Benzylic Substitutions, Benzylation
A metal-free carbon-carbon bond-forming coupling between tosylhydrazones and boronic acids is very general and functional-group tolerant. As the required tosylhydrazones are easily generated from carbonyl compounds, it can be seen as a reductive coupling of carbonyls, a process of high synthetic relevance that requires several steps using other methodologies.
J. Barluenga, M. Tomás-Gamasa, F. Aznar, C. Valdés, Nat. Chem., 2009, 1, 494-499.
The reaction of secondary and tertiary alkyl halides with benzylic or allylic Grignard reagents in the presence of a catalytic amount of silver nitrate in ether yielded the corresponding cross-coupling products in high yields. The coupling reaction provides efficient access to quaternary carbon centers.
H. Someya, H. Ohmiya, H. Yorimitsu, K. Oshima, Org. Lett., 2008, 10, 969-971.
Activation of tertiary benzylic alcohols with SOCl2 or concentrated HCl followed by treatment with trimethylaluminum allows the synthesis of m-tert-alkylbenzenes in good yields. This reaction sequence is successful in the presence of a variety of functional groups, including acid-sensitive and Lewis-basic groups. In addition to t-Bu groups, 1,1-dimethylpropyl and 1-ethyl-1-methylpropyl groups can also be installed.
J. A. Hartsel, D. T. Craft, Q.-H. Chen, M. Ma, P. R. Carlier, J. Org. Chem., 2012, 77, 3127-3133.
Sarcosine is an excellent ligand for cobalt-catalyzed carbon-carbon cross-coupling of Grignard reagents with allylic and vinylic bromides. The system performs efficiently when phenyl and benzyl Grignards are coupled with alkenyl bromides. Notably, previously unachievable Co-catalyzed coupling of allylic bromides with Grignards to linearly coupled α-products was also realized.
R. Frlan, M. Sova, S. Gobec, G. Stavber, Z. Časar, J. Org. Chem., 2015, 80, 7803-7809.
The use of the Xantphos ligand in a mild palladium-catalyzed Kumada-Corriu reaction of secondary benzylic bromides with aryl and alkenyl Grignard reagents minimizes the undesired β-elimination pathway. The corresponding cross-coupling products can be isolated in good yields with inversion of the configuration.
A. López-Pérez, J. Adrio, J. C. Carretero, Org. Lett., 2009, 11, 5514-5517.
The reaction of benzylic trichloroacetimidates with trimethylaluminum under Lewis acid promoted conditions provides the corresponding methylated products. Most benzylic trichloroacetimidates undergo ready displacement, with electron deficient systems being the exception. The use of an enantiopure imidate showed significant racemization, implicating the formation of a cationic intermediate.
N. S. Mahajani, J. D. Chisholm, J. Org. Chem., 2018, 83, 4131-4139.
Bu4NI as additive accelerates the palladium(0)-catalyzed cross-coupling between benzylic zinc bromides and aryl or alkenyl triflates. Remarkably, it further enables a new nickel(0)-catalyzed cross-coupling between functionalized benzylic zinc reagents and primary alkyl iodides under mild reaction conditions.
M. Piber, A. E. Jensen, M. Rottländer, P. Knochel, Org. Lett., 1999, 1, 1323-1326.
An insoluble, amphiphilic and polymeric palladium catalyst (PdAS) is an excellent catalyst for the Suzuki-Miyaura reaction. The catalyst is reusable after easy work up and showed good stability in any reaction medium.
Y. M. A. Yamada, K. Takeda, H. Takashashi, S. Ikegami, J. Org. Chem., 2003, 68, 7733-7741.
An enantioselective nickel-catalyzed Negishi cross-coupling of racemic secondary benzylic bromides and chlorides is described. The catalyst components are commercially available and air-stable, and the reaction is not highly oxygen- or moisture-sensitive.
F. O. Arp, G. C. Fu, J. Am. Chem. Soc., 2005, 127, 10482-10483.
Alkenyltrifluoroborates can be cross-coupled with allyl and benzyl chlorides using KOH as base in acetone-water (3:2) at 50 °C and low catalyst loadings of a 4-hydroxyacetophenone oxime derived palladacycle giving the corresponding 1,4-dienes and allylarenes, respectively. The use of overheated water as solvent and K2CO3 as base allows a coupling of alkenyltrifluoroborates with aryl and heteroaryl bromides.
