Journal of the American Chemical Society
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catalyzed α-alkylation of amines by C(sp3)‒H bond activation. Gonnard,
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For a review on the hydricity of lithium amides, see: Reduction
L.; Guérinot, A.; Cossy, J. Tetrahedron 2019, 75, 145-163; s)
Construction of N-Heterocycles through Cyclization of Tertiary Amines.
Liu, S.; Zhao, Z.; Wang, Y. Chem. Eur. J. 2019, 25, 2423-2441.
with lithium dialkylamides. Majewski, M.; Gleave, D. M. J. Organomet.
Chem. 1994, 470, 1-16.
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Precedent for these types of reactions is limited: a)
(3)
Selected recent reports on amine C–H functionalization: a)
Regioselective 2-alkylation and 2-arylation of piperidine and pyrrolidine
via organolithiation of cyclic imines. Scully, F. E. J. Org. Chem. 1980, 45,
Palladium-catalysed transannular C–H functionalization of alicyclic
amines. Topczewski, J. J.; Cabrera, P. J.; Saper, N. I.; Sanford, M. S.
Nature 2016, 531, 220-224; b) Native functionality in triple catalytic
cross-coupling: sp3 C–H bonds as latent nucleophiles. Shaw, M. H.;
Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.; MacMillan, D. W. C.
Science 2016, 352, 1304-1308; c) Enantioselective amine α-
functionalization via palladium-catalysed C–H arylation of thioamides.
Jain, P.; Verma, P.; Xia, G.; Yu, J.-Q. Nat. Chem. 2017, 9, 140-144; d)
Palladium-Catalyzed Enantioselective C–H Activation of Aliphatic
Amines Using Chiral Anionic BINOL-Phosphoric Acid Ligands. Smalley,
A. P.; Cuthbertson, J. D.; Gaunt, M. J. J. Am. Chem. Soc. 2017, 139, 1412-
1415; e) Synthesis of Ring-Fused 1-Benzazepines via [1,5]-Hydride
Shift/7-Endo Cyclization Sequences. Suh, C. W.; Kwon, S. J.; Kim, D. Y.
Org. Lett. 2017, 19, 1334-1337; f) Direct Intermolecular C–H
Functionalization Triggered by 1,5-Hydride Shift: Access to N-
Arylprolinamides via Ugi-Type Reaction. Zhen, L.; Wang, J.; Xu, Q.-L.;
Sun, H.; Wen, X.; Wang, G. Org. Lett. 2017, 19, 1566-1569; g) Synthesis
of Spirooxindoles via the tert-Amino Effect. Ramakumar, K.; Maji, T.;
Partridge, J. J.; Tunge, J. A. Org. Lett. 2017, 19, 4014-4017; h)
Construction of the tetrahydroquinoline spiro skeleton via cascade [1,5]-
hydride transfer-involved C(sp3)-H functionalization "on water". Zhu, S.;
Chen, C.; Xiao, M.; Yu, L.; Wang, L.; Xiao, J. Green Chem. 2017, 19,
5653-5658; i) Organocatalytic C(sp3)–H Functionalization via
Carbocation-Initiated Cascade [1,5]-Hydride Transfer/Cyclization:
Synthesis of Dihydrodibenzo[b,e]azepines. Li, S.-S.; Zhou, L.; Wang, L.;
Zhao, H.; Yu, L.; Xiao, J. Org. Lett. 2018, 20, 138-141; j) Intramolecular
hydride transfer onto arynes: redox-neutral and transition metal-free
C(sp3)-H functionalization of amines. Idiris, F. I. M.; Majeste, C. E.;
Craven, G. B.; Jones, C. R. Chem. Sci. 2018, 9, 2873-2878; k) Redox-
1515-1517; b)
A
Convenient Preparation of 3-Aza-2-phenyl
Bicyclo[3.2.2]nonane and Related 2-Substituted Cyclic Amines. Healy,
M. A. M.; Smith, S. A.; Stemp, G. Synth. Commun. 1995, 25, 3789-3797.
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Examples of imine activation with BF3 etherate or TMS
triflate: a) 1. Boron trifluoride activated 3-thiazolines. An efficient
preparation of functionalized thiazolidines. Meltz, C. N.; Volkmann, R. A.
Tetrahedron Lett. 1983, 24, 4503-4506; b) Addition of alkynyl anions to
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aldimines containing α-hydrogens:
a
novel synthesis of β-
aminoacetylenes. Wada, M.; Sakurai, Y.; Akiba, K.-y. Tetrahedron Lett.
