Categories: C-C Bond Formation > Arenes >

Alkylation, Arylation

Related:

Name Reactions

Friedel-Crafts Acylation followed by Deoxygenation

Versatile Cross Coupling Methods:

Hiyama Coupling (R-X + R'-SiR''₃)

Hiyama-Denmark Coupling (R-X + R-SiMe₂OH)

Kumada Coupling (R-X + R'-MgX)

Negishi Coupling (R-X + R'-ZnX)

Stille Coupling (R-X + R'-SnR''₃)

Suzuki Coupling (R-X + R'-BY₃)

Recent Literature

An efficient cobalt-catalyzed alkylation of aromatic Grignard reagents is performed in good yields in the presence of CoCl₂/TMEDA (1:1) as catalytic system. Primary and secondary cyclic or acyclic alkyl bromides were used successfully. The reaction tolerates ester, amide, and keto groups, is inexpensive and very easy to carry out on a larger scale.
G. Cahiez, C. Chaboche, C. Duplais, A. Moyeux, Org. Lett., 2009, 11, 277-280.

A slow and regular addition of primary alkyl and aryl Grignard reagent enables a high-yielding copper-catalyzed alkylation with alkyl bromides in the absence of ligands. With secondary and tertiary alkyl Grignard reagents, the presence of benzonitrile as a very simple ligand is sufficent. A copper-catalyzed alkylation of organolithium compounds was also studied.
G. Cahiez, O. Gager, J. Buendia, Synlett, 2010, 299-303.

The Pd-catalyzed cross-coupling of aryl bromides or triflates with cyclopropylmagnesium bromide in the presence of substoichiometric amounts of zinc bromide produces cyclopropyl arenes in very good yields. The cross-coupling of other alkyl, cycloalkyl, and aryl Grignard reagents with aryl bromides under the same conditions gives the corresponding substituted arenes in good yields.
C. Shu, K. Sidhu, L. Zhang, X.-j. Wang, D. Krishnamurthy, C. H. Senanayake, J. Org. Chem., 2010, 75, 6677-6680.

Nickel-Catalyzed Negishi Cross-Coupling Reactions of Secondary Alkylzinc Halides and Aryl Iodides
A. Joshi-Pangu, M. Ganesh, M. R. Biscoe, Org. Lett., 2011, 13, 1218-1221.

Zn-Mediated, Pd-Catalyzed Cross-Couplings in Water at Room Temperature Without Prior Formation of Organozinc Reagents
A. Krasovskiy, C. Duplais, B. H. Lipshutz, J. Am. Chem. Soc., 2009, 131, 15592-15593.

Palladium complexes derived from air-stable secondary phosphine oxides or chlorides enabled challenging Kumada-Corriu cross-couplings of unactivated alkyl chlorides bearing β-hydrogens and proved applicable to transformations of alkyl-substituted organometallics.
L. Ackermann, A. R. Kapdi, C. Schulzke, Org. Lett., 2010, 12, 2298-2301.

An efficient, nickel-catalyzed direct reductive cross-coupling of equimolar amounts of alkyl halides with aryl halides in the presence of manganese is generally high-yielding, highly functional-group-tolerant, and easy to perform. The reaction appears to avoid the formation of intermediate organomanganese species, and a synergistic effect was found when a mixture of two ligands was employed.
D. A. Everson, R. Shrestha, D. J. Weix, J. Am. Chem. Soc., 2010, 132, 920-921.

An operationally simple cross-coupling reaction between aryl halides and alkyl halides with high selectivity utilizes CoCl₂/Me₄-DACH as a catalyst system. The underlying domino process exhibits high sustainability as it obviates the need for the pre-formation and handling of stoichiometric amounts of hazardous Grignard compounds.
W. M. Czaplik, M. Mayer, A. J. von Wangelin, Synlett, 2009, 2931-2934.

Simple, cheap, and toxicologically benign iron salts turned out to be highly efficient precatalysts for cross-coupling reactions of alkyl or aryl Grignard reagents, zincates, or organomanganese species with aryl and heteroaryl chlorides, triflates, and even tosylates. Aryl bromides and iodides are prone to a reduction of their C-X bonds in the presence of the iron catalyst. The exceptionally mild reaction conditions tolerate a series of functional groups such as esters, ethers, nitriles, sulfonates, sulfonamides, thioethers, acetals, alkynes, and -CF₃ groups.
A. Fuerstner, A. Leitner, M. Méndez, H. Krause, J. Am. Chem. Soc., 2002, 124, 13856-13863.

