Categories: Synthesis of N-Heterocycles > Synthesis of cyclic amines >
Synthesis of pyrrolidines
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 chiral amine-derived iridacycle complex catalyzes a highly economical borrowing
hydrogen annulation to provide chiral N-heterocycles directly from
simple racemic diols and primary amines. This catalytic method enabled a rapid
access to a wide range of diversely substituted enantioenriched pyrrolidines
including key precursors to valuable drugs.
Y. Liu, H. Diao, G. Hong, J. Edward, T. Zhang, G. Yang, B.-M. Yang, Y. Zhao, J. Am. Chem. Soc.,
2023, 145, 5007-5016.
The combination of readily available and stable O-benzoylhydroxylamines
as alkyl nitrene precursors and a proficient rhodium catalyst provides various
pyrrolidines in very good yields.
H. Noda, Y. Asada, M. Shibasaki,
Org. Lett., 2020, 22, 8769-8773.
An acid-promoted synthesis of azaheterocycles from N-carbamate-protected
amino alcohols involves the activation of the hydroxyl group via the use of
orthoesters. Despite the reduced nucleophilicity of carbamate nitrogen, this
reaction system provides several types of pyrrolidines and piperidines in very
good yields.
H. Park, Y. Kwon, J. E. Shin, W.-J. Kim, S. Hwang, S. Lee, S. Kim, Synthesis, 2017,
49, 2761-2767.
2-substituted pyrrolidines, including nornicotine, can be prepared from very
simple materials, such as carbonyl compounds (mainly aromatic aldehydes) and
3-chloropropylamine. In the case of imines derived from aliphatic ketones and
aldehydes, this methodology gives significantly lower yields.
M. Yus, T. Soler, F. Foubelo, J. Org. Chem., 2001,
66, 6207-6208.
A synergistic combination of a nickel catalyst and benzaldehyde enables
C(sp3)-H alkylation and arylation of amides and thioethers employing simple aryl
or alkyl halides. Readily available starting materials, mild reaction conditions,
a good functional-group tolerance, and a broad substrate scope make this
methodology attractive and practical.
X. Si, L. Zhang, A. S. K. Hashmi,
Org. Lett., 2019, 21, 6259-6263.
Enantioselective, Palladium-Catalyzed α-Arylation of N-Boc-pyrrolidine
K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer, C.-Y. Chen, J. Am. Chem. Soc.,
2006, 128, 3538-3539.
The combination of inexpensive cerium and nickel catalysts enables the use of
easily accessible free alcohols as operationally simple and robust carbon
pronucleophiles in selective C(sp3)-C(sp2) cross-couplings
with the extrusion of formaldehyde. A broad range of free alcohols and aromatic
halides can be employed in this transformation.
Y. Chen, X. Wang, X. He, Q. An, Z. Zuo, J. Am. Chem. Soc.,
2021, 143, 4896-4902.
Highly efficient catalyst-tuned regio- and enantioselective hydroalkylation
reactions of readily available 3-pyrrolines provide chiral C2-alkylated
pyrrolidines in the presence of a Co catalyst and C3-alkylated pyrrolidines in
the presence of a Ni catalyst. These divergent methods use readily available
catalysts, chiral BOX ligands, and reagents.
X. Wang, J. Xue, Z.-Q. Rong, J. Am. Chem. Soc.,
2023, 145, 15456-15464.
Highly efficient catalyst-tuned regio- and enantioselective hydroalkylation
reactions of readily available 3-pyrrolines provide chiral C2-alkylated
pyrrolidines in the presence of a Co catalyst and C3-alkylated pyrrolidines in
the presence of a Ni catalyst. These divergent methods use readily available
catalysts, chiral BOX ligands, and reagents.
X. Wang, J. Xue, Z.-Q. Rong, J. Am. Chem. Soc.,
2023, 145, 15456-15464.
The combination of B2pin2 and KOtBu enables a
chemoselective, metal-free reduction of aromatic nitro compounds to the
corresponding amines in very good yields in isopropanol. The reaction tolerates
various reducible functional groups.
H. Lu, Z. Geng, J. Li, D. Zou, Y. Wu, Y. Wu, Org. Lett.,
2016, 18, 2774-2776.
[FeIII(TF4DMAP)Cl] efficiently catalyzes an
intermolecular sp3 C-H amination using aryl azides and intramolecular
sp3 C-H amination of alkyl azides in good yields. The reaction offers
high chemo- and regioselectivity with broad substrate scope and can be used for
late-stage functionalization of complex natural/bioactive molecules.
Y.-D. Du, Z.-J. Xu, C.-Y. Zhou, C.-M. Che, Org. Lett., 2019, 21,
895-899.
A Tf2O-promoted intramolecular Schmidt reaction of 2-substituted
ω-azido carboxylic acids provides a series of 2-substituted pyrrolidines.
X.-J. Wang, Y. Su, R. Li, P. Gu, J. Org. Chem., 2018, 83,
5816-5824.
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.
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.
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.
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.
A facile method provides N-aryl-substituted azacycles from arylamines
and cyclic ethers in the presence of POCl3 and DBU. Using this method,
various azacycloalkanes, isoindolines, and tetrahydroisoquinolines were prepared
in high yields. This synthetic method offers an efficient approach to the
production of five- and six-membered azacycles.
