 61, e202201712.

1. For the synthesis of Annotinolide C.

Reduction of the nitrile to the corresponding aldehyde.

J. Am. Chem. Soc. 2021, 143, 11951. Open access.

This post is about oxidation reactions in organic chemistry. These are reactions that change the oxidation state of the atoms on the substrate. Thus, oxidation occurs when the oxidation number of an atom becomes larger. The scope of this post is limited to the oxidation of the carbon atom. The post is active and growing, so you can expect more examples to be added over time. Please be sure to come back. The updates will be announced on my instagram account.

Last update 23/08/27.

In forming chemical bonds, atoms donate, acquire, or share electrons from their valence shell. Knowing their behavior, makes it possible to assign every atom an oxidation number. The oxidation number specifies the number of electrons of a given atom that can be involved in forming bonds with other atoms. From the particular atoms in a molecule and their known bonding capacities, the bonding pattern within a molecule is determined, and each atom is regarded as being in a specific oxidation state, expressed by an oxidation number.

Unlike metals, which are almost always in a positive oxidation state, the oxidation state of carbon can vary from -4 (in CH4) to +4 (in CO2 or CCl4). By definition, the oxidation state of an atom is the charge that atom would carry if the compound were purely ionic. Even though the charge on the carbon is not really +4 or –4, the oxidation state formalism helps us keep track of where the electrons are going. For example, in a C–H bond, the H is treated as if it has an oxidation state of +1. This means that every C–H bond will decrease the oxidation state of carbon by 1. In contrast, in a C–Cl bond, the Cl is treated as if it has an oxidation state of -1; every C–Cl bond will increase the oxidation state of carbon by 1. Therefore, if a primary alcohol, RCH2OH, is oxidized to the corresponding aldehyde, RCHO, the oxidation state of the C goes from (-2+1=-1) to (-1+2=+1).

As a rule of thumb, every bond between C and C does not affect the oxidation state. Every bond between C and H will decrease the oxidation state by 1. And every single bond between C and a more electronegative element (O, N, Cl) will increase its oxidation state by 1.

Oxidation reactions where the alpha position of a carbonyl compound gets hydroxylated.

The alpha hydroxylation of a ketone is a chemical reaction that involves the addition of a hydroxyl group to the carbon atom adjacent to a carbonyl group. This process is often used in organic synthesis to create a variety of useful compounds and to add functionality onto the molecule. The reaction typically involves the use of an oxidizing agent, such as hydrogen peroxide, to add the hydroxyl group to the ketone. The resulting product will vary depending on the specific conditions used.

3. For the synthesis of Ginkgolide C.

An α-hydroxylation with the Davis’ oxaziridine.

J. Am. Chem. Soc. 2022, 144, 17792.

2. For the synthesis of Euphorikanin A.

An α-hydroxylation with the Davis’ oxaziridine. The use of 2-(phenylsulfonyl)-3-phenyloxaziridine (Davis reagent) or similar oxaziridine reagents allows the oxidation of enolates generated in situ from ketones or esters to provide α-hydroxylated compounds.

J. Am. Chem. Soc. 2021, 143, 8261.

1. For the synthesis of Euonyminol.

Rubottom oxidation: alpha-hydroxylation of a ketone by the chemical reaction between silyl enol ethers and peroxyacids. 

J. Am. Chem. Soc. 2021, 143, 699.

Organic reactions where a ketone is oxidized to the corresponding alpha,beta-unsaturted ketone. In some cases, the enone is the end product from the oxidation of another substrate.

6. For the synthesis of Asnovolin A.

IBX was identified as an optimal oxidant to effect desaturation of the ketone to produce the enone with complete regiocontrol in good yield (72%). Addition of 4 Å molecular sieves and Na2HPO4 was crucial to prevent acetal hydrolysis.

