Categories: Synthesis of N-Heterocycles > Synthesis of Cyclic Amines >
Synthesis of piperidines
Recent Literature
A new efficient method for the N-heterocyclization of primary amines
with diols catalyzed by a Cp*Ir complex was developed. A variety of five-,
six-, and seven-membered cyclic amines were synthesized in good to excellent
yields.
K.-I. Fujita, T. Fujii, R. Yamaguchi, Org. Lett., 2004, 6,
3525-3528.
A simple, one-pot preparation of cyclic amines via efficient chlorination of
amino alcohols with use of SOCl2 obviates the need for the classical
N-protection/O-activation/cyclization/deprotection sequence
commonly employed for this type of transformation. The reaction pathways and the
general scope of this method have also been investigated.
F. Xu, B. Simmons, R. A. Reamer, E. Corley, J. Murry, D. Tschaen, J. Org. Chem., 2008,
73, 312-315.
A one-pot synthesis of nitrogen-containing heterocycles from alkyl dihalides
and primary amines and hydrazines occurs under microwave irradiation via a
simple and efficient cyclocondensation in an alkaline aqueous medium.
Y. Ju, R. S. Varma, J. Org. Chem., 2006, 71, 135-141.
A practical continuous flow reaction of readily accessible N-(tert-butylsulfinyl)-bromoimine
with Grignard reagents provides various enantioenriched α-substituted
piperidines in good yields and high diastereoselectivities within minutes. The
reaction can be scaled-up smoothly and an efficient synthesis of a drug
precursor further showcases its utility.
C. Shan, J. Xu, L. Cao, C. Liang, R. Cheng, X. Yao, M. Sun, J. Ye, Org. Lett.,
2022, 24, 3205-3240.
An intramolecular amination of organoboronates provides azetidines,
pyrrolidines, and piperidines via a 1,2-metalate shift of an aminoboron "ate"
complex.
P. Xu, M. Zhang, B. Ingoglia, C. Allais, A.-M. R. Dechert-Schmitt, R. A.
Singer, J. P. Morken, Org. Lett., 2021, 23,
3379-3383.
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.
Optically pure C2-symmetrical cyclic amines were
efficiently synthesized from the corresponding diols obtained from an
enantioselective borohydride reduction of diketones in the presence of a chiral
β-ketoiminato cobalt(II) catalyst.
M. Sato, Y. Gunji, T. Ikeno, T. Yamada, Synthesis, 2004,
1434-1438.
Mild, rhodium-catalyzed hydroaminations of unactivated olefins with primary and
secondary alkylamines form the corresponding five- and six-membered products in
excellent yields. A variety of functional groups such as hydroxyl, halo, cyano,
and carboalkoxyl groups were tolerated.
Z. Liu, J. F. Hartwig, J. Am. Chem. Soc., 2008,
130, 1570-1571.
HCl·DMPU induces the formation of (thiomethyl)methyl carbenium ion from DMSO
under mild conditions. A subsequent reaction of this electrophile with
homoallylic amines generates 4-chloropiperidines in good yields. The method
applies to both aromatic and aliphatic amines. The reaction has a broad
substrate scope and offers good chemical yields with high functional group
tolerance and scalability.
R. Ebule, S. Mudshinge, M. H. Nantz, M. S. Mashuta, G. B. Hammond, B. Xu, J. Org. Chem., 2019, 84,
3249-3259.
Formation of alkyl radicals via activation of alkyl bromides through cobalt/iridium
catalysis enables a reductive radical conjugate addition under mild and less
toxic conditions. The reaction conditions tolerate benzylic halides and halides
containing free alcohols, silanes, and chlorides.
R. A. Escobar, J. W. Johannes, Org. Lett., 2021, 23,
6046-6051.
The use of monodentate chiral spiro phosphoramidite ligands enables a highly
enantioselective nickel-catalyzed intramolecular hydroalkenylation of easily
accessible N- or O-tethered 1,6-dienes to provide very useful six-membered N-
and O-heterocycles with high regioselectivity as well as excellent
stereoselectivity under mild reaction conditions.
K. Li, M.-L. Li, Q. Zhang, S.-F. Zhu, Q.-L. Zhou, J. Am. Chem. Soc.,
2018,
140, 7458-7461.