M. T. La, S. Kang, H.-K. Kim, J. Org. Chem., 2019, 84,
6689-6696.
Co2(CO)8 catalyzes chemodivergent syntheses of
pyrrolidines and pyrrolidones from levulinic acid and aromatic amines under
slightly different hydrosilylation conditions. 1.5 and 3 equiv of phenylsilane
selectively yielded pyrrolidone and pyrrolidine, respectively.
S. Panda, A. Nanda, R. Saha, R. Ghosh, B. Bagh, J. Org. Chem., 2023, 88,
16997-17009.
Dirhodium-catalyzed intramolecular nitrene insertion into sp3 C-H
bonds enables a regio- and diastereoselective synthesis of N-unprotected
pyrrolidines at rt without external oxidants, nitrene stabilizing groups, or
directing functionality.
S. Munnuri, A. M. Adebesin, M. P. Paudyal, M. Yousufuddin, A. Dalipe, J. R.
Falck, J. Am. Chem. Soc., 2017,
139, 18288-18294.
A copper-catalyzed intermolecular carboamination of potassium N-carbamoyl-β-aminoethyltrifluoroborates
with terminal, 1,2-disubstituted, and 1,1-disubstituted vinylarenes bearing a
number of functional groups provides 2-arylpyrrolidines. 1,3-Dienes are also
good substrates, and their reactions give 2-vinylpyrrolidines.
C. Um, S. R. Chemler, Org. Lett.,
2016, 18, 2515-2518.
A novel gold-catalyzed tandem cycloisomerization/hydrogenation of chiral
homopropargyl sulfonamides provides various enantioenriched pyrrolidines in
excellent yields and excellent enantioselectivities.
Y.-F. Yu, C. Shu, T.-D. Tan, L. Li, S. Rafique, L.-W. Ye, Org. Lett.,
2016, 18, 5178-5181.
An operationally simple direct δ-amination reaction of sp3
C-H bonds, employing molecular iodine (I2) as the sole oxidant under
transition-metal-free conditions, provides facile, efficient access to
pyrrolidines and related heterocyclic derivatives from readily accessible
substrates.
W. Ye, H. Xiong, M. Wang, J. Chang, W. Yu, J. Org. Chem., 2024, 89,
3481-3490.
Stereoselective syntheses of pyrrolidines and piperidines bearing hydrophobic
chains have been achieved through a metal free, Lewis acid-mediated 5/6-endo-dig
reductive hydroamination cascade of enynyl amines. The brevity of the developed
strategy allowed for the collective stereoselective total synthesis of various
alkaloids.
S. J. Gharpure, R. K. Patel, K. S. Gupta, Org. Lett., 2023, 25,
5850-5855.
Pd-catalyzed alkene carboamination and carboalkoxylation reactions of a wide
range of (hetero)arylthianthrenium triflates afforded the corresponding
biologically important pyrrolidine and tetrahydrofuran derivatives. Mechanistic
studies indicated that this reaction proceeds through a syn-heteropalladation
mechanistic pathway.
B. Peng, L. Dai, R. Liu, Org. Lett., 2023, 25,
2606-2610.
The use of Et3SiH and a catalytic amount of I2 enables
transition-metal-free, intramolecular hydroalkoxylation/reduction and
hydroamination/reduction of unactivated alkynes at room temperature to provide
2,4- and 2,5-disubstituted pyrrolidines as well as a 2,3-disubstituted
tetrahydrofurans with high diastereoselectivity.
S. Fujita, M. Shibuya, Y. Yamamoto, Synthesis, 2017,
49, 4199-4204.
A metal-free method for a direct anti-Markovnikov hydroamination of unsaturated
amines is enabled by irradiation of the amine substrates with visible light in
the presence of catalytic quantities of easily synthesized
9-mesityl-10-methylacridinium tetrafluoroborate and thiophenol as a
hydrogen-atom donor. The reaction furnished nitrogen-containing heterocycles
with complete regiocontrol.
T. M. Nguyen, D. A. Nicewicz, J. Am. Chem. Soc., 2013,
135, 9588-9591.
A Mn-catalyzed N-F bond activation enables a visible-light-promoted
generation of amidyl radicals from N-fluorosulfonamides. In the presence
of a cheap silane, (MeO)3SiH as hydrogen-atom donor and F-atom
acceptor, intra- and intermolecular hydroaminations of alkenes, two-component
carboamination of alkenes, and even three-component carboamination of alkenes
can be realized.
Y.-X. Ji, J. Li, C.-M. Li, S. Qu, B. Zhang, Org. Lett., 2021, 23,
207-212.
A highly enantioselective iridium-catalyzed hydrogenation of cyclic enamines is
efficient method for the synthesis of optically active cyclic tertiary amines
including natural product crispine A.
G.-H. Hou, J.-H. Xie, P.-C. Yan, Q.-L. Zhou, J. Am. Chem. Soc., 2009,
131, 1366-1367.
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.
(terpy)NiBr2 catalyzes a regioselectively difunctionalisation of
unactivated olefins with tethered alkyl halides and arylzinc reagents to provide
(arylmethyl)carbo- and heterocyclic scaffolds. The reaction shows an excellent
functional group tolerance (such as ketones, esters, nitriles, halides, and
base-sensitive racemizable stereocenters).