J. Am. Chem. Soc. 2022, 144, 12970.

5. For the synthesis of Undulifoline.

Saegusa oxidation, a chemical reaction used in organic chemistry as a method to introduce α-β unsaturation in carbonyl compounds. The reaction involves formation of a silyl enol ether followed by treatment with palladium(II) acetate and benzoquinone (oxygen gas in this case) to yield the corresponding enone.

Angew. Chem. Int. Ed. 2021, 60, 12392

4. For the synthesis of Undulifoline.

The α,β-unsaturated ketone was synthesized by a one-pot procedure from the starting ketone in 80% yield on treatment of its lithium enolate salt with N-tert-butyl phenylsulfinimidoyl chloride under mild reaction conditions. Further references regarding this innovative procedure: Chem. Lett. 2000, 29, 1250.

Angew. Chem. Int. Ed. 2021, 60, 12392.

3. For the synthesis of Phomarol.

Formation of the silyl enol ether followed by oxidation with 2-iodoxybenzoic acid, IBX. 

CCS Chem. 2021, 3, 348. Open access.

2. For the synthesis of Norzoanthamine.

Babler-Dauben oxidation. Pyridinium chlorochromate (PCC) was first used as the oxidant, but it led to the decomposition of the acid-sensitive substrate. Therefore, the milder oxidant pyridinium dichromate (PDC) was applied at 65 ºC and afforded the desired penta-substituted cyclohexanone in 70% yield on decagram scale.

Angew. Chem. Int. Ed. 2021, 60, 12807.

1. For the synthesis of Cephanolide A.

Riley oxidation: The selenium dioxide-mediated oxidation of olefins at the allylic position. This transformation allows the formation of the allylic alcohol that is later oxidized to the corresponding enone by the use of Dess–Martin periodinane.

J. Am. Chem. Soc. 2021, 143, 2710.

Oxidation of alkenes to yield the corresponding epoxide products.

7. For the synthesis of Ginkgolide C.

J. Am. Chem. Soc. 2022, 144, 17792.

6. For the synthesis of 10,22-Dioxokopsane.

For this transformation, sodium hypochlorite (14.5 wt.% aqueous solution, 3.0 equiv.) was used as a good source of oxygen for olefin epoxidation under mild reaction conditions. The reaction was carried out in pyridine at 0 ºC for 30 min, yielding the desired product in 88% yield.

Angew. Chem. Int. Ed. 2022, 61, e202201712.

5. For the synthesis of Ambiguine G.

J. Am. Chem. Soc. 2021, 143, 10872. Open access.

4. For the synthesis of Euonyminol.

Shi asymmetric epoxidation. For the epoxidation of alkenes with oxone (potassium peroxymonosulfate) and a fructose-derived catalyst, the Shi ketone.

J. Am. Chem. Soc. 2021, 143, 699.

3. For the synthesis of Phomarol.

Bromohydroxylation of the double bond, followed by cyclization using KOH as a base gave the desired epoxide.

CCS Chem. 2021, 3, 348. Open access.

2. For the synthesis of Pladienolide B.

Sharpless asymmetric epoxidation. The product was obtained in 31% yield, 95% ee, and >20:1 dr.

Angew. Chem. Int. Ed. 2021, 60, 13923.

1. For the synthesis of Lefamulin.

Exposure of the olefin to mCPBA resulted in syn epoxidation of the carbamate.

J. Med. Chem. 2021, 64, 3604.

Oxidation of alcohols to the corresponding aldehydes, ketones or carboxylic acids.

10. For the synthesis of Longiborneol.

Nature Chem. 2022, 14, 450.

9. For the synthesis of Alstonlarsine A.

Corey-Kim oxidation: for the synthesis of aldehydes and ketones from primary and secondary alcohols using N-chlorosuccinimide (NCS), dimethyl sulfide (DMS), and an organic base (TEA).

Angew. Chem. Int. Ed. 2022, 61, e202210297.

8. For the synthesis of Alstonlarsine A.

Angew. Chem. Int. Ed. 2022, 61, e202210297.

