Categories: C-N Bond Formation > Amines >
Synthesis of α-Amino ketones, acids, esters, nitriles and related compounds
A mild and efficient monocarboxymethylation of a broad range of primary amines takes place under aqueous conditions at room temperature. Treatment of primary amines with two equivalents of glyoxylic acid leads to N-formyl glycine derivatives. Subsequent hydrolysis of the crude reaction solution gives monocarboxymethylated products in very good yield.
T. J. K. Gibbs, M. Boomhoff, N. C. O. Tomkinson, Synlett, 2007, 1573-1575.
A class of axially chiral pyridoxamines bearing a lateral amine arm exhibited high catalytic activity and excellent enantioselectivity in asymmetric transamination of α-keto acids, to give various α-amino acids in very good yields and with high ee's. The lateral amine arm likely participates in cooperative catalysis as the Lys residue does in biological transamination and enhances both the activity and the enantioselectivity.
Y. E. Liu, Z. Lu, B. Li, J. Tian, F. Liu, J. Zhao, C. Hou, Y. Li, L. Niu, B. Zhao, J. Am. Chem. Soc., 2016, 138, 10730-10733.
In the presence of catalytic copper(II) bromide, a direct α-amination of ketones, esters, and aldehydes takes place to produce synthetically useful α-amino-substituted motifs. The transformation is proposed to proceed via a catalytically generated α-bromo carbonyl species followed by nucleophilic displacement of the bromide by the amine, which delivers the α-amino carbonyl adduct while the catalyst is reconstituted.
R. W. Evans. J. R. Zbieg, S. Wu, W. Li, D. W. C. MacMillan, J. Am. Chem. Soc., 2013, 135, 16074-16077.
The use of visible light and a silane reductant enables a carbonyl alkylative amination reaction that combines a wide range of primary amines, α-ketoesters, and alkyl iodides to form functionally diverse all-alkyl α-tertiary amino esters. A Brønsted acid-mediated formation of a ketiminium species is followed by rapid 1,2-addition of an alkyl radical (generated from an alkyl iodide).
J. H. Blackwell, R. Kumar, M. J. Gaunt, J. Am. Chem. Soc., 2021, 143, 1598-1609.
The use of ammonium iodide as the catalyst and sodium percarbonate as the co-oxidant enables a transition-metal-free direct α-C-H amination of ketones. A wide range of ketone ((hetero)aromatic or nonaromatic ketones) and amine (primary/secondary amines, anilines, or amides) substrates undergo cross-coupling to generate synthetically useful α-amino ketones.
Q. Jiang, B. Xu, A. Zhao, J. Jia, T. Liu, C. Guo, J. Org. Chem., 2014, 79, 8750-8756.
The use of N-bromosuccinimide enables a metal-free one-pot strategy for the synthesis of pharmaceutically important α-amino ketones from readily available benzylic secondary alcohols and amines. This reaction proceeds via three consecutive steps involving oxidation of alcohols, α-bromination of ketones, and nucleophilic substitution of α-bromo ketones to give α-amino ketones.
S. Guha, V. Rajeshkumar, S. S. Kotha, G. Sekar, Org. Lett., 2015, 17, 406-409.
A new α-amino acid esters formation via decarboxylation is distinguished by readily accessible starting materials, environmentally benign reaction conditions and waste streams, and wide substrate scope.
J. Zhang, J. Jiang, Y. Li, Y. Zhao, X. Wang, Org. Lett., 2013, 15, 3222-3225.
An efficient TfOH-catalyzed N-H insertion between anilines and α-alkyl and α-aryl-α-diazoacetates provides unnatural α-amino esters in good yieds.
S. Hu, J. Wu, Z. Lu, J. Wang, Y. Tao, M. Jiang, F. Chen, J. Org. Chem., 2021, 86, 3223-3231.
A convenient Ir-catalyzed amidation of silyl ketene acetals with an oxycarbonylnitrenoid provides α-amido esters. Silyl ketene acetals were prepared from esters, without separate purification. The α-amidation was facile for both α-aryl and α-alkyl esters.