S. KC, P. Basnet, S. Thapa, B. Shrestha, R. Giri, J. Org. Chem., 2018, 83,
2920-2936.
A combination of a photoredox and a palladium catalyst catalyzes a
dehydrative coupling reaction of alkyl amines with allylic alcohols to provide a
range of homoallylic amines.
Y. Masuda, M. Ito, M. Murakami,
Org. Lett., 2020, 22, 4467-4470.
Regioselective protonolytic C-C bond cleavage of acylated aminomethyl
cyclopropanes can be achieved using trifluoroacetic acid to provide
2,2-substituted pyrrolidines via an intermediate tertiary carbenium ion. The
strength of the acid and the amine substituent are important factors to achieve
high regioselectivity, suggesting intramolecular proton transfer from the
protonated amide function.
M. Skvorcova, A. Jirgensons, Org. Lett.,
2017, 19, 2478-2481.
N-Iodosuccinimide promotes an attractive and productive protocol for the
position-selective intramolecular C-H amination of aliphatic groups
(Hofmann-Löffler reaction) employing sulfonimides as nitrogen sources initiated
by visible light. The overall transformation provides pyrrolidines under mild
and selective conditions as demonstrated for 17 different substrates.
C. Q. O'Broin, P. Fernández, C. Martínez, Kilian Muñiz, Org. Lett., 2016, 18,
436-439.
The combination of phthaloyl peroxide with commercially available halide salts
provides an unique halogenating system for Hofmann-Löffler-Freytag-type
reactions to produce N-chloroamides, δ-brominated products, and even
biologically relevant pyrrolidines under mild conditions in good yields.
D. Chang, R. Zhao, C. Wei, Y. Yao, Y. Liu, L. Shi, J. Org. Chem., 2018, 83,
3305-3315.
Efficient Ti-catalyzed radical formal [3+2] cycloadditions of N-acylaziridines
and alkenes provide pyrrolidines from readily available starting materials. The
overall redox-neutral reaction was achieved via a redox-relay mechanism, which
harnesses radical intermediates for selective C-N bond cleavage and formation.
W. Hao, X. Wu, J. Z. Sun, J. C. Siu, S. N. MacMillan, S. Lin, J. Am. Chem. Soc., 2017,
139, 12141-12144.
With the aid of visible light irradiation, the reaction of photocatalytically
generated alkyl radicals possessing pendant leaving groups with imines provides
substituted pyrrolidines, piperidines, and azepanes under mild, redox-neutral
conditions.
L. R. E. Pantaine, J. A. Milligan, J. K. Matsui, C. B. Kelly, G. A. Molander,
Org. Lett., 2019, 21, 2317-2321.
Subjecting pyrrolidines or piperidines to a mixture of hydrochloric acid,
acetic acid, and acetic anhydride in an undivided electrochemical cell at a
constant current results in stereoselective conversion to the corresponding
α-acetoxy-β-chloro derivative. The α-position can be readily substituted with a
range of other groups, including alkyl, aryl, allyl, alkynyl, alkoxy, or azido
functionalities.
G. Kundu, T. H. Lambert, J. Am. Chem. Soc.,
2024, 146, 1794-1798.
The union of vinyl sulfones with photoredox-generated α-amino radicals enables
direct C-H vinylations of N-aryl tertiary amines, as well as
decarboxylative vinylations of N-Boc α-amino acids, to provide allylic
amines of broad diversity in high yield and with excellent olefin geometry
control. The utility of this reaction has been demonstrated via the syntheses of
several natural products and a number of established pharmacophores.
A. Noble, D. W. C. MacMillan, J. Am. Chem. Soc., 2014,
136, 11602-11605.
The air- and moisture-stable CoBr2·6H2O catalyzes a
convenient reductive cyclization of enynes and diynes in the presence of H2
as a reductant to provide the corresponding cyclized products in good yields
without olefin isomerization and over-reduction.
K. Isoda, Y. Sato, Org. Lett., 2023, 25,
2103-2107.
An enantioselective cross-electrophile divinylation reaction of
2-bromo-1,6-dienes offers a mild route to chiral cyclic architectures, which are
key structural motifs found in various biologically active compounds. The use of
chiral t-Bu-pmrox and 3,5-difluoro-pyrox ligands resulted in the
formation of divinylated products with high chemo-, regio-, and
enantioselectivity.
J.-B. Qiao, Y.-Q. Zhang, Q.-W. Yao, Z.-Z. Zhao, X. Peng, X.-Z. Shu, J. Am. Chem. Soc.,
2021, 143, 12961-12967.
A metal-free C(sp3)-H aroylation of amines via visible-light
photoredox catalysis provides useful α-amino aryl ketones. A series of
experiments indicate that this transformation undergoes a photoredox catalytic
radical-radical cross-coupling pathway.
G.-Q. Xu, T.-F. Xiao, G.-X. Feng, C.-Liu, B. Zhang, P.-F. Xu, Org. Lett., 2021, 23,
2846-2852.
