Tertiary Alkyl Halides Research Articles

Selective Radical Fluorination of Tertiary Alkyl Halides at Room Temperature.

Direct fluorination of tertiary alkyl bromides and iodides with Selectfluor is described. The halogen-exchange fluorination proceeds efficiently in acetonitrile at room temperature under metal-free conditions and exhibits a wide range of functional group compatibility. Furthermore, the reactions are highly selective in that alkyl chlorides and primary and secondary alkyl bromides remain intact. A radical mechanism is proposed for this selective fluorination.

Nickel-Catalyzed Reductive Allylation of Tertiary Alkyl Halides with Allylic Carbonates.

The construction of all C(sp3 ) quaternary centers has been successfully achieved under Ni-catalyzed cross-electrophile coupling of allylic carbonates with unactivated tertiary alkyl halides. For allylic carbonates bearing C1 or C3 substituents, the reaction affords excellent regioselectivity through the addition of alkyl groups to the unsubstituted allylic carbon terminus. The allylic alkylation method also exhibits excellent functional-group compatibility, and delivers the products with high E selectivity.

Nickel‐Catalyzed Reductive Allylation of Tertiary Alkyl Halides with Allylic Carbonates

AbstractThe construction of all C(sp3) quaternary centers has been successfully achieved under Ni‐catalyzed cross‐electrophile coupling of allylic carbonates with unactivated tertiary alkyl halides. For allylic carbonates bearing C1 or C3 substituents, the reaction affords excellent regioselectivity through the addition of alkyl groups to the unsubstituted allylic carbon terminus. The allylic alkylation method also exhibits excellent functional‐group compatibility, and delivers the products with high E selectivity.

Nickel-Catalyzed Defluorinative Reductive Cross-Coupling of gem-Difluoroalkenes with Unactivated Secondary and Tertiary Alkyl Halides.

Herein, we described a nickel-catalyzed monofluoroalkenylation through defluorinative reductive cross-coupling of gem-difluoroalkenes with alkyl halides. Key to the success of this strategy is the combination of C-F cleavage with alkyl halides activation. This reaction enables the convenient synthesis of a large variety of functionalized monofluoroalkenes under mild reaction conditions with broad functional group compatibility and excellent Z-selectivity. The combination of Ni catalysis with (Bpin)2/K3PO4 as terminal reductant promoted the efficient C(sp2)-C(sp3) formation especially the generation of all-carbon quaternary centers with high chemoselectivity.

Preparation of Alkyl Halide as Intermediate Compound in Synthesis Cationic Surfactant Alkyl Trimethyl Ammonium Chloride

Cationic surfactant alkyl trimethyl ammonium chloride was synthesized by quartenerisation of tertiary amines. Materials used in quartenerization are tertiary amine and alkyl halide. Alkyl halide is a hydrocarbon derivative in which one or more hydrogen is replaced with halogen. In this research, thionyl chloride is used as a reactant . Thionyl chloride (SOCl2) is often used because it is easier to make, the yield is greater and byproducts are volatile. Alkyl halide is synthesized from the reaction of hexadecyl alcohol with thionyl chloride (SOCl2) at a temperature of 80 C for 24 hours in a reflux reactor. This study managed to get hexadecyl chloride from the reaction hexadecyl alcohol and thionyl chloride. It can be seen from the results of FTIR, LC/MS and GC/MS

N-Alkylation and Aminohydroxylation of 2-Azidobenzenesulfonamide Gives a Pyrrolobenzothiadiazepine Precursor Whereas Attempted N-Alkylation of 2-Azidobenzamide Gives Benzotriazinones and Quinazolinones

N-Alkylation of 2-azidobenzenesulfonamide with 5-bromopent-1-ene gave an N-pentenyl sulfonamide, which underwent intramolecular aminohydroxylation to give an N-(2-azidoaryl)sulfonyl prolinol, a precursor for the synthesis of a pyrrolobenzothiadiazepine. The attempted N-alkylation of 2-azidobenzamide gave a separable mixture (∼1:1) of a benzotriazinone and a quinazolinone in a 72% combined yield. Other primary alkyl halides (3 examples) gave similar mixtures of benzotriazinones and quinazolinones. Benzylic, allylic, and secondary and tertiary alkyl halides (5 examples) gave only benzotriazinones in moderate yields. The results of mechanistic studies show the likely involvement of nitrene intermediates in the quinazolinone pathway and a second pathway involving a dimethylsulfoxide or dimethylsulfide-mediated conversion of 2-azidobenzamide into benzotriazinones.

