Reduction of imines
Hitchhiker's guide to reductive
E. Podyacheva, O. I. Afanasyev, A. A. Tsygankov, M. Makarova, D. Chusov
By optimizing the metal hydride/ammonia mediated reductive amination of aldehydes and hemiacetals, primary amines were selectively prepared with no or minimal formation of the usual secondary and tertiary amine byproduct. The methodology was performed on a range of functionalized aldehyde substrates, including in situ formed aldehydes from a Vasella reaction.
E. M. Dangerfield, C. H. Plunkett, A. L. Win-Mason, B. L. Stocker, M. S. M. Timmer, J. Org. Chem., 2010, 75, 5470-5477.
Cp*Ir complexes bearing a 2-picolinamide moiety effectively catalyze a direct reductive amination of ketones to give primary amines under transfer hydrogenation conditions using ammonium formate as both the nitrogen and hydrogen source.
K. Tanaka, T. Miki, K. Murata, A. Yamaguchi, Y. Kayaki, S. Kuwata, T. Ikariya, M. Watanabe, J. Org. Chem., 2019, 84, 10962-10977.
Borane-trimethylamine is an efficient reducing agent for the selective methylation and formylation of amines with 1 atm CO2 under metal-free conditions. 6-Amino-2-picoline serves as a highly efficient catalyst for the methylation of various secondary amines, whereas in its absence, the formylation of primary and secondary amines was achieved in high yield with high chemoselectivity.
Y. Zhang, H. Zhang, K. Gao, Org. Lett., 2021, 23, 8282-8286.
A simple and convenient procedure enables the reductive alkylation of primary and secondary amines and N,N-dimethylation of amino acids using sodium borohydride as reducing agent in 2,2,2- trifluoroethanol without use of a catalyst or any other additive. The solvent can be revovered and reused.
M. Taibakhsh, R. Hosseinzadeh, H. Alinezhad, S. Ghahari, A. Heydari, S. Khaksar, Synthesis, 2011, 490-496.
Sodium triacetoxyborohydride is a general, mild, and selective reducing agent for the reductive amination of various aldehydes and ketones. 1,2-Dichloroethane (DCE) is the preferred reaction solvent, but reactions can also be carried out in tetrahydrofuran and occasionally in acetonitrile. Acetic acid may be used as catalyst with ketone reactions. Acid sensitive functional groups such as acetals and ketals, and reducible functional groups such as C-C multiple bonds and cyano and nitro groups are tolerated.
A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff, R. D. Shah, J. Org. Chem., 1996, 61, 3849-3862.
In the reductive amination of some aldehydes with primary amines where dialkylation is a problem, a stepwise procedure involving imine formation in MeOH followed by reduction with NaBH4 was developed.
A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff, R. D. Shah, J. Org. Chem., 1996, 61, 3849-3862.
Trimethyl borate promotes a solvent-free reductive amination of aldehydes and ketones with aliphatic and aromatic amines in very good yields in the presence of ammonia borane as reductant.
P. V. Ramachandran, S. Choudhary, A. Singh, J. Org. Chem., 2021, 86, 4274-4280.
Stannous chloride catalyzes a chemoselective reductive amination of various carbonyl compounds with aromatic amines using inexpensive polymethylhydrosiloxane as reducing agent in methanol. The present method is applicable for the synthesis of tertiary and secondary amines.
O. S. Nayal, V. Bhatt, S. Sharma, N. Kumar, J. Org. Chem., 2015, 80, 5912-5918.
Reductive amination between aldehydes or ketones and amines occurs smoothly within the hydrophobic cores of nanomicelles in water. A broad range of substrates can be converted under mild conditions in the presence of 0.20 mol % Pd/C and triethylsilane, leading to high chemical yields of the desired secondary and tertiary amines.
R. R. Thakore, B. S. Takale, G. Casotti, E. S. Gao, H. S. Jin, B. H. Lipshutz, Org. Lett., 2020, 22, 6324-6329.
Dibutyltin dichloride catalyzes a direct reductive amination of aldehydes and ketones in the presence of phenylsilane as a stoichiometric reductant. Suitable amines included anilines and dialkylamines but not monoalkylamines.