1984, 25, 1083-1084; c) The Activation of Imines to Nucleophilic Attack
by Grignard Reagents. Brook, M. A.; Jahangir Synth. Commun. 1988, 18,
893-898; d) Alkylation of 3,4-Dihydro-beta-carboline. Kawate, T.;
Nakagawa, M.; Yamazaki, H.; Hirayama, M.; Hino, T. Chem. Pharm.
Bull. 1993, 41, 287-291; e) BF3-Mediated Addition of Lithium
Phenylacetylide to an Imine: Correlations of Structures and Reactivities.
BF3·R3N Derivatives as Substitutes for BF3·Et2O. Aubrecht, K. B.;
Winemiller, M. D.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 11084-
11089; f) BF3-Mediated Additions of Organolithiums to Ketimines:ꢀ X-ray
Crystal Structures of BF3−Ketimine Complexes. Ma, Y.; Lobkovsky, E.;
Collum, D. B. J. Org. Chem. 2005, 70, 2335-2337.
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For the activation of imines with TMS benzotriazole see: 1-
(Trimethylsilyl)benzotriazole-Assisted Addition of Grignard Reagents to
Imines: A Versatile Approach to Aliphatic Secondary Amines. Katritzky,
A. R.; Hong, Q.; Yang, Z. J. Org. Chem. 1994, 59, 7947-7948.
(13) For the addition of organometallics to BF3-activated pyridines,
see: a) Transition-Metal-Free BF3-Mediated Regioselective Direct
Alkylation and Arylation of Functionalized Pyridines Using Grignard or
Organozinc Reagents. Chen, Q.; du Jourdin, X. M.; Knochel, P. J. Am.
Chem. Soc. 2013, 135, 4958-4961; b) Transition-Metal-Free BF3-
Mediated Oxidative and Non-Oxidative Cross-Coupling of Pyridines.
Chen, Q.; León, T.; Knochel, P. Angew. Chem. Int. Ed. 2014, 53, 8746-
8750.
triggered
cascade
dearomative
cyclizations
enabled
by
hexafluoroisopropanol. Li, S.-S.; Lv, X.; Ren, D.; Shao, C.-L.; Liu, Q.;
Xiao, J. Chem. Sci. 2018, 9, 8253-8259; l) Second-Generation Palladium
Catalyst System for Transannular C–H Functionalization of
Azabicycloalkanes. Cabrera, P. J.; Lee, M.; Sanford, M. S. J. Am. Chem.
Soc. 2018, 140, 5599-5606; m) Chiral Magnesium Bisphosphate-
Catalyzed Asymmetric Double C(sp3)–H Bond Functionalization Based
on Sequential Hydride Shift/Cyclization Process. Mori, K.; Isogai, R.;
Kamei, Y.; Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2018, 140,
6203-6207; n) C–H Functionalization of Amines via Alkene-Derived
Nucleophiles through Cooperative Action of Chiral and Achiral Lewis
Acid Catalysts: Applications in Enantioselective Synthesis. Shang, M.;
Chan, J. Z.; Cao, M.; Chang, Y.; Wang, Q.; Cook, B.; Torker, S.; Wasa,
M. J. Am. Chem. Soc. 2018, 140, 10593-10601; o) Borane-Catalyzed
Synthesis of Quinolines Bearing Tetrasubstituted Stereocenters by
Hydride Abstraction-Induced Electrocyclization. Maier, A. F. G.; Tussing,
S.; Zhu, H.; Wicker, G.; Tzvetkova, P.; Flörke, U.; Daniliuc, C. G.;
Grimme, S.; Paradies, J. Chem. Eur. J. 2018, 24, 16287-16291.
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For instance, 1-piperideine has a strong propensity to trimerize:
Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines.
Fandrick, D. R.; Hart, C. A.; Okafor, I. S.; Mercadante, M. A.; Sanyal, S.;
Masters, J. T.; Sarvestani, M.; Fandrick, K. R.; Stockdill, J. L.; Grinberg,
N.; Gonnella, N.; Lee, H.; Senanayake, C. H. Org. Lett. 2016, 18, 6192-
6195.
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Selected applications of imine trimers: a) Facile synthesis of N-
acyl-2-pyrrolines. Kraus, G. A.; Neuenschwander, K. J. Org. Chem. 1981,
46, 4791-4792; b) Introduction of carbon unit at the alpha-position of
alicyclic amines utilizing a decarboxylative reaction with malonic acid
derivatives. Fukawa, H.; Terao, Y.; Achiwa, K.; Sekiya, M. Chem. Lett.
