Hitchhiker’s Guide to Reductive Amination

Kuchuk E., Muratov K., Perekalin D.S., Chusov D.

A new class of anthracene–metal complexes with central ring coordination was tested in catalysis. A simple and efficient protocol for reductive amination without an external hydrogen source has been developed.

HAMADI H., JAVADI S.

An efficient one-pot procedure for the direct reductive amination of aldehyde and ketones was achieved in the presence of sodium borohydride by using B(OSO3H)3/SiO2(SBSA) as the reusable solid catalyst in acetonitrile and solvent-free conditions. Both aromatic and aliphatic aldehyde reacted well to give the corresponding amines in excellent yields. All the products are known and well-characterized. The catalyst is recoverable and could be easily recycled by filtration and reused several times without any significant loss of its activity. SBSA acts as a dual Brønsted/Lewis acid that is an air-stable and cost-effective solid acid.

Mao F., Sui D., Qi Z., Fan H., Chen R., Huang J.

Heterogeneous Co@NC catalysts were prepared, characterized and applied for the general synthesis of secondary and tertiary amines by Co-catalyzed reductive amination with H2gas.

Xie H., Li Y., Bai C., Wang R., Liu C., Hao C., Lin B., Cheng M., Zhao D.

Epidemiological studies have identified that the risk of cardiovascular events increases due to the decreased levels of high density lipoprotein-cholesterol and the elevated levels of low density lipoprotein-cholesterol. Herein, we report a novel series of N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which were identified as potent cholesteryl ester transfer protein (CETP) inhibitor. The initial lead compound L10 (IC50 8.06 μM) was found by pharmacophore-based virtual screening (Dong-Mei Zhao et al., Chin. Chem. Lett.2014, 25, 299). After systematic structure variation and biological testing against CETP, two different series were identified as scaffolds for potent CETP inhibitors. One is N,N-3-phenyl-3-benzylaminopropanamide derivatives, which were investigated in our previous paper (Bioorg. Med. Chem.2015, doi: http://dx.doi.org/10.1016/j.bmc.2015.12.010). The most potent compound HL16 in that series has the IC50 of 0.69 μM. The other series is N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which was investigated in current study. Further optimization of the structure-activity relationship (SAR) resulted in H16 (IC50 0.15 μM), which was discovered as a potent CETP inhibitor in vitro by BODIPY-CE fluorescence assay. In addition, the results of pharmacodynamics studies showed that H16 exhibited both favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. It also has an excellent stability in rat liver microsomal.

Afanasyev O.I., Tsygankov A.A., Usanov D.L., Perekalin D.S., Shvydkiy N.V., Maleev V.I., Kudinov A.R., Chusov D.

A catalyst of a new type, cyclobutadiene complex [(C4Et4)Rh(p-xylene)]PF6, was found to promote selective reductive amination in the presence of carbon monoxide under mild conditions (1–3 bar, 90 °C). The reaction demonstrated perfect compatibility with a wide range of functional groups prone to reduction by conventional reducing agents. The developed system represents the first systematic investigation of cyclobutadiene metal complexes as catalysts.

Wu J., Lu S., Ge D., Gu H.

A highly efficient and environmentally friendly method for the synthesis of tertiary amines by direct interaction of aldehydes with secondary amines was reported over a Pt NWs catalyst under mild reaction conditions.

Yagafarov N.Z., Usanov D.L., Moskovets A.P., Kagramanov N.D., Maleev V.I., Chusov D.

An efficient method for the rhodium on carbon matrix catalyzed preparation of secondary and tertiary amines, cyanoesters, and nitriles through the reductive amination/alkylation of carbonyl compounds was developed, including a convenient procedure for the tandem formal reductive addition of acetonitrile to aldehydes. The catalyst could be reused, and at least three consecutive reaction cycles were performed with comparable efficiency. The method was shown to be compatible with functional groups prone to reduction by hydrogen and complex hydrides.

Kolesnikov P.N., Yagafarov N.Z., Usanov D.L., Maleev V.I., Chusov D.

A ruthenium-catalyzed reductive amination without an external hydrogen source has been developed using carbon monoxide as the reductant and ruthenium(III) chloride (0.008-2 mol %) as the catalyst. The method was applied to the synthesis of antianxiety agent ladasten.

Clark R.B., He M., Deng Y., Sun C., Chen C., Hunt D.K., O’Brien W.J., Fyfe C., Grossman T.H., Sutcliffe J.A., Achorn C., Hogan P.C., Katz C.E., Niu J., Zhang W., et. al.