A Rh-catalyzed oxygenative carbofunctionalization of terminal alkynes
provides cyclic carboxylic acid derivatives. The generation of a disubstituted
Rh vinylidene complex upon C-C bond formation at the terminal alkyne is followed
by a transfer oxygenation. The newly formed rhodium-complexed ketene
intermediate reacts with a variety of heteroatom nucleophiles to give the
desired products.
D.-K. Kim, M. Keum, H. Yun, I. Kim, J. M. Joo, C. Lee, Org. Lett., 2023, 25,
1889-1894.
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.
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.
A cationic manganese porphyrin catalyst enables a formal [3+2] cycloaddition
between aziridines and styrenes to give the corresponding pyrrolidines.
T. Ozawa, T. Kurahashi, S. Matsubara, Synlett, 2013, 24,
2763-2767.
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.
[Ir(COD)Cl]2 is an effective precatalyst for the intramolecular
hydroamination of a range of unactivated alkenes with pendant secondary amines.
The catalyst can be used at relatively low loadings and without the need for
added ligands or other cocatalysts.
K. D. Hesp, M. Stradiotto, Org. Lett., 2009,
11, 1449-1452.
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.
Homogeneous carboamination, carboalkoxylation and carbolactonization of terminal
alkenes are realized via oxidative gold catalysis, providing expedient access to
various substituted N- or O-heterocycles. Deuterium-labeling studies established
the nature of the alkene functionalization and the indispensible role of Au(I)/Au(III)
catalysis.
G. Zhang, L. Cui, Y. Wang, L. Zhang, J. Am. Chem. Soc., 2010,
132, 1474-1475.
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.
AgHMDS/DTBM-Segphos or Ag2O/CA-AA-Amidphos catalytic systems achieve
stereodivergent [3 + 2] cycloadditions of iminoesters with various α-substituted
acrylates to provide chiral C4-ester-quaternary exo- or endo-pyrrolidines
with high yields and excellent diastereo- and enantioselectivities.
Z. Chen, W. Zhong, S. Liu, T. Zou, K. Zhang, C. Gong, W. Guo, F. Kong, L. Nie,
S. Hu, H. Wang, Org. Lett., 2023, 25,
3391-3396.
AgHMDS/DTBM-Segphos or Ag2O/CA-AA-Amidphos catalytic systems achieve
stereodivergent [3 + 2] cycloadditions of iminoesters with various α-substituted
acrylates to provide chiral C4-ester-quaternary exo- or endo-pyrrolidines
with high yields and excellent diastereo- and enantioselectivities.
Z. Chen, W. Zhong, S. Liu, T. Zou, K. Zhang, C. Gong, W. Guo, F. Kong, L. Nie,
S. Hu, H. Wang, Org. Lett., 2023, 25,
3391-3396.
Dual Rh(II)/Pd(0) relay catalysis of N-sulfonyl triazoles and
2-hydroxymethylallyl carbonates provides N-sulfonyl pyrrolidines in good
yields with high diastereoselectivities. The reaction proceeds via a relay
mechanism involving O-H insertion onto the α-imino Rh(II)-carbene,
[3,3]-sigmatropic rearrangement, dipole formation through Pd(0)-catalyzed
decarboxylation, and intramolecular N-allylation.
L.-Z. Huang, Z. Xuan, J.-U. Park, J. H. Kim, Org. Lett.,
2022, 24, 6951-6956.
A CO2 extrusion, nickel capture, migratory insertion sequence with
terminal and internal alkynes provides stereodefined functionalized olefins from
carboxylic acids. A hydrogen atom transfer enables even a direct vinylation of
unactivated C-H bonds.
N. A. Till, R. T. Smith, D. W. C. MacMillan, J. Am. Chem. Soc.,
2018,
140, 5701-5705.
A catalyst composed of Pd(OAc)2 and S-Phos allows the conversion
of aryl chlorides as electrophiles in Pd-catalyzed alkene carboamination and
carboetherification, minimizes N-arylation, and prevents formation of
regiosisomieric mixtures. Various heterocycles, including pyrrolidines,
isoxazolidines, tetrahydrofurans, and pyrazolidines, are efficiently generated
with this method.
B. R. Rosen, J. E. Ney, J. P. Wolfe, J. Org. Chem., 2010,
75, 2756-2759.
The stereoselective synthesis of N-acyl- and N-Boc-protected
pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and
γ-(N-Boc-amino) alkenes with aryl bromides proceeds with generally high
levels of diastereoselectivity by formation of two bonds in a single operation.
M. B. Bertrand, J. P. Wolfe, Tetrahedron, 2005,
61, 6447-6459.
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.
The gold(I)-catalyzed reaction of methylenecyclopropanes with sulfonamides
produces the corresponding pyrrolidine derivatives in moderate to good
yields via a domino ring-opening ring-closing hydroamination process.
M. Shi, L.-P. Liu, J. Tang, Org. Lett.,
2006, 8, 4043-4046.
A simple iron-catalyzed intramolecular hydroamination of unactivated olefins
proceeds under mild conditions and tolerates aminoolefins containing halide
moieties.
