Categories: C-C Bond Formation > Oxygen-, Nitrogen-containing molecules

Substitution of active methylenes

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Recent Literature

F. Stauffer, R. Neier, Org. Lett., 2000, 2, 3535-3537.

A hypervalent iodine mediated α-alkylative umpolung reaction of carbonyl compounds with dialkylzinc as the alkyl source is applicable to a broad range of ketones including 1,3-dicarbonyl compounds and regular ketones via their lithium enolates. The α-alkylated carbonyl products are formed in very good yield. Meticulous analysis, NMR studies, trapping and crossover experiments, and computational studies suggest an ionic mechanism.
O. S. Shneider, E. Pisarevsky, P. Fristrup, A. M. Szpilman, Org. Lett., 2015, 17, 282-285.

A one-pot procedure for the synthesis of 2-alkyl-2-arylcyanoacetates based on a Pd(OAc)₂/dppf-catalyzed enolate arylation followed by in situ alkylation tolerates a diverse range of aryl and heteroaryl bromides, and provides a rapid entry to a wide range of products in very good to yield.
X. Wang, A. Guram, E. Bunel, G.-Q. Cao, J. R. Allen, M. M. Faul, J. Org. Chem., 2008, 73, 1643-1645.

Simple dialkyl malonate esters exhibit limited scope as carbon nucleophiles in the Mitsunobu reaction. In contrast, bis(2,2,2-trifluoroethyl) malonates readily undergo dehydrative alkylation with primary and some secondary alcohols.
J. M. Takacs, Z. Xu, X.-T. Jiang, A. P. Leonov, G. C. Theriot, Org. Lett., 2002, 4, 3843-3845.

Visible-light-driven dual HAT catalysis overcomes the inherent polarity-mismatch and achieves hydroalkylation of unactivated olefins using catalytic amounts of an amine-borane and an in situ generated thiol as the hydrogen atom abstractor and donor, respectively. The reaction is completely atom-economical and exhibits a broad scope.
G. Lei, M. Xu, R. Chang, I. Funes-Ardoiz, J. Ye, J. Am. Chem. Soc., 2021, 143, 11251-11261.

Combining an organophotocatalyst and lithium thiophenoxide in a Lewis acid/Brønsted base/hydrogen atom transfer (HAT) multifunctional catalytic system enables highly efficient α-alkylation reactions of active methylene and methine compounds with nonactivated alkenes under blue-light irradiation. The reaction was performed with a higher degree of efficiency under continuous-flow.
Y. Yamashita, Y. Ogasawara, T. Banik, S. Kobayashi, J. Am. Chem. Soc., 2023, 145, 22735-22744.

AuCl₃/AgOTf catalyzes a highly efficient intermolecular addition of 1,3-diketones to alkenes. A proposed mechanism for the reaction is based on α-C-H activation.
X. Yao, C.-J. Li, J. Am. Chem. Soc., 2004, 126, 6884-6885.

Perchloric acid-catalyzed additions of various β-dicarbonyl compounds to a series of secondary alcohols and alkenes could be conveniently conducted in commercial solvent and gave good yields. Moreover, silica gel-supported HClO₄ could also catalyze the heterogeneous addition for a series of substrates with similar or even higher yields. The supported catalyst could be readily recovered and reused for four runs.
P. N. Liu, L. Dang, Q. W. Wang, S. L. Zhao, F. Xia, Y. J. Ren, X. Q. Gong, J. Q. Chen, J. Org. Chem., 2010, 75, 5019-5020.

A cationic iridium catalyst enables an intermolecular hydroalkylation of 1,3-diketones with unactivated terminal alkenes under neutral conditions to provide Markovnikov products in good yield.
R. Takeuchi, J. Sagawa, M. Fujii, M. Fujii, J. Waser, Org. Lett., 2019, 21, 741-744.

Environmentally benign additions of various 1,3-dicarbonyl compounds to alkenes and alcohols in the presence of solid acid catalysts have been described.
K. Motokura, N. Fujita, K. Mori, T. Mizugaki, K. Ebitani, K. Kaneda, Angew. Chem. Int. Ed., 2006, 45, 2605-2609.