The C-8 position of the tetracyclines has been largely underexplored because of limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at the C-7 and C-8 positions, enabling the generation of structure-activity relationships for overcoming the two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) and efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive and Gram-negative bacteria, including pathogens bearing both types of tetracycline-resistance mechanisms. Compounds were screened in a murine systemic infection model to rapidly identify compounds with oral bioavailability, leading to the discovery of several compounds that exhibited efficacy when administered orally in murine pyelonephritis and pneumonia models.

KIKUGAWA Y., KURAMOTO M., SAITO I., YAMADA S.

The reaction of 2-or 4-substituted pyridines and quinolines and 1-or 3-substituted isoquinolines with sodium borohydride was examined. The substituent groups which are usually resistant to reduction with sodium borohydride were reducible through the electronic influence of the heteromatic ring. The solvent effects on the reduction with sodium borohydride were also examined.

Alinezhad H., Tajbakhsh M., Hamidi N.

A simple and convenient procedure for the preparation of amines from aldehydes and ketones with sodium borohydride activated by silica chloride as a catalyst under solvent-free conditions is described. A variety of aliphatic and aromatic aldehydes, ketones and amines when mixed with NaBH4/silica chloride at room temperature, afforded excellent yield of the corresponding amines.

Alinezhad H., Tajbakhsh M., Zare M.

A regioselective and convenient procedure for preparation of amines by reductive amination of aldehydes and ketones using sodium borohydride in the presence of sulfuric acid supported on silica gel as an active, inexpensive, and recoverable catalyst under heterogeneous and solvent-free conditions at room temperature is described.

Tripathi R., Verma S., Pandey J., Tiwari V.

Reductive amination is one of the most useful and versatile methods for the preparation of amines in chemistry and biology. The present review focuses on the development of catalytic reductive amination from beginning to recent ones, where we have attempted to thoroughly illustrate an account of utility of various reagents including organocatalyst, symmetric and asymmetric (Ru, Rh, Ir) complexes, boron, tin or silicon reagents etc for enantio- and/or chemoselective reactions under different reaction conditions with emphasis on the yields of the reaction products and stability of the reagents used. Emerging applications of this reaction for the development of chiral ligands, pharmacologically active molecules, combinatorial scaffold, and key step in the total synthesis of some interesting natural products is also reviewed briefly.

Reddy P.S., Kanjilal S., Sunitha S., Prasad R.B.

Reductive amination of carbonyl compounds using sodium borohydride is conducted in the Bronsted acidic ionic liquid, 1-methyl imidazolium tetrafluoroborate ([HMIm][BF4]). The ionic liquid plays the dual role of solvent as well as catalyst for efficient conversion of aldehydes and ketones to amines in excellent yields without the formation of side products.

Abdel-Magid A.F., Mehrman S.J.

Losev M.A., Afanasyev O.I., Chusov D.

Rooney C.L., Sun Q., Shang B., Wang H.

Ohnishi T., Irie R., Inai M., Kan T., Oikawa M.

Abstract A convergent, iterative, and split-couple strategy for synthesis of the homogeneous polymer of 1,3-propanediamine (long-chain polyamine, LCPA) has been developed by employing 1,3-dibromopropane as a glue in subunit couplings. By using this synthetic strategy, 7-, 11-, and 15-mer LCPAs were successfully synthesized. This synthetic strategy solved problems that had arisen with previous methods, such as variable reactivity and poor reproducibility.

Zhang Z., Xi C.

AbstractDue to its nontoxic nature, cost‐effectiveness, and natural abundance, carbon dioxide (CO2) is increasingly recognized as a valuable C1 source in organic synthesis. In addition to the building block for molecular construction, the role of CO2 as a promoter or catalyst to enhance reaction rates and selectivity is gaining attention. Acting as a reversible covalent Lewis acid, CO2 can function as an activating group in the transformation of various compounds, such as alcohols and amines, facilitating the dissociation of hydroxyl or activation of amino. It can also modulate the reactivity of nucleophilic reagents, including H2O, N‐heterocyclic carbenes (NHCs), cyanide (CN), and nucleophilic reductants like borohydride (BH4−). When CO2 interacts with these nucleophiles, it can exhibit Brønsted acidity or hydrogen‐bond donating capabilities and can also act as a coordinating ligand to transition metals in its carboxylate form (─CO2−). In this review, we mainly summarize and classify the synthetic applications and mechanistic insights of CO2‐promoted reactions according to different functional groups and bonding types, which include CO2‐promoted functional transformation of alcohols, CO2‐promoted functional transformation of amines; CO2‐promoted reactions in protic solvent; CO2‐promoted reactions via adducts of CO2 and nucleophiles, CO2‐promoted reductive reaction.