7. For the synthesis of Aberrarone.

Parikh-Doering oxidation: The oxidation that uses dimethyl sulfoxide as the oxidant, activated by sulfur trioxide pyridine complex in the presence of a base such as DIPEA or triethylamine.

J. Am. Chem. Soc. 2022, 144, 15475.

6. For the synthesis of Euphorikanin A.

A Parikh-Doering oxidation.

J. Am. Chem. Soc. 2021, 143, 8261.

5. For the synthesis of Thebainone A.

Angew. Chem. Int. Ed. 2021, 60, 13507.

4. For the synthesis of Cyclobutastellettolide B.

Swern oxidation: The oxidation of alcohols by DMSO and oxalyl chloride.

J. Am. Chem. Soc. 2021, 143, 18287.

3. For the synthesis of Codonopiloneolignanin A.

Ley-Griffith oxidation: The tetra propylammonium perruthenate (TPAP) catalyzed oxidation of primary or secondary alcohols to aldehydes or ketones. The co-oxidant N-methylmorpholine N-oxide (NMO) is used in stoichiometric amounts to reoxidize the ruthenium catalyst (RuV -> RuVII) and mantain the catalytic cycle.

Org. Lett. 2021, 23, 5684.

2. For the synthesis of Annotinolide C.

Oxidation of the secondary alcohol to the ketone with Dess–Martin periodinane, DMP.

J. Am. Chem. Soc. 2021, 143, 11951. Open access.

1. For the synthesis of Lemborexant.

A one-pot two step oxidation of the primary alcohol to the carboxylic acid facilitated by TEMPO and NaOCl, followed by treatment with NaClO2 and pH adjustment.

J. Med. Chem. 2021, 64, 3604.

2. For the synthesis of Asnovolin A.

Baeyer-Villiger Oxidation. 

J. Am. Chem. Soc. 2022, 144, 12970.

1. For the synthesis of Maytenone.

Regioselective Friedel–Crafts acetylation and a Baeyer–Villiger oxygenation.

Angew. Chem. Int. Ed. 2021, 60, 14967.

2. For the synthesis of Drupacine.

The tertiary amine was oxidized to amide using NBS.

Angew. Chem. Int. Ed. 2021, 60, 12060.

1. For the synthesis of Annotinolide C.

A Pinnick Oxidation. 

J. Am. Chem. Soc. 2021, 143, 11951. Open access.

This post is about reactions happening to the carbonyl group of a given molecule, including but not limited to compounds such as aldehydes, ketones, carboxylic acids, esters, amides, enones, acyl halides, acid anhydrides, and imides. The post is active and growing, so you can expect more examples to be added over time. Please be sure to come back. The updates will be announced on my instagram account.

Last update 22/12/10.

Organic reactions where a nucleophile adds to the carbonyl carbon of a substrate to form a larger molecule.

9. For the synthesis of Gymnothelignan N.

A diastereoselective aldol addition of the chlorotitanium enolate of thiazolidinethione propionate with 5-methoxypiperonal afforded the desired syn-aldol adduct in 97% yield.

J. Org. Chem. 2022, 87, 4316.

8. For the synthesis of Iezoside.

The tertiary allylic alcohol was synthesized from the Weinreb amide via two consecutive Grignard reactions using methyl magnesium bromide and vinyl magnesium bromide, respectively.

J. Am. Chem. Soc. 2022, 144, 11019.

7. For the synthesis of Norzoanthamine.

A hydroxymethyl group was introduced at the alpha position of the ketone through a base-mediated aldol reaction, leading to the formation of the compound on the upper right.

A second hydroxymethyl group was introduced via a Baylis-Hillman reaction.

Angew. Chem. Int. Ed. 2021, 60, 12807.

6. For the synthesis of Euonymine.

A Baylis-Hillman reaction.

J. Am. Chem. Soc. 2021, 143, 21037.

5. For the synthesis of Dysiherbol A.

Cerium chloride is a Lewis acid and thus has a high affinity for oxygen atoms. This makes it an effective additive for 1,2-additions, where the Ce3+ ion coordinates to the oxygen atom of the carbonyl group and activates it toward nucleophilic attack.