Iron-Catalyzed Heck-Type Alkenylation of Functionalized Alkyl Bromides

The ability of iron to controllably generate alkyl radicals from alkyl halides as a key step in atom transfer radical polymerization (ATRP) has been adapted to facilitate a formal Heck cross-coupling between styrenes and functionalized alkyl bromides. A simple FeCl2 catalyst in a coordinating solvent gave excellent activity without the need for expensive ligands. Tertiary, secondary, and even primary alkyl bromides are tolerated to give the products in moderate to good yields (up to 94% yield). The easily accessible reagents and operational simplicity make this reaction a method of choice for the alkenylation of alkyl halides, especially for functionalized tertiary alkyl halides, which are difficult to target by classic palladium-catalyzed Heck reactions because of the competing β-hydride elimination.

ChemInform Abstract: Manganese‐Catalyzed Borylation of Unactivated Alkyl Chlorides.

AbstractA mild and convenient synthesis of alkyl bispinacolato esters is developed using primary, secondary and even tertiary alkyl halides in the presence of MnBr2 and TMEDA as low cost catalysts.

Palladium-Catalyzed Cross Coupling of Secondary and Tertiary Alkyl Bromides with a Nitrogen Nucleophile.

We report a new class of catalytic reaction: the thermal substitution of a secondary and or tertiary alkyl halide with a nitrogen nucleophile. The alkylation of a nitrogen nucleophile with an alkyl halide is a classical method for the construction of C–N bonds, but traditional substitution reactions are challenging to achieve with a secondary and or tertiary alkyl electrophile due to competing elimination reactions. A catalytic process could address this limitation, but thermal, catalytic coupling of alkyl halides with a nitrogen nucleophile and any type of catalytic coupling of an unactivated tertiary alkyl halide with a nitrogen nucleophile are unknown. We report the coupling of unactivated secondary and tertiary alkyl bromides with benzophenone imines to produce protected primary amines in the presence of palladium ligated by the hindered trialkylphosphine Cy2t-BuP. Mechanistic studies indicate that this amination of alkyl halides occurs by a reversible reaction to form a free alkyl radical.

ChemInform Abstract: Visible‐Light‐Mediated, Nitrogen‐Centered Radical Amination of Tertiary Alkyl Halides under Metal‐Free Conditions to Form α‐Tertiary Amines.

A mild and operationally convenient amino-functionalization of a range of tertiary alkyl halides by reaction with iminoiodinanes (PhINNs) and I2 has been developed. According to the mechanistic experiments described within, the reaction is speculated to proceed through a light-promoted, N-centered radical pathway involving a N,N-diiodosulfonamide reactive species. This method of direct N-incorporation offers an attractive alternative to the production of α-tertiary amines, a synthetically challenging structural class found in a variety of bioactive molecules.

Amine synthesis via iron-catalysed reductive coupling of nitroarenes with alkyl halides.

(Hetero)Aryl amines, an important class of organic molecules in medicinal chemistry, are most commonly synthesized from anilines, which are in turn synthesized by hydrogenation of nitroarenes. Amine synthesis directly from nitroarenes is attractive due to improved step economy and functional group compatibility. Despite these potential advantages, there is yet no general method for the synthesis of (hetero)aryl amines by carbon–nitrogen cross-coupling of nitroarenes. Here we report the reductive coupling of nitroarenes with alkyl halides to yield (hetero)aryl amines. A simple iron catalyst enables the coupling with numerous primary, secondary and tertiary alkyl halides. Broad scope and high functional group tolerance are demonstrated. Mechanistic study suggests that nitrosoarenes and alkyl radicals are involved as intermediates. This new C–N coupling method provides general and step-economical access to aryl amines.

ChemInform Abstract: Intermolecular Photocatalytic C—H Functionalization of Electron‐Rich Heterocycles with Tertiary Alkyl Halides.

AbstractThe utility of the method is demonstrated by its application in a flow reactor and by the preparation of a biologically active molecule [c.f.

Silicon-Carbon Bond Formation via Nickel-Catalyzed Cross-Coupling of Silicon Nucleophiles with Unactivated Secondary and Tertiary Alkyl Electrophiles.