Janssen M.A., Rappard R., Dekker T., Heiming M., Beens M., Pieters D., Kuijpers B.H., Benningshof J.C., Wijtmans M., de Esch I.J., Blanco‐Ania D., Rutjes F.P.

AbstractCyclobutanes have attracted significant interest in medicinal chemistry because of their unique structure and potential advantages in pharmacological properties. Nevertheless, 1,2‐disubstituted cyclobutanes remain underrepresented, both in the general chemical space and in fragment‐based drug discovery libraries. In this study, a two‐diversification‐point library of cyclobutanesulfonamides was synthesized through a hyperbaric [2+2] cycloaddition reaction between ethenesulfonyl fluoride and tert‐butyl vinyl ether as the key step. The sulfonyl fluoride was subsequently transformed into various sulfonamides, whereas the tert‐butyl ether was converted into carbamates and triazoles to synthesize a fragment library. Overall, this synthesis contributes to addressing the underrepresentation of 1,2‐disubstituted cyclobutane fragments, making a valuable addition to the field of fragment‐based drug discovery.

Snyder M.J., Alawaed A.A., Li C., Pacentine S., Hamann H.J., Ramachandran P.V.

Reductive alkylation of amines with carboxylic acids is achieved using BH3–NH3 and TiF4, yielding free amines or their borane-complexes.

Lu J., Yuan K., Zheng J., Zhang H., Chen S., Ma J., Liu X., Tu B., Zhang G., Guo R.

AbstractAllylic amines are prevalent and vital structural components present in many bioactive compounds and natural products. Additionally, they serve as valuable intermediates and building blocks, with wide‐ranging applications in organic synthesis. However, direct α‐C(sp3)−H alkenylation of feedstock amines, particularly for the preparation of α‐alkenylated cyclic amines, has posed a longstanding challenge. Herein, we present a general, mild, operationally simple, and transition‐metal‐free α‐alkenylation of various readily available amines with alkenylborate esters in excellent E/Z ‐ and diastereoselectivities. This method features good compatibility with water and oxygen, broad substrate scope, and excellent functional group tolerance, thereby enabling the late‐stage modification of various complex molecules. Mechanistic studies suggest that the formation of a photoactive electron donor‐acceptor complex between 2‐iodobenzamide and the tetraalkoxyborate anion, which subsequently undergoes photoinduced single electron transfer and intramolecular 1,5‐hydrogen atom transfer to generate the crucial α‐amino radicals, is the key to success of this chemistry.

Lu J., Yuan K., Zheng J., Zhang H., Chen S., Ma J., Liu X., Tu B., Zhang G., Guo R.

AbstractAllylic amines are prevalent and vital structural components present in many bioactive compounds and natural products. Additionally, they serve as valuable intermediates and building blocks, with wide‐ranging applications in organic synthesis. However, direct α‐C(sp3)−H alkenylation of feedstock amines, particularly for the preparation of α‐alkenylated cyclic amines, has posed a longstanding challenge. Herein, we present a general, mild, operationally simple, and transition‐metal‐free α‐alkenylation of various readily available amines with alkenylborate esters in excellent E/Z ‐ and diastereoselectivities. This method features good compatibility with water and oxygen, broad substrate scope, and excellent functional group tolerance, thereby enabling the late‐stage modification of various complex molecules. Mechanistic studies suggest that the formation of a photoactive electron donor‐acceptor complex between 2‐iodobenzamide and the tetraalkoxyborate anion, which subsequently undergoes photoinduced single electron transfer and intramolecular 1,5‐hydrogen atom transfer to generate the crucial α‐amino radicals, is the key to success of this chemistry.

Zenner A., Steinmetzer J., Ueberschaar N., Freesmeyer M., Weigand W., Greiser J.