E. Alacid, C. Nájera, J. Org. Chem., 2009, 74, 2321-2327.
A Ni-catalyzed asymmetric reductive cross-coupling between vinyl bromides and benzyl chlorides provides direct access to enantioenriched products bearing aryl-substituted tertiary allylic stereogenic centers from simple, stable starting materials. A broad substrate scope can be converted under mild reaction conditions without pregeneration of organometallic reagents and the regioselectivity issues commonly associated with allylic arylation.
A. H. Cherney, S. E. Reisman, J. Am. Chem. Soc., 2014, 136, 14365-14366.
An Ir-catalyzed enantioselective benzylation reaction of allylic electrophiles can occur directly from aryl acetic acids via stereoselective carbon-carbon bond formation followed by decarboxylation as the terminal event. The absence of a highly basic nucleophile offers broad functional group compatibility that would not be possible employing established protocols.
P. J. Moon, Z. Wei, R. J. Lundgren, J. Am. Chem. Soc., 2018, 140, 17418-17422.
The air-stable nickel(II) complex trans-(PCy2Ph)2Ni(o-tolyl)Cl enables an internally selective Mizoroki-Heck-type coupling of substituted benzyl chlorides with terminal alkenes at room temperature. This operationally simple and highly regioselective reaction provides rapid, convergent access to substituted allylbenzene derivatives in high yield and can be carried out on the benchtop with no purification or degassing of solvents or reagents.
E. A. Standley, T. F. Jamison, J. Am. Chem. Soc., 2013, 135, 1585-1592.
Nickel-catalyzed intermolecular benzylation and heterobenzylation of unactivated alkenes with benzyl chlorides provides functionalized allylbenzene derivatives. In contrast to analogous palladium-catalyzed processes, all reactions described herein employ electronically unbiased aliphatic olefins (including ethylene), proceed at room temperature, and provide 1,1-disubstituted olefins with very high selectivity.
R. Matsubara, A. C. Gutierrez, T. F. Jamison, J. Am. Chem. Soc., 2011, 133, 19020-19023.
Electrochemistry enables smooth Zn-mediated allylic alkylations in aqueous media under air in the presence of a Pd catalyst between a full range of alkyl halides (primary, secondary, and tertiary) and substituted allylic halides.
Y.-L. Lai, J.-M. Huang, Org. Lett., 2017, 19, 2022-2025.
A photoinduced, copper-catalyzed, three-component reaction of haloalkane, alkenes, and alkyne under mild reaction conditions helps to introduce privileged functionalities into propargylic systems.
Y. Zhang, D. Zhang, J. Org. Chem., 2020, 85, 3213-3223.
The combination of a halogen bond donor with trimethylsilyl halide is an efficient cocatalytic system for a direct dehydroxylative coupling reaction of alcohol with various nucleophiles, such as allyltrimethylsilane and trimethylcyanide, to give the corresponding adduct in moderate to excellent yields.
M. Saito, N. Tsuji, Y. Kobayashi, Y. Takemoto, Org. Lett., 2015, 17, 3000-3003.
A room temperature Pd-catalyzed allylic substitution of a wide range of soft nucleophiles derived from diarylmethane provides rapid access to the corresponding allylated products. A procedure for Pd-catalyzed allylic substitutions to afford diallylation products with quaternary centers is also described.
S.-C. Sha, J. Zhang, P. J. Carroll, P. J. Walsh, J. Am. Chem. Soc., 2013, 135, 17602-17609.
An sp3 C-H bond-transformation reaction of methylarenes provides the corresponding allylbenzene derivatives in good yields in the presence of tetrabutylammonium iodide and tert-butyl hydroperoxide at 80 °C.
F. Shahsavari, A. Abbasi, M. Ghaznafarpour-Darjjani, S. M. Ghafelebashi, M. Daftari-Besheli, Synlett, 2017, 28, 1646-1648.
The Suzuki-Miyaura cross-coupling reaction between a diborylmethane derivative and allyl halides or benzyl halides proceeded efficiently in the presence of an appropriate Pd-catalyst at room temperature. The present approach provides functionalized homoallylboronates and alkylboronates with excellent regio- and chemoselectivities.
K. Endo, T. Ohkubo, T. Ishioka, T. Shibata, J. Org. Chem., 2012, 77, 4826-4831.
CsF with 1.1 equiv of H2O effects highly efficient protodeboronation on tertiary diarylalkyl boronic esters with essentially complete retention of configuration, whereas TBAFˇ3H2O can be used for tertiary aryldialkyl boronic esters. Furthermore, substituting D2O for H2O provides ready access to deuterium-labeled enantioenriched tertiary alkanes. A short synthesis of the sesquiterpene (S)-turmerone is described.