Various types of substrates were found to undergo effective cross-coupling with Grignard reagents in the presence of a low-valent iron complex within minutes even at -20°C.
R. Martin, A. Fuerstner, Angew. Chem. Int. Ed., 2004, 43, 3955-3957.

Butylmethylimidazolium tetrachloroferrate (bmim-FeCl₄) was found to be a very effective and completely air stable catalyst for the biphasic Grignard cross-coupling with primary and secondary alkyl halides bearing α-hydrogens. The product was simply isolated in the ethereal layer and the ionic liquid catalyst was successfully recycled four times.
K. Bica, P. Gaertner, Org. Lett., 2006, 8, 733-735.

An iron-catalyzed cross-coupling reaction of a primary or secondary alkyl halide with an aryl Grignard reagent proceeds under mild conditions to give the corresponding coupled product in excellent yield.
M. Nakamura, K. Matsuo, S. Ito, E. Nakamura, J. Am. Chem. Soc., 2004, 126, 3686-3687.

Iron-catalyzed cross-coupling of primary and secondary alkyl sulfonates with arylzinc reagents, prepared from the corresponding aryllithium or magnesium reagents with ZnI₂, proceeds smoothly in the presence of excess TMEDA and a concomitant magnesium salt.
S. Ito, Y.-i. Fujiwara, E. Nakamura, M. Nakamura, Org. Lett., 2009, 11, 4306-4309.

A Ni-catalyzed process for the cross-coupling of tertiary alkyl nucleophiles and aryl bromides is extremely general for a wide range of electrophiles and generally occurs with little isomerization. The same procedure also accommodates the use of aryl triflates, vinyl chlorides, and vinyl bromides as the electrophilic component.
A. Joshi-Pangu, C.-Y. Wang, M. R. Biscoe, J. Am. Chem. Soc., 2011, 133, 8478-8481.

Suzuki cross-coupling reactions of an unprecedented array of unactivated primary and secondary alkyl halides with arylboronic acids can be accomplished through the use of nickel/amino alcohol-based catalysts. Both the nickel precatalysts and the amino alcohols are commcercially available and air-stable.
F. González-Bobes, G. C. Fu, J. Am. Chem. Soc., 2006, 128, 5360-5361.

Palladium-catalyzed Negishi cross-coupling involving primary and secondary alkyls, even in the presence of β-H, can be achieved using chelating phosphine ligands containing an electron-deficient olefin. The superior effects of the ligands were shown not only in the desired cross-coupling product yields but also in the fast reaction at mild conditions.
X. Luo, H. Zhang, H. Duan, Q. Liu, L. Zhu, T. Zhang, A. Lei, Org. Lett., 2007, 9, 4571-4574.

Negishi Coupling of Secondary Alkylzinc Halides with Aryl Bromides and Chlorides
C. Han, S. L. Buchwald, J. Am. Chem. Soc., 2009, 131, 7532-7533.

The use of [PdCl(C₃H₅)]₂/cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane as a catalyst allows the Suzuki coupling of a range of aryl bromides and chlorides with alkylboronic acids in good yields. The functional group tolerance on the aryl halide is remarkable. Furthermore, this catalyst can be used at low loading, even for reactions of sterically hindered aryl bromides.
I. Kondolff, H. Doucet, M. Santelli, Tetrahedron, 2004, 60, 3813-3818.

A novel method for the palladium-catalyzed cross-coupling of alkyl chlorides and Grignard reagents has been developed. Good to excellent yields of the coupling products were obtained at room temperature, and functional groups such as ethers, esters, acetals, fluorides, nitriles, aryl and benzyl were tolerated.
A. C. Frisch, N. Shaikh, A. Zapf, M. Beller, Angew. Chem. Int. Ed., 2002, 41, 4056-4059.

Screening of a 15-member library of phosphaadamantane ligands has allowed for the rapid determination of the most suitable ligand for facilitating Suzuki-type couplings of alkyl halides or tosylates containing β-hydrogens with either boronic acids or alkylboranes.
T. Brenstrum, D. A. Gerristma, G. M. Adjabeng, C. S. Frampton, J. Britten, A. J. Robertson, J. McNulty, A. Capretta, J. Org. Chem., 2004, 69, 7635-7639.

A versatile method has been developed for the cross-coupling of boronic acids with unactivated alkyl electrophiles at room temperature. It has been demonstrated that Pd(P(t-Bu)₂Me)₂ undergoes oxidative addition under surprisingly mild conditions and that the resulting adduct is sufficiently stable toward β-hydride elimination.
J. H. Kirchhoff, M. R. Netherton, I. D. Hill, G. C. Fu, J. Am. Chem. Soc., 2002, 124, 13662-13663.