J. Gwon, M. Lee, D. Kim, S. Chang, Org. Lett., 2022, 24, 1088-1093.
An intermolecular electrochemical coupling of benzylic C(sp3)-H bonds with various secondary amines provides a direct access to α-amino esters in high yields under mild conditions. A series of acyclic/cyclic secondary amines and α-aryl acetates were tested.
Y. K. Nagare, I. A. Shah, J. Yadav, A. P. Pawar, R. Choudhary, P. Chauhan, I. Kumar, J. Org. Chem., 2021, 86, 9682-9691.
A copper(I)/2,2′-bipyridyl complex catalyzes an amination reaction of silyl ketene acetals with N-chloroamines to give α-amino esters in good yield.
T. Miura, M. Morimoto, M. Murakami, Org. Lett., 2012, 14, 5214-5217.
An aza analogue of the Rubottom oxidation of silyl enol ethers takes place at ambient temperature and provides primary α-aminoketones. The use of hexafluoroisopropanol (HFIP) as the solvent is crucial for the success of this facile aza-functionalization reaction.
Z. Zhou, Q.-Q. Cheng, L. Kürti, J. Am. Chem. Soc., 2019, 141, 2242-2246.
A metal-free insertion of sulfoxonium ylides into arylamines employs water as solvent at mild temperature and is amenable to the late-stage modification of structurally complex bioactive compounds.
H. He, K. Yan, J. Li, R. Lai, Y. Luo, M. Guan, Y. Wu, Synthesis, 2020, 52, 1841-1846.
The combination of dirhodium(II)/Xantphos catalyzes a three-component reaction of readily accessible amines, diazo compounds, and allylic compounds to afford various architecturally complex and functionally diverse α-quaternary α-amino acid derivatives in good yields with high atom and step economy.
B. Lu, X. Liang, J. Zhang, Z. Wang, Q. Peng, X. Wang, J. Am. Chem. Soc., 2021, 143, 11799-11810.
A Xantphos-containing dinuclear palladium complex catalyzes a geminal aminoallylation of diazocarbonyl compounds to provide a range of quaternary α-amino esters. Direct N-H insertion, allylic alkylation of amino nucleophiles, and diene formation were not observed under standard conditions.
P. Ou, L. Zhu, Y. Yu, L. Ma, X. Huang, Org. Lett., 2022, 24, 4109-4113.
A diastereoselective α-amination of amides employing simple azides proceeds under mild conditions with release of nitrogen gas. The reaction is fully chemoselective for amides even in the presence of esters or ketones and lends itself to preparation of optically enriched products.
V. Tona, A. de la Torre, M. Padmanaban, S. Ruider, L. González, N. Maulide, J. Am. Chem. Soc., 2016, 138, 8348-8351.
By rendering the α-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate α-functionalized amides.
C. R. Gonçalves, M. Lemmerer, C. J. Teskey, P. Adler, D. Kaiser, B. Maryasin, L. González, N. Maulide, J. Am. Chem. Soc., 2019, 141, 18437-18443.
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 highly efficient copper-catalyzed asymmetric insertion of α-diazoesters into N-H bonds using chiral spiro bisoxazoline ligands affords α-amino acid derivatives in high yields with excellent enantioselectivities.
B. Liu, S.-F. Zhu, W. Zhang, C. Chen, Q.-L. Zhou, J. Am. Chem. Soc., 2007, 129, 5834-5835.
Dibenzenesulfonimide is a nitrogen source of choice in terms of the yields and the reaction time in a transition-metal-free intermolecular N-H insertion of α-diazocarbonyl compounds. Primary mechanistic experiments suggest that a pathway involves a sequence of protonation and nucleophilic substitution.
X. Luo, G. Chen, L. He, X. Huang, J. Org. Chem., 2016, 81, 2943-2949.
A new Cu/chiral bipyridine catalyst for the asymmetric insertion of α-diazocarbonyl compounds into the N-H bonds of carbamates generate an array of easily deprotected arylglycines in good ee.