1982, 11, 231-232; c) A New Method for the Introduction of Arylthio
Groups at the alpha-Position of Alicyclic Amines. Terao, Y.; Yasumoto,
Y.; Ikeda, K.; Sekiya, M. Chem. Pharm. Bull. 1986, 34, 105-108; d) A
new route to ene carbamates, precursors to benzoindolizinones through
sequential asymmetric hydrogenation and cyclization. Couture, A.;
Deniau, E.; Lebrun, S.; Grandclaudon, P.; Carpentier, J.-F. J. Chem. Soc.,
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Early
transition
metal-catalyzed
C–H
alkylation:
hydroaminoalkylation for Csp3–Csp3 bond formation in the synthesis of
selectively substituted amines. Edwards, P. M.; Schafer, L. L. Chem.
Commun. 2018, 54, 12543-12560.
Perkin Trans.
1 1998, 1403-1408; e) Design and Photochemical
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Tantalum Catalyzed Hydroaminoalkylation for the Synthesis of
Characterization of a Biomimetic Light-Driven Z/E Switcher. Sampedro,
D.; Migani, A.; Pepi, A.; Busi, E.; Basosi, R.; Latterini, L.; Elisei, F.; Fusi,
S.; Ponticelli, F.; Zanirato, V.; Olivucci, M. J. Am. Chem. Soc. 2004, 126,
9349-9359; f) The reaction of cyclic imines with the Ruppert–Prakash
reagent. Facile approach to α-trifluoromethylated nornicotine, anabazine,
and homoanabazine. Shevchenko, N. E.; Vlasov, K.; Nenajdenko, V. G.;
Röschenthaler, G.-V. Tetrahedron 2011, 67, 69-74.
α- and β-Substituted N-Heterocycles. Payne, P. R.; Garcia, P.;
Eisenberger, P.; Yim, J. C. H.; Schafer, L. L. Org. Lett. 2013, 15, 2182-
2185.
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Electrochemical
Aminoxyl-Mediated
α-Cyanation
of
Secondary Piperidines for Pharmaceutical Building Block Diversification.
Lennox, A. J. J.; Goes, S. L.; Webster, M. P.; Koolman, H. F.; Djuric, S.
W.; Stahl, S. S. J. Am. Chem. Soc. 2018, 140, 11227-11231.
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See the Supporting Information for details.
Discovering risperidone: the LSD model of psychopathology.
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a) Über Lithium diäthylamid als Hydrid Donator. Wittig, G.;
Schmidt, H. J.; Renner, H. Chem. Ber. 1962, 95, 2377-2383; b) Zur
Reaktionsweise N-metallierter acyclischer und cyclischer sekundärer
Amine. Wittig, G.; Hesse, A. Liebigs Ann. Chem. 1971, 746, 149-173; c)
Hydrid-Übertragung von Lithium-pyrrolidid auf Azomethine. Wittig, G.;
Hesse, A. Liebigs Ann. Chem. 1971, 746, 174-184; d) Über die Reaktivität
von metallierten Aminen als Hydrid-Donatoren. Wittig, G.; Häusler, G.
Liebigs Ann. Chem. 1971, 746, 185-199.
Colpaert, F. C. Nat. Rev. Drug Discov. 2003, 2, 315-320.
(18) a) LiCl-Mediated Br/Mg Exchange Reaction for the
A
Preparation of Functionalized Aryl- and Heteroarylmagnesium
Compounds from Organic Bromides. Krasovskiy, A.; Knochel, P. Angew.
Chem. Int. Ed. 2004, 43, 3333-3336; b) Progress and developments in the
turbo Grignard reagent i-PrMgCl·LiCl: a ten-year journey. Li-Yuan Bao,
R.; Zhao, R.; Shi, L. Chem. Commun. 2015, 51, 6884-6900; c) Improving
the Halogen–Magnesium Exchange by using New Turbo-Grignard
Reagents. Ziegler, D. S.; Wei, B.; Knochel, P. Chem. Eur. J. 2019, 25,
2695-2703.
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Direct α-C–H bond functionalization of unprotected cyclic
amines. Chen, W.; Ma, L.; Paul, A.; Seidel, D. Nat. Chem. 2018, 10, 165.
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