Angew. Chem. Int. Ed. 2021, 60, 14915. Open access.

4. For the synthesis of Curcusone A.

Owing to their oxophilicity, the authors tried to carry out this transformation in the presence of additives such as cerium chloride and lanthanum chloride, which have been used to promote 1,2-additions (see reaction above, entry #5). Unfortunately, both failed. Eventually, the 1,2-addition was improved by increasing the amount of the lithiated ethyl vinyl ether to 10 equivalents, and the crude product was carried forward to the next step without further purification.

J. Am. Chem. Soc. 2021, 143, 4379.

3. For the synthesis of Curcusone A.

A Mukaiyama aldol addition: a Lewis acid-catalyzed aldol addition that uses a silyl enol ether as an enolate equivalent. First, formation of the extended silyl enol ether followed by the nucleophilic addition to the electrophile species generated in situ from ethyl orthoformate.

J. Am. Chem. Soc. 2021, 143, 4379.

2. For the synthesis of Codonopiloneolignanin A.

A Grignard addition reaction.

Org. Lett. 2021, 23, 5684.

1. For the synthesis of Annotinolide C.

J. Am. Chem. Soc. 2021, 143, 11951. Open access.

Organic reactions where a nucleophile adds at the C-4 atom of an enone to form the 1,4-adduct. Also called conjugate additions.

4. For the synthesis of Heilonine.

A Robinson annulation. Conjugate addition (Michael addition) followed by an intramolecular aldol condensation.

J. Am. Chem. Soc. 2021, 143, 16394. Open access.

3. For the synthesis of Euphorikanin A.

Conjugate addition (Me2CuLi) followed by aldol addition of the intermediate enolate with the aldehyde. Copper iodide is often used to mediate conjugate addition reactions. 

J. Am. Chem. Soc. 2021, 143, 8261.

2. For the synthesis of Annotinolide C.

Nagata hydrocyanation. Named after Japanese chemist Kenkichi Nagata, this reaction involves the addition of hydrogen cyanide (HCN) to an unsaturated organic compound in the presence of a metal catalyst. 

J. Am. Chem. Soc. 2021, 143, 11951. Open access.

1. For the synthesis of Curindolizine.

Umpolung reaction, where the carbonyl carbon becomes a nucleophile in a 1,4-addition. A stable carbanion was made using NaHMDS in the presence of LiCl; this species was added to the alpha,beta-unsaturated ketone, giving a 64% yield of the coupled product after quenching with N-iodosuccinimide.

J. Am. Chem. Soc. 2021, 143, 2970.

Acylation and Alkylation reactions. Excluded those in the alpha position of a carbonyl compound (vide infra).

1. For the synthesis of Peficitinib.

When the substrate was reacted with sec-BuLi, the TIPS protecting group was critical to block C-2, directing lithiation to C-5. An ethyl chloroformate quench yielded the desired C-5-substituted ethyl ester, which was deprotected with TBAF to provide the desired azaindole.

J. Med. Chem. 2021, 64, 3604.

Alkylation reactions that take place at the alpha position of a carbonyl compound. Some acylation reactions also included.

7. For the synthesis of Incargranine A.

α-Acylation of the lactam was carried out using sodium bis(trimethylsilyl)amide (NaHMDS) and diethyl carbonate.

Angew. Chem. Int. Ed. 2023, e202314308. Open access.

6. For the synthesis of Cephalotaxus Alkaloids.

The KOtBu mediated Dieckmann ring closure yielded the tetracyclic system. In situ etherification of the enolate intermediate with dimethyl sulfate afforded the depicted product.

Angew. Chem. Int. Ed. 2021, 60, 12060.

5. For the synthesis of Annotinolide C.

An acylation reaction.

