Diazo Carbon Atom Research Articles

Synthetic and Computational Studies on RhIII-Catalyzed Redox-Neutral Cascade of Carbenoid Functionalization and Dephosphonylative Annulation.

A Rh(III)-catalyzed regioselective redox-neutral cascade process of carbenoid functionalization followed by dephosphonylative annulation of benzoic acids with α-diazo-β-keto phosphonate has been realized, which led to the direct synthesis of a privileged 3-substituted isocoumarin scaffold. To the best of our knowledge, this is the first report of a complete redox neutral method to synthesize isocoumarins using C-H functionalization strategy. In the catalytic cycle of this reaction, there are two possible pathways for the C-C coupling between ortho-positioned carbon atom of benzoic acid and the diazo carbon atom: (i) concerted 1,2-aryl shift and (ii) stepwise metal-carbene formation followed by migratory insertion. DFT study has predicted that the concerted pathway has lower activation energy as compared to the stepwise pathway by 1.5 kcal/mol.

Rearrangements in radical cations of diazoketones: A DFT mechanistic study

Abstract The mechanism of the Wolff rearrangement of some radical cations of diazocarbonyl compounds has been studied using density functional calculations. The C C bond of diazoketones weakens slightly on cation formation, which lowers the barrier to the syn-anti isomerization of the radical cations, as compared to that of the neutral analogue. The effect of substitution on both carbonyl carbon and diazocarbon of the diazoethanal radical cation has been explored. The planarity of the syn and anti conformers is lost on reduction of diazoketones, and in most of the cases of substitution at the carbonyl carbon, the diazo moiety is out of the plane of the C O group. The 1, 2-rearrangement of radical cations preferably takes place in a stepwise manner, which involves the oxirene radical cation as an intermediate. The oxirene radical cation rearranges to the final product, the ketene radical cation, without any energy barrier. However, the carbene radical cation is involved in the Wolff rearrangement of the diazoethanal radical cation substituted at the diazocarbon atom by Ph, OMe or NH2.

The Mechanism of Action of (-)-Lomaiviticin A.

(-)-Lomaiviticin A (4) is a complex C2-symmetric bacterial metabolite that contains two diazofluorene functional groups. The diazofluorene consists of naphthoquinone, cyclopentadiene, and diazo substituents fused through a σ- and π-bonding network. Additionally, (-)-lomaiviticin A (4) is a potent cytotoxin, with half-maximal inhibitory potency (IC50) values in the low nanomolar range against many cancer cell lines. Because of limitations in supply, its mechanism of action had remained a "black box" since its isolation in the early 2000s. In this Account, I describe how studies directed toward the total synthesis of (-)-lomaiviticin A (4) provided a platform to elucidate the emergent properties of this metabolite and thereby connect chemical reactivity with cellular phenotype. We first developed a convergent strategy to prepare the diazofluorene (9 + 10 → 13). We then adapted this chemistry to the synthesis of lomaiviticin aglycon (21/22) and the natural monomeric diazofluorene (-)-kinamycin F (3). The key step in the lomaiviticin aglycon (21/22) synthesis involved the stereoselective oxidative coupling of two monomeric diazofluorenes (2 × 18 → 20) to establish the cojoining carbon-carbon bond of the target. As the absolute stereochemistry of the aglycon and carbohydrate residues of (-)-lomaiviticin A (4) were unknown, we developed a semisynthetic route to the metabolite that proceeds in one step and 42% yield by diazo transfer to the more abundant isolate (-)-lomaiviticin C (6). This allowed us to complete the stereochemical assignment of (-)-lomaiviticin A (4) and provided a renewable source of material. Using this material, we established that the remarkable cytotoxic effects of (-)-lomaiviticin A (4) derive from the induction of highly toxic double-strand breaks (DSBs) in DNA. At the molecular level, 1,7-nucleophilic additions to each electrophilic diazofluorene trigger homolytic decomposition pathways that produce sp2 radicals at the carbon atoms of each diazo group. These radicals abstract hydrogen atoms from the deoxyribose of DNA, a process known to initiate strand cleavage. NMR spectroscopy and molecular mechanics simulations were used to elucidate the mode of DNA binding. These studies showed that both diazofluorenes of (-)-lomaiviticin A (4) penetrate into the duplex. This mode of non-covalent binding places each diazo carbon atom in close proximity to each DNA strand. Throughout these studies, isolates containing one diazofluorene, such as (-)-lomaiviticin C (6) and (-)-kinamycin C (2), were used as controls. Consistent with our mechanistic model, these compounds do not induce DSBs in DNA and are several orders of magnitude less potent. Reactivity studies suggest that (-)-lomaiviticin A (4) is more electrophilic than simple monomeric diazofluorenes. We attribute this to through-space delocalization of the developing negative charge in the transition state for 1,7-addition. Consistent with this mechanism of action, (-)-lomaiviticin A (4) displays selective low-picomolar potencies toward DNA DSB repair-deficient cell types. The emergent properties of (-)-lomaiviticin A (4) derive from the specific arrangement of diazo, naphthoquinone, cyclopentadiene, and ketone functional groups. These functional groups work together to yield, essentially, a masked vinyl radical that can be exposed under biological conditions. Furthermore, the rotational symmetry of the metabolite, deriving from dimerization, allows it to interact with the antiparallel symmetry of DNA and affect cleavage of the duplex.