R. Apodaca, W. Xiao, Org. Lett., 2001, 3, 1745-1748.
The [RuCl2(p-cymene)]2/Ph2SiH2 catalytic system is very efficient for the reductive amination of aldehydes with anilines to provide secondary amines and tertiary amines in good yields. The method is highly chemoselective and tolerates a wide range of functional groups, such as NO2, CN, CO2Me, F, Cl, Br, OMe, Me, furyl and alkyl.
B. Li, J. Zheng, W. Zeng, Y. Li, L. Chen, Synthesis, 2017, 49, 1349-1355.
In a straightforward process for the N-alkylation of amines, readily available carboxylic acids and silanes as the hydride source enable an effective C-N bond construction under mild conditions and allow obtaining a broad range of alkylated secondary and tertiary amines, including fluoroalkyl-substituted anilines as well as the bioactive compound Cinacalcet HCl.
I. Sorribes, K. Jung, M. Beller, J. Am. Chem. Soc., 2014, 136, 14314-14319.
Aldehydes and ketones were easily converted to the corresponding amines by the reaction of amines in methanol using decaborane (B10H14) at room temperature under nitrogen. The reaction is simple and efficient.
J. W. Bae, S. H. Lee, Y. J. Cho, C. M. Yoon, J. Chem. Soc., Perkin Trans. 1, 2000, 145-146.
A cyclopentadienyl iron(II) tricarbonyl complex is able to catalyze a chemoselective reductive alkylation of various functionalized amines with functionalized aldehydes at room temperature. The reaction tolerates alkenes, esters, ketones, acetals, unprotected hydroxyl groups, and phosphines.
A. Lator, Q. G. Gaillard, D. S. Mérel, J.-F. Lohier, S. Gaillard, A. Poater, J.-L. Renau, J. Org. Chem., 2019, 84, 6813-6829.
An iridium complex catalyzes an environmentally friendly, efficient, and facile one-pot transfer hydrogenation of C=C bond of enones and reductive amination of C=N bond of imines in the presence of formic acid as hydrogen source in aqueous medium. This reaction provides a wide range of α-alkylated amines in excellent yield.
Y. Xia, L. Ouyang, J. Liao, X. Yang, R. Luo, Synthesis, 2021, 53, 1821-1827.
Cobalt-rhodium heterobimetallic nanoparticles catalyze a tandem reductive amination of aldehydes with nitroaromatics without any additives under mild conditions (1 atm H2 and 25 °C). This procedure can be scaled up to the gram scale, and the catalyst can be reused more than six times without loss of activity.
I. Choi, S. Chun, Y. K. Chung, J. Org. Chem., 2017, 82, 12771-12777.
A copper-catalyzed protocol for reductive methylation of amines and imine with formic acid as a C1 source and phenylsilane as a reductant provides the corresponding methylamines in good to excellent yields under mild conditions.
C. Qiao, X.-F. Liu, X. Liu, L.-N. He, Org. Lett., 2017, 19, 1490-1493.
Reductive amination of aldehydes and ketones with the InCl3/Et3SiH/MeOH system is highly chemoselective and can be applied to various cyclic, acyclic, aromatic, and aliphatic amines. Functionalities including ester, hydroxyl, carboxylic acid, and olefin are tolerated.
O.-Y. Lee, K.-L. Law, C.-Y. Ho, D. Yang, J. Org. Chem., 2008, 73, 8829-8837.
A simple and convenient procedure allows the reductive amination of aldehydes and ketones using sodium borohydride as reducing agent and boric acid, p-toluenesulfonic acid monohydrate or benzoic acid as activator under solvent-free conditions.
B. T. Cho, S. K. Kang, Tetrahedron, 2005, 61, 5725-5734.
N-heterocyclic carbene boranes (NHC-boranes) are among the most nucleophilic classes of neutral hydride donors. Reductions of highly electron-poor C=N and C=C bonds provide hydrogenation products along with new, stable borylated products. The results suggest that NHC-boranes have considerable untapped potential as neutral organic reductants.
M. Horn, H. Mayr, E. Lacôte, E. Merling, J. Deaner, S. Well, T. McFadden, D. P. Curran, Org. Lett., 2012, 14, 82-85.
Reductive aminations of shelf-stable bisulfite addition compounds of aldehydes can be run under aqueous micellar catalysis conditions with readily available α-picolineborane as the stoichiometric hydride source. Recycling of the aqueous reaction medium is easily accomplished.