K. Komeyama, T. Morimoto, K. Takaki, Angew. Chem. Int. Ed., 2006, 45, 2938-2941.
An unstabilized azomethine ylide generated from commercial trimethylamine N-oxide
undergoes a remarkable 1,3-dipolar cycloaddition with electron-rich and
unpolarized olefins to give challenging 3,4-disubstituted pyrrolidines in good
yield. A broad range of substituents on the alkenes are tolerated provided they
are compatible with excess LDA.
J. E. Davoren, D. L. Gray, A. R. Harris, D. M. Nason, W. Xu, Synlett, 2010,
2490-2492.
Organoselenium catalysis enables an efficient synthesis of oxygen and nitrogen
heterocycles via exo-cyclization under mild conditions in the presence of
1-fluoropyridinium triflate. The reaction offers good functional group tolerance
and excellent regioselectivity.
R. Guo, J. Huang, H. Huang, X. Zhao, Org. Lett., 2016, 18,
504-507.
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.
Enantioselective intramolecular oxidative amidation of alkenes has been
achieved using a (pyrox)Pd(II)(TFA)2 as catalyst and O2 as the stoichiometric oxidant. The reactions
proceed at room temperature in very good yields and with high
enantioselectivity. Catalyst-controlled stereoselective
cyclization reactions are demonstrated for a number of chiral substrates.
R. I. McDonald, P. W. White, A. B. Weinstein, C. P. Tam, S. S. Stahl, Org. Lett., 2011,
13, 2830-2833.
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.
Palladium-catalyzed intramolecular amination of unactivated C-H bonds at the
γ and δ positions of picolinamide (PA) protected amine substrates enables the
synthesis of azetidine, pyrrolidine, and indoline compounds. The method features
relatively low catalyst loading, use of inexpensive reagents, convenient
operating conditions and predictable selectivities.
G. He, Y. Zhao, S. Zhang, C. Lu, G. Chen, J. Am. Chem. Soc., 2012,
134, 3-6.
4-CN-pyridine is an effective cyanation reagent under catalyst-free,
paired electrochemical reaction conditions. Mechanistic studies support a nucleophilic reaction pathway,
and the cyanation protocol can be applied to diverse substrates including N,N-dialkyl
anilines, indole derivatives and amino acids (via decarboxylative cyanation).
G. S. Kumar, P. S. Shinde, H. Chen, K. Muralirajan, R. Kancherla, M. Rueping, Org. Lett.,
2022, 24, 6357-6363.
A wide variety of mixed anhydrides formed in situ from carboxylic acids and acyl
chlorides can subsequently undergo metal insertion-decarboxylation-recombination
to provide ketones in very good yield when subjected to metallaphotoredox
catalysis. A three-step synthesis of the medicinal agent edivoxetine is also
described.
C. Le, D. W. C. MacMillan, J. Am. Chem. Soc., 2015,
137, 11938-11941.
Lithium iodide promotes a convenient [3 + 2]-cycloaddition reaction between
N-tosylaziridines and α,β-unsaturated ketones under mild conditions to
provide N-tosylpyrrolidines in high yields. Quaternary carbon-possessing
3,3-disubstituted pyrrolidines including spiro compounds can also be obtained.
An intramolecular version can be used for the synthesis of tropane derivatives.
Y. Nakagawa, K. Yamaguchi, S. Hosokawa, J. Org. Chem., 2021, 86,
7787-7796.
Depending on the use of copper(I) and silver(I) complexes with (S)-DM- or (S)-DTBM-Segphos
as ligands, a catalytic enantioselective 1,3-dipolar cycloaddition between imino
esters and electrophilic alkenes provides diastereodivergently exo- or
endo-cycloadducts. Functional groups of the dipolarophile and the choice of the
catalyst play an important role in promoting reverse diastereoselectivities.
G. S. Caleffi, O. Larrañaga, M. Ferrándiz-Saperas, P. R. R. Costa, C. Nájera,
A. de Cózar, F. P. Cossío, J. M. Sansano, J. Org. Chem., 2019,
84, 10593-10605.
In the presence of MgI2 as Lewis acid, donor-acceptor cyclopropanes
or corresponding cyclobutanes react with 1,3,5-triazinanes, leading to the
2-unsubstituted pyrrolidines and piperidines under mild conditions in good
yields. This protocol tolerates various functional groups and provides an
efficient entry to pyrrolidines and piperidines.
L. K. B. Garve, A. Kreft, P. G. Jones, D. B. Werz, J. Org. Chem.,
2017, 82, 9235-9242.
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.
1,3-Dipolar cycloaddition of in situ generated azomethine ylides to electron
deficient olefins catalyzed by tris(pentafluorophenyl)borane is described.
P. Srihari, S. R. Yaragorla, D. Basu, S. Chandrasekhar, Synthesis, 2006, 2646-2648.
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.
Under selected conditions, the Zr-catalyzed reaction of EtMgCl with imines
produces C,N-dimagnesiated compounds, which can be further trapped with
electrophiles. The overall transformation provides a new route to
bifunctional or cyclic nitrogen-containing compounds such as
1-azaspirocyclic γ-lactams, pyrrolidines and azetidines.
V. Gandon, P. Bertus, J. Szymoniak, Synthesis, 2002, 1115-1120.
Ph3PAuOTf catalyzes efficient intra- and intermolecular
hydroamination of unactivated olefins with sulfonamides.
