Conformational, steric and electronic effects on the site- and chemoselectivity of the metal-catalyzed reaction of N-bis(trimethylsilyl)methyl, N-(2-indolyl)methyl α-diazoamides

The Rh(II)- and Cu(II)-catalyzed reactions of N-bis(trimethylsilyl)methyl, N-(2-indolyl)methyl α-diazoamides are investigated to delineate how conformational, steric and electronic factors influence the site- and chemoselectivity of the metallocarbenoid reaction. The N-bis(trimethylsilyl)methyl (N-BTMSM) group is found to be essential in promoting the metallocarbenoid reaction at the N-(2-indolyl)methyl moiety as well as providing subtle but effective conformational influence about the amide N-C(α) sigma bond in diazoamides carrying an N-C(α) alkoxymethyl side-chain, to afford excellent site- and chemoselectivity. In general, the metal-catalyzed reactions are found to favor metallocarbenoid addition to the indole C(2)-C(3) double bond over C-H insertion to give cyclopropanated products (tetracyclic γ-lactams); however, chemoselectivity is also affected by steric effects, as revealed in the N-[2-(3-methylindolyl)]methyl diazoamides, and to some extent by the nature of the catalyst employed, as seen in the N-C(α)-alkoxymethyl diazoamides. The tetracyclic γ-lactams are found to rearrange to give good to high yields of the tricyclic indole derivatives under the metallocarbenoid reaction conditions or under acidic conditions. The propensity of the tetracyclic γ-lactams to undergo rearrangement is found to be dependent on the nature of the α-substituent on the original diazo carbon and the indole N-substituent.     

Di- and trisubstituted γ-lactams via Rh(II)-carbenoid reaction of N-Cα-branched, N-bis(trimethylsilyl)methyl α-diazoamides. Synthesis of (±)-α-allokainic acid

Acyclic N-C(α)-branched, N-bis(trimethylsilyl)methyl (N-BTMSM) diazoamides undergo regio-, chemo-, and diastereoselective Rh(II)-carbenoid C-H insertion to give 4,5-disubstituted and 3,4,5-trisubstituted γ-lactams. The conformational influence of the N-BTMSM group and the electronic effect of the O-pivaloyl moiety of the C(α)-oxymethylene unit are essential for the observed regioselectivity. The synthesis of α-allokainic acid demonstrates the utility of the method.     

Metal-catalyzed reaction of N-(2-indolyl)methyl, N-bis(trimethylsilyl)methyl diazoamides: an entry into the beta-carboline ring system

The intramolecular metal-catalyzed reaction of N-(2-indolyl)methyl, N-bis(TMS)methyl diazoamides proceeds with high conformational control and chemoselectivity to give cyclopropyl derivatives, which rearrange to beta-carboline products.     

CX_2(X=H,F,Cl)与甲基异丙基醚C-H键插入反应的理论研究

用从头计算方法在MP2 /6 31G(d)水平上研究了CX2 (X =H ,F ,Cl)与甲基异丙基醚的C -H键插入反应。CCl2 与甲基异丙基醚两个不同的α C的C -H键插入势垒分别为 117.2kJ/mol (甲基 )和 2 0 .6kJ/mol (异丙基 )。CF2 与异丙基α C的C -H键上插入势垒为 12 0 .0kJ/mol,在插入甲基上C -H键时会引起C -O键的断裂。CH2 的插入反应则不需要势垒。对CX2 与二甲醚、甲乙醚、甲基异丙基醚、甲基苄基醚上各种不同的C -H键插入势垒进行了比较 ,甲基和苯基都促使其毗邻的C -H键更容易被CX2 所插入     

New strategic reactions for organic synthesis: catalytic asymmetric C-H activation alpha to oxygen as a surrogate to the aldol reaction

The C-H activation of silyl ethers by means of rhodium carbenoid-induced C-H insertion represents a very direct method for the stereoselective synthesis of silyl-protected beta-hydroxy esters. The reaction can proceed with very high regio-, diastereo-, and enantioselectivity and represents a surrogate to the aldol reaction. The reaction is catalyzed by the rhodium prolinate complex Rh(2)(S-DOSP)(4). A critical requirement for the high chemoselectivity is the use of donor/acceptor-substituted carbenoids such as those derived from methyl aryldiazoacetates. A range of silyl ethers may be used such as allyl silyl ethers, tetraalkoxysilanes, and even simple trimethylsilyl alkyl ethers. In general, C-H activation preferentially occurs at methylene sites, as the reactivity is controlled by a delicate balance between steric and electronic effects.     

