Categories: C-N Bond Formation > Amines >
Synthesis of secondary and tertiary amines
Cesium hydroxide promotes a selective N-monoalkylation of primary amines to prepare various secondary amines efficiently. This methodology is highly chemoselective, favoring mono-N-alkylation over dialkylation.
R. N. Salvatore, A. S. Nagle, S. E. Schmidt, K. W. Jung, Org. Lett., 1999, 1, 1893-1896.
A Cp*Ir complex bearing a functional 2,2′-bibenzimidazole ligand is a highly effective and general catalyst for the N-methylation of a variety of amines with methanol in the presence of a weak base.
R. Liang, S. Li, R. Wang, L. Lu, F. Li, Org. Lett., 2017, 19, 5790-5793.
Iridium complexes bearing an N-heterocyclic carbene (NHC) ligand exhibited high catalytic performance for the N-methylation of both aliphatic and aromatic primary amines using methanol as the methylating agent. For aliphatic amines, selective N,N-dimethylation was achieved at low temperatures. For aromatic amines, selective N-monomethylation and selective N,N-dimethylation were accomplished.
G. Toyooka, A. Tuji, K.-i. Fujita, Synthesis, 2018, 50, 4617-4626.
[(p-cymene)Ru(2,2'-bpyO)(H2O)] is a general and efficient catalyst for the N-methylation of amines and sulfonamides with methanol in the presence of a carbonate salt. The reaction tolerates a series of sensitive substituents, such as nitro, ester, cyano, and vinyl groups.
P. Liu, N. T. Tung, X. Xu, J. Yang, F. Li, J. Org. Chem., 2021, 86, 2621-2631.
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.
An iridium catalyst bearing an N-heterocyclic carbene mediates an N,N-dimethylamination of primary alcohols with aqueous dimethylamine in the absence of additional organic solvents via an atom-efficient and environmentally benign borrowing hydrogen process.
J. Jeong, K.-i. Fujita, J. Org. Chem., 2021, 86, 4053-4060.
Cp*-iridium half-sandwich complexes are highly reactive and selective catalysts for the alkylation of amines with alcohols. [Cp*Ir(Pro)Cl] (Pro = prolinato) is active under mild conditions in either toluene or water without the need for base or other additives, tolerates a wide range of alcohols and amines, and gives secondary amines in good to excellent isolated yields.
A. Wetzel, S. Wöckel, M. Schelwies, M. K. Brinks, F. Rominger, P. Hofmann, M. Limbach, Org. Lett., 2013, 15, 266-269.
A simple amino amide ligand enables a ruthenium-catalyzed one-pot alkylation of primary and secondary amines with simple alcohols. Using the alcohol as solvent, alkylation was achieved under mild conditions with high conversion and selectivity. Reactions can also be carried out at high temperatures in organic solvent with high selectivity using stoichiometric amounts of the alcohol.
A. B. Enyong, B. Moasser, J. Org. Chem., 2014, 79, 7559-7563.
Microwave heating enables a Borrowing Hydrogen strategy to form C-N bonds from alcohols and amines, removes the need for solvent and reduces the reaction times, while the results are comparable with those using thermal heating.
A. J. A. Watson, A. C. Maxwell, J. M. J. Williams, J. Org. Chem., 2011, 76, 2328-2331.
The addition of 4 Å molecular sieves enables an efficient cobalt(II)-catalyzed N-alkylation of both aromatic and aliphatic amines with alcohols with high chemoselectivity (amines vs imines). A hydrogen-borrowing mechanism is responsible for the tandem acceptorless dehydrogenation/condensation/hydrogenation process.
G. Zhang, Z. Yin, S. Zheng, Org. Lett., 2016, 18, 300-303.
A silver-loaded titanium dioxide (Ag/TiO2) photocatalyst enables a facile N-methylation of amines with methanol at room temperature under UV-vis light irradiation. This method tolerates various functional groups including N-benzyl, N-allyl, N-Boc, hydroxyl, ether, acetal, carboxamide, formamide, and olefin groups.
V. N. Tsarev, Y. Morioka, J. Caner, Q. Wang, R. Ushimaru, A. Kudo, H. Naka, S. Saito, Org. Lett., 2015, 17, 2530-2533.
A magnesium-catalyzed reduction of linear and cyclic carbamates, including N-Boc protected amines, provides N-methyl amines and amino alcohols which are of significant interest due to their presence in many biologically active molecules. Furthermore, the reduction can be extended to the formation of N-trideuteromethyl labeled amines.