J. Am. Chem. Soc. 2021, 143, 11951. Open access.

4. For the synthesis of Pladienolide B.

The unprotected epoxide was exposed to the dienolate derived from tert-butyl acetoacetate followed by acetic anhydride to form the product of epoxide ring opening in 86% yield.

Angew. Chem. Int. Ed. 2021, 60, 13923.

3. For the synthesis of Euphorikanin A.

Alkylation of the ketone employing LiN(SiMe3)2 and chloro dithiane afforded the product in 90% yield as a single diastereomer. Cleavage of the dithiane was achieved by treatment of the substrate with PIFA in aqueous acetonitrile, giving the aldehyde in excellent yield (95%).

J. Am. Chem. Soc. 2021, 143, 8261.

2. For the synthesis of Arborisidine.

Mannich reaction with the Eschenmoser salt and subsequent elimination to install the methyl group.

Angew. Chem. Int. Ed. 2021, 60, 12732.

1. For the synthesis of Curcusone B.

α-methylation of the enone at C2 position.

J. Am. Chem. Soc. 2021, 143, 4379.

5. For the synthesis of Lefamulin.

A Curtius rearrangement.

J. Med. Chem. 2021, 64, 3604.

4. For the synthesis of Metaphanine.

First, the coupling reaction of TMS cyanohydrin and the mesylate was carried out with LiHMDS followed by treatment with TBAF to give the ketone in 78% yield.

J. Am. Chem. Soc. 2021, 143, 2699.

3. For the synthesis of Heilonine.

Seyferth-Gilbert homologation through the use of the Bestmann-Ohira reagent.

J. Am. Chem. Soc. 2021, 143, 16394. Open access.

2. For the synthesis of Dysiherbol A.

The ketone was converted into the enol triflate by treatment with LDA and N-phenyl triflimide.

Angew. Chem. Int. Ed. 2021, 60, 14915. Open access.

1. For the synthesis of (S)-Cularine.

Ellman’s Sulfinamide.

Org. Lett. 2021, 23, 236.

This post is about cross-coupling reactions recently employed for the synthesis of natural products and drugs. You will find different reaction conditions for each of the cross-coupling reactions presented here. The post is active and growing, so you can expect more examples to be added over time. Please be sure to come back. The updates will be announced on my instagram account.

Last update 23/12/09.

A cross-coupling reaction is a type of chemical reaction in which two molecules are joined together by a covalent bond. This reaction is mediated by a metal catalyst, such as palladium or nickel. Cross-coupling reactions are important in organic synthesis because they allow for the construction of complex molecules from simple starting materials. By carefully choosing the substrates and the coupling agents, chemists can create molecules with almost any desired structure. However, these reactions are not without their challenges. One of the biggest challenges is that they often require very precise conditions in order to work correctly.

Despite these challenges, cross-coupling reactions are an essential part of synthetic organic chemistry and have led to the synthesis of many important molecules. Follow us along to find out what strategies scientists used to prepare, in some cases, even just a few milligrams of these natural products and drugs. 

The Buchwald-Hartwig coupling is the Pd-catalyzed C–N or C–O bond formation between aryl halides and amines or alcohols in the presence of a stoichiometric amount of base.

3. For the synthesis of Tenapanor hydrochloride.

Buchwald-Hartwig introduction of benzenethiol to give the mercaptan product.

J. Med. Chem. 2021, 64, 3604.

2. For the synthesis of Upadacitinib.

Palladium-catalyzed Buchwald-Hartwig amination provided the ethyl carbamate.

J. Med. Chem. 2021, 64, 3604.

1. For the synthesis of Erdafitinib.

J. Med. Chem. 2021, 64, 3604.

Carbonylation reactions that introduce carbon monoxide into an organic substrate, delivering the corresponding carboxylic acid or ester.

2. For the synthesis of 10,22-Dioxokopsane.

Angew. Chem. Int. Ed. 2022, 61, e202201712.