Selectivity control in alkylidene carbene-mediated C-H insertion and allene formation

Regioselectivity of alkylidene carbene-mediated C-H insertion was explored utilizing electronic, conformational, steric, and stereoelectronic effects. Relying on these factors, highly regio- and chemoselective carbene insertion reaction of C-H bonds in different environments could be obtained. The observed selectivity clearly indicates that an electronic effect plays a more important role than steric effect. In general, C-H bonds in conformationally rigid cyclic environments are less reactive than those in acyclic systems toward carbene insertion, and in this situation, a competing intermolecular reaction between alkylidene carbene and trimethylsilyldiazomethane led to the formation of allenylsilanes. The formation of allenylsilane becomes more favorable as the concentration of reaction becomes higher, as well as the C-H bonds undergoing insertion becomes electronically and conformationally deactivated.     

A Linear Free Energy Correlation Study of Rh(Ⅱ)-Mediated Carbenoid Intramolecular C-H Insertion

The reaction mechanism of Rh(Ⅱ)-mediated carbenoid intramolecular C-H insertion have been intensively investigated. The reaction has been observed to be affected by the electrophilicity of the Rh(Ⅱ)-carbene intermediate, the substituents on the carbon at which the C-H insertion occurs, and steric and conformational factors.¹ It has been well documented that the electronic property of the ligands of the Rh(Ⅱ) catalyst has marked influence over the electrophylicity of Rh(Ⅱ)-carbene intermediate. In addition, the α-substituent on the carbenoid carbon are expected to exert similar affect on the reactivity of Rh(Ⅱ)-carbene. According to the reaction mechanism proposed by Doyle, an electron-donating α-substituent decreases the electrophilicity of the Rh(Ⅱ)-carbene complex and causes the C-H insertion to occur with a later transition state,while an electron withdrawing α-substituent operates in the opposite way. However, this prediction is still lack of solid support by experimental data. Most of the studies on the electronic effects have so far been concentrated on electron-withdrawing α-substituent, such as ester or acetyl group. The α-substituent effect, although important, is generally subtle and may be readily overridden by other effects, such as steric and conformational effects. This makes it difficult to accurately evaluate the α-substituenteffect.     

Synthesis and structural characterization of novel silenes stabilized by intramolecular coordination of a dialkylamino group

Two intramolecularly donor-stabilized silenes, 1-(8-dimethylamino-1-naphthyl)-1,2,2-tris(trimethylsilyl)silene (6a) and 1-(2-dimethylaminomethylphenyl)-1,2,2-tris(trimethylsilyl)silene (6b), were synthesized according to a novel one-step process by the reaction of (dichloromethyl)tris(trimethylsilyl)silane (1) with a twofold molar excess of 8-dimethylamino-1-naphthyllithium or 2-(dimethylaminomethyl)phenyllithium, respectively. Compounds 6a and 6b are thermally stable compounds. X-ray structural analyses of both silenes revealed strong donor-acceptor interactions between the dialkylamino groups and the electrophilic silene silicon atoms (Si-N distances: 6a: 1.751(3) A; 6b: 1.749(3) A) that lead to pyramidalization at the silicon centers. In contrast, the configuration at the silene carbon atoms was found to be planar. The Si=C distances (6a: 1.751(3) A; 6b: 1.749(3) A) fit with literature data of comparable compounds. Addition of water or methanol to the Si=C bonds of 6a,b afforded the silanols 7a,b and the methoxysilanes 8a,b, respectively. The compound 1-(8-dimethylaminomethyl-1-naphthyl)-1,2,2-tris(trimethylsilyl)silene (6c), generated following the same procedure by the reaction of 1 with 8-(dimethylaminomethyl)-1-naphthyllithium (molar ratio 1:2) proved to be unstable at room temperature and underwent rapid insertion of the Si=C group into a methylene C-H bond of the dimethylaminomethylnaphthyl ligand to afford the 1-silaacenaphthene 9.     

Stereospecific entry to [4.5]spiroketal glycosides using alkylidenecarbene C-H insertion

[reaction: see text] A novel method for the stereospecific preparation of [4.5]spiroketal glycosides utilizing the 1,5 C-H bond insertion of alkylidenecarbenes is described. Treatment of 2-oxopropyl beta-pyranosides A with lithium (trimethylsilyl)diazomethane in THF at -78 degrees C afforded 1,6-dioxaspiro[4,5]decenes B in good yield. Submission of the corresponding alpha-glycosides C to the same reagent gave the isomeric insertion products D in moderate to high yield.     

Regioselectivity of rhodium nitrene insertion. Syntheses of protected glycals of l-daunosamine, d-saccharosamine, and l-ristosamine

[reaction: see text] The carbamate-protected glycals of naturally occurring 3,4-cis-3-amino-2,3,6-trideoxyhexoses (l-daunosamine, d-saccharosamine, and l-ristosamine) were prepared from noncarbohydrate starting materials. The short, high-yield syntheses are based on the chemoselective insertion of a rhodium nitrene in an allylic C-H bond rather than in a C-H bond that is alpha to an oxygen substituent.     