1,4-Diazepane-6-amine (DAZA) can be alkylated with three 2-hydroxybenzyl pendant arms, resulting in hexadentate chelators suitable for coordination of radiometals like 68 Ga. These chelators, N ,1,4-tri(alkoxy-2-hydroxybenzyl)-DAZA, can be produced via a one-pot synthesis, with the first step being a carbonyl amine condensation of DAZA with two respective 4-alkoxy-2-hydroxybenzaldehydes, followed by reductive amination with sodium borohydride. While the first step of this reaction is predictable, the subsequent reductive amination can result in either mono-, di- or tri(alkoxy-hydroxybenzyl)-DAZA compounds. Seeking to identify dependencies that might allow a specific reaction control towards the formation of either of the three possible products, and particularly towards the favoured trialkylated DAZA compounds, a variety of synthesis trials were performed. Additionally, computational methods were employed to evaluate the underlying reaction mechanism. Synthesis trials verified that the trialkylated DAZA compounds are formed via direct reductive amination of the dialkylated DAZA compounds. Subsequently, a synthetic method was established, leading to an increase in the percentage of the trialkylated DAZA compounds, which allowed the successful isolation of those hexadentate chelators. Additionally, an alternative pathway proceeding via aminal C–N bond insertion of an attacking third carbonyl moiety was evaluated by means of quantum chemical calculations but so far remains entirely hypothetical.

Smirnov I.V., Biriukov K.O., Shvydkiy N.V., Perekalin D.S., Afanasyev O.I., Chusov D.

Lin H., Li L., Liu L., Li Z., Nguyen T., Jouffroy M., Gramage-Doria R.

The mechanism of the iridium-catalysed direct reductive amination between aliphatic partners was studied by DFT calculations leading to important changes in the rate-determining step depending on the nature of the ligand coordinating to iridium.

Resende L.F., Pliego J.R.

Nucleophilic substitution reactions of aliphatic amines with alkyl halides represent a simple and direct mechanism for obtaining higher-order aliphatic amines. However, it is well known that these reactions suffer from low selectivity due to multiple alkylations, which is attributed to the higher reactivity of the newly formed amine. In order to provide a detailed explanation for this kind of system, we have investigated the reactivity of primary and secondary amines with 1-bromopropane and 2-bromopropane. The free energy profile in acetonitrile solution was obtained and a detailed microkinetic analysis was needed to analyze this complex reaction system. We have found that the product of the first alkylation is an ion pair corresponding to the protonated secondary amine and the bromide ion, which can transfer the proton to the reactant primary amine. Then, the newly formed secondary amine can also react, leading to a second alkylation to produce a tertiary protonated amine. Our modeling points out that both the proton transfer equilibria and the similar reactivity of the primary and secondary amines produce reduced selectivity. The proton transfer equilibria also contribute to slowing down the kinetics of the first alkylation. The exploration of the mechanism was done by geometry optimization using the CPCM/X3LYP/ma-def2-SVP method, followed by harmonic frequency calculation at this same level of theory. A composite approach was used to obtain the free energy profile, using the more accurate ωB97X-D3/ma-def2-TZVPP level of theory for electronic energy and the SMD model for the solvation free energy. These calculations were performed with the ORCA 4 program. The detailed microkinetic analysis was done using the Kintecus program.

Maneesha M., Aneeja T., Anilkumar G.

Rhodium-catalyzed domino reactions have achieved tremendous progress in recent times. Rhodium compounds are nowadays often used as catalysts in organic synthesis due to their high reaction efficiency and outstanding regio- stereo- and enantioselectivity. The recent novel studies in the field of domino reactions facilitated by rhodium are highlighted in this review.

Reber S., Blumer N., Leuenberger D., Fleischer T., Renneberg D., Abele S., Schäfer G.

Kim W.H., Song S.B., Lee D.E., Goswami P., Chung Y.K., Choi S., Jung W.H., Choi S.U., Ham S., Oh Y., Kim K.H., Huh J., Bae H.Y.

α-Secondary alkyl amines are structural motifs frequently encountered in a wide variety of natural products and pharmaceuticals. The N-benzyloxycarbonyl (Cbz) compound is a widely used precursor, acknowledged for its efficacy in implementing a masked amine strategy to access a privileged moiety. Although reductive amination is conducted as a crucial portion of the pharmaceutical industry, direct catalytic access to alkyl Cbz-amine is still rare due to the low reactivity of carbamate. Here, we show a superacid organocatalyst enabled direct access to bioactive Cbz-protected α-secondary alkyl amines using general ketones as the starting material. Through the highly selective and robust catalytic process, a wide substrate scope including drug precursor scaffolds in preparative scalability (up to >99% yield) with practical pharmaceutical syntheses is achieved. The obtained N-Cbz products are found to possess strong cytotoxicities in in vitro bioactivity evaluations, indicating their potential as promising candidates for new anticancer drug discovery.