J. Zhang, C.-G. Yang, C. He, J. Am. Chem. Soc.,
2006, 128, 1798-1799.
An efficient alkene aza-Cope-Mannich cyclization between 2-hydroxy homoallyl
tosylamine and aldehydes in the presence of iron(III) salts gives
3-alkyl-1-tosyl pyrrolidines in good yields via a γ-unsaturated iminium ion,
2-azonia-[3,3]-sigmatropic rearrangement, and intramolecular Mannich reaction.
The cyclization of 2-hydroxy homopropargyl tosylamines gives dihydro-1H-pyrroles.
R. M. Carballo, M. Purino, M. A. Ramírez, V. S. Martín, J. I. Padrón, Org. Lett., 2010,
12, 5334-5337.
Oxetane desymmetrization enables an asymmetric synthesis of chiral
pyrrolidines bearing an all-carbon quaternary stereocenter in the 3-position
either using a readily available tert-butylsulfinamide chiral auxiliary
or a catalytic system with a chiral phosphoric acid as the source of chirality.
R. Zhang, M. Sun, Q. Yan, X. Lin, X. Li, X. Fang, H. H. Y. Sung, J. D. Williams,
J. Sun, Org. Lett.,
2022, 24, 2359-2364.
A P(NMe2)3-mediated tandem (1 + 4) annulation
between aroylformates and δ-tosylamino enones provides functionalized
pyrrolidines in good yields with exclusive chemoselectivity and high
diastereoselectivity. The reaction proceeds through an unprecedented P(NMe2)3-mediated
reductive amination/base-catalyzed Michael addition cascade.
R. Liu, J. Liu, J. Cao, R. Li, R. Zhou, Y. Qiao, W.-C. Gao,
Org. Lett., 2020, 22, 6922-6926.
Bisphosphine-catalyzed mixed double-Michael reactions between amino-acid-derived
pronucleophiles as Michael donors and electron-deficient acetylenes as acceptors
afford β-amino carbonyl derivatives of oxazolidines, thiozolidines, and
pyrrolidines in excellent yields and with high diastereoselectivities under
operationally simple and mild conditions.
V. Sriramurthy, G. A. Barcan, O. Kwon, J. Am. Chem. Soc., 2007,
129, 12928-12929.
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.
The aza-Payne rearrangement of 2,3-aziridin-1-ols under basic conditions gives
epoxy amines. Subsequent nucleophilic attack of the epoxide by
dimethylsulfoxonium methylide yields a bis-anion, which upon a 5-exo-tet
ring-closure yields the desired pyrrolidine. This process takes place with
complete transfer of stereochemical fidelity and can be applied to sterically
hindered aziridinols.
J. M. Schomaker, S. Bhattacharjee, J. Yan, B. Borhan, J. Am. Chem. Soc., 2007,
129, 1996-2003.
J. M. Schomaker, S. Bhattacharjee, J. Yan, B. Borhan, J. Am. Chem. Soc., 2007,
129, 1996-2003.
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.
A mild and convenient free-radical cyclization of organohalides in the presence
of a NiCl2 • DME/Pybox complex as the catalyst and zinc powder in
methanol efficiently gives carbo-, oxa-, and azacycles as products in high
yields from unsaturated alkyl halides.
H. Kim, C. Lee, Org. Lett., 2011,
13, 2050-2053.
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 copper(I)/ClickFerrophos complex catalyzed the asymmetric 1,3-dipolar
cycloaddition of methyl N-benzylideneglycinates with electron deficient alkenes
to give exo-2,4,5-trisubstituted and 2,3,4,5-substituted pyrrolidines in
good yields with high diastereo- and enantioselectivities.
S.-i. Fukuzawa, H. Oki, Org. Lett., 2008,
10, 1747-1750.
An l-tert-leucine-derived AmidPhos/silver(I) catalytic system enables an
asymmetric [3+2] cycloaddition of azomethine ylides with electronic-deficient
alkenes. Under optimal conditions, highly functionalized endo-4-pyrrolidines
were obtained in very good yields and enantioselectivities.
Z. Zhou, X. Zheng, J. Liu, J. Li, P. Wen, H. Wang,
Synlett, 2017, 28, 999-1003.
Highly Endo-Selective and Enantioselective 1,3-Dipolar Cycloaddition of
Azomethine Ylide with α-Enones Catalyzed by a Silver(I)/ThioClickFerrophos
Complex
I. Oura, K. Shimizu, K. Ogata, S.-i. Fukuzawa, Org. Lett., 2010,
12, 1752-1755.
A successful stereochemical reversal in AgOAc catalyzed [3+2] cycloaddition is
based on the formation of hydrogen bonding between ligand and reactant. Simple
ligand design provides an efficient and convenient route to prepare both
enantiomers of a chiral compound.
W. Zeng, G.-Y. Chen, Y.-G. Zhou, Y.-X. Li, J. Am. Chem. Soc., 2007,
129, 750-751.
Chiral complexes of calcium promote asymmetric 1,4-addition reactions and [3+2]
cycloaddition reactions of α-amino acid derivatives with α,β-unsaturated
carbonyl compounds. The reactions proceeded smoothly in the presence of 5-10 mol
% of the chiral calcium catalyst to afford the desired adducts in high yields
with high diastereo- and enantioselectivities.
