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Synthesis of benzylamines


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A Mannich-like zinc-mediated three-component reaction of aromatic halides, amines, and paraformaldehyde allows the straightforward synthesis of a range of functionalized tertiary benzylamines. This procedure involves the in situ formation of arylzinc reagents.
E. Le Gall, A. Decompte, T. Martens, M. Troupel, Synthesis, 2010, 249-254.

Suzuki-Miyaura cross-coupling reactions of Boc-protected aminomethyltrifluoroborate with a variety of both aryl and hetaryl chlorides gives aminomethylated arenes in very good yields. Potassium Boc-protected aminomethyltrifluoroborate can successfully be synthesized through a one-pot process.
G. A. Molander, I. Shin, Org. Lett., 2011, 13, 3956-3959.

Suzuki-Miyaura cross-coupling enables a one-pot primary aminomethylation of aryl halides, triflates, mesylates, and tosylates via coupling with sodium phthalimidomethyltrifluoroborate followed by deamidation with ethylenediamine.
N. Murai, M. Miyano, M. Yonaga, K. Tanaka, Org. Lett., 2012, 14, 2818-2821.

Scope and limitations of the Suzuki-Miyaura reaction of N,N-dialkylaminomethyltrifluoroborates with aryl halides were investigated. Aryl chlorides, iodides, and triflates coupled in good to excellent yields to give N,N-dialkylbenzylic amines.
G. A. Molander, P. E. Gormisky, D. L. Sandrock, J. Org. Chem., 2008, 73, 2052-2057.

The combination of chiral bicyclo[3.3.0]octadiene ligands, an active rhodium hydroxide complex, and neutral reaction conditions enabled a highly enantioselective rhodium-catalyzed arylation of aliphatic N-tosylaldimines in high yield. The application of this method is demonstrated by the enantioselective synthesis of chiral 2-aryl pyrrolidines and piperidines in a one-pot procedure.
Z. Cui, H.-J. Yu, F.-F. Yang, W.-Y. Gao, C.-G. Feng, G.-Q. Lin, J. Am. Chem. Soc., 2011, 133, 12394-12397.

The synthesis of free α-chiral amines by a one-pot multicomponent procedure involves the formation of N-diphenylphosphinoylimines from commercially available starting materials and the subsequent enantioselective addition of diakylzinc reagents using an air-stable precatalyst complex.
A. Cote, A. B. Charette, J. Org. Chem., 2005, 70, 10864-10867.

An asymmetric arylation of N-tosylimines with arylboronic acids was realized by using a chiral cationic C2-symmetric N-heterocyclic carbene Pd2+ diaquo complex as catalyst in combination with K3PO4 • 3 H2O in THF at 4°C in the presence of powdered 4 Å MS to afford the corresponding adducts in excellent yields and good enantioselectivities.
G.-N. Ma, T. Zhang, M. Shi, Org. Lett., 2009, 11, 875-878.

A nickel/photoredox dual catalysis strategy enables a site-selective α-arylation of various trialkylamines with exclusive N-Me selectivity under mild conditions, even in the context of late-stage arylation of pharmaceutical compounds bearing this common structural motif.
Y. Shen, T. Rovis, J. Am. Chem. Soc., 2021, 143, 16364-16369.

A nickel-catalyzed asymmetric decarboxyarylation of NHP esters via reductive cross-coupling provides structurally diverse chiral benzylamines. This method has demonstrated excellent catalytic efficiency, high enantioselective control, mild conditions, and good functional group tolerance.
C.-Y. Wang, Y.-L. Huang, W.-C. Xu, G. Gao, P. Liu, Y.-X. Bi, G.-K. Liu, X.-S. Wang, Org. Lett., 2023, 25, 6925-6930.

ert-Butylperoxyamido acetals can be generated in high yields under mild conditions via oxidative functionalization of C-H bonds adjacent to the amide nitrogen atom. Treatment with Grignard reagents enables the synthesis of α-substituted amides.
H. Yu, J. Shen, Org. Lett., 2014, 16, 3204-3207.

A highly efficient Bi(OTf)3-catalyzed multicomponent synthesis of amidomethylated arenes and heteroarenes from readily available starting materials proceeds under mild conditions and has a broad substrate scope with water as the only side product.
A. E. Schneider, G. Manolikakes, Synlett, 2013, 24, 2057-2060.

A copper-catalyzed Petasis-type reaction of imines, acid chlorides, and organoboranes gives α-substituted amides. This reaction does not require the use of activated imines or the transfer of special units from the organoboranes and represent a useful generalization of the Petasis reaction.
M. S. T. Morin, Y. Lu, D. A. Black, B. A. Arndtsen, J. Org. Chem., 2012, 77, 2013-2017.

A highly efficient three-component coupling reaction between thioformamides and organolithium and Grignard reagents was developed. The generality of the process has been demonstrated by using various combinations of reactants and reagents.
T. Murai, F. Asai, J. Am. Chem. Soc., 2007, 129, 780-781.

A highly efficient asymmetric intermolecular Ni-catalyzed reductive dicarbofunctionalization of vinyl amides, vinyl boranes, or vinyl phosphonates with two distinct readily available electrophiles, namely, Csp2- and Csp3-halides, provides chiral products in a highly regio- and enantioselective manner.
X. Wei, W. Shu, A. García-Domínguez, E. Merino, C. Nevado, J. Am. Chem. Soc., 2020, 142, 13515-13522.

Sequential addition reactions of Grignard reagents to thioformamides give tertiary amines in an efficient manner. The addition of different Grignard reagents can be accomplished by using one equivalent of arylmagnesium reagent in the first step followed by alkyl, alkenyl, aryl, or alkynyl reagents to afford the corresponding amines in good to high yields.
T. Murai, K. Ui, Narengerile, J. Org. Chem., 2009, 74, 5703-5706.

A general aminoalkylation of aryl halides with α-silylamines overcomes intolerance of free amines in nickel-mediated C-C coupling. The reaction features broad functional group tolerance and high efficiency. The fast desilylation is facilitated by single-electron transfer (SET) in the presence of carbonate to provide α-amino radicals, which then engage in nickel-mediated C-C coupling.
W. Dong, S. O. Badir, X. Zhang, G. A. Molander, Org. Lett., 2021, 23, 4250-4255.

A mild, versatile, copper-catalyzed three-component coupling of organoindium reagents with imines and acid chlorides provides α-substituted amides or N-protected amines in a single step with the sole byproduct being indium trichloride.
D. A. Black, B. A. Arndtsen, Org. Lett., 2006, 8, 1991-1993.

Highly regioselective and efficient Heck reactions of aryl triflates with N-acyl-N-vinylamines were achieved using Pd2(dba)3, dppf, and diethylisopropylamine in dioxane. The coupling products easily underwent acidic hydrolysis to the corresponding aryl methyl ketones or in situ hydrogenation in the presence of (Ph3P)3RhCl under a hydrogen atmosphere to provide the N-acyl derivatives of benzylic amines.
A. L. Hansen, T. Skydstrup, J. Org. Chem., 2005, 70, 5997-6003.

A nickel-catalyzed reductive cross-coupling of cyclopropylamine NHP esters with (hetero)aryl halides provides direct access to 1-arylcyclopropylamines, a bioisosteric motif commonly used in small molecule drug discovery. The reaction proceeds rapidly (<2 h) with excellent functional group tolerance. The method can also be extended to the arylation of four-membered strained rings.
M. S. West, A. L. Gabbey, M. P. Huestis, S. A. L. Rousseaux, Org. Lett., 2022, 24, 8441-8446.