S. Nave, R. P. Sonawane, T. G. Elford, V. K. Aggarwal, J. Am. Chem. Soc., 2010, 132, 17096-17098.
Various acetals or alcohols react with allyl(trimethyl)silane or 1-phenyl-2-(trimethylsilyl)acetylene in the presence of a catalytic amount of the Brřnsted acid o-benzenedisulfonimide under mild conditions to give good yields of the allylated products. The catalyst can be easily recovered and purified for use in further reactions.
M. Barbero, S. Bazzi, S. Cadamuro, S. Dughera, C. Piccinini, Synthesis, 2010, 315-319.
An enhanced Lewis acid system of InCl3 and Me3SiBr can be used to promote a wide range of direct coupling reactions between alcohols and silyl nucleophiles in non-halogenated solvents. Highly chemoselective allylations toward a hydroxyl moiety over ketone and acetoxy ones have been demonstrated.
T. Saito, Y. Nishimoto, M. Yasuda, A. Baba, J. Org. Chem., 2006, 71, 8516-8522.
The reaction of alkoxides with boron trichloride results in the generation of cations that can be allylated in subsequent transformations. The absence of Brřnsted acids can make a significant difference in such syntheses.
G. W. Kabalka, M.-L. Yao, S. Borella, J. Am. Chem. Soc., 2006, 128, 11320-11321.
Aryl aldehydes couple readily with allylmetals to afford haloallylated products in the presence of boron trihalides. The reactions tolerate a variety of functional groups. Simple aqueous workup of haloallylation reactions, followed by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene, provides a straightforward route to synthetically useful (E)-1,3-dienes.
M. P. Quinn, M.-L. Yao, G. W. Kabalka, Synthesis, 2011, 3815-3820.
An efficient Fe(III)-catalyzed direct coupling of alkenes with alcohols and cross-coupling of alcohols with alcohols gives the corresponding substituted (E)-alkenes stereospecifically. Mild conditions, atom efficiency, environmental soundness, and stereospecificity are features that make this procedure very attractive. Additionally, this reaction could be scaled up.
Z.-Q. Liu, Y. Zhang, L. Zhao, Z. Li, J. Wang, H. Li, L.-M. Wu, Org. Lett., 2011, 13, 2208-2211.
C-O bond cleavage of lithium alkoxides occurs readily at room temperature in the presence of titanium(IV) halides. Capture of the resultant carbocation by alkynes provides an efficient route to trisubstituted (E)-alkenyl halides with high stereoselectivity.
M.-L. Yao, T. R. Quick, Z. Wu, M. P. Quinn, G. W. Kabalka, Org. Lett., 2009, 11, 2647-2649.
An efficient protocol for the palladium-catalyzed Heck alkynylation using XPhos as ligand and Cs2CO3 as the base, couples a wide range of functionalized terminal alkynes and substituted benzyl chlorides. An excess amount of base and higher reaction temperatures allows the synthesis of allenes in a one-pot procedure.
C. H. Larsen, K. W. Anderson, R. E. Tundel, S. L. Buchwald, Synlett, 2006, 2941-2946.
In the presence of Pd(OAc)2 and Xphos, alkynyl carboxylic acids smoothly underwent a decarboxylative coupling reaction with various benzyl halides or aryl halides, providing internal alkynes in good yields. It is noteworthy that the optimal conditions are compatible with a wide range of aryl halides.
W.-W. Zhang, X.-G. Zhang, J.-H. Li, J. Org. Chem., 2010, 75, 5259-5264.
A highly efficient palladium-catalyzed Sonogashira coupling of benzylic ammonium salts with terminal alkynes provides a series of internal alkyne derivatives in good yields. The reaction offers a broad substrate scope and high functional group tolerance.
S. Xu, Z. Zhang, C. Han, W. Hu, T. Xiao, Y. Yuan, J. Zhao, J. Org. Chem., 2019, 84, 12157-12164.
The reaction of alkynylboron dihalides with benzylic, allylic, and propargylic alcohols provides an efficient route to internal acetylenes without isomerization of the product alkynes under the reaction conditions.