S. Saito, T. Tsubogo, S. Kobayashi, J. Am. Chem. Soc., 2007,
129, 5364-5365.
A nucleophilic addition/ring-contractive rearrangement of α-bromo N-alkoxylactams
with organometallic reagents provides an efficient access to α-acylpyrrolidines
with good yields and a broad substrate scope. Moreover, a diastereoselective
reaction of a chiral N-alkoxylactam is also described.
N. Takeda, Y. Kobori, K. Okamura, M. Yasui, M. Ueda, Org. Lett., 2020, 22,
9740-9744.
Using a confined imidodiphosphate catalyst, a highly enantioselective
intramolecular carbonyl-ene reaction of olefinic aldehydes delivers diverse
trans-3,4-disubstituted carbo- and heterocyclic five-membered rings in high
yields and with good to excellent diastereo- and enantioselectivities.
L. Liu, M. Leutzsch, Y. Zheng, M. W. Alachraf, W. Thiel, B. List, J. Am. Chem. Soc., 2015,
137, 13268-13271.
A [3 + 2]-annulation of N-Ts-α-amino aldehydes and
1,3-bis(silyl)propenes allows an efficient, stereoselective synthesis of
densely functionalized pyrrolidines.
P. Restorp, A. Fischer, P. Somfai, J. Am. Chem. Soc., 2006, 128, 12646-12647.
A remarkable Pd-catalyzed diamination of unactivated alkenes using N-fluorobenzenesulfonimide
(NFBS) as an aminating reagent is described. The reaction incorporates one
nitrogen donor from the substrate and the other from the NFBS, thereby
generating cyclic diamine derivatives in a single step. The products are
differentially protected at both nitrogens, allowing for maximal synthetic
flexibility.
P. A. Sibbald, F. E. Michael, Org. Lett., 2009,
11, 1147-1149.
The reaction of 1,1-cyclopropandiesters with aldimines, generated in situ
by the condensation of primary amines or anilines with aldehydes, in the
presence of Yb(OTf)3 as catalyst leads to pyrrolidines in good
yields.
C. A. Carson, M. A. Kerr, J. Org. Chem., 2005, 70, 8242-8244.
A tandem ring-opening-cyclization reaction of cyclopropanes with imines in
the presence of 5 mol% of scandium triflate was developed for the highly
diastereoselective synthesis of multisubstituted pyrrolidines.
Y.-B. Kang, Y. Tang, X.-L. Sun, Org. Biomol. Chem., 2006, 4, 299-301.
Successive nucleophilic and electrophilic allylation of a bis-Boc-carbonate derived from 2-methylene-1,3-propane diol
provides enantiomerically enriched 2,4-disubstituted pyrrolidines. An initial
enantioselective iridium-catalyzed transfer hydrogenative carbonyl C-allylation
is followed by Tsuji-Trost N-allylation using 2-nitrobenzenesulfonamide
and a Mitsunobu cyclization.
G. Luo, M. Xiang, M. J. Krische,
Org. Lett., 2019, 21, 2493-2497.
A palladium-catalyzed cascade cyclization-coupling reaction with suppressed β-hydride
elimination provides an efficient synthetic route to
4-methylene-3-arylmethylpyrrolidines. One of the N-sulfonyl oxygens is suggested to coordinatively stabilize an alkylpalladium
intermediate, thus preventing the intermediate from the usual β-elimination.
C.-W. Lee, K. S. Oh, K. S. Kim, K. H. Ahn,
Org. Lett., 2000, 2, 1213-1216.
An iron catalyst enables a reductive cyclization of 1,6- and 1,7-enynes. Alcohol,
ketone, ester, ether, halide, amine, amide, imine, nitrile, silyl, and alkyne
groups are tolerated under the mild reaction conditions. An enantioselective
transformation was also conducted.
T. Xi, X. Chen, H. Zhang, Z. Lu, Synthesis, 2016,
48, 2837-2844.
Indium hydride generated from readily available Et3SiH and InCl3
offers mild conditions and low toxicity, and is therefore a promising
alternative to Bu3SnH.
N. Hayashi, I. Shibata, A. Baba, Org. Lett., 2004, 6,
4981-4983.
A new methodology for the cycloisomerization of dienes using a Grubbs carbene
complex and trimethylsilyl vinyl ether has been established. The utility of this
reaction was demonstrated by in the synthesis of exo-methylene
heterocyclic compounds, which could act as key intermediates for
pharmacologically active compounds.
Y. Terada, M. Arisawa, A. Nishida, Angew. Chem. Int. Ed., 2004,
43,
4063-4067.
An enantioselective, palladium-catalyzed [3 + 2] cycloaddition of
trimethylenemethane (TMM) with imines in the presence of novel phosphoramidite
ligands gives the corresponding pyrrolidine cycloadducts with excellent yields
and selectivities.
B. M. Trost, S. M. Silverman, J. Am. Chem. Soc., 2012,
134, 4941-4954.
FeCl2 and an iminopyridine ligand form in the presence of
diethylzinc and magnesium bromide etherate an active catalyst for the reductive
cyclization of N- and O-tethered 1,6-enynes to give pyrrolidine and tetrahydrofuran derivatives.
