Elevated Catalytic Activity of Ruthenium(II)–Porphyrin‐Catalyzed Carbene/Nitrene Transfer and Insertion Reactions with N‐Heterocyclic Carbene Ligands

Bis(NHC)ruthenium(II)–porphyrin complexes were designed, synthesized, and characterized. Owing to the strong donor strength of axial NHC ligands in stabilizing the trans M?CRR′/M?NR moiety, these complexes showed unprecedently high catalytic activity towards alkene cyclopropanation, carbene C? H, N? H, S? H, and O? H insertion, alkene aziridination, and nitrene C? H insertion with turnover frequencies up to 1950 min^?1. The use of chiral [Ru(D₄‐Por)(BIMe)₂] ( 1 g ) as a catalyst led to highly enantioselective carbene/nitrene transfer and insertion reactions with up to 98 % ee. Carbene modification of the N terminus of peptides at 37 °C was possible. DFT calculations revealed that the trans axial NHC ligand facilitates the decomposition of diazo compounds by stabilizing the metal–carbene reaction intermediate.     

Synthesis of Di-substituted Proazaphosphatrane and Its Application in Carbon-carbon Double-bond Isomerization

Diisopropyltren was synthesized from the reaction of tren with benzaldehyde in toluene, followed by reducing the imine intermediate with NaBH 4 , and debenzylation catalyzed by 10% Pd/C in methanol. It was then converted to its corresponding azaphosphatrane via ring-closing reaction of HMPT and triflic acid. Deprotonation of azaphosphatrane with potassium t-butoxide afforded the target diisopropyl proazaphosphatrane 1d. A comparative study of compound 1d for isomerization of allylic system and methylene-interrupted diene system revealed that compound 1d is more efficient than its tri-substituted analoque(1b). In acetonitrile at 40 °C, allylaromatics were selectively isomerized to 1-arylpropene generally in an isolated yield more than 95% with trans, cis molar ratios in a range of 87/13 to 96/4. Allyl phenylsulfide was converted to 1-phenylthiopropene(molar ratio of Z/E=54/46) in a yield of 93%―95%. Methylene-interrupted dienes were also isomerized in high yield.     

Synthesis of 6-methyl-6H-indolo[3,2-c]isoquinoline and 6-methyl-6H-indolo[2,3-c]isoquinoline: two new unnatural isoquinoline isomers of the cryptolepine series

11H-indolo[3,2-c]isoquinoline has been synthesized in two steps starting from 4-bromoisoquinoline and 2-bromoaniline via a selective Buchwald-Hartwig reaction followed by a Pd-catalyzed intramolecular direct arylation involving C(sp²)-H activation. The synthesis of 7H-indolo[2,3-c]isoquinoline was achieved by a combination of a Suzuki reaction with an intramolecular nitrene insertion reaction starting from 4-bromoisoquinoline and {2-[(2,2-dimethylpropanoyl)amino]phenyl}boronic acid. Selective methylation of the tetracyclic skeletons yielded the title compounds 6-methyl-6H-indolo[3,2-c]isoquinoline and 6-methyl-6H-indolo[2,3-c]isoquinoline, which have never been described in the literature before.     

Facile and efficient synthesis of 4-azidotetrafluoroaniline: a new photoaffinity reagent

p-Azidotetrafluoroaniline (1) was synthesized in 65-73% yield by two different methods employing a stable carbamate intermediate. The first method trapped the intermediate isocyanate generated via a modified Curtius rearrangement with 2-methyl-2-propanol or 2-(trimethylsilyl)ethanol to form the stable carbamates 2d and 2e, respectively. Benzoic acid 2c was first converted to its acid chloride with PCl(5). Displacement of the chloride by NaN(3) in acetone/water formed the acyl azide. Thermal rearrangement followed by the addition of the appropriate alcohols provided the carbamates. The acid labile carbamate 2d was deprotected with HCl/AcOH to provide 1, while trifluoroacetic acid was required to deprotect 2e and afford 1. In the second path, 1 was synthesized in five steps from pentafluoronitrobenzene (3a) in 65% overall yield. Compound 3a was converted into 4-azidotetrafluoronitrobenzene (3b) with NaN(3) in 93% yield and was used without further purification to form 1, 4-diaminotetrafluorobenzene (3c) by Sn/HCl reduction in 85% yield. The mono-9-fluorenylmethoxycarbonyl (FMOC) derivative 3d was formed from 3c with FMOC-Cl and pyridine in EtOAc in 92% yield. Diazotization of 3d under anhydrous conditions with TFA/NaNO(2) and NaN(3) gave 3e in 87% yield. The aryl azide was formed with concurrent nitration of the 2-position of the fluorenyl system. The protecting group was removed with piperidine to afford 1 in 93% yield. Irradiation of 1 with 254 nm light in cyclohexane gave cyclohexylamine 11, diamine 3c, and azobenzene 12 as the primary products. The formation of C-H insertion product 11 indicates that 1 forms a singlet nitrene upon photolysis. Two heterobifunctional photoaffinity reagents iodoacetamide 9 and dansyl derivative 10 were prepared.     