G. W. Kabalka, M.-L. Yao, S. Borella, Org. Lett., 2006, 8, 879-881.
An enantioselective Cu-catalyzed borylative cross-coupling reaction of alkenes, bis(pinacolato)diboron, and methyl iodide provides the desired methylboration products with excellent diastereoselectivities and enantioselectivities.
B. Chen, P. Cao, Y. Liao, M. Wang, J. Liao, Org. Lett., 2018, 20, 1346-1349.
A simple Cu(I) catalyst, generated in situ, is highly effective for C-benzylation of nitroalkanes using abundant benzyl bromides and related heteroaromatic compounds. This process proceeds via a thermal redox mechanism and allows access to a variety of complex nitroalkanes under mild reaction conditions.
P. G. Gildner, A. A. S. Gietter, D. Cui, D. A. Watson, J. Am. Chem. Soc., 2012, 134, 9942-9945.
A direct asymmetric copper hydride (CuH)-catalyzed coupling of α,β-unsaturated carboxylic acids with aryl alkenes provides chiral α-aryl dialkyl ketones. The reaction tolerates various substrate substitution patterns, sensitive functional groups, and heterocycles.
Y. Zhou, J. S. Bandar, S. L. Buchwald, J. Am. Chem. Soc., 2017, 139, 8126-8129.
Cyclopentanone as an electron pair donor proved highly efficient for the stabilization of allyl and vinyl cations in combination with a calcium-based catalyst system. The system enabled a transition-metal-free intermolecular carbohydroxylation of alkynes with allyl and propargyl alcohols.
T. Stopka, M. Niggemann, Org. Lett., 2015, 17, 1437-1440.
An enantioselective Ni-catalyzed reductive cross-coupling of acid chlorides with racemic secondary benzyl chlorides in the presence of Mn0 as a stoichiometric reductant generates acyclic α,α-disubstituted ketones in good yields and high enantioselectivity. The mild, base-free reaction conditions tolerate various functional groups on both coupling partners.
A. H. Cherney, N. T. Kadunce, S. E. Reisman, J. Am. Chem. Soc., 2013, 135, 7442-7445.
The simple and inexpensive combination of TiCl4(2,4,6-collidine) and manganese powder afforded a low-valent titanium reagent, which facilitated homolytic cleavage of benzylic C-OH bonds. Radical conjugate addition reactions of various benzyl alcohol derivatives with electron-deficient alkenes furnished the corresponding adducts in good yields.
T. Suga, S. Shimazu, Y. Ukaji, Org. Lett., 2018, 20, 5389-5392.
An enantioselective Ni-catalyzed cross-coupling of N-hydroxyphthalimide esters with vinyl bromides proceeds under mild conditions and uses tetrakis(N,N-dimethylamino)ethylene as a terminal organic reductant. Good functional group tolerance is demonstrated, with over 20 examples of reactions that proceed with excellent enantioselectivity.
N. Suzuki, J. L. Hofstra, K. E. Poremba, S. E. Reisman, Org. Lett., 2017, 19, 2150-2153.
A highly regio- and enantioselective copper-catalyzed reductive hydroxymethylation of styrenes and 1,3-dienes with 1 atm of CO2 readily provides important chiral homobenzylic alcohols. Moreover, various 1,3-dienes were converted to chiral homoallylic alcohols with high yields and excellent regio-, enantio-, and Z/E-selectivities.
Y.-Y. Gui, N. Hu, X.-W. Chen, L-L. Liao, J.-H. Ye, Z. Zhang, J. Li, D.-G. Yu, J. Am. Chem. Soc., 2017, 139, 17011-17014.
Very low loadings of iridium(I) complexes having an imidazol-2-ylidene ligand with benzylic wingtips efficiently catalyze the β-alkylation of secondary alcohols with primary alcohols and acceptorless dehydrogenative formation of quinolines from 2-aminobenzyl alcohol and ketones through a borrowing hydrogen pathway to provide the desired products in good yields.
S. Genç, B. Arslan, S. Gülcemal, S. Günnaz, B. Çetinkaya, D. Gülcemal, J. Org. Chem., 2019, 84, 6286-6297.
RuCl2(PPh3)3 as a precatalyst enables a simple cross dehydrogenative coupling between two different primary alcohols via a borrowing-hydrogen approach. The present methodology is applicable to a large variety of alcohols including long chain aliphatic alcohols and heteroaryl alcohols.