E. C. Lee, G. C. Fu, J. Am. Chem. Soc., 2007, 129, 12066-12067.
An oxo-amination process with readily available N-bromosuccinimide (NBS) and secondary amines as N-sources and dimethyl sulfoxide (DMSO) as the oxidant provides amino alcohols in a single step. For the first time, the formation of reactive Me2S+-O-Br species generated by the interaction of NBS with DMSO has been proven.
P. K. Prasad, R. N. Reddi, A. Sudalai, Org. Lett., 2016, 18, 500-503.
Use of cinchona ligands with an anthraquinone (AQN) core, in place of the usual phthalazine (PHAL) core, in the asymmetric aminohydroxylation of cinnamates causes dramatic reversal of the regioselection, so that phenyl serines are obtained in high enantiomeric excess. Hence, the regioselectivity is controlled by the ligand and not the substrate.
B. Tao, G. Schlingloff, K. B. Sharpless, Tetrahedron Lett., 1998, 39, 2507-2510.
D. F. Taber, R. B. Sheth, P. V. Joshi, J. Org. Chem., 2005, 70, 2851-2854.
A straightforward three-component reaction of preformed aromatic or in situ generated benzylic organozinc reagents with amines and ethyl glyoxylate allows the synthesis of a range of α-amino esters in very good yields. The procedure, which is characterized by its simplicity, allows the concise synthesis of esters bearing a phenylglycine or a phenylalanine scaffold.
C. Haurena, E. Le Gall, S. Sengmany, T. Martens, M. Troupel, J. Org. Chem., 2010, 75, 2645-2650.
C. Haurena, E. Le Gall, S. Sengmany, T. Martens, M. Troupel, J. Org. Chem., 2010, 75, 2645-2650.
A simple, commercially available iridium catalyst allows the use of sulfoxonium ylides as a carbene source for various intra- and intermolecular X-H bond insertions, including a practical ring-expansion strategy for lactams. The safety and stability of sulfoxonium ylides recommend them as preferable surrogates to traditional diazo ketones and esters.
I. K. Mangion, I. K. Nwamba, M. Shevlin, M. A. Huffman, Org. Lett., 2009, 11, 3566-3569.
A readily accessible chiral copper catalyst can achieve a photoinduced, enantioconvergent coupling of a variety of racemic tertiary alkyl electrophiles with aniline nucleophiles to generate a new C-N bond with good ee at the fully substituted stereocenter of the product.
H. Cho, H. Suematsu, P. H. Oyala, J. C. Peters, G. C. Fu, J. Am. Chem. Soc., 2022, 144, 4550-4558.
An efficient, safe, and environmentally friendly TBHP-mediated rearrangement of aryl/alkylidene malononitrile with anilines produces in situ HCN as the cyanide source for the synthesis of substituted α-aminonitriles and α-aminoamides in very good yields. This method features good functional group tolerance, and the in situ-generated HCN bypasses the use of an external cyanide source.
S. P. Bhoite, A. H. Bansode, G. Suryavanshi, J. Org. Chem., 2020, 85, 14858-14865.
The use of iodosobenzene (PhIO) as oxidant and p-toluenesulfonamide (TsNH2) as aminating reagent in the presence of a catalytic amount of perchlorate zinc hexahydrate enables a direct α-amination of β-dicarbonyl compounds. The reaction proceeds quickly at rt to provide the corresponding α-N-tosylamido β-dicarbonyl compounds very good yields.
J. Yu, S.-S. Liu, J. Cui, X.-S. Hou, C. Zhang, Org. Lett., 2012, 14, 832-835.
N-Triflylimino-λ3-iodanes, which can be generated in situ from iodosylarene and triflylamide, can be used for imidations of phosphines and α-amidations of 1,3-dicarbonyl compounds without any other additives. The imino-λ3-iodanes can also be catalytically generated from an iodoarene precatalyst with oxone and triflylamide.