Disilylation of N-(2-Halophenyl)-2-phenylacrylamides with hexamethyldisilane via trapping the spirocyclic palladacycles

The palladium-catalyzed disilylation of the spirocyclic palladacycles with hexamethylaisilane has been realized. The key spirocyclic palladacycles are generated from N-(2-haloaryl)-2-arylacrylamide via intramolecular Heck reaction and followed remote C-H activation. A range of 3-((trimethylsilyl)methyl)-3-(2-(trimethylsilyl)phenyl)indolin-2-ones are obtained in good to excellent yields from readily available starting material under mild conditions.     

Theoretical analysis of the mechanism of palladium(II) acetate-catalyzed oxidative Heck coupling of electron-deficient arenes with alkenes: effects of the pyridine-type ancillary ligand and origins of the meta-regioselectivity

A systematic theoretical study is carried out on the mechanism for Pd(II)-catalyzed oxidative cross-coupling between electron-deficient arenes and alkenes. Two types of reaction pathways involving either a sequence of initial arene C-H activation followed by alkene activation, or the reverse sequence of initial alkene C-H activation followed by arene activation are evaluated. Several types of C-H activation mechanisms are discussed including oxidative addition, σ-bond metathesis, concerted metalation/deprotonation, and Heck-type alkene insertion. It is proposed that the most favored reaction pathway should involve an initial concerted metalation/deprotonation step for arene C-H activation by (L)Pd(OAc)(2) (L denotes pyridine type ancillary ligand) to generate a (L)(HOAc)Pd(II)-aryl intermediate, followed by substitution of the ancillary pyridine ligand by alkene substrate and direct insertion of alkene double bond into Pd(II)-aryl bond. The rate- and regio-determining step of the catalytic cycle is concerted metalation/deprotonation of arene C-H bond featuring a six-membered ring transition state. Other mechanism alternatives possess much higher activation barriers, and thus are kinetically less competitive. Possible competing homocoupling pathways have also been shown to be kinetically unfavorable. On the basis of the proposed reaction pathway, the regioselectivity predicted for a number of monosubstituted benzenes is in excellent agreement with experimental observations, thus, lending further support for our proposed mechanism. Additionally, the origins of the regioselectivity of C-H bond activation is elucidated to be caused by a major steric repulsion effect of the ancillary pyridine type ligand with ligands on palladium center and a minor electronic effect of the preinstalled substituent on the benzene ring on the cleaving C-H bond. This would finally lead to the formation of a mixture of meta and para C-H activation products with meta products dominating while no ortho products were detected. Finally, the multiple roles of the ancillary pyridine type ligand have been discussed. These insights are valuable for our understanding and further development of more efficient and selective transition metal-catalyzed oxidative C-H/C-H coupling reactions.     

Thiyl radicals abstract hydrogen atoms from the (alpha)C-H bonds in model peptides: absolute rate constants and effect of amino acid structure

Thiyl radicals are important intermediates in biological oxidative stress and enzymatic reactions, for example, the ribonucleotide reductases. On the basis of the homolytic bond dissociation energies (BDEs) only, the (alpha)C-H bonds of peptides and proteins would present suitable targets for hydrogen abstraction by thiyl radicals. However, additional parameters such as polar and conformational effects may control such hydrogen-transfer processes. To evaluate the potential of thiyl radicals for hydrogen abstraction from (alpha)C-H bonds, we provide the first absolute rate constants for these reactions with model peptides. Thiyl radicals react with (alpha)C-H bonds with rate constants between 1.7 x 10(3) M(-1) s(-1) (N-acetylproline amide) and 4 x 10(5) M(-1) s(-1) (sarcosine anhydride). However, the correlation of rate constants with BDEs is poor. Rather, these reactions may be controlled by conformation and dynamic flexibility around the (alpha)C-H bonds.     

Rh(II)络合物催化分解重氮酰胺和重氮酯的研究

报道了有关二价铑络合物催化的重氮酰胺和重氮酯的分解反应研究 .这些重氮化合物在二价铑催化下所显示的不同反应途径说明铑 (II)卡宾的反应除了电子效应之外 ,还可能受到反应底物的构象控制 .在一些情况下 ,反应底物的构象可能成为控制反应化学选择性的主要因素 .     

Synthesis of Cp-Re complexes via olefinic C-H activation and successive formation of cyclopentadienes

Treatment of an alpha,beta-unsaturated ketimine with an alpha,beta-unsaturated carbonyl compound in the presence of a rhenium complex, Re2(CO)10, gave a cyclopentadienyl-rhenium complex. This reaction proceeds via rhenium-catalyzed C-H bond activation of an olefinic C-H bond, insertion of an alpha,beta-unsaturated carbonyl compound into a Re-C bond of the alkenylrhenium intermediate, intramolecular nucleophilic cyclization, reductive elimination, elimination of aniline to give a cyclopentadiene derivative, followed by the formation of a cyclopentadienyl-rhenium complex from the cyclopentadiene derivative and the rhenium complex.     