A wide array of cross-coupling methods for the formation of C-C bonds from unactivated alkyl electrophiles have been described in recent years. In contrast, progress in the development of methods for the construction of C-heteroatom bonds has lagged; for example, there have been no reports of metal-catalyzed cross-couplings of unactivated secondary or tertiary alkyl halides with silicon nucleophiles to form C-Si bonds. In this study, we address this challenge, establishing that a simple, commercially available nickel catalyst (NiBr2·diglyme) can achieve couplings of alkyl bromides with nucleophilic silicon reagents under unusually mild conditions (e.g., -20 °C); especially noteworthy is our ability to employ unactivated tertiary alkyl halides as electrophilic coupling partners, which is still relatively uncommon in the field of cross-coupling chemistry. Stereochemical, relative reactivity, and radical-trap studies are consistent with a homolytic pathway for C-X bond cleavage.

ChemInform Abstract: N‐Acyl Amino Acid Ligands for Ruthenium(II)‐Catalyzed meta‐C—H tert‐Alkylation with Removable Auxiliaries.

AbstractRuthenium (II) complexes obtained from monoprotected amino acids are highly active catalysts for the meta‐functionalization of various anilines as well as pyridyl‐, pyrimidyl‐, and pyrazolyl‐ substituted arenes with removable directing groups using tertiary alkyl halides.

ChemInform Abstract: Nickel‐Catalyzed Reductive Coupling of Aryl Bromides with Tertiary Alkyl Halides.

AbstractElectron‐deficient aryl bromides react with tertiary alkyl bromides under mild conditions in the presence of pyridine or DMAP and imidazolium salts.

Intermolecular Photocatalytic C–H Functionalization of Electron-Rich Heterocycles with Tertiary Alkyl Halides

The coupling of tertiary alkyl halides with electron-rich arenes is promoted by visible-light photoredox catalysis. Tris[2-phenylpyridinato-<i>C</i> ²,<i>N</i>]iridium(III) [Ir(ppy)₃] was the optimal catalyst, enabling direct reduction of the halide from the excited state, and thereby eliminating the requirement for a stoichiometric electron donor. High yields were obtained when the aromatic component was used in excess, although equimolar amounts afforded only slightly diminished yields. The reaction tolerates a number of functional groups, including allyl, ester, amide, or carbamate. The efficiency of this reaction has been improved through demonstration of scale-up in flow, and a new substituted Ir(ppy)₃ derivative was isolated and characterized.

Visible-light-mediated, nitrogen-centered radical amination of tertiary alkyl halides under metal-free conditions to form α-tertiary amines.

A mild and operationally convenient amino-functionalization of a range of tertiary alkyl halides by reaction with iminoiodinanes (PhI[double bond, length as m-dash]NNs) and I2 has been developed. According to the mechanistic experiments described within, the reaction is speculated to proceed through a light-promoted, N-centered radical pathway involving a N,N-diiodosulfonamide reactive species. This method of direct N-incorporation offers an attractive alternative to the production of α-tertiary amines, a synthetically challenging structural class found in a variety of bioactive molecules.