Use of a base-free Pd(DMSO)2(TFA)2 catalyst enables the
synthesis of six-membered nitrogen heterocycles via a Wacker-type aerobic
oxidative cyclization of alkenes. Various heterocycles, including morpholines,
piperidines, piperazines and piperazinones, are accessible by this method.
Z. Lu, S. S. Stahl, Org. Lett., 2012,
14, 1234-1237.
A Pd-catalyzed reaction of vinyl iodides and N-tosylhydrazones assembles
η3-allyl ligands through carbene insertion. Intramolecular trapping
with nitrogen nucleophiles generates good yields of cinnamyl and pentadienyl
amines like those found in alkaloid natural products.
A. Khanna, C. Maung, K. R. Johnson, T. T. Luong, D. L. Van Vranken, Org. Lett., 2012,
14, 3233-3235.
The combination of carbaboranylmercuric chloride as a bulky Lewis acid and
silver triflate efficiently catalyzes a cycloisomerization of 1,3-dienes at room
temperature to give allyl-substituted azacycles and cycloalkanes in excellent
yields with very high regioselectivity.
H. Yamamoto, I. Sasaki, S. Shiomi, N. Yamasaki, H. Imagawa, Org. Lett., 2012,
14, 2250-2253.
The use of 5 mol % of AlCl3 as the catalyst and 2 equiv of a
trimethylsilyl halide as the halide source enables aza-Prins cyclization of N-tosyl
homoallylamine or Prins cyclization of homoallylic alcohol with carbonyl
compounds to provide the corresponding trans-2-substituted-4-halopiperidines
or cis-2-substituted-4-halotetrahydropyrans in high yields and
satisfactory diastereoselectivity.
G.-Q. Liu, B. Cui, R. Xu, X.-M. Li, J. Org. Chem.,
2016,
81, 5144-5161.
A Pd-catalyzed enantioselective aminochlorination of alkenes via a 6-endo
cyclization provides convenient access to a wide array of structurally diverse
3-chloropiperidines in good yields with excellent enantioselectivities. Notably,
both the sterically bulky chiral pyridinyl-oxazoline (Pyox) ligand and an
electrophilic chlorination reagent (NCS) are crucial to the successful reaction.
Y. Zhang, Y. He, T. Liu, W. Guo, Org. Lett., 2023, 25,
2680-2684.
In the presence of 1.1 equiv of (Diacetoxyiodo)benzene (PIDA) and suitable
halogen sources, a variety of olefins underwent haloamidation,
haloetherification, and halolactonization to the corresponding 1,2-bifunctional
cyclic skeletons in very good isolated yields. Subsequent mild nucleophilic
substitution gives key intermediates for biologically interesting compounds in
high yields.
G.-Q. Liu, Y.-M. Li, J. Org. Chem.,
2014,
79, 10094-10109.
Iodocyclization of unsaturated tosylamides promoted by Oxone oxidation of KI
afforded, in good yields, N-tosyl iodopyrrolidines and piperidines. A
new, simple method for the conversion of alcohols to tosylamides is
presented.
M. C. Marcotullio, V. Campagna, S. Sternativo, F. Costantino, M. Curini, Synthesis, 2006, 2760-2766.
A mild, effective gold(I)-catalyzed hydroamination of unactivated olefins to
form protected nitrogen heterocycles has been developed. The substrate scope
is broader than in reactions realized with late-transition-metal catalyst
systems.
X. Han, R. A. Widenhoefer, Angew. Chem. Int. Ed., 2006, 45, 1747-1749.
Treatment of an N-4-pentenyl or N-5-hexenyl urea with a
catalytic 1:1 mixture of a gold(I) N,N-diaryl imidazol-2-ylidine complex and
AgOTf gave the corresponding nitrogen heterocycle in excellent yield via an
intramolecular exo-hydroamination.
C. F. Bender, R. A. Widenhoefer, Org. Lett., 2006, 8, 5303-5305.
A mild and facile Pd-catalyzed intramolecular hydroamination of unactivated
alkenes takes place at room temperature and tolerates acid-sensitive functional
groups. The tridentate ligand on Pd effectively inhibits β-hydride elimination, thus
the formation of hydroamination products is preferred over oxidative amination
products.
