and related compounds
Hantzsch esters, which are products of the Hantzsch Dihydropyridine Synthesis, are mild reducing agents, that are often used in transfer hydrogenations of activated C=C bonds, C=O bonds in carbonyl compounds, and C=N bonds in imines. The presence of a Lewis or Brønstedt acid catalyst for further activation of the hydrogen acceptor is often required. In case of chiral catalysts, transfer hydrogenations can occur enantioselectively.
An efficient and highly enantioselective conjugate transfer hydrogenation of α,β-unsaturated ketones is catalyzed by a salt made from tert-butyl valinate and a recently introduced powerful chiral phosphoric acid catalyst (TRIP).
N. J. A. Martin, B. List, J. Am. Chem. Soc., 2006, 128, 13368-13369.
The use of a chiral imidazolidinone catalyst has provided a new organocatalytic strategy for the enantioselective reduction of β,β-substituted α,β-unsaturated aldehydes to generate β-stereogenic aldehydes using ethyl Hantzsch ester as the hydrogen source. In addition, an acceleration of E-Z isomerization prior to selective E-olefin reduction allows the use of geometrically impure enals in this operationally simple protocol.
S. G. Ouellet, J. B. Tuttle, D. W. C. MacMillan, J. Am. Chem. Soc., 2005, 7, 32-33.
Bis-methylamido Hantzsch dihydropyridine is an effective transfer hydrogenation reagent for the reduction of α,β-unsaturated ketones. Unreacted Hantzsch amide and the bis-methylamidopyridine byproduct are effectively removed by extraction in contrast to the commonly used Hantzsch diethyl ester. The reaction is more effective for conjugated aromatic substrates than for aliphatics.
S. A. Van Arman, A. J. Zimmet, I. E. Murray, J. Org. Chem., 2016, 81, 3528-3532.
The formation of an alkyl thianthrenium salt/Hantzsch ester electron donor-acceptor complex enables a photocatalyst- and metal-free generation of an alkyl radical and a subsequent C(sp3)-C(sp3) bond formation with activated olefins. This protocol tolerates a broad range of functionality and can successfully be used in late-stage functionalization of pharmaceuticals.
X. Li, W. Si. Z. Liu, H. Qian, T. Wang, S. Leng, J. Sun, Y. Jiao, X. Zhang, Org. Lett., 2022, 24, 4070-4074.
A visible-light-induced cobalt-catalyzed asymmetric reductive 1,2-addition of aryl iodides to aldehydes provides chiral benzyl alcohols in very good yield, and high ee. This methodology offers mild reaction conditions, good functionality tolerance, excellent enantiocontrol, the avoidance of mass metal wastes, and the use of precious metal catalysts.
X. Jiang, H. Jiang, Q. Yang, Y. Cheng, L.-Q. Lu, J. A. Tunge, W.-J. Xiao, J. Am. Chem. Soc., 2022, 144, 8347-8354.
A radical-mediated addition strategy of diazo compounds to diverse alkenes achieves a difunctionalization - either through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT) or formation of azidoalkylation products through an iron catalytic cycle. The methods proceed under mild reaction conditions and show high functional group tolerance.
Y.-L. Su, G.-X. Liu, J.-W. Liu, L. Tram, H. Qiu, M. P. Doyle, J. Am. Chem. Soc., 2020, 142, 13846-13855.
Hantzsch ester as reducing agent enables a cascade Knoevenagel condensation-reduction approach in water. Various reduced Knoevenagel adducts could be easily prepared by direct alkylation of malononitrile, ethyl 2-cyanoacetate, and 2-(4-nitrophenyl)acetonitrile, respectively.
T. He, R. Shi, Y. Gong, G. Jiang, M. Liu, S. Qian, Z. Wang, Synlett, 2016, 27, 1864-1869.
The photoexcitation of Hantzsch ester can directly activate chromium reagents through a single-electron transfer process. The synthetic application was demonstrated through a photoredox decarboxylative allylation of aldehydes with feedstock butadiene without exogenous photocatalysts, metallic reductants, or additives.