X. Li, K. S. Iyer, R. R. Thakore, D. K. Leahy, J. D. Bailey, B. H. Lipshutz, Org. Lett., 2021, 23, 7205-7208.
An effective reductive alkylation of electron-deficient o-chloroarylamines was developed. The derived N-alkylated o-chloroarylamines were elaborated to N-alkylazaindoles and N-alkylindoles via a novel one-pot process comprising copper-free Sonogashira alkynylation and a base-mediated indolization reaction.
M. McLaughlin, M. Palucki, I. W. Davies, Org. Lett., 2006, 8, 3307-3310.
An efficient methodology for the reductive alkylation of secondary amines with aldehydes and Et3SiH using an iridium complex as a catalyst has been developed. In addition, a cheaper, easy-to-handle, and environmentally friendly reducing reagent such as polymethylhydrosiloxane (PMHS) in place of Et3SiH was also useful.
T. Mizuta, S. Sakaguchi, Y. Ishii, J. Org. Chem., 2005, 70, 2195-2199.
An oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Brønsted acid catalysis in DMPU as solvent enables a mild and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure of amines with alcohols.
I. A. Khan, A. K. Saxena, J. Org. Chem., 2013, 78, 11656-11669.
Copper N-heterocyclic carbene complexes serve as catalysts for both aerobic oxidation of alcohols to aldehydes and reduction of imines to amines. A one-pot tandem synthetic strategy affords useful secondary amines from benzylic alcohols and anilines via an oxidation-reduction strategy.
L.-W. Zhan, L. Han, P. Xing, B. Jiang, Org. Lett., 2015, 17, 5990-5993.
Cooperative catalysis of an Ir(III)-diamine complex and a chiral phosphoric acid or its conjugate base enables a direct reductive amination of a wide range of ketones.
C. Li, B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc., 2009, 131, 6967-6969.
A direct and efficient palladium-catalyzed reductive coupling of nitroarenes with phenols provides various N-cyclohexylaniline derivatives in good yields using safe and inexpensive sodium formate as the hydrogen donor.
K.-J. Liu, X.-L. Zeng, Y. Zhang, Y. Wang, X.-S. Xiao, H. Yue, M. Wang, Z. Tang, W.-M. He, Synthesis, 2018, 50, 4637-4644.
A reductive cross-amination between imine intermediates generated through partial hydrogenation of aniline or nitroarene derivatives and alkylamines provides N-alkylated cyclohexylamine derivatives in the presence of heterogeneous Rh/Pt bimetallic nanoparticles under mild conditions. The catalyst was recovered and reused for five runs, keeping high activity.
A. Suzuki, H. Miyamura, S. Kobayashi, Synlett, 2019, 30, 387-392.
Use of porous TiO2 nanosheets-supported Pt nanoparticles (Pt/P-TiO2) as heterogeneous catalyst enables a challenging reductive amination of biomass-derived levulinic acid at ambient temperature and H2 pressure. Pt/P-TiO2 also showed good applicability for reductive amination of levulinic esters, 4-acetylbutyric acid, 2-acetylbenzoic acid, and 2-carboxybenzaldehyde.
C. Xie, J. Song, H. Wu, Y. Hu, H. Liu, Z. Zhang, P. Zhang, B. Chen, B. Han, J. Am. Chem. Soc., 2019, 141, 4002-4009.
α-Imino esters derived from aryl and alkyl keto esters could be reduced to the corresponding α-amino esters in excellent yields and in high enantiomeric excesses using 5 mol-% of a chiral phosphoric acid as catalyst, Hantzsch ester as hydride donor, and toluene as solvent.
G. Li, Y. Liang, J. C. Antilla, J. Am. Chem. Soc., 2007, 129, 5830-5831.
Brønsted acid catalysis enables highly efficient, regioselective, and enantioselective transfer hydrogenation of α-keto ketimines and reductive amination of diketones. A series of chiral α-amino ketones is prepared in high yields, excellent regioselectivities, and enantioselectivities.