F. E. Michael, B. M. Cochran, J. Am. Chem. Soc.,
2006, 128, 4246-4247.
A ruthenium catalyzed, atom-economical domino redox isomerization/cyclization of
easily available, linear aminopropargyl alcohols provides added-value nitrogen
heterocycles in a single catalytic step and displays a broad scope and
functional group tolerance.
B. M. Trost, N. Maulide, R. C. Livingston, J. Am. Chem. Soc., 2008,
130, 16502-16503.
Hoveyda-Grubbs catalyst in combination with BF3·OEt2 efficiently promotes
tandem cross metathesis intramolecular aza-Michael reaction between enones and
unsaturated carbamates resulting in the creation of β-amino carbonyl units. The
use of microwave irradiation dramatically accelerates the process, but also inverts the
stereoselectivity in the addition process.
S. Fustero, D. Jiménez, M. Sánchez-Roselló, C. del Pozo, J. Am. Chem. Soc., 2007,
129, 6700-6701.
Key step of an eco-friendly and highly diastereoselective synthesis of
substituted cis-2,6-piperidines and cis-2,6-tetrahydropyrans is an
iron-catalyzed thermodynamic equilibration of 2-alkenyl 6-substituted
piperidines and 2-alkenyl 6-substituted tetrahydropyrans allowing the isolation
of enriched mixtures of the most stable cis-isomers.
A. Guérinot, A. Serra-Muns, C. Gnamm, C. Bensoussan, S. Reymond, J. Cossy, Org. Lett., 2010,
12, 1808-1811.
An asymmetric intramolecular hydroamination of allenes catalyzed by
phosphinegold(I)-bis-p-nitrobenzoate complexes is applicable to the
enantioselective formation of vinyl pyrrolidines and piperidines in high ee.
R. L. LaLonde, B. D. Sherry, E. J. Kang, F. D. Toste, J. Am. Chem. Soc., 2007,
129, 2452-2453.
The Au(I)-catalyzed intramolecular hydroamination of N-allenyl
carbamates was effective for the formation of various cyclic amines. γ-Hydroxy
and δ-hydroxy allenes underwent Au-catalyzed intramolecular
hydroalkoxylation to form the corresponding
oxygen heterocycles in good yield. 2-Allenyl indoles
underwent Au-catalyzed intramolecular hydroarylation to form 4-vinyl tetrahydrocarbazoles in good yield.
Z. Zhang, C. Liu, R. E. Kinder, X. Han, H. Qian, R. A. Widenhoefer, J. Am. Chem. Soc.,
2006, 128, 9066-9073.
tert-Butyl hypoiodite is a mild and powerful reagent for the
cyclization of N-alkenylamides leading to various N-heterocycles.
N-alkenylsulfonamides gave three- to six-membered saturated N-heterocycles
in good yields, whereas alkenylbenzamide derivatives afforded
N-, O- or N-, S-heterocycles.
S. Minakata, Y. Morino, Y. Oderaotoshi, M. Komatsu, Org. Lett.,
2006, 8, 3335-3337.
An intramolecular anti-Markovnikov hydroamination of
1-(3-aminopropyl)vinylarenes occurred in the presence of [Rh(COD)(DPPB)]BF4
as catalyst to form 3-arylpiperidines in high yield. Reactants with substituents
β to the amino group formed 3,5-disubstituted piperidines with high
diastereomeric excess, whereas substituents in α and γ gave mostly enamines and
isomerized starting materials.
A. Takemiya, J. F. Hartwig, J. Am. Chem. Soc.,
2006, 128, 6042-6043.
A novel approach to 2,4-disubstituted piperidines involves the radical
cyclization of 7-substituted-6-aza-8-bromooct-2-enoates. An enhancement in
diastereoselectivity using tris(trimethylsilyl)silane instead of tributyltin
hydride is discussed.
L. A. Gandon, A. G. Russel, T. Güveli, A. E. Brodwolf, B. M. Kariuki, N.
Spencer, J. S. Snaith, J. Org. Chem., 2006, 71, 5198-5207.