Jianrong (Steve) Zhou

Angewandte Chemie International EditionVolume 55, Issue 15 p. 4636-4636 Author ProfileFree Access Jianrong (Steve) Zhou First published: 03 December 2015 https://doi.org/10.1002/anie.201510761AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “The worst advice I have ever given was ‘it won't work’. If I were not a scientist, I would be a historian ...” This and more about Jianrong (Steve) Zhou can be found on page 4636. 1 Table 1. Jianrong (Steve) Zhou Date of birth: September 12, 1975 Position: Assistant Professor, Nanyang Technological University, Singapore E-mail: jrzhou@ntu.edu.sg Homepage: http://www.spms.ntu.edu.sg/cbc/FacultyResearch/Individual%20Faculty/SZhou.html Education: 1988 BSc, National University of Singapore 2000 MSc with Prof. Teck-Peng Loh, National University of Singapore 2005 PhD with Prof. Gregory Fu, Massachusetts Institute of Technology 2005–2008 Postdoc with Prof. John Hartwig, Yale University and University of Illinois at Urbana–Champaign Awards: 2013 GSK Green and Sustainable Manufacturing Award Research: Transition metal catalysis and asymmetric catalysis for fundamental bond-forming reactions Hobbies: Reading, movies, and travel The worst advice I have ever given was “it won't work”. If I were not a scientist, I would be a historian. My favorite films of all time are The Godfather I—III. The most significant scientific advance of the last 100 years was the invention of NMR spectroscopy and X-ray crystallography. The biggest problem that scientists face is the energy crisis. There has not been a sustainable solution to date. When I'm frustrated, I read a book and go to sleep. Tomorrow will be a new day. I chose chemistry as a career because I was lucky to have excellent chemistry teachers in high school and university. My not-so-secret passion is to find good food in Singapore, which can be difficult. The most exciting thing about my research is to discover new reactions. My biggest motivation is to see co-workers grow intellectually and solve problems independently. I can never resist to share my new ideas with co-workers. My 5 top papers: References 1“A General Palladium-Catalyzed Method for Alkylation of Heteroarenes Using Secondary and Tertiary Alkyl Halides”: X. Wu, J. W. T. See, K. Xu, H. Hirao, J. Roger, J.-C. Hierso, J. Zhou, Angew. Chem. Int. Ed. 2014, 53, 13573; Angew. Chem. 2014, 126, 13791. (A good method for the introduction of alkyl groups to many electron-deficient heteroarenes.) 2“Nickel-Catalyzed Asymmetric Transfer Hydrogenation of Olefins for the Synthesis of α- and β-Amino Acids”: P. Yang, H. Xu, J. Zhou, Angew. Chem. Int. Ed. 2014, 53, 12210; Angew. Chem. 2014, 126, 12406. (Use of nickel catalysts in transfer hydrogenation with formic acid.) 3“Asymmetric Intermolecular Heck Reaction of Aryl Halides”: C. Wu, J. Zhou, J. Am. Chem. Soc. 2014, 136, 650. (Simple hydrogen-bond donors promoted the ionization of neutral arylpalladium halides.) 4“Intermolecular Mizoroki–Heck Reaction of Aliphatic Olefins with High Selectivity for Substitution at the Internal Position”: L. Qin, X. Ren, Y. Lu, Y. Li, J. Zhou, Angew. Chem. Int. Ed. 2012, 51, 5915; Angew. Chem. 2012, 124, 6017. (Regioselective Heck reaction of common aliphatic olefins using a designed bisphosphine, dnpf, which is now commercially available.) 5“Arene C−H⋅⋅⋅O Hydrogen Bonding in Palladium-Catalyzed Arylation and Vinylation of Lactones”: Z. Huang, Z. Chen, L. H. Lim, G. C. Phan Quang, H. Hirao, J. Zhou, Angew. Chem. Int. Ed. 2013, 52, 5807; Angew. Chem. 2013, 125, 5919. (Stereoselectivity was guided by weak attractive interactions between non-acidic C−H bonds and enolate oxygen atoms.) Volume55, Issue15April 4, 2016Pages 4636-4636 ReferencesRelatedInformation

N-Acyl Amino Acid Ligands for Ruthenium(II)-Catalyzed meta-C-H tert-Alkylation with Removable Auxiliaries.

Acylated amino acid ligands enabled ruthenium(II)-catalyzed C-H functionalizations with excellent levels of meta-selectivity. The outstanding catalytic activity of the ruthenium(II) complexes derived from monoprotected amino acids (MPAA) set the stage for the first ruthenium-catalyzed meta-functionalizations with removable directing groups. Thereby, meta-alkylated anilines could be accessed, which are difficult to prepare by other means of direct aniline functionalizations. The robust nature of the versatile ruthenium(II)-MPAA was reflected by challenging remote C-H transformations with tertiary alkyl halides on aniline derivatives as well as on pyridyl-, pyrimidyl-, and pyrazolyl-substituted arenes. Detailed mechanistic studies provided strong support for an initial reversible C-H ruthenation, followed by a SET-type C-Hal activation through homolytic bond cleavage. Kinetic analyses confirmed this hypothesis through an unusual second-order dependence of the reaction rate on the ruthenium catalyst concentration. Overall, this report highlights the exceptional catalytic activity of ruthenium complexes derived from acylated amino acids, which should prove instrumental for C-H activation chemistry beyond remote functionalization.

Nickel-Catalyzed Reductive Coupling of Aryl Bromides with Tertiary Alkyl Halides.

A mild Ni-catalyzed reductive arylation of tertiary alkyl halides with aryl bromides has been developed that delivers products bearing all-carbon quaternary centers in moderate to excellent yields with excellent functional group tolerance. Electron-deficient arenes are generally more effective in inhibiting alkyl isomerization. The reactions proceed successfully with pyridine or 4-(dimethylamino)pyridine, while imidazolium salts slightly enhance the coupling efficiency.