A combination of nickel(II) acetylacetonate and (Z)-3,3-dimethyl-1,2-bis(diphenylphosphino)but-1-ene catalyzes cross-coupling reactions of alkyl aryl sulfides and alkenyl alkyl sulfides with primary and secondary alkyl Grignard reagents.
S. Kanemura, A. Kondoh, H. Yorimitsu, K. Oshima, Synthesis, 2008, 2659-2660.

The superacid-catalyzed reaction of various olefinic amines and related compounds with benzene gives addition products in good yields. The formation of reactive, dicationic electrophiles is proposed.
Y. Zhang, A. McElrea, G. V. Sanchez, Jr., D. Do, A. Gomez, S. L . Aguirre, R. Rendy, D. A. Klumpp, J. Org. Chem., 2003, 68, 5119-5122.

Palladium catalyzed Suzuki-Miyaura coupling with aryl chlorides using a bulky phenanthryl N-heterocyclic carbene ligand
C. Song, Y. Ma, Q. Chai, C. Ma, W. Jiang, M. B. Andrus, Tetrahedron, 2005, 61, 7438-7446.

Aryl bromides (4 eq.) were coupled efficiently with organotin (1 eq.) using the tetra(triphenylphosphine)palladium/polyethylene glycol 400 catalytic system in the presence of sodium acetate as base at 100°C, providing excellent yields of the corresponding substituted aryls in short reaction times.
H. Huang, H. Jiang, K. Chen, H. Liu, J. Org. Chem., 2009, 74, 5599-5602.

Microscale parallel experimentation was used to discover catalyst systems capable of coupling secondary organotrifluoroborates with aryl chlorides and bromides. A ligand-dependent β-hydride elimination/reinsertion mechanism was implicated in the cross-coupling of more hindered substrates, leading to isomeric mixtures of coupled products in some cases.
S. D. Dreher, P. G. Dormer, D. L. Sandrock, G. A. Molander, J. Am. Chem. Soc., 2008, 130, 9257-9259.

Suitable conditions enable the Suzuki-Miyaura coupling reaction of potassium cyclopropyl- and cyclobutyltrifluoroborates in moderate to excellent yield with electron-rich, electron-poor, and hindered aryl chlorides to give various substituted aryl cyclopropanes and cyclobutanes.
G. A. Molander, P. E. Gormisky, J. Org. Chem., 2008, 73, 7481-7485.

G. A. Molander, P. E. Gormisky, J. Org. Chem., 2008, 73, 7481-7485.

The palladium-catalyzed cross-coupling reaction of tricyclopropylbismuth with aryl and heterocyclic halides and triflates tolerates numerous functional groups and does not require anhydrous conditions. The method was successfully extended to the cross-coupling of triethylbismuth.
A. Gagnon, M. Duplessis, P. Alsabeh, F. Barabé, J. Org. Chem., 2008, 73, 3452-3459.

Using commercially available Ph₃PAuCl and readily prepared, benign arylsilanes, a gold-catalyzed oxyarylation of alkenes proceeds smoothly in air. The oxidant, Selectfluor, not only facilitates entry to the Au(I/III) manifold but also provides a fluoride anion for silane activation, thereby avoiding the need for addition of a stoichiometric base.
L. T. Ball, M. Green G. C. Lloyd-Jones, C. A. Russel, Org. Lett., 2010, 12, 4724-4727.

Kinetic vs thermodynamic deprotonation studies on secondary and tertiary sulfonamides using n-BuLi have been carried out. Application of the developed conditions allows the synthesis of diverse sulfonamide products (E=Me).
S. L. MacNeil, O. B. Familoni, V. Snieckus, J. Org. Chem, 2001, 66, 3662-3670.

By treatment with s-BuLi/TMEDA at -78°C, unprotected 2-methoxybenzoic acid is deprotonated exclusively in the position ortho to the carboxylate. A reversal of regioselectivity is observed when the acid is treated with n-BuLi/t-BuOK.
T.-H. Nguyen, A.-S. Castanet, J. Mortier, Org. Lett., 2006, 8, 765-768.

The mild cross-coupling reaction of alkyl- and arylmanganese reagents with o-chloro- or o-bromoaryl ketones gives substituted ketones in high yields with excellent chemoselectivity.
G. Cahiez, D. Luart, F. Lecomte, Org. Lett., 2004, 6, 4395-4398.

The Rh-catalyzed cross-coupling between ArZnI and TMSCH₂I gave various functionalized benzylsilanes in good yields. A mechanism is proposed.
H. Takahashi, K. M. Hossain, Y. Nishihara, T. Shibata, K. Takagi, J. Org. Chem., 2006, 71, 671-675.