Umsetzungen des Tetrakis[bis(trimethylsilyl)methyl]dialans(4) mit Methylisothiocyanat und Phenylisocyanat – Insertion in die Al?Al-Bindung bzw. Fragmentierung

Reactions of Tetrakis[bis(trimethylsilyl)methyl]dialane(4) with Methylisothiocyanate and Phenylisocyanate – Insertion into the Al? Al Bond and Fragmentation Tetrakis[bis(trimethylsilyl)methyl]dialane(4) 1 reacts with methyl isothiocyanate under cleavage of the C?S double bond and insertion of the remaining isonitrile fragment into the Al? Al bond. As shown by crystal structure determination a three-membered AlCN heterocycle ( 4 ) is formed by the interaction of the nitrogen lone pair with one unsaturated Al atom leading to an acute angle at the aluminium center N? Al? C of 36.6°. In contrast the reaction with the hard base phenyl isocyanate yields a mixture of many unknown compounds, from which only one ( 5 ) could be isolated in a very poor yield. The crystal structure of 5 reveals only one dialkyl aluminium fragment and a chelating ligand formed by the trimerization of the isocyanate under loss of one CO group and addition of a hydrogen atom. 5 was also synthesized by the specific reaction of the chloro dialkyl aluminium compound (R = CH(SiMe₃)₂) with Li[H₅C₆? N?C(O)? N(C₆H₅)? C(O)? N(H)? C₆H₅].     

Rh(II)络合物催化分解重氮酰胺和重氮酯的研究

报道了有关二价铑络合物催化的重氮酰胺和重氮酯的分解反应研究。这些重氮 化合物在二价铑催化下所显示的不同反应途径说明铑（II）卡宾的反应除了电子效 应之外，还可能受到反应底物的构象控制。在一些情况下，反应底物的构象可能成 为控制反应化学选择性的主要因素。     

Rhodium(II)-catalyzed carbocyclization reaction of alpha-diazo carbonyls with tethered unsaturation

o-Alkynyl-substituted alpha-diazoketones undergo internal cyclization to produce indenone derivatives upon treatment with catalytic quantities of Rh(II)-carboxylates. A variety of structural influences were encountered by varying the nature of the substituent group attached to the diazo center. The cyclization reaction involves addition of a rhodium-stabilized carbenoid onto the acetylenic pi-bond to generate a cycloalkenone carbenoid. The cyclized carbenoid was found to undergo both aromatic and aliphatic C-H insertion as well as cyclopropanation across a tethered pi-bond. Subjection of diazo phenyl acetic acid 3-phenylprop-2-ynyl ester to Rh(II) catalysis furnished 8-phenyl-1, 8-dihydro-2-oxacyclopenta[a]indenone in high yield. The formation of this compound involves cyclization of the initially formed carbenoid onto the alkyne to produce a butenolide which then undergoes C-H insertion into the neighboring aromatic system. When a vinyl ether is added, the initially formed rhodium carbenoid intermediate can be intercepted by the electron-rich pi-bond prior to cyclization. Different rhodium catalysts were shown to result in significant variation in the product ratios. The competition between bimolecular cyclopropanation, 1,2-hydrogen migration, and internal cyclization was probed using several enol ethers as well as diazoesters which possess different substituent groups on the ester backbone. The specific path followed was found to depend on electronic, steric, and conformational factors.     

Biaryl formation from 5-(2-bromobenzyl)-substituted piperidin-2-ones via palladacycles

The reaction of piperdin-2-ones with a 2-bromobenzyl substituent in the 5-position in the presence of a palladium catalyst leads to biaryl compounds. Their formation can be explained via initial C-H insertion of the aryl palladium species into the allylic C-H bond of the piperidinone. This eventually leads to a metallacycle containing Pd(II) that inserts another aryl bromide, promoting the formation of the biaryl bond.     

Application of Fast Radical Rearrangement in the Mechanistic Investigation of Intramolecular C-H Insertion by Rh(Ⅱ)-Mediated Carbenoids

IntramolecularC-HinsertionbyRh(II)-mediatedcarbenoidhasbecomeareactionofconsiderableimportanceinrecentyears'.InadditiontoitsnumeroussyntheticaPplications',therehavebeenextensiveinvestigationsonthemechanismofthisreaction3.AlthoughithasbeengenerallybeIievedthattheC-Hinsertionproceedsthroughaconcertedmechanism,thesuspicionexistSthatradicalorionicpairsndghtbeinvolvedinthereaction.Forexample,DoyIe"andPirrung,'reportedthattheC-HinsertionscatalyzedbyRh2(O2CCF3)4proceededwithstatisticalproduct…