S. Lin, Y. Chen, H. Yan, Y. Liu, Y. Sun, E. Hao, C. Shi, D. Zhang, N. Zhu, L. Shi, Org. Lett., 2021, 23, 8077-8081.
A highly enantioselective hydrogenation of enamides is catalyzed by a dual chiral-achiral acid system. By employing a substoichiometric amount of a chiral phosphoric acid and acetic acid, low catalyst loadings of the chiral catalyst were sufficient to provide excellent yield and enantioselectivity of the reduction product.
G. Li, J. C. Antilla, Org. Lett., 2009, 11, 1075-1078.
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.
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.
A thiourea-catalyzed transfer hydrogenation of various aromatic as well as aliphatic aldimines through hydrogen-bonding activation with Hantzsch 1,4-dihydropyridine as the hydrogen source gives the respective amines under acid- and metal-free reaction conditions.
Z. Zhang, P. R. Schreiner, Synlett, 2007, 1455-1457.
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 chemoselective activation of a secondary amide with triflic anhydride in the presence of 2-fluoropyridine enables a mild reduction using triethylsilane, a cheap and rather inert reagent. Imines can be isolated after a basic workup or readily transformed to the aldehydes following an acidic workup. The amine moiety can be accessed by addition of Hantzsch ester to the reaction mixture.
G. Pelletier, W. S. Bechara, A. B. Charette, J. Am. Chem. Soc., 2010, 132, 12817-12819.
A metal-free photocatalytic coupling reaction of α-diazoacetates and alkyl N-hydroxyphthalimide esters provides structurally and functionally diverse N-alkyl hydrazones. By employing Rose Bengal as a photocatalyst with yellow LEDs irradiation and Hantzsch ester as both an electron donor and proton source, over 60 N-alkyl hydrazones were synthesized.
C.-M. Chan, Q. Xing, Y.-C. Chow, S.-F. Hung, W.-Y. Yu, Org. Lett., 2019, 21, 8037-8043.
Catalyst-free debrominations and dechlorinations of aromatic α-haloketones under visible light irradiation in the presence of Hantzsch ester provide products in excellent yield and tolerate a broad spectrum of substrates.
Z. Lu, Y.-Q. Yang, Synthesis, 2019, 51, 508-515.
Acetates of benzoin derivatives can be effectively reduced using catalytic amounts of [Ru(bpy)3]Cl2 as photoredox catalyst in combination with Hantzsch ester and triethylamine as a sacrificial electron donor. This mild and operationally simple method is applicable to a broad range of substrates providing deoxygenated counterparts in good yields.
E. Speckmeier, C. Padié, K. Zeitler, Org. Lett., 2015, 17, 4818-4821.
The combination of a chiral Co complex and a photocatalyst mediates a highly regio- and enantioselective reductive coupling of internal alkynes with aldehydes to provide enantioenriched allylic alcohols in excellent regio-, stereo-, and enantioselectivity. The method offers mild reaction conditions, broad substrate scope, and good functional group compatibility.
Y.-L. Li, S.-Q. Zhang, J. Chen, J.-B. Xia, J. Am. Chem. Soc., 2021, 143, 7306-7313.
A kinetic-controlled photocatalyst-free visible-light-induced stereoselective synthesis of synthetically important α,α-gem-difluoro-Z-allyl esters was succeeded at room temperature in good yields and excellent Z-selectivity through a reductive radical ethoxycarbonyldifluoromethylation of terminal aryl alkynes with blue LED (465 nm)-excited Hantzsch ester.
J. Hao, W. Ding, Z. Zheng, L. Sun, J. Dong, M. Li, W. Wan, J. Org. Chem., 2022, 87, 13750-13756.
An inert, rigid chiral-at-metal iridium(III) complex enables a highly efficient catalytic asymmetric transfer hydrogenation of β,β′-disubstituted nitroalkenes. The catalysis does not involve any direct metal coordination but operates exclusively through weak interactions with functional groups properly arranged in the ligand sphere of the iridium complex.
L-A. Chen, W. Xu, B. Huang, J. Ma, L. Wang, J. Xi, K. Harms, L. Gong, E. Meggers, J. Am. Chem. Soc., 2013, 135, 10598-10601.