Nitrenes and the Decomposition of Carbonylazides

The decomposition of organic carbonylazides can lead to the formation of nitrenes. Ethoxycarbonylnitrene is formed in the photolytic and thermal decomposition of ethyl azidoformate and by α-elimination from N-(p-nitrobenzenesulfonyloxy)urethan. Both of the possible electronic states of this nitrene take part in intermolecular reactions. Pure singlet nitrene is formed by α-elimination from the urethan and on thermal decomposition of ethyl azidoformate, but changes so rapidly into the triplet form that the reactions of both forms are observed. Singlet ethoxycarbonylnitrene undergoes selective and stereospecific insertion into C? H bonds and adds stereospecifically to olefins. Triplet ethoxycarbonylnitrene, however, does not undergo insertion into C? H bonds, and adds to olefins with complete loss of the geometric configuration. By following quantitatively the stereospecificity of the addition reaction and by selective interception of the triplet and singlet forms of the nitrene, it can be shown that the photolysis of ethyl azidoformate leads directly to nitrene of which one third is in the triplet state. In the decomposition of aryl- and alkylcarbonylazides (acid azides), the removal of nitrogen is accompanied by a synchronous rearrangement to isocyanates (Curtius rearrangement). In this system, nitrenes are obtained only by photolysis. They add to double bonds and undergo very selective insertion into C? H bonds, but do not rearrange at a measurable rate to isocyanates. The photolytic Curtius rearrangement is also a concerted reaction.     

Novel intramolecular reactivity of oximes: synthesis of cyclic and spiro-fused imines

Under conventional heat (135-145 degrees C) or microwave irradiation and 1 equiv of acetic anhydride, ortho-substituted aryl-oximes undergo a novel sp3 C-H activated cyclization to produce the corresponding isoindoles, and aliphatic oximes afford the corresponding dihydropyrroles. The cyclization occurs with various substrates in good yield (46-82%) leading to unique spiro-fused and cyclic imines. An initial mechanistic investigation suggests the reaction occurs via a nitrenium or vinyl nitrene intermediate. [reaction: see text]     

梳型接枝共聚物的合成（Ⅲ）——氯代乙酸（降冰片稀基）甲酯的制备

从双环戊二烯与烯丙醇进行Diels-Alder反应合成了5－羟甲基2－降冰片烯2，后者在N.N－二甲基苯胺存在下与a－氯代乙酰氯反应，首次合成了氯乙酸降冰片烯甲酯2，考察了反庆条件（温度、反应物摩尔比等）对各步反应收率的影响，并对各步反应产物结构进行表征。     

Uncatalyzed Oxidative C−H Amination of 9,10-Dihydro-9-Heteroanthracenes: A Mechanistic Study

A new method for the one-step C−H amination of xanthene and thioxanthene with sulfonamides is reported, without the need for any metal catalyst. A benzoquinone was employed as a hydride (or two-electron and one-proton) acceptor. Moreover, a previously unknown and uncatalyzed reaction between iminoiodanes and xanthene, thioxanthene and dihydroacridines (9,10-dihydro-9-heteroanthracenes or dihydroheteroanthracenes) is disclosed. The reactions proceed through hydride transfer from the heteroarene substrate to the iminoiodane or benzoquinone, followed by conjugate addition of the sulfonamide to the oxidized heteroaromatic compounds. These findings may have important mechanistic implications for metal-catalyzed C−H amination processes involving nitrene transfer from iminoiodanes to dihydroheteroanthracenes. Due to the weak C−H bond, xanthene is an often-employed substrate in mechanistic studies of C−H amination reactions, which are generally proposed to proceed via metal-catalyzed nitrene insertion, especially for reactions involving nitrene or imido complexes that are less reactive (i.e., less strongly oxidizing). However, these substrates clearly undergo non-catalyzed (proton-coupled) redox coupling with amines, thus providing alternative pathways to the widely assumed metal-catalyzed pathways.     