S. Manojveer, S. Salahi, O. F. Wendt, M. T. Johnson, J. Org. Chem., 2018, 83, 10864-10870.
Iron complexes are cheap and effective catalysts for a series of "umpolung" nucleophilic additions of hydrazones at room temperature. The catalytic system offers chemoselectivity and a broad substrate scope.
C.-C. Li, X.-J. Dai, H. Wang, D. Zhu, J. Gao, C.-J. Li, Org. Lett., 2018, 20, 3801-3805.
Boron Lewis acid promoted formal insertion of aryldiazoalkane into the C-H bond of both aromatic and aliphatic aldehydes enables a novel, catalytic enantioselective route to α-tertiary aryl ketones. In the presence of a chiral (S)-oxazaborolidinium ion catalyst, the reaction proceeded in good yields with excellent enantioselectivities.
B. C. Kang, D. G. Nam, G.-S. Hwang, D.-H. Ryu, Org. Lett., 2015, 17, 4810-4813.
An ionic cobalt-PNP complex enables an efficient α-alkylation of ketones with primary alcohols. A broad range of ketone and alcohol substrates provides alkylated ketones in good yields. The method was also successfully applied to a greener synthesis of quinoline derivatives using 2-aminobenzyl alcohol as the alkylating reagent.
G. Zhang, J. Wu, H. Zeng, S. Zhang, Z. Yin, S. Zheng, Org. Lett., 2017, 19, 1080-1083.
A manganese-catalyzed C-alkylation of carboxylic acid derivatives with alcohols operates via hydrogen autotransfer and ideally produces water as the only side product. Importantly, aliphatic-, benzylic-, and heterocyclic-containing alcohols can be used as alkylating reagents, eliminating the need for mutagenic alkyl halides.
Y. K. Jang, T. Krückel, M. Rueping, O. El-Sepelgy, Org. Lett., 2018, 20, 7779-7783.
The use of 4-benzyl Hantzsch esters enables the construction of molecules with all-carbon quaternary centers by visible light-induced photoredox catalysis via transfer alkylation. Reactions of 4-alkyl Hantzsch nitriles as tertiary radical donors joined two contiguous all-carbon quaternary centers intermolecularly.
W. Chen, Z. Liu, J. Tian, J. Li, J. Ma, X. Cheng, G. Li, J. Am. Chem. Soc., 2016, 138, 12312-12315.
Visible-light photoredox catalysis realizes an external-reductant-free cross-electrophile coupling of tetraalkyl ammonium salts with carbonyl compounds and CO2. The byproduct trimethylamine serves as the electron donor. Moreover, this protocol exhibits mild reaction conditions, broad substrate scope, good functional group tolerance, low catalyst loading, and facile scalability.
L.-L. Liao, G.-M. Cao, J.-H. Ye, G.-Q. Sun, W.-J. Zhou, Y.-Y. Gui, S.-S. Yan, G. Shen, D.-G. Yu, J. Am. Chem. Soc., 2018, 140, 17338-17342.
A Ni-catalyzed carboxylation of benzyl halides with CO2 proceeds under mild conditions at room temperature under atmospheric pressure. The method does not require well-defined and sensitive organometallic reagents and thus is user-friendly and operationally simple.
T. León, A. Correa, R. Martin, J. Am. Chem. Soc., 2013, 135, 1221-1224.
A nickel-catalyzed reductive carboxylation of styrenes using CO2 proceeds under mild conditions using diethylzinc as the reductant. The catalyst system is very robust and will fixate CO2 in good yield even if exposed to only an equimolar amount introduced into the headspace above the reaction.
C. M. Williams, J. B. Johnson, T. Rovis, J. Am. Chem. Soc., 2008, 130, 14936-14937.
Transition metal carbenes can directly be generated from readily available and stable 1-sulfonyl-1,2,3-triazoles in the presence of chiral Rh(II) carboxylates and can be used in a highly efficient enantioselective C-H insertion of azavinyl carbenes into unactivated alkanes to access various β-chiral sulfonamides.
S. Chuprakov, J. A. Malik, M. Zibinsky, V. V. Fokin, J. Am. Chem. Soc., 2011, 133, 10352-10355.
A bis(diisopropylamino)cyclopropenimine-substituted bis-protonated proton sponge can be used as a bifunctional phase-transfer catalyst. The catalyst operates simultaneously as a hydrogen bond donor and a phase-transfer catalyst, facilitating the movement of charged intermediates from the interface to the organic phase.
L. Belding, P. Stoyanov, T. Dudding, J. Org. Chem., 2016, 81, 553-558.