M. Magre, M. Szewczyk, M. Rueping, Org. Lett., 2020, 22, 3209-3214.
A catalytic system generated in situ from a tetranuclear Ru-H complex with a catechol ligand enables a direct deaminative coupling of two primary amines to form secondary amines. The analogous coupling of aniline with primary amines formed aryl-substituted secondary amines.
P. T. K. Arachchige, H. Lee, C. S. Yi, J. Org. Chem., 2018, 83, 4932-4947.
The selective mono-alkylation of aliphatic amines by unactivated, hindered halides is a challenge in organic synthesis. Primary aliphatic amines can be cleanly mono-alkylated by unactivated secondary alkyl iodides in the presence of visible light and a copper catalyst. The method operates under mild conditions (-10 °C) and displays good functional-group compatibility.
C. D. Matier, J. Schwaben, J. C. Peteres, G. C. Fu, J. Am. Chem. Soc., 2017, 139, 17707-17710.
A one-pot two-step sequence involving an oxidation/imine-iminium formation/reduction allowed the N-alkylation of amines by alcohols. Optically active alcohols and amines can be converted without any epimerization.
C. Guérin, V. Bellosta, G. Guillamot, J. Cossy, Org. Lett., 2011, 13, 3478-3481.
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.
Using 0.5 mol % [Ru(p-cymene)Cl2]2 with the bidentate phosphines dppf or DPEphos as the catalyst, primary amines have been converted into secondary amines, and secondary amines into tertiary amines. N-Heterocyclization reactions of primary amines have been achieved, as well as alkylation reactions of primary sulfonamides.
M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C. Maytum, A. J. A. Watson, J. M. J. Williams, J. Am. Chem. Soc., 2009, 131, 1766-1774.
An efficient, environmentally benign and practical one-pot reductive tandem mono-N-alkylation of both aromatic and aliphatic azides using dialkylboron triflates as alkylating agents enables the syntheses of various secondary alkyl as well as aryl amines, including the synthesis of N10-butylated pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones via in situ azido reductive-cyclization process.
N. Shankaraiah, N. Markandeya, V. Srinivasulu, K. Sreekanth, C. S. Reddy, L. S. Santos, A. Kamal, J. Org. Chem., 2011, 76, 7017-7026.
An iridium complex catalyzes pH-dependent selective N-allylation or N-alkylation of amines with allylic alcohols in outstanding yields with water as the environmental benign solvent.
N. Luo, Y. Zhong, H. Shui, R. Luo, J. Org. Chem., 2021, 86, 15509-15521.
Manganese dioxide is employed as an in situ oxidant for the one-pot conversion of alcohols into imines. In combination with polymer-supported cyanoborohydride (PSCBH), a one-pot oxidation-imine formation-reduction sequence enables alcohols to be converted directly into both secondary and tertiary amines.
L. Blackburn, R. J. K. Taylor, Org. Lett., 2001, 3, 1637-1639.
(Cyanomethyl)phosphonium iodides are easy to prepare and to handle. These reagents efficiently promote the direct, intermolecular N-alkylation of amines with alcohols.
F. Zaragoza, H. Stephensen, J. Org. Chem, 2001, 66, 2518-2521.
Well-defined Co(II) complexes stabilized by a PCP ligand catalyze efficient alkylations of aromatic amines by primary alcohols into mono-N-alkylated amines in very good yields. The inexpensive, earth-abundant nonprecious metal catalysts make this acceptorless alcohol dehydrogenation concept environmentally benign.
M. Mastalir, G. Tomsu, E. Pittenauer, G. Allmaier, K. Kirchner, Org. Lett., 2016, 18, 3462-3465.
A direct, stereospecific amination of alkylboronic and borinic esters can be accomplished by treatment with methoxyamine and potassium tert-butoxide. In addition, this process also enables the direct amination of tertiary boronic esters in an efficient fashion.
E. K. Edelstein, A. C. Grote, M. D. Palkowitz, J. P. Morken, Synlett, 2018, 29, 1749-1752.
A highly enantio- and regioselective copper-catalyzed hydroamination reaction of alkenes with hydroxylamine esters in the presence of diethoxymethylsilane enables the conversion of a wide variety of substituted styrenes, including trans-, cis-, and β,β-disubstituted styrenes, to yield α-branched amines. In addition, aliphatic alkenes gave exclusively the anti-Markovnikov hydroamination products.
S. Zhu, N. Niljianskul, S. L. Buchwald, J. Am. Chem. Soc., 2013, 135, 15746-15749.
A method for highly selective anti-Markovnikov hydroamination of terminal alkenes involves hydroboration of the alkene followed by a novel electrophilic amination of the alkyl borane catalyzed by an NHC-Cu complex. Terminal alkenes are successfully transformed into tertiary alkyl amines in the presence of a variety of functional groups in very good yields ranging with excellent regioselectivity.