An efficient method of constructing 4-benzyl piperidines and related substances is described. This protocol tolerates a wide variation in both reaction partners. The concise formation of a variety of building blocks, such as those described here, has found wide applicability in our drug discovery programs.
S. Vice, T. Bara, A. Bauer, C. A. Evans, J. Fort, H. Josien, S. McCombie, M. Miller, D. Nazzareno, A. Palani, J. Tagat, J. Org. Chem, 2001, 66, 2487-2492.

The catalytic iridium-catalyzed 1,6-addition of aryl boronic acids to electron-deficient dienes gave high yields of the corresponding δ-arylated carbonyl compounds with perfect 1,6-selectivity.
T. Nishimura, Y. Yasuhara, T. Hayashi, Angew. Chem. Int. Ed., 2006, 45, 5164-5166.

An iridium/chiral diene complex enabled a catalytic, asymmetric 1,6-addition of arylboroxines to α,β,γ,δ-unsaturated carbonyl compounds to give δ-arylated carbonyl compounds in high yields with excellent enantioselectivity.
T. Nishimura, Y. Yashuhara, T. Sawano, T. Hayashi, J. Am. Chem. Soc., 2010, 132, 7872-7873.

The superacid-catalyzed (triflic acid) reaction of olefinic amines and related compounds with benzene gives addition products in good yields. A reactive, dicationic species is reported.
Y. Zhang, A. McElrea, G. V. Sanchez, D. Do, A. Gomez, S. L . Aguirre, R. Rendy, D. A. Klumpp, J. Org. Chem., 2003, 68, 5119-5122.

Superelectrophilic reactivity of α,β-unsaturated amides towards weak nucleophiles such as arenes and cyclohexane is initiated either with triflic acid or with excess AlCl₃. Condensation with aromatics in the presence of AlCl₃ gives 3-arylpropionamides in excellent yields, while a selective ionic hydrogenation of some amides with cyclohexane gives saturated amides.
K. Y. Koltunov, S. Walspurger, J. Sommer, Eur. J. Org. Chem., 2004, 4039-4047.

Potassium trifluoro(organo)borates, which are highly stable and easily prepared organoboron derivatives, were able to react with various dehydroamino esters to alanine derivatives in good to high yields. This reaction, catalyzed by rhodium complexes, tolerates a great variety of amino protecting groups.
L. Navarre, S. Darses, J.-P. Genet, Eur. J. Org. Chem., 2004, 69-73.

Rhodium-catalyzed conjugate addition of potassium trifluoro(organo)borates to dehydroalanine derivatives, using chiral ligands such as fluorophos and in situ enantioselective protonation with guaiacol (2-methoxyphenol), afforded a variety of protected α-amino esters with high yields and enantiomeric excesses up to 95%.
L. Navarre, R. Martinez, J.-P. Genet, S. Darses, J. Am. Chem. Soc., 2008, 130, 6159-6169.

A new approach to 2-(arylmethyl)aldehydes begins with a silylformylation reaction of terminal acetylenes with aryl- or heteroarylsilanes, followed by treatment of the products with TBAF to induce a 1,2-anionotropic rearrangement of the aryl group.
L. A. Aronica, P. Raffa, A. M. Caporusso, P. Salvadori, J. Org. Chem., 2003, 5, 9292-9298.

A new, stereoselective, palladium-catalyzed method for the synthesis of substituted tetrahydrofurans from γ-hydroxy alkenes and aryl bromides forms both a C-C and a C-O bond with diastereoselectivities of up to >20:1. The reactions probably proceed via the intramolecular insertion of an olefin into a Pd(Ar)(OR) intermediate.
J. P. Wolfe, M. A. Rossi, J. Am. Chem. Soc., 2004, 126, 1620-1621.

The Rh-catalyzed reaction of 9-aryl-9-borabicyclo[3.3.1]nonanes with α,β-unsaturated ketones and aldehydes gave high yields of tandem 1,4-addition-aldol reaction products with high syn selectivity. The mechanism is discussed.
K. Yoshida, M. Ogasawara, T. Hayashi, J. Am. Chem. Soc., 2002, 124, 10984-10985.

The use of an equimolar amount of base with a diborylmethane enabled a chemoselective Pd-catalyzed Suzuki–Miyaura cross-coupling reaction for the synthesis of various benzylboronate derivatives in very good yields. Reactions of sterically hindered aryl bromides can give products in good yields.
K. Endo, T. Ohkubo, T. Shibata, Org. Lett., 2011, 13, 3368-3371.