A. Lin, Z.-W. Zhang, J. Yang, Org. Lett., 2014,
16, 386-389.
A Rh-catalyzed [4 + 1] cycloaddition of 3-methyleneazetidines to diazo
compounds provides 4-methyleneproline derivatives under very mild conditions
with a high degree of chemoselectivity. This method can incorporate the proline
ester scaffold in pharmaceuticals and natural products. An intramolecular
version of the reaction effectively provides proline-fused tricyclic
heterocycles.
W. Cai, J. Wu, H. Zhang, H. B. Jalani, G. Li, H. Lu, J. Org. Chem., 2019,
84, 10877-10891.
A rhodium-catalyzed asymmetric arylative cyclization of nitrogen-tethered
alkyne-enoate with arylboronic acids, in which two new carbon-carbon bonds and
one stereocenter are formed, provides access to pyrrolidines and piperidines
with good enantioselectivities by to the use of a C1-symmetric
chiral monosubstituted diene ligands.
F. Serpier, B. Flamme, J.-L. Brayer, B. Folléas, S. Darses, Org. Lett.,
2015,
17, 1720-1723.
Palladium-catalyzed inter- and intramolecular enyne coupling
reactions were developed. The
reaction involves the acetoxypalladation of the alkyne, followed by the
insertion of the alkene and the protonolysis of the carbon-palladium bond. The coupling
allows the construction of synthetically important carbo- and
heterocycles.
L. Zhao, X. Lu, W. Xu, J. Org. Chem., 2005, 70, 4059-4063.
A novel alkenylative cyclization of enyne was developed using Cp*RuCl(cod)
under ethylene gas at room temperature.
M. Mori, N. Saito, D. Tanaka, M. Takimoto, Y. Sato, J. Am. Chem. Soc., 2003, 125, 5606-5607.
A convenient two-step preparation of alkylidenepyrrolidines is reported.
M. C. Elliot, S. V. Wordingham, Synthesis, 2006, 1162-1170.
Catalytic hydrogenation of acetylenic aldehydes using a chirally modified
cationic rhodium catalysts enables highly enantioselective reductive
cyclization to afford cyclic allylic alcohols. Using an achiral
hydrogenation catalyst, some chiral racemic acetylenic aldehydes engage in
highly syn-diastereoselective reductive cyclizations.
J. U. Rhee, M. J. Krische, J. Am. Chem. Soc., 2006, 128, 10674-10675.
Reductive
radical cyclization of N-allyl-N-dimethylphosphinoyl-2-aminopropyl
phenyl selenide using tris(trimethylsilyl)silane (TTMSS) / AIBN under UV
irradiation gave the corresponding pyrrolidine in 74% yield and a cis/trans ratio of 10/1
which was superior to thermal cyclization
D. Shanks, S. Berlin, M. Besev,
H. Ottosson, L. Engman, J. Org. Chem., 2004, 69,
1487-1491.
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.
An enantioselective catalytic Suzuki-Miyaura reaction of meso
1,2-diborylcycloalkanes provides enantiomerically enriched substituted
carbocycles and heterocycles that retain a synthetically versatile boronic
ester. With appropriately constructed substrates, compounds bearing additional
stereogenic centers and fully substituted carbon atoms can be generated in a
straightforward fashion.
M. Zhang, P. S. Lee, C. Allais, R. A. Singer, J. P. Morken, J. Am. Chem. Soc.,
2023, 145, 8308-8313.
A chiral iridium diphosphine complex catalyzes an enantioselective
intramolecular Pauson-Khand-type reaction to give various chiral bicyclic
cyclopentenones. A low partial pressure of carbon monoxide is important to
achieve excellent enantioselectivity.
T. Shibata, N. Toshida, M. Yamasaki, S. Maekawa, K. Takagi, Tetrahedron, 2005,
61, 9974-9979.
The reaction of various 1,6-enynes with N2CHSiMe3 in the
presence of RuCl(COD)Cp* as catalyst precursor leads to the general formation of
alkenylbicyclo[3.1.0]hexanes at room temperature in good yield with high
stereoselectivity. The catalytic formation of alkenylbicyclo[3.1.0]hexanes also
takes place in the presence of N2CHCO2Et or N2CHPh.
F. Monnier, C. Vovard-Le Bray, D. Castillo, V. Aubert, S. Dérien, P. H.
Dixneuf, L. Toupet, A. Ienco, C. Mealli, J. Am. Chem. Soc., 2007,
129, 6037-6049.
F. Monnier, C. Vovard-Le Bray, D. Castillo, V. Aubert, S. Dérien, P. H.
Dixneuf, L. Toupet, A. Ienco, C. Mealli, J. Am. Chem. Soc., 2007,
129, 6037-6049.
A new Pd-catalyzed oxidation reaction for the stereospecific conversion of
enynes into cyclopropyl ketones proceeds with net inversion of geometry with
respect to the starting olefin. This result is consistent with a mechanism in
which the key cyclopropane-forming step involves nucleophilic attack of a
tethered olefin onto the PdIV-C bond.
L. L. Welbes, T. W. Lyons, K. A. Cychosz, M. S. Sanford, J. Am. Chem. Soc., 2007,
129, 5836-5837.