Mechanistic Insights into the Substrate‐Controlled Stereochemistry of Glycals in One‐Pot Rhodium‐Catalyzed Aziridination and Aziridine Ring Opening

We carried out a principle study on the reaction mechanism of rhodium‐catalyzed intramolecular aziridination and aziridine ring opening at a sugar template. A sulfamate ester group was introduced at different positions of glycal to act as a nitrene source and, moreover, to allow the study of the relative reactivity of the nitrene transfer from different sites of the glycal molecule. The structural optimization of each intermediate along the reaction pathway was extensively done by using BPW91 functional. The crucial step in the reaction is the Rh‐catalyzed nitrene transfer to the double bond of the glycal. We found that the reaction could proceed in a stepwise manner, whereby the N atom initially induced a single‐bond formation with C1 on the triplet surface or in a single step through intersystem crossing (ISC) of the triplet excited state of the rhodium–nitrene transition state to the singlet ground state of the aziridine complexes. The relative reactivity for the conversion of the nitrene species to the aziridine obtained from the computed potential energy surface (PES) agrees well with the reaction time gained from experimental observation. The aziridine ring opening is a spontaneous process because the energy barrier for the formation of the transition state is very small and disappears in the solution calculations. The regio‐ and stereoselectivity of the reaction product is controlled by the electronic property of the anomeric carbon as well as the facial preference for the nitrene insertion, and the nucleophilic addition.     

Chemoselective Intramolecular Formal Insertion Reaction of Rh–Nitrenes into an Amide Bond Over C−H Insertion

The past few decades have witnessed extensive efforts to disclose the unique reactivity of metal–nitrenes, because they could be a powerful synthetic tool for introducing the amine functionality into unactivated chemical bonds. The reactivity of metal–nitrenes, however, is currently mainly confined to aziridination (an insertion into a C=C bond) and C−H amination (an insertion into a C−H bond). Nitrene insertion into an amide C−N bond, however, has not been reported so far. In this work we have developed a rhodium-catalyzed one-nitrogen insertion into amide C−N and sulfonamide S−N bonds. Experimental and theoretical analyses based on density functional theory indicate that the formal amide insertion proceeds via a rhodium-coordinated ammonium ylide formed between the nitrene and the amide nitrogen, followed by acyl group transfer concomitant with C−N bond cleavage. Mechanistic studies have allowed rationalization of the origin of the chemoselectivity observed between the C−H and amide insertion reactions. The methodology presented herein is the first example of an insertion of nitrene into amide bonds and provides facile access to unique diazacyclic systems with an N−N bond linkage.     

The Reaction of Tin Tetracarbamates with Organyl Chlorosilanes: A Novel Synthetic Route Towards O-Silylurethanes

Russian Journal of General Chemistry - O-Silylurethanes have been synthesized in up to 87% yield via the reaction of tin tetracarbamates with organyl chlorosilanes in the presence of tertiary amines.     

Synthetic studies on indolocarbazoles: total synthesis of staurosporine aglycon

A synthesis of staurosporine aglycon and its analogs was achieved in a 28-36% overall yield starting from 2-methylindole. The prominent key steps for the synthesis of the indolocarbazole alkaloids involved electrocyclization and nitrene insertion reactions.     

Total synthesis of oxidized welwitindolinones and (-)-N-methylwelwitindolinone C isonitrile

We report the total synthesis of (-)-N-methylwelwitindolinone C isonitrile, in addition to the total syntheses of the 3-hydroxylated welwitindolinones. Our routes to these elusive natural products feature the strategic use of a deuterium kinetic isotope effect to improve the efficiency of a late-stage nitrene insertion reaction. We also provide a computational prediction for the stereochemical configuration at C3 of the hydroxylated welwitindolinones, which was confirmed by experimental studies.     

A facile and efficient carbocatalytic route to quaternary C-bearing N-tosylaziridines from Morita-Baylis-Hillman adduct in water

Graphene oxide (GO)/GO-I₂ co-catalyzed green synthesis of tosylaziridine bearing keto and nitrile/ester functional groups is reported. The strategy involves sequential GO-catalyzed oxidation of benzylic alcohol and GO-I₂ catalyzed nitrene insertion into olefin of Morita-Baylis-Hillman adduct. Operational simplicity, use of water as solvent, ambient reaction conditions, excellent yield of products (88–96%) and recyclability of catalyst up to five times without any substantial change in morphology as well as catalytic efficiency are the salient features of the envisaged protocol.     