S. Sunagawa, F. Morisaki, T. Baba, A. Tsubouchi, A. Yoshimura, K. Miyamoto, M. Uchiyama, A. Saito, Org. Lett., 2022, 24, 5230-5234.
The use of arylhydroxylamines as aminating agents enables a direct Fe-catalyzed α-amination of 1,3-dicarbonyl compounds. This operationally simple procedure, that works at low temperatures in short reaction times and produces high yields with excellent N-selectivity, allows convenient access to α-amino carbonyl derivatives.
S. Murru, C. S. Lott, F. R. Fronczek, R. S. Srivastava, Org. Lett., 2015, 17, 2122-2125.
The intriguing Rh2(OAc)4 and chiral Brønsted acid cocatalyzed three-component Mannich-type reaction of a diazo compound, a carbamate, and an imine provides rapid and efficient access to both syn- and anti-α-substituted α,β-diamino acid derivatives with a high level control of chemo-, diastereo-, and enantioselectivity.
J. Jiang, H.-D. Xu, J.-B. Xi, B.-Y. Ren, F.-P. Lv, X. Guo, L.-Q. Jiang, Z.-Y. Zhang, W.-H. Hu, J. Am. Chem. Soc., 2011, 133, 8428-8431.
C-Acylimines undergo intermolecular amidation with amides to produce monoacyl gem-diamino acid derivatives in the presence of Cu(OTf)2 and PPh3 under mild conditions. This method provides an efficient access to gem-diamino acid equivalents with good to excellent yields.
S. Zhu, J. Dong, S. Fu, H. Jiang, W. Zeng, Org. Lett., 2011, 13, 4914-4917.
Chelated amino acid ester enolates react with aromatic nitro compounds in a 1,3-addition mode at the nitro group giving amino acids bearing an aryl(hydroxy)amino side chain. Two equivalents of enolate are necessary for complete conversion, because one equivalent is oxidized during the reaction.
D. Stolz, U. Kazmaier, R. Pick, Synthesis, 2006, 3341-3347.
Different aldehydes and amines react with acyl cyanides in the presence of a catalytic amount of the Schreiner thiourea catalyst to give the corresponding N-acyl amino nitriles in high yields. The scope of the reaction is broad and allows the use of both aromatic and aliphatic aldehydes and amines.
S. C. Pan, B. List, Synlett, 2007, 318-320.
The regio- and stereoselective aminochlorination of α,β-unsaturated ketones with N,N-dichloro-p-toluenesulfonamide (4-TsNCl2) and CuOTf as catalyst provides an easy access to vicinal haloamino ketones, with excellent regioselectivity and good yields. Aromatic and aliphatic enones give opposite regioselectivity.
D. Chen, C. Timmons, S. Chao, G. Li, Eur. J. Org. Chem., 2004, 3097-3101.
A highly regio- and enantioselective hydroxyamination of aldehydes with in situ generated nitrosocarbonyl compounds from hydroxamic acid derivatives was realized by combining TEMPO and BPO as oxidants in the presence of a binaphthyl-modified amine catalyst.
T. Kano, F. Shirozu, K. Maruoka, J. Am. Chem. Soc., 2013, 135, 17735-17738.
A Cu-catalyzed propargylic amination of amines with propargylic cyclic carbonates provides chiral acyclic α-quaternary α-amino ketones. This protocol offers wide functional group tolerance and high asymmetric induction.
W. Guo, L., Zuo, M. Cui, B. Yan, S. Ni, J. Am. Chem. Soc., 2021, 143, 7629-7634.
L-Proline-catalyzed asymmetric α-amination of ketones proceeds with various azodicarboxylates as the nitrogen source in high yields and excellent enantioselectivities. The scope and potential of the reaction are demonstrated by further transformation of the α-hydrazino ketones formed to both optically active syn and anti-α-amino alcohol derivatives.