1. For the synthesis of Ubrogepant.

J. Med. Chem. 2021, 64, 3604.

1. For the synthesis of Gardmultimine A.

A Ir-catalyzed borylation of  a substituted indole. The tricyclic ester was initially borylated with high selectivity in 40% yield and then subjected to Chan−Lam coupling with methanol to afford the desired ester in 60% yield.

Org. Lett. 2020, 22, 2022.

Alternative cross-coupling reactions.

1. For the synthesis of GB22.

Radical coupling of an aryl bromide with a siloxycyclopropane, which was achieved using nickel–photoredox dual catalysis.

Science. 2022, 375, 1270.

1. For the synthesis of Ambiguine G.

A cyanation reaction.

J. Am. Chem. Soc. 2021, 143, 10872.

The Heck coupling allows the reaction between an unsaturated halide or triflate and an alkene in the presence of a base and a palladium catalyst.

2. For the synthesis of Hinckdentine A.

Org. Lett. 2021, 23, 2169.

1. For the synthesis of Exatecan.

J. Med. Chem. 2021, 64, 3604.

The Negishi coupling is the nickel or palladium-catalyzed stereoselective reaction of organozincs and organic halides for the formation of carbon-carbon bonds.

1. For the synthesis of Allomatrine.

J. Am. Chem. Soc. 2022, 144, 19695.

The Sonogashira cross-coupling is the copper-palladium catalyzed reaction of terminal alkynes with aryl or vinyl halides.

2. For the synthesis of Aberrarone.

J. Am. Chem. Soc. 2022, 144, 15475.

1. For the synthesis of Rubrolide E.

Org. Lett. 2021, 23, 5605.

The Stille coupling is the palladium-catalyzed reaction between stannanes and halides to generate a new C–C sigma bond.

2. For the synthesis of Codonopiloneolignanin A.

 Stille cross coupling to introduce the carbon−carbon double bond.

Org. Lett. 2021, 23, 5684.

1. For the synthesis of Ambiguine G.

The vinyl triflate was prepared from the corresponding ketone with the aid of the Comins’ reagent, a triflyl-donating reagent.

J. Am. Chem. Soc. 2021, 143, 10872. Open access.

The Suzuki coupling is a palladium catalyzed reaction between organoboronic acids or esters and organic halides or triflates under basic conditions.

6. For the synthesis of Undulifoline.

Angew. Chem. Int. Ed. 2021, 60, 12392.

5. For the synthesis of Cephanolide A.

The indanone and the pyrone components were successfully linked with a two-carbon fragment by an iterative cross-coupling sequence. The sp2-sp3 Suzuki cross-coupling reactions took place with the depicted organoborane, which was generated in situ from hydroboration of potassium vinyltrifluoroborate, vinylBF3K, with 9-BBN in THF at rt for 3 h. (The resulting mixture was transferred to the coupling reaction via cannula.)

J. Am. Chem. Soc. 2021, 143, 2710.

4. For the synthesis of Dalesconol A.

The Suzuki coupling was preceded by the Miyaura borylation reaction, which enables the synthesis of boronates by cross-coupling of bis(pinacolato)diboron, B2pin2, with the aryl bromide.

J. Am. Chem. Soc. 2021, 143, 21270.

3. For the synthesis of Trifarotene.

In this example, the boronic acid was generated via Li-halogen exchange and quench with triisopropylborate.

J. Med. Chem. 2021, 64, 3604.

2. For the synthesis of Upadacitinib.

Suzuki-Miyaura reaction with ethylboronic acid provided 4-ethylpyrrolidine.

J. Med. Chem. 2021, 64, 3604.

1. For the synthesis of Erdafitinib.

Suzuki coupling between the aryl chloride and the pyrazole delivered the corresponding aryl bromide, giving way to another cross-coupling reaction. 

J. Med. Chem. 2021, 64, 3604.

1. For the synthesis of Incargranine A.

A Ullmann coupling between an aryl bromide and pyrrolidinone using catalytic copper iodide and 1,2-dimethylethylenediamine.

Angew. Chem. Int. Ed. 2023, e202314308. Open access.