Cyclization of α‐Diazo Esters Triggered by Oxidation: A Facile Preparation of 5‐Aryl‐2,3‐dihydrofuran‐4‐carboxylates

AbstractA method for the preparation of 5‐aryl‐2,3‐dihydrofuran‐4‐carboxylates has been developed. Exposure of 4‐(arylmethyl)oxy‐2‐diazobutyrates to 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) effected oxidative generation of oxocarbenium intermediates, which underwent intramolecular attack of the diazo carbon atom and subsequent β‐elimination to give 5‐aryl‐2,3‐dihydrofurancarboxylates in modest to good yields. In particular, tertiary arylmethyl ethers offer the advantages of enhanced reactivity toward DDQ and higher product yields due to a Thorpe−Ingold effect. To demonstrate the synthetic utility of the cyclization reaction, selective transformations of an aromatization‐prone dihydrofuran product are also described.

Kinetics and mechanism of acid-catalyzed hydrolysis of the diazo functional groups of 1-diazo-2-indanone and 2-diazo-1-indanone in aqueous solution

Rates of hydrolysis of 1-diazo-2-indanone and 2-diazo-1-indanone were measured in dilute aqueous perchloric acid solutions using both H2O and D2O as the solvent, and rates of hydrolysis of the latter substrate were measured in dilute aqueous (H2O only) formic acid buffer solutions as well. The data for 1-diazo-2-indanone gave the hydronium ion catalytic coefficient kH+ = 5.7 × 10–3 (mol/L)–1 s–1 and the isotope effect kH+/kD+ = 2.9. The normal direction (kH/kD > 1) of this isotope effect was taken as evidence for a reaction mechanism involving rate-determining hydron transfer from the hydronium ion to the substrate's diazo carbon atom; followed by rapid displacement of diazo nitrogen by a water molecule, giving the observed 1-hydroxy-2-indanone product. The data for 2-diazo-1-indanone, on the other hand, gave a hydronium ion catalytic coefficient two orders of magnitude greater than the value for 1-diazo-2-indanone (kH+ = 5.9 × 10–1 (mol/L)–1 s–1), and an isotope effect near unity (kH+/kD+ = 1.2). It is argued that this isotope effect represents a situation in which diazo carbon hydronation and displacement of diazo nitrogen are each partly rate determining, a conclusion supported by incipient saturation of buffer catalysis in the formic acid buffer solutions. The 100-fold difference in hydronium ion catalytic coefficients for the two substrates is rationalized in terms of differing electron densities on the diazo carbon atoms.Key words: diazo compound hydrolysis, solution kinetics, acid catalysis, solvent isotope effects, buffer catalysis saturation.

How nucleophilic are diazo compounds?