R. P. Rucker, A. M. Whittaker, H. Dang, G. Lalic, J. Am. Chem. Soc., 2012, 134, 6571-6574.
A base-mediated hydroamination protocol with substoichiometric amounts of a hydrosilane and potassium tert-butoxide operates under mild conditions. Many aryl- and heteroatom-substituted olefins as well as arylamines are tolerated, affording the desired products with complete regioselectivity.
P. Li, B. C. Lee, X. Zhang, M. J. Koh, Synthesis, 2022, 54, 1566-1576.
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.
A new synthetic method for the preparation of potassium organotrifluoroborates through nucleophilic substitution of potassium bromo- and iodomethyltrifluoroborates is described. Potassium halomethyltrifluoroborates have been prepared via in situ reaction of n-BuLi with dibromo- and diiodomethane, respectively, in the presence of trialkyl borates, followed by treatment with KHF2.
G. A. Molander, J. Ham, Org. Lett., 2006, 8, 2031-2034.
A copper-catalyzed electrophilic amination of simple and functionalized aryl, heteroaryl-, benzyl, n-alkyl, sec-alkyl, and tert-alkyl diorganozinc nucleophiles with R2NOC(O)Ph and RHNOC(O)Ph reagents as electrophilic nitrogen sources provides tertiary and secondary amines, respectively, in generally good yields. In many cases, the product may be isolated analytically pure after a simple extractive workup. A Cu-catalyzed amination of Grignard reagents using cocatalysis by ZnCl2 is described.
A. M. Berman, J. S. Johnson, J. Org. Chem., 2006, 71, 219-224.
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.
An iron-catalyzed hydroamination and hydroamidation of allylic alcohols provides γ-amino and γ-amido alcohols, respectively. The catalytic system, consisting of a pincer Fe-PNP complex, a weak base, and a nonpolar solvent, offers exclusive anti-Markovnikov selectivity, broad substrate scope, and good functional group tolerance.
W. Ma, X. Zhang, J. Fan, Y. Liu, W. Tang, D. Xue, C. Li, J. Xiao, C. Wang, J. Am. Chem. Soc., 2019, 141, 13506-13515.
Selective mono-N-alkylation of 3-amino alcohols relies on formation of a stable chelate with 9-BBN. Three prototypical amino alcohols featuring various bridging units led selectively to the monoalkylated derivatives in very high yields.
G. Bar-Haim, M. Kol, Org. Lett., 2004, 6, 3549-3551.
A wide range of chiral propargylamines can be prepared in a one-pot three-component reaction between an alkyne, an aldehyde and a secondary amine at room temperature in the presence of CuBr and (R)-quinap in good yield and good enantioselectivity.
N. Gommermann, C. Koradin, K. Polborn, P. Knochel, Angew. Chem., 2003, 115, 5941-5944.
An efficient palladium-catalyzed asymmetric amination of 2,3-allenyl phosphates with nitrogen nucleophiles such as amines, hydroxylamines, and imides can be performed in presence of SEGPHOS or MeOBIPHEP ligand, affording the corresponding optically active 1-aminated derivatives with high enantiomeric excess.
Y. Imada, M. Nishida, K. Kutsuwa, S.-I. Murahashi, T. Naota, Org. Lett., 2005, 7, 5837-5839.
An aryloxotitanium complex is a highly chemo- and regioselective catalyst for intermolecular hydroamination of terminal alkynes. Branched imines are obtained in good yield with various primary aromatic and aliphatic amines.
V. Khedkar, A. Tillak, M. Beller, Org. Lett., 2003, 5, 4767-4770.
A polymer-bound, triphenylphosphine-supported reagent allows a one-pot, two-step synthesis of secondary amines from the corresponding azide and a reactive alkyl halide.
S. Ayesa, B. Samuelsson, B. Classon, Synlett, 2008, 89-93.
β-Piperidinoethylsulfides can be oxidized by m-chloroperbenzoic acid to intermediates containing both N-oxide and sulfone functions. These undergo a Cope-type elimination to a vinylsulfone that can be captured by amines to afford β-aminoethylsulfones. The synthetic methodology developed can be utilized in multiple-parallel format and has numerous potential applications in medicinal chemistry.
R. J. Gruffin, A. Henderson, N. J. Curtin, A. Echalier, J. A. Endicott, I. R. Hardcastle, D. R. Newell, M. E. M. Noble, L.-Z. Wang, B. T. Golding, J. Am. Chem. Soc., 2006, 128, 6012-6013.