K. Motokura, N. Fujita, K. Mori, T. Mizugaki, K. Ebitani, K. Kaneda, Angew. Chem. Int. Ed., 2006, 45, 2605-2609.

Iridium catalyzes a branch-selective hydroalkylation of simple aliphatic and aromatic alkenes with malonic amides and malonic esters under neutral reaction conditions. A substrates bearing bromine, chlorine, ester, 2-thienylcarboxylate, silyl, and phthalimide groups are suitable for this hydroalkylation. Selective transformations of hydroalkylated products to 1,3-diamines or monoamides are reported.
T. Sawano, M. Ono, A. Iwasa, M. Hayase, J. Funatsuki, A. Sugiyama, E. Ishikawa, T. Yoshikawa, K. Sakata, R. Takeuchi, J. Org. Chem., 2023, 88, 1545-1559.

A highly enantioselective catalytic alkylation of cyanoacetates was achieved using a chiral phase-transfer catalyst to give α,α-disubstituted α-cyanoacetates which have a chiral quaternary carbon.
K. Nagata, D. Sano, T. Itoh, Synlett, 2007, 547-550.

An intermolecular addition of malononitrile and related pronucleophiles to several 1,3-disubstituted acyclic 1,3-dienes in the presence of a Pd-PHOX catalyst provides products with quaternary stereogenic centers in good yield, excellent er, and in most cases as a single regioisomer. The products undergo oxidative functionalization to afford β,γ-unsaturated carboxylic acid derivatives.
N. J. Adamson, S. Park, P. Zhou, A. L. Nguyen, S. J. Malcolmson, Org. Lett., 2020, 22, 2017-2021.

A recyclable, convenient, and efficient catalytic system allows the C-acylation of 1,3-dicarbonyl compounds and malononitrile with acid chlorides in moderate to excellent yields under mild conditions.
Q. Shen, W. Huang, J. Wang, X. Zhou, Org. Lett., 2007, 9, 4491-4494.

A photo-organocatalytic enantioselective α- and γ-alkylation of aldehydes and enals with bromomalonates occurs under illumination by a fluorescent light bulb in the presence of a commercially available aminocatalyst without any external photoredox catalyst. Mechanistic investigations reveal the ability of transiently generated enamines to directly reach an electronically excited state while reactive radical species from the organic halides are formed.
M. Silvi, E. Arceo, I. D. Jurberg, C. Cassani, P. Melchiorre, J. Am. Chem. Soc., 2015, 137, 6120-6123.

CuO catalyzes a three-component reaction of α-ketoaldehydes, 1,3-dicarbonyl compounds, and organic boronic acids in water to provide a wide range of products containing 1,3- and 1,4-diketones. The method offers use of readily available starting materials, wide substrate scope, excellent yields, gram-scale synthesis, and mild reaction conditions.
Q. Xia, X. Li, X. Fu, Y. Zhou, Y. Peng, J. Wang, G. Song, J. Org. Chem., 2021, 86, 9914-9923.

The merger of photoredox catalysis and primary amine catalysis enables a direct construction of all-carbon quaternary stereocenters via α-photoalkylation of β-ketocarbonyls with high efficacy and enantioselectivities.
Y. Zhu, L. Zhang, S. Luo, J. Am. Chem. Soc., 2014, 136, 14642-14645.

An efficient method enables the synthesis of α-cyanomethyl-β-dicarbonyls in good yields from MeCN and simple 1,3-dicarbonyls. A radical mechanism is proposed.
C. Wang, Y. Li, M. Gong, Q. Wu, J. Zhang, J. K. Kim, M. Huang, Y. Wu, Org. Lett., 2016, 18, 4151-4153.

An enantiopure hydrogen bond donor catalyst enables an enantioselective addition of dialkyl malonates to Boc-derivatized α-amino sulfones in the presence of K₂CO₃. The diastereomeric salt is similarly applied to additions of nitroalkanes. Precautions to exclude air or moisture are unnecessary.
H. Joshi, S. K. Ghosh, J. A. Gladysz, Synthesis, 2017, 49, 3905-3915.