The kinetics of the reactions of benzhydryl cations with eight diazo compounds 1 a-g were investigated photometrically in dichloromethane. The nucleophilicity parameters N and slope parameters s of these diazo compounds were derived from the equation log k (20 degrees C)=s (E+N) and compared with the nucleophilicities of other pi systems (alkenes, arenes, silyl enol ethers, silyl ketene acetals). It is shown that the nucleophilic reactivities of diazo compounds cover more than ten orders of magnitude, being comparable to that of styrene on the low reactivity end and to that of enamines on the high reactivity end. The rate-determining step of these reactions is the electrophilic attack at the diazo-carbon atom to yield diazonium ions, which rapidly lose nitrogen.

Kinetics and mechanism of acid‐catalyzed hydrolysis of the diazo functional group of diazophenylacetamide

AbstractThe acid‐catalyzed hydrolysis of diazophenylacetamide giving mandelamide as product was found to occur with a normal (kH/kD>1) hydronium ion isotope effect and to be subject to general acid rather than specific hydronium ion catalysis. This shows that the reaction occurs by rate‐determining hydron transfer from the catalyzing acid to the diazo carbon atom of the substrate, followed by rapid displacement of the diazo group by water. Comparison of the rate of this reaction with those of the same process for other diazophenylacetic acid functional derivatives, PhCN2COX, reveals that the reactivity of these substrates is controlled by the electron‐releasing resonance ability of the group X. Copyright © 2003 John Wiley & Sons, Ltd.

Kinetics and mechanism of hydrolysis of 3-diazobenzofuran-2-one and its hydrolysis product (3-hydroxybenzofuran-2-one)

Rates of acid-catalyzed hydrolysis of 3-diazobenzofuran-2-one, measured in concentrated aqueous perchloric acid and hydrochloric acid solutions, were found to correlate well with the Cox–Yates Xo excess acidity function, giving kH+ = 1.66 × 10–4 M–1 s–1, m‡ = 0.86 and kH+ /kD+ = 2.04. The normal direction (kH/kD > 1) of this isotope effect indicates that hydrolysis occurs by rate-determining protonation of the substrate on its diazo-carbon atom. It was found previously that the next higher homolog of the present substrate, 4-diazoisochroman-3-one, also undergoes hydrolysis by this reaction mechanism but with a rate constant 15 times greater than that for the present substrate; this difference in reactivity can be understood in terms of the various resonance forms that contribute to the structures of these substrates. The product of the present hydrolysis reaction is 3-hydroxybenzofuran-2-one, which itself quickly undergoes subsequent acid-catalyzed hydrolysis to 2-hydroxymandelic acid. The acidity dependence of this subsequent hydrolysis is much shallower than that of the diazo compound precursor, and rates of reaction correlate as well with [H+] as with Xo. This is due in part to incursion of a nonproductive protonation on the hydroxy group of 3-hydroxy benzo furan-2-one that impedes hydrolysis and produces saturation of acid catalysis. Rates of hydrolysis of the hydroxy compound were also measured in dilute HClO4 and NaOH solutions as well as in CH3CO2H, H2PO4–, (CH2OH)3CNH3+, and NH4+ buffers, and the rate profile constructed from these data showed the presence of uncatalyzed and hydroxide ion-catalyzed reactions. This hydroxide-ion catalysis became saturated at [NaOH] [Formula: see text] 0.05 M, implying occurrence of yet another nonproductive substrate ionization. Key words: diazo compound hydrolysis, lactone hydrolysis, Cox–Yates excess acidity, acid catalysis, alcohol protonation.

Acid-catalyzed hydrolysis of 4-diazo-isothiochroman-3-one. Comparison with the acyclic analog and the corresponding oxygen system

The acid-catalyzed hydrolysis of the cyclic diazothiolactone, 4-diazoisochroman-3-one (3) was found to occur with the hydronium-ion isotope effect, [Formula: see text] and to give the ring-contracted product, 1,3-dihydrobenzo[c]thiophene-1-carboxylic acid (4). This shows that protonation of the diazo carbon atom occurs in the rate-determining step and that the reaction also involves migration of the thio group. The hydronium-ion catalytic coefficient for this reaction, [Formula: see text], is 45 times less than that for hydrolysis of its acyclic thio ester analog, S-methyl phenyldiazothioacetate (5). Semiempirical AM1 molecular orbital calculations support the idea that this difference in reactivity is the result of increased delocalization of negative charge into the aromatic ring in the case of the cyclic substrate, which reduces the negative charge on the diazo carbon atom and makes it less susceptible to protonation. Key words: hydrolysis, diazoalkanes, charge delocalization, AM1 calculations, thio group migration.