Non‐isocyanate synthesis and application of telechelic polyurethanes via polycondensation of diurethanes obtained from ethylene carbonate and diamines

Aliphatic polyurethanes could be obtained in high yield via a non‐isocyanate method based on the self‐polycondensation of dihydroxyurethanes obtained by the reaction of diamines and ethylene carbonate. The polycondensation under a N₂ atmosphere yielded [6,2]polyurethane with a M_n value of 5300 in 87% yield. Two‐step polycondensation, consisting of the polycondensation under a N₂ atmosphere followed by that under reduced pressure, was effective to improve the yield and the molecular weight up to 90% and 10,000, respectively. Although the second polycondensation step at 180 °C was accompanied by formation of urea groups, this side reaction was relatively suppressed at 150 °C. The resulting polyurethane having hydroxyl groups at both of the end groups was converted to polyurethane methacrylate via a reaction with glycidyl methacrylate, and the polyurethane methacrylate served as a crosslinker for radical polymerization of methyl acrylate. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Synthesis of L-epi-capreomycidine derivatives via C-H amination

The L-epi-capreomycidine (Cpm) derivatives were efficiently and stereoselectively synthesized via nitrene C-H insertion starting from a readily available D-Tyr. Design of a substrate that takes into account hydrogen bonding is a critical feature in order to achieve high selectivity. Our synthetic strategy could be a new access to epi-Cpm and its derivatives, which are found in several biologically active natural products.     

Facile amine formation by intermolecular catalytic amidation of carbon-hydrogen bonds

A simple copper-based catalytic system has been developed for the carbon-hydrogen amidation reaction. The copper-homoscorpionate complex Tp(Br3)Cu(NCMe) catalyzes the transfer of the nitrene unit NTs (Ts = p-toluenesulfonyl) and its subsequent insertion into the sp(3) C-H bonds of alkyl aromatic and cyclic ethers or the sp(2) C-H bonds of benzene using PhI=NTs as the nitrene source, affording the corresponding trisubstitued NR(1)HTs amines in moderate to high yields. The use of the environmentally friendly chloramine-T has also proven effective, with the advantage that sodium chloride is formed as the only byproduct. A tandem, one-pot consecutive nitrene-carbene insertion system has been developed to yield amino acid derivatives.     

A DFT Study on the Mechanism of Rh2II,II‐Catalyzed Intramolecular Amidation of Carbamates

The potential‐energy surfaces of the reactions of dirhodium tetracarboxylate (Rh₂^II,II) catalyzed nitrene (NR) insertion into C H bonds were examined by a DFT computational study. A pure Becke exchange functional (B88) rather than a hybrid exchange functional (B3, BHandH) was found to be appropriate for the calculation of the energy difference between the singlet and triplet Rh₂^II,II–NH nitrene species. Rh₂^II,II–NR¹ (R¹=(S)‐2‐methyl‐1‐butylformyl) is thermodynamically more favorable with a free energy lower than that of Rh₂^II,II–N(PhI)R¹. The singlet and triplet states of Rh₂^II,II–NR¹ have similar stability. Singlet Rh₂^II,II–NR¹ undergoes a concerted NR insertion into the C H bond with simultaneous formation of the N H and N C bonds during C H bond cleavage; triplet Rh₂^II,II–NR¹ undergoes H atom abstraction to produce a diradical, followed by subsequent bond formation by diradical recombination. The singlet pathway is favored over the triplet in the context of the free energy of activation and leads to the retention of the chirality of the C atom in the NR insertion product. The reactivities of the C H bonds toward the nitrene‐insertion reaction follow the order tertiary>secondary>primary. Relative reaction rates were calculated for the six reaction pathways examined in this work.     

Short synthesis of carbazole alkaloids: Ekeberginine,murrayaquinone A,and glycozoline

Three differently substituted, naturally occurring, biologically active carbazole derivatives (viz. ekeberginine, murrayaquinone A, and glycozoline) were synthesized in good yield using short and simple routes. The prenyl group was selectively introduced at the C4 position using a Stille coupling reaction in the synthesis of ekeberginine. Murrayaquinone A was synthesized using Raney nickel–mediated desulfurization of dithiane as a key step. Synthesis of glycozoline was achieved in two steps from 3-methyl carbazole via an intermediate 3-bromo-6-methyl carbazole.     

Encapsulation and dynamic behavior of two H2 molecules in an open-cage C70

An open-cage C70 derivative having a 13-membered ring opening (2) was synthesized by a three-step reaction; thermal reaction of C70 with a pyridazine derivative, oxidative cleavage of the CC double bond, and insertion of a sulfur atom to the opening. The structure of 2 was determined by X-ray analysis. One H2 molecule was introduced into 2 to give H2@2 in 97% yield. Furthermore, two H2 molecules were encapsulated in 2 in 3% yield. The positional exchange of two H2 molecules inside 2 was clearly observed by the dynamic low-temperature NMR measurements.