Hantzsch Ester
Diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate
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.
Recent Literature
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.
The merger of photoredox and nickel catalysis enables a direct carboxylation
of unactivated secondary alkyl bromides. Site-selectivity is dictated by a
kinetically controlled insertion of CO2 at the initial C(sp3)-Br
site by the rapid formation of Ni(I)-alkyl species, thus avoiding undesired
β-hydride elimination and chain-walking processes.
J. Davies, J. R. Lyonnet, B. Carvalho, B. Sahoo, C. S. Day, F.
Juliá-Hernández, Y. Duan, Á. Velasco-Rubio, M. Obst, P.-O. Norrby, K. H. Hopmann,
R. Martin, J. Am. Chem. Soc.,
2024, 146, 1753-1759.
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 radical strategy (1e-) through metal-hydride hydrogen atom transfer (MHAT)
using photoredox cobalt and titanium dual catalysis for aldehyde crotylation
with butadiene achieves excellent regio- and diastereoselectivity.
H. Yan, J.-R. Shan, F. Zhang, Y. Chen, X. Zhang, Q. Liao, E. Hao, L. Shi, Org. Lett., 2023, 25,
7694-7699.
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 organocatalyst delivers nitroalkanes from β,β-disubstituted nitroalkenes
with a generality otherwise achievable only by a combination of several organo-
and organometallic catalysts. The catalyst improves yield and/or
enantioselection of the reduction of some major classes of nitroalkenes.
Z. Deng, M. A. Padalino, J. E. L. Jan, S. Park, M. W. Danneman, J. N.
Johnston, J. Am. Chem. Soc.,
2024, 146, 1269-1275.
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 organocatalyst delivers nitroalkanes from β,β-disubstituted nitroalkenes
with a generality otherwise achievable only by a combination of several organo-
and organometallic catalysts. The catalyst improves yield and/or
enantioselection of the reduction of some major classes of nitroalkenes.
Z. Deng, M. A. Padalino, J. E. L. Jan, S. Park, M. W. Danneman, J. N.
Johnston, J. Am. Chem. Soc.,
2024, 146, 1269-1275.
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.
Gold-catalyzed intramolecular hydroarylation and transfer hydrogenation of
N-aryl propargylamines provides tetrahydroquinolines and 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines
in good yields. The method offers simple reaction conditions, good substrate
compatibility, high efficiency, and excellent regioselectivity.
N. Yi, Y. Liu, Y. Xiong, H. Gong, J.-P. Tan, Z. Fang, B. Yi, J. Org. Chem., 2023, 88,
11945-11953.
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.
Boronic acid catalyzed one-pot reductions of quinolines with Hantzsch ester
followed by N-arylations via external base-free Chan-Evans-Lam coupling
provide N-aryl tetrahydroquinolines under mild reaction conditions. The
use of an inexpensive N-arylation protocol, aerobic reaction conditions,
and functional group diversity are important practical features.
D. Bhattacharyya, S. K. Senapati, A. Das, Synlett, 2023,
34,
651-656.
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.