An organocatalytic asymmetric cascade Michael reaction of α,β-unsaturated aldehydes with bromomalonates, efficiently catalyzed by chiral diphenylprolinol TMS ether in the presence of base 2,6-lutidine, gives cyclopropanes in high enantio- and diastereoselectivities. Using NaOAc as base, a spontaneous ring-opening of cyclopropanes leads to (E) α-substituted malonate α,β-unsaturated aldehydes.
H. Xie, L. Zu, H. Li, J. Wang, W. Wang, J. Am. Chem. Soc., 2007, 129, 10886-10894.

Alkylation of the aza-enolate of valerolactim methyl ether with electrophiles affords α-alkyl lactims. Subsequent mild, acidic hydrolysation gives the corresponding α-alkyl-δ-amino esters hydrochloride salts. Neutralisation of these salts with base results in smooth intramolecular cyclisation to afford α-alkyl lactams in excellent yield.
P. J. M. Taylor, S. D. Bull, P. C. Andrews, Synlett, 2006, 1347-1350.

In the presence of PdCl₂(MeCN)₂, CuCl₂, and PEG-400, various alkenyl β-keto esters and amides underwent a selective cyclization to give six-membered carbocycles in good to excellent yields. The PdCl₂(MeCN)₂/CuCl₂/PEG-400 system could be recycled and reused five times without any loss of catalytic activity.
J.-H. Li, Q.-M. Zhu, Y. Liang, D. Yang, J. Org. Chem., 2005, 70, 5347-5349.

An expeditious synthesis of α-substituted tert-butyl acrylates from commercially available aldehydes and Meldrum's acid includes a telescoped condensation-reduction sequence to afford 5-monosubstituted Meldrum's acid derivatives followed by a Mannich-type reaction triggered by a rapid cycloreversion of the dioxinone ring on heating with tert-butyl alcohol.
C. G. Frost, S. D. Penrose, R. Gleave, Synthesis, 2009, 627-635.

β-Ketoesters can directly be transformed to the corresponding α-hydroxymalonic esters, tartronic esters, with molecular oxygen catalyzed by calcium iodide under visible light irradiation from a fluorescent lamp. This convenient tandem oxidation/rearrangement reduces consumption of energy, time, and solvents.
N. Kanai, H. Nakayama, N. Tada, A. Itoh, Org. Lett., 2010, 12, 1948-1951.

An efficient enantioselective catalysis in the Mannich-type reactions of diketones and ketoester equivalents with aldimines was developed using a chiral combined salt of chiral 1,1′-binaphthyl-2,2′-disulfonic acid with 2,6-diarylpyridine, which acted as convenient chiral tailor-made Brønsted acid-base organocatalysts in situ.
M. Hatano, T. Maki, K. Moriyama, M. Arinobe, K. Ishihara, J. Am. Chem. Soc., 2008, 130, 16858-16860.

Achiral and chiral phosphorodiamidic acids were developed as efficient Brønsted acid catalysts for the direct Mannich reaction of N-acyl imines with 1,3-dicarbonyl compounds.
M. Terada, K. Sorimachi, D. Uraguchi, Synlett, 2006, 133-134.

Catalytic asymmetric direct Mannich-type reactions of α-substituted nitroacetates using a new bench-stable homodinuclear Ni₂-Schiff base complex gave Mannich products in high ee, that serve as precursors for anti-α,β-diamino acids with an α-tetrasubstituted carbon stereocenter. The Ni complex was also applicable to direct Mannich-type reactions of malonates and β-keto ester.
Z. Chen, H. Morimoto, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc., 2008, 130, 2170-2171.

Efficient carbon-carbon bond formation of N-carbobenzyloxy amines with 1,3-dicarbonyl compounds at the α-position of nitrogen was established by a one-pot oxidative Mannich reaction using N-tert-butylbenzenesulfinimidoyl chloride as an oxidant.
J-I. Matsuo, Y. Tanaki, H. Ishibashi, Org. Lett., 2006, 8, 4371-4374.