W. Wen, Y. Zeng, L.-Y. Peng, L.-N. Fu, Q.-X. Guo, Org. Lett., 2015, 17, 3922-3925.
A direct reductive amination of ketones using the Hantzsch ester in the presence of S-benzyl isothiouronium chloride as a recoverable organocatalyst converts a wide range of ketones as well as aryl amines to the expected products in good yields.
Q. P. B. Nguyen, T. H. Kim, Synthesis, 2012, 44, 1977-1982.
A biomimetic direct reductive amination of ketones relies on selective imine activation by hydrogen bond formation with thiourea as hydrogen bond donor and utilizes the Hantzsch ester for transfer hydrogenation. The method allows the efficient synthesis of structurally diverse amines.
D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter, S. Rudolph, Org. Lett., 2006, 8, 741-744.
A hydrogen-bond-catalyzed, acid- and metal-free direct reductive amination of aldehydes uses thiourea as organocatalyst and the Hantzsch ester for transfer-hydrogenation. This methods allows for the high-yielding synthesis of diverse amines.
D. Menche, F. Arikan, Synlett, 2006, 841-844.
A selective and direct access to secondary amines by reductive mono-N-alkylation of primary amines with carbonyl compounds in the presence of Ti(i-PrO)4 and NaBH4 gave exclusively secondary amines.
H. J. Kumpaty, S. Bhattacharyya, E. W. Rehr, A. M. Gonzalez, Synthesis, 2003, 2206-2210.
An experimentally simple Microwave-assisted reductive alkylation of methyl carbamate with a range of aldehydes provides, after basic work-up, structurally diverse primary amines. This method is particularly amenable to high-throughput synthesis.
F. Lehmann, M. Scobie, Synthesis, 2008, 1679-1681.
Treatment of ketones with ammonia in ethanol and titanium(IV) isopropoxide, followed by in situ reduction with sodium borohydride allows a highly chemoselective reductive mono-alkylation of ammonia. A simple workup afforded primary amines in good to excellent yields. Reductive alkylation of ammonia with aldehydes afforded the corresponding symmetrical secondary amines selectively.
B. Miriyala, S. Bhattacharyya, J. S. Williamson, Tetrahedron, 2004, 60, 1463-1471.
A mild and efficient one-pot reductive amination of aldehydes and ketones with amines using α-picoline-borane as a reducing agent in the presence of small amounts of AcOH is described. The reaction has been carried out in MeOH, in H2O, and in neat conditions. This is the first successful reductive amination in water and in neat conditions.
S. Sato, T. Sakamoto, E. Miyazawa, Y. Kikugawa, Tetrahedron, 2004, 60, 7899-7906.
N-Alkylaminobenzenes were prepared in a simple and efficient one-pot synthesis by reduction of nitrobenzenes followed by reductive amination with decaborane (B10H14) in the presence of 10% Pd/C.
J. W. Bae, Y. J. Cho, S. H. Lee, C.-O. M. Yoon, C. M. Yoon, Chem. Commun., 2000, 1857-1858.
An efficient, directed reductive amination of β-hydroxy-ketones allows the stereoselective preparation of 1,3-syn-amino alcohols using Ti(iOPr)4 for coordination of the intermediate imino alcohol and PMHS as the reducing agent.
D. Menche, F. Arikan, J. Li, S. Rudolph, Org. Lett., 2007, 9, 267-270.
An efficient method for the direct reductive alkylation of hydrazine derivatives with α-picoline-borane provided various N-alkylhydrazine derivatives upon fine-tuning of the substrates and the reagent equivalency in a one-pot manner. The method was applied to the synthesis of active pharmaceutical ingredients of therapeutic drugs such as isocarboxazid.
Y. Kawase, T. Yamagishi, J.-y. Kato, T. Kutsuma, T. Kataoka, T. Iwakuma, T. Yokomatsu, Synthesis, 2014, 46, 455-464.
An achiral amine in combination with a catalytic amount of a chiral Brønsted acid can accomplish an aldol addition-dehydration-conjugate reduction-reductive amination with 2,6-diketones to provide cyclohexylamines as potential intermediates of pharmaceutically active compounds in good yields and excellent enantioselectivities.
J. Zhou, B. List, J. Am. Chem. Soc., 2007, 129, 7498-7499.