A highly efficient and highly enantioselective Hantzsch ester mediated conjugate transfer hydrogenation of β,β-disubstituted nitroolefins is catalyzed by a Jacobsen-type thiourea catalyst.
N. J. A. Martin, L. Ozores, B. List, J. Am. Chem. Soc., 2007, 129, 8976-8977.
A highly efficient and enantioselective Hantzsch ester mediated conjugate reduction of β-nitroacrylates is catalyzed by a Jacobsen thiourea catalyst. The reaction is a key step in a new route to optically active β2-amino acids.
N. J. A. Martin, X. Chen, B. List, J. Am. Chem. Soc., 2008, 130, 13862-13863.
An operationally simple, tin-free reductive dehalogenation system allows the reduction of activated C-X bonds in good yields with excellent functional-group tolerance and chemoselectivity over aryl and vinyl C-X bonds in the presence of the well-known visible-light-activated photoredox catalyst Ru(bpy)3Cl2 in combination with iPr2NEt and HCO2H or Hantzsch ester as the hydrogen atom donor.
J. M. R. Narayanam, J. W. Tucker, C. R. J. Stephenson, J. Am. Chem. Soc., 2009, 131, 8756-8757.
A catalyst-induced defluorinative, alkylation or metal-free hydroalkylation of gem-difluoroalkenes provides a mild and practical approach to important and monofluoroalkenes and difluoromethylene-containing compounds under visible light irradiation with good yields.
F. Liu, Z. Zhuang, Q. Qian, X. Zhang, C. Yang, J. Org. Chem., 2022, 87, 2730-2739.
The use of TFSP, a readily available trifluoromethylation reagent prepared from DMAP and Tf2O, enables a general method for the hydrotrifluoromethylation of styrenes under photoredox catalysis without polymerization. The substrate scope was further extended to unactivated alkenes, acrylates, acrylamides, and vinyl-heteroatom-substituted alkenes.
Y.-F. Yang, J.-H. Lin, J.-C. Xiao, Org. Lett., 2021, 23, 9277-9282.
The reaction of redox-active esters as radical precursors and the commercially available 2-bromo-3,3,3-trifluoropropene (BTP) as a radical acceptor provides a wide range of secondary trifluoromethylated alkyl bromides in good to excellent yields with broad functional group tolerance.
P. Guo, M. Tao, W.-W. Xu, A.-J. Wang, W. Li, Q. Yao, J. Tong, C.-Y. He, Org. Lett., 2022, 24, 2145-2148.
A mild, rapid, straightforward visible-light-mediated sulfonamide ethylation of easily available redox active esters or alkyl iodides with vinylsulfonamides provides a diverse array of compounds with C(sp3)-sulfonamide skeletons. This method offers a broad substrate scope and has and potential utility for late-stage functionalization of natural products and synthetic medicines.
M. Zhang, M. Yu, Z. Wang, Y. Liu, Q. Wang, Org. Lett., 2022, 24, 3932-3937.
NAD(P)H mimic reactions with Hantzsch 1,4-dihydropyridine provide three-, five- and seven-membered ring compounds. The method offers readily available starting materials, very high yields, mild conditions, and simple workup.
X.-Q. Zhu, H.-Y. Wang, J.-S. Wang, Y.-C. Liu, J. Org. Chem., 2001, 66, 344-347.
Substoichiometric amounts of a Gd(OTf)3 mediate the addition of tertiary carbon radicals generated from N-(acyloxy)phthalimide esters to cyclic α,β-unsaturated ketones and lactones. The reaction is accomplished by irradiation with visible light in the presence of Hantzsch ester without the use of a photosensitizer.
S. P. Pitre, T. K. Allred, L. E. Overman, Org. Lett., 2021, 23, 1103-1106.
A highly enantioselective catalytic protocol for the intramolecular reductive coupling of ketones and hydrazones furnishes cyclic syn 1,2-amino alcohol derivatives with excellent levels of diastereo- and enantioselectivity. The reaction proceeds through neutral ketyl radical intermediates generated via a concerted proton-coupled electron transfer event jointly mediated by a chiral phosphoric acid catalyst and a photoredox catalyst.
L. J. Rono, H. G. Yayla, D. Y. Wang, M. F. Armstrong, R. R. Knowles, J. Am. Chem. Soc., 2013, 135, 17735-17738.
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.