A Pd-catalyzed, asymmetric 6-endo aminoacetoxylation of unactivated
alkenes provides chiral β-acetoxylated piperidines with excellent chemo-, regio-
and enantioselectivities under very mild reaction conditions using a designed
pyridine-oxazoline (Pyox) ligand.
X. Qi, C. Chen, C. Hou, L. Fu, P. Chen, G. Liu, J. Am. Chem. Soc.,
2018,
140, 7415-7419.
The combination of photoredox, cobaloxime, and amine catalysis mediates a
radical cyclization of aldehydes with pendant alkenes to provide a variety of
5-, 6-, and 7-membered ring products with alkene transposition in good yields.
The reaction exhibits wide functional group compatibility and occurs under mild
conditions with extrusion of H2.
J. Li, J.-L. Tu, F. Liu,
Org. Lett., 2020, 22, 7369-7372.
Secondary alicyclic amines are converted to α-aminonitriles via oxidation of amine-derived lithium amides with simple ketone oxidants
to imines and a subsequent addition of TMSCN.
Amines with an existing α-substituent undergo regioselective α′-cyanation. Amine α-arylation can be
combined with α′-cyanation to generate difunctionalized products in a single
operation.
F. Yu, D. A. Valles, W. Chen, S. D. Daniel, I. Ghiviriga, D. Seidel, Org. Lett.,
2022, 24, 6364-6368.
An intramolecular iodo-aldol cyclization of prochiral α-substituted enoate
aldehydes and ketones produces hetero- and carbocycles containing quaternary centers adjacent
to secondary or tertiary centers. The reactions occur in good yields and are
highly trans-selective with hydroxyl and iodomethyl
groups on opposite faces of the ring system.
F. Douelle, A. S. Capes, M. F. Greaney, Org. Lett., 2007,
9, 1931-1934.
An efficient method to activate hydroxyl groups of amino alcohols has been
developed, which avoids the use of toxic reagents and tolerates various
functional groups. This strategy has been applied to the synthesis of
functionalized p-methoxyphenyl-protected azetidines, pyrrolidines,
and piperidines.
R. M. de Figueiredo, R. Fröhlich, M. Christmann, J. Org. Chem., 2006, 71, 4147-4154.
A highly enantioselective rearrangement of β-amino alcohols was realized by
using a catalytic amount of trifluoroacetic anhydride.
T.-X. Métro, D. G. Pardo, J. Cossy, J. Org. Chem.,
2007,
72, 6556-6561.
Depending on the steric hindrance of the ligand, a regioselective
palladium-catalyzed diamination of unactivated alkenes, provides either
amino-functionalized piperidines or pyrrolidines. 6-Endo diamination
occurred with a less sterically hindered quinox ligand to afford
3-aminopiperidines, while 5-exo diamination occurred with a bulky pyox
ligand to give amino-substituted pyrrolidines.
X. Liu, C. Hou, Y. Peng, P. Chen, G. Liu, Org. Lett., 2020, 22, 9371-9375.
A borane catalyzed metal-free transfer hydrogenation of pyridines furnishes
various piperidines in good yields with good cis-selectivities in the
presence of ammonia borane as a hydrogen source. The ease in handling without
requiring high pressure H2 makes this transfer hydrogenation
practical and useful.
Q. Zhou, L. Zhang, W. Meng, X. Feng, J. Yang, H. Du, Org. Lett.,
2016, 18, 5189-5191.
A mild, complete hydrogenation of aromatic rings catalyzed by heterogeneous 10%
Rh/C proceeds at 80 °C in water under 5 atm of H2 pressure and is
applicable to the hydrogenation of various carbon and heteroaromatic compounds
such as alkylbenzenes, biphenyls, pyridines and furans.
Maegawa, A. Akashi, H. Sajiki, Synlett,
2006, 1440-1442.
The use of ammonium formate and palladium on carbon enables an efficient
reduction of pyridine N-oxides to piperidines. The advantages of this
procedure are simplicity of the reaction, high yield, mild conditions, and the
avoidance of strong acid and harsh reagents.
B. Zacharie, N. Moreau, C. Dockendorff, J. Org. Chem., 2001,
66, 5264-5265.