N. Kumaragurubaran, K. Juhl, W. Zhuang, A. Gogevig, K. A. Jorgensen, J. Am. Chem. Soc., 2002, 124, 6254-6255.
Chiral tertiary α-hydroxy esters were transformed to α-azido esters by Mitsunobu reaction with HN3. Reactions proceed at room temperature with high chemical yield using 1,1-(azodicarbonyl)dipiperidine (ADDP) and trimethylphosphine (PMe3) with complete inversion of configuration at the α-carbon. Several α,α-disubstituted amino acids were synthesized in high overall chemical yield and optical purity.
J. E. Green, D. M. Bender, S. Jackson, M. J. O'Donnell, J. R. McCarthy, Org. Lett., 2009, 11, 807-810.
A novel enantioselective synthesis of α-amino acids has been developed, which is broad in scope, simple in application, and advantageous for many α-amino acids of interest in chemistry, biology, medicine.
E. J. Corey, J. O. Link, J. Am. Chem. Soc., 1992, 114, 1906-1908.
In a one-pot cascade transformation of ketones into α-imidoketones, N-bromosuccinimide (NBS) provides both electrophilic bromine and nucleophilic nitrogen sources, and diazabicyclo[5.4.1]undec-7-ene (DBU) functions as a base and a nucleophilic promoter for the activation of NBS. α-Bromination is supposed as the key step in the process.
Y. Wei, S. Lin, F. Liang, Org. Lett., 2012, 14, 4202-4205.
A synthesis of various amino phosphonates has been achieved via phosphonate substituted carbene insertion into the N-H bond of aniline catalyzed by readily available copper salt under mild reaction conditions in water. Using this environmentally benign methodology a large number of biologically important amino phosphonates have been synthesized in good isolated yields.
K. Ramakrishna, J. M. Thomas, C. Sivasankar, J. Org. Chem., 2016, 81, 9826-9835.
A cascade reaction of carboxylic acids with vinyl azides enables an efficient synthesis of α-amidoketone derivatives. This method offers catalyst-free conditions, broad substrate scope, good tolerance of a wide range of functional groups, and high efficiency.
C. Gao, Q. Zhou, X. Zhang, X. Fan, J. Org. Chem., 2020, 85, 13710-13720.
N-Sulfonyl-1,2,3-triazoles react with water in the presence of a rhodium catalyst to produce α-amino ketones in high yield. This transformation formally achieves 1,2-aminohydroxylation of terminal alkynes in a regioselective fashion in combination with a copper(I)-catalyzed 1,3-dipolar cycloaddition with N-sulfonyl azides.
T. Miura, T. Biyajima, T. Fujii, M. Murakami, J. Am. Chem. Soc., 2012, 134, 194-196.
Umpolung reactions of N-trimethylsilyl α-iminoester with organometallics provide deprotected N-alkylaminoesters. Furthermore, tandem N,N- or N,C-dialkylation reactions enable efficient syntheses of pyrrolidines, piperidines, and iminodiacetate derivatives.
I. Mizota, Y. Tadano, Y. Nakamura, T. Haramiishi, M. Hotta, M. Shimizu, Org. Lett., 2019, 21, 2663-2667.
A totally regioselective transformation of aromatic N-4-methoxyphenylaziridine 2-carboxamides into 2-aminoamides is promoted by active manganese (Mn*). α-Amino ketones can be readily obtained by reaction of morpholine-derived 2-aminoamides with organolithium compounds.
J. M. Concellón, H. Rodríguez-Solla, V. del Amo, P. Díaz, J. Org. Chem., 2010, 75, 2407-2410.
Structurally and functionally diverse N-carbamoylamino acids were obtained through the alkylation of monosubstituted parabanic acids followed by hydrolysis of the intermediate products in very good yields and excellent purity.
A. V. Bogolubsky, S. V. Ryabukhin, G. G. Pakhomov, E. N. Ostapchuk, A. N. Shivanyuk, A. A. Tolmachev, Synlett, 2008, 2279-2282.