The combination of Brønsted acid catalysis with visible-light induction enables a highly enantioselective synthesis of 2-substituted tetrahydroquinolines from 2-aminoenones through a relay visible-light-induced cyclization/chiral phosphoric acid-catalyzed transfer hydrogenation reaction.
W. Xiong, S. Li, B. Fu, J. Wang, Q.-A. Wang, W. Yang, Org. Lett., 2019, 21, 4173-4176.
A chiral phosphoric acid as the sole catalyst enables an enantioselective synthesis of tetrahydroquinolines from 2-aminochalcones via chiral phosphoric acid-catalyzed dehydrative cyclization, followed by chiral phosphoric acid-catalyzed asymmetric reduction with Hantzsch ester. Various 2-aminochalcones could be applicable to this protocol, and the desired tetrahydroquinolines were obtained in excellent yields and with excellent enantioselectivities.
D. Y. Park, S. Y. Lee, J. Jeon, C.-H. Cheon, J. Org. Chem., 2018, 83, 12486-12495.
A highly efficient gold-catalyzed tandem hydroamination/asymmetric transfer hydrogenation provides tetrahydroquinolines in excellent yields and enantioselectivities in the presence of a chiral phosphate. In this reaction, the gold catalyst acts as a π-Lewis acid in the hydroamination step and as an effective chiral Lewis acid in the asymmetric hydrogen-transfer.
Y.-L. Du, Y. Hu, Y.-F. Zhu, X.-F. Tu, Z.-Y. Han, L.-Z. Gong, J. Org. Chem., 2015, 80, 4754-4759.
Consecutive hydroamination/asymmetric transfer hydrogenation under relay catalysis of an achiral gold complex/chiral Brønsted acid binary system allows a direct transformation of 2-(2-propynyl)aniline derivatives into tetrahydroquinolines with high enantiomeric purity.
Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J. Am. Chem. Soc., 2009, 131, 9182-9183.
A boronic acid catalyzed one-pot tandem reduction of quinolines to tetrahydroquinolines followed by reductive alkylation with a carbonyl compound provides N-alkyl tetrahydroquinolines in the presence of Hantzsch ester under mild reaction conditions. The organoboron catalysts behave as both Lewis acids and hydrogen-bond donors.
P. Adhikari, D. Bhattacharyya, S. Nandi, P. K. Kancharla, A. Das, Org. Lett., 2021, 23, 2437-2442.
A versatile and efficient access to 1H-isochromenes via a domino cycloisomerization/reduction reaction process starting from a wide range of functionalized ortho-alkynylbenzaldehydes is catalyzed by dichloro(2-pyridinecarboxylato)gold ([AuCl2(Pic)]).
E. Tomás-Mendivil, J. Starck, J.-C. Ortuno, V. Michelet, Org. Lett., 2015, 17, 6126-6129.
An efficient reductive cyclization of o-nitrocinnamoyl compounds was achieved by employing Hantzsch 1,4-dihydropyridine diethyl ester as a biomimetic reducing agent in the presence of catalytic palladium on carbon. This approach was successfully applied to the synthesis of substituted quinolines.
R.-G. Xing, Y.-N. Li, Q. Liu, Y.-F. Han, X. Wei, J. Li, B. Zhou, Synthesis, 2011, 2066-2072.
Visible light-mediated metallaphotoredox catalysis enables a highly chemoselective deoxygenation of N-heterocyclic N-oxides using Hantzsch esters as the stoichiometric reductants and only a tiny amount of the catalyst within a few minutes at room temperature. The reaction tolerates a wide range of functional groups, such as carbamates, esters, ketones, nitrile groups, nitro groups, and halogens.
J. H. An, K. D. Kim, J. H. Lee, J. Org. Chem., 2021, 86, 2876-2894.
A Brønsted acid catalyzed transfer hydrogenation of indole derivatives with Hantzsch dihydropyridine as the hydrogen source enables an efficient synthesis of various optically active indolines with high enantioselectivities.
M. Rueping, C. Brinkmann, A. P. Antonchick, I. Atoresei, Org. Lett., 2010, 12, 4604-4607.