Acid‐catalyzed hydrolysis of phenyldiazoacetic acid. Effect of an α‐diazo group on carboxylic acid acidity

AbstractRates of acid‐catalysed hydrolysis of phenyldiazoacetic acid were measured in aqueous solution at 25°C across the entire acidity range pC = 1–13. The reaction was found to occur through both the non‐ionized and inonized forms of the substrate, with the ionized form reacting faster by a factor of 650. Appreciable solvent isotope effects in the normal direction (kH/kD > 1) and the occurrence of general acid analysis show that hydrolysis occurs by rate‐determining proton transfer to the diazocarbon atom of the substrate. Analysis of the rate profile for the reaction provides an estimate of the acidity constant of phenyldiazoacetic acid, pKa = 3·70, which is apparently the first determination of the acid strength of an α‐diazocarboxylic acid. Comparison of this result with the pKa of phenylacetic acid shows the diazo group to have a mild (4×) acid‐strengthening effect, whose modest magnitude is attributed to opposing resonance and polar effects.

Methylthio group migration in the acid-catalyzed hydrolysis of S-methyl phenyldiazothioacetate. Kinetics and mechanism of the reaction

The acid-catalyzed hydrolysis of S-methyl phenyldiazothioacetate, C 6 H 5 C(=N 2 )COSCH 3 , in aqueous solution at 25 o C was found to occur with the hydronium ion isotope effect k H+ +k D+ =3.08 and to give a Bronsted relation, based on carboxylic acid catalysts, whose exponent is α=0.70. This is taken to mean that the reaction occurs by rate-determining proton transfer to the diazo carbon atom. The principal product of the reaction, however, is α-(methylthio)-α-phenylacetic acid, C 6 H 5 CH(SCH 3 )-CO 2 H, which must be formed by 1,2-shift of the methylthio group

A kinetic study of the reaction of diazoalkanes with triphenylphosphine: structure and reactivity in a biphilic process

Second-order rate coefficients and activation parameters are reported for the reaction in solution of triphenylphosphine with a series of diazoalkanes (Ar2CN2) having two aromatic groups attached to the diazo-carbon atom, 9-diazofluorene (DAF), 5-diazo-5H-dibenzo[a,d]cycloheptene (DBSE), its 10,11-dihydro analogue (DBSA), and diazodiphenylmethane (DDM). Although the product phosphazine Ar2CNNPPh3 arises formally by nucleophilic attack of phosphorus on the terminal nitrogen atom of the diazoalkane, the pattern of reactivity approximates to that for proton transfer from acetic acid to the diazoalkane under similar conditions, highlighting the biphilic nature of the reaction. The results can be rationalised in terms of qualitative FMO theory taking into account both HOMO(Ph3P)–LUMO (Ar2CN2) and HOMO(Ar2CN2)–LUMO (Ph3P) interactions. This is lent qualified support by MNDO calculations on Ar2CN2 based on molecular parameters from the X-ray crystal structure of DAF itself and of the ketones corresponding to DBSE, DBSA, and DDM.The reactivity of DDM and the effect of 4,4′-disubstitution by CH3O–, CH3–, and Cl–, which gives rise to a U-shaped Hammett ρσ correlation, is not easily interpreted within the FMO framework. Conformational changes which affect the interacting orbitals as the reactants are transformed into transition states offer an alternative interpretation.

Nucleophile-induced cyclisation of 2-diazo-2′-thiocyanatoacetophenone: 2-(cyanohydrazono)- and 2-(triphenylphosphoranylidenehydrazono)benzo[b]thiophen-3(2H)-one

2-Diazo-2′-thiocyanatoacetophenone (Va) dissolves in cold dilute alkali and acidification of the solution provides 2-(cyanohydrazono)benzo[b]thiophen-3(2H)-one (IXa). The potassium salt of the latter, obtained by the interaction of the diazo-ketone and potassium cyanide, on acidic hydrolysis gives 2-semicarbazonobenzo[b]-thiophen-3(2H)-one(IXc), identical with that obtained by condensing 2,2-dibromