Regioselective Insertion of o‐Carborynes into the α‐CH Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C? H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C? H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Regioselective Insertion of o‐Carborynes into the α‐C?H Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Dual Nucleophilic Substitution Reactions of O,O‐Diethyl 2,4‐dinitrophenyl Phosphate and Thionophosphate Triesters

The reactions of the title compounds with phenoxides, secondary alicyclic (SA) amines, and pyridines, in 44 wt% ethanol–water, at 25°C and an ionic strength of 0.2 M, were subjected to kinetic and product studies. From analytical techniques (HPLC and NMR), two pathways were detected (nucleophilic attack at the phosphoryl center and at the C‐1 aromatic carbon) for the reactions of all the nucleophiles with the phosphate ( 2 ) and for the pyridinolysis of the thionophosphate ( 1 ). Only aromatic nucleophilic substitution was found for the reactions of 1 with phenoxides and SA amines. For the dual reactions, the nucleophilic rate constants (k_N) were separated in two terms: $k_{\rm N}^{\rm P}$ and $k_{\rm N}^{{\rm Ar}}$, which are the rate constants for the corresponding electrophilic centers. The absence of a break in the Brønsted‐type plots for the attack at P is consistent with concerted mechanisms. The Brønsted slopes, β_Ar 0.32–0.71, for the attack at the aromatic C‐1, are in agreement with stepwise mechanisms where formation of a Meisenheimer complex is the rate‐determining step. © 2013 Wiley Periodicals, Inc. Int J Chem Kinet 45: 202–211, 2013     

Reagents for specific modification of biopolymers 8. Synthesis of 2,7-diaminophenazinium salts by nucleophilic substitution of hydrogen

Direct nucleophilic substitution in quaternary 2-N-alkylacetamidophenazinium salts with primary and secondary amines can serve as a convenient method for the introduction of two different substituents under mild conditions.For part 7, see Ref. l.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 2059–2062, August, 1996.     

Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α‐functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone‐promoted oxidation to access O‐bound quinol‐intermediates that undergo nucleophilic substitution reactions. These quinol‐intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α‐thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α‐branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.     

Enantioselective Nucleophilic Aromatic Substitution with Small‐Molecule Chiral Selectors

Small‐molecule rationally designed chiral selectors have been shown to influence the stereochemical outcome of a variety of organic transformations. For instance, in a recent report, we demonstrated that a chiral selector (in conjunction with an achiral phase‐transfer catalyst) could selectively inhibit one enantiomer of electron‐deficient aromatic amides from forming Meisenheimer adducts (Scheme 2). We now extend this methodology to performing enantioselective nucleophilic aromatic substitutions. Initial studies involved biphasic kinetic resolutions with a chiral selector in conjunction with an achiral phase‐transfer catalyst (Scheme 3). The results are consistent with previous data taken for biphasic reactions (e.g., Scheme 1) where the chiral selector effectively shields the more highly complexed enantiomer from reaction. With neutral nucleophiles such as amines, the enantioselective nucleophilic aromatic substitutions can also be conducted in single‐phase systems. Several examples are given.     

Quaternary ammonium and sulfonium derivatives of 2-chloromethylbutadiene and poly-2-chloromethylbutadiene

2-Chloromethylbutadiene has been converted to quaternary ammonium and sulfonium monomers which have been polymerized at room temperature. They show a very great tendency to dimerize on heating in water solution. The aqueous quaternary monomer dimerized 25 times as fast as the aqueous sulfonium monomer and nearly 10⁵ times as fast as neat isoprene at 50°C. The quaternary monomer dimerized with itself in a water solution to which 2-hydroxymethylbutadiene has been added as an example of a nonionic diene. The latter monomer did not dimerize rapidly in water, nor did 2-aminomethylbutadiene. The hydrochlorides of 2-aminomethylbutadiene and 2-dimethylaminomethylbutadiene dimerized at rates comparable to that of the sulfonium monomer. Poly 2-chloromethylbutadiene contains reactive chlorine except for the structure resulting from the minor extent of 1,2 addition. Water-soluble derivatives have been made from it with nucleophilic tertiary amines and sulfides. Cationic polymers are substantive to paper pulp, and the sulfonium polymers can be cured in paper to give improved wet strength.     

Diastereoselective isothiourea iodocyclization for manzacidin synthesis

We have devised a novel strategy for the total synthesis of the manzacidins. Our approach utilizes an isothiourea iodocyclization strategy to directly form the heterocyclic core, and in the process induce stereoselectivity at the quaternary center. We have found that cyclization can be achieved using an isothiourea as the nucleophilic partner. Cyclization proceeds smoothly using IBr at low temperature, affording an advanced intermediate along our proposed route to manzacidin A in 92% yield. We have demonstrated the scope of the reaction by preparing several cyclic isothioureas, including an intermediate on our proposed route for the synthesis of manzacidin D.     

Sulfinylnitriles: Sulfinyl–Metal Exchange–Alkylation Strategies

Adding organolithiums, Grignard reagents, or zincates to sulfinylnitriles triggers a facile sulfinyl–metal exchange to afford N‐ or C‐metalated nitriles. Sulfinyl–magnesium exchange–alkylations efficiently install quaternary and tertiary centers, even in the case of tertiary sulfinylnitriles that contain a highly acidic methine proton. α‐Sulfinylalkenenitriles afford moderately nucleophilic magnesiated nitriles, and the reactivity can be dramatically increased by conversion to the corresponding magnesiates. The sulfinyl‐metal exchange is extremely fast, proceeds efficiently with quaternary, tertiary, and vinylic α‐sulfinylnitriles, and exhibits an exceptional functional group tolerance in nitrile alkylations.     

One‐Pot Asymmetric Synthesis of Quaternary Pyrroloindolones through a Multicatalytic N‐Allylation/Hydroacylation Sequence

An intramolecular, quaternary carbon center forming hydroacylation of α‐substituted acrylates has been discovered. This interesting transformation can be readily incorporated into a multicatalytic tandem process enabled by a combination of nucleophilic tertiary amine and N‐heterocyclic carbene catalysis. With no additional stoichiometric base required, this transformation affords the quaternary pyrroloindolones with high levels of enantioselectivity.     

Reaction of 2,4,6-trichloro-1,3,5-triazine with nucleophilic reagents in the presence of tertiary amines

A mechanism for the nucleophilic substitution of halogen in cyanuric chloride in the presence of tertiary amines is proposed. When carboxylic acids react with cyanuric chloride in the presence of tertiary amines, quaternary acylammonium salts are formed which can be used as acylating agents.     

Dynamic Covalent Chemistry of Nucleophilic Substitution Component Exchange of Quaternary Ammonium Salts

Dynamic covalent libraries (DCLs) of quaternary ammonium cations were set up by reversible nucleophilic substitution (S_N2′ and S_N2) exchange reactions of ammonium salts and tertiary amines. The reactions were conducted at 60 °C to generate thermodynamically and kinetically controlled mixtures of quaternary ammonium compounds and tertiary amines, and were accelerated by using iodide as a nucleophilic catalyst. Microwave irradiation was used to assist the exchange reaction between the pyridinium salts and pyridine derivatives. Finally, experiments towards the generation of dynamic ionic liquids were performed. The results of this study pave the way for the extension of dynamic combinatorial chemistry to nucleophilic substitution reactions.     

Intramolecular vinylation of secondary and tertiary organolithiums

Deprotonation of benzylic ureas, carbamates, and thiocarbamates bearing N'-alkenyl substituents generates carbanions which undergo intramolecular migration of the alkenyl group to the carbanionic center. Solvolysis of the urea products generates α-alkenylated amines. With an enantiomerically pure starting urea, migration proceeds stereospecifically, generating in enantiomerically enriched form products containing allylic quaternary stereogenic centers bearing N. Computational and in situ IR studies suggest that the reaction, formally a nucleophilic substitution at an sp(2) carbon atom, proceeds by a concerted addition-elimination pathway.     

Synthesis and Comparison of the Reactivity of 3,4,5‐1H‐Trinitropyrazole and Its N‐Methyl Derivative

3,4,5‐Trinitro‐1H‐pyrazole ( 1 ) has been obtained via nitration of 3,5‐dinitropyrazole with mixture of sulfuric and nitric acids. Compound 1 reacts with excess ammonia and aliphatic amines, in the presence of bases with NH‐azoles, phenols, thiols, and triflouroethanol at mild conditions in water. All these reactions occur as the nucleophilic substitution of the nitro‐group at position 4 in 1 affording 4‐R‐3,5‐dinitropyrazoles. The product of methylation of 1 , N‐methyl‐3,4,5‐trinitropyrazole ( 4 ), also reacts with thiols, phenols, oximes, ammonia, amines, and NH‐azoles. The reactions proceed with high yields but nucleophilic substitutions in these cases occur regioselectively at position 5 in 4 to afford 5‐R‐3,4‐dinitropyrazoles.     

Direct Nucleophilic Addition to N‐Alkoxyamides

While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long‐standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N‐alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N‐alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N‐alkoxy group formed a five‐membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL‐H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter‐ and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered α‐trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five‐ and six‐membered lactams, and macrolactams.     

A pitfall of using 2‐[(2E)‐3‐(4‐tert‐butylphenyl)‐2‐methylprop‐2‐enylidene]malononitrile as a matrix in MALDI TOF MS: chemical adduction of matrix to analyte amino groups

2‐[(2E)‐3‐(4‐tert‐Butylphenyl)‐2‐methylprop‐2‐enylidene]malononitrile (DCTB) has been considered as an excellent matrix for matrix‐assisted laser desorption/ionization (MALDI) of many types of synthetic compounds. However, it might provide troublesome results for compounds containing aliphatic primary or secondary amino groups. For these compounds, strong extra ion peaks with a mass difference of 184.1 Da were usually observed, which might falsely indicate the presence of some unknown impurities that were not detected by other matrices. On the basis of the possible mechanisms proposed, these extra ions are the products of nucleophilic reactions between analyte amino groups and DCTB molecules or radical cations. In these reactions, an amino group replaces the dicyanomethylene group of DCTB forming a matrix adduct via a ? C?N‐bond. An aliphatic primary amine could react easily with DCTB and the reaction could start once they are mixed in a MALDI solution. For an aliphatic secondary amine, on the other hand, the reaction most likely occurs in the gas phase. Protonation of amino groups by adding acid seems to be a useful way to stop DCTB adduction for compounds with one single amino group, but not for compounds with multiple amino groups. Unlike aliphatic primary or secondary amines, aliphatic tertiary amines and aromatic amines do not yield DCTB adducts. This is because tertiary amines do not have the required transferrable H‐(N) atom to form an extra ? C?N‐bond, while aromatic amines are not sufficiently nucleophilic to attack DCTB. In view of the possible matrix adduction, care should be taken in MALDI time‐of‐flight mass spectrometry (TOF MS) when DCTB is used as the matrix for compounds containing amino group(s). Copyright © 2010 John Wiley & Sons, Ltd.     

Diphenylprolinol Silyl Ether Catalyzed Asymmetric Michael Reaction of Nitroalkanes and β,β‐Disubstituted α,β‐Unsaturated Aldehydes for the Construction of All‐Carbon Quaternary Stereogenic Centers

The asymmetric Michael reaction of nitroalkanes and β,β‐disubstituted α,β‐unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4‐addition products with an all‐carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for β‐substituents such as β‐aryl and β‐alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)‐ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,β‐unsaturated aldehydes, the retro‐Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.     

Synthesis of (Z)‐Trisubstituted Olefins by Decarboxylative Grob‐Type Fragmentations: Epothilone D,Discodermolide, and Peloruside A

Methyl‐branched (Z)‐trisubstituted olefins are found in many polyketides with interesting biological activity, such as epothilone D ( 1 ), discodermolide ( 3 ), and peloruside A ( 2 ). Despite the employment of numerous different strategies, this motif has often been the weak point in total synthesis. Thus, we present a novel hydroxide‐ induced Grob‐type fragmentation as an easy access to trisubstituted olefins. In our case, β‐mesyloxy δ‐lactones with three stereogenic centers were chosen whose fragmentation underlies a high stereoelectronic control. Major challenges in the syntheses were the installation of quaternary stereocenters, achieved by enzymatic desymmetrization of meso‐diesters and by aluminium‐promoted stereoselective rearrangement of chiral epoxides, respectively. Different aldol strategies were developed for the formation of the fragmentation precursors. Additionally a short survey about nucleophilic additions to aldehydes with quaternary α‐centers is presented.     

Gold(I)/Chiral Brønsted Acid Catalyzed Enantioselective Hydroamination–Hydroarylation of Alkynes: The Effect of a Remote Hydroxyl Group on the Reactivity and Enantioselectivity

The catalytic enantioselective hydroamination–hydroarylation of alkynes under the catalysis of (R₃P)AuMe/(S)‐3,3′‐bis(2,4,6‐triisopropylphenyl)‐1,1′‐binaphthyl‐2,2′‐diyl hydrogenphosphate ((S)‐TRIP) is reported. The alkyne was reacted with a range of pyrrole‐based aromatic amines to give pyrrole‐embedded aza‐heterocyclic scaffolds bearing a quaternary carbon center. The presence of a hydroxyl group in the alkyne tether turned out to be very crucial for obtaining products in high yields and enantioselectivities. The mechanism of enantioinduction was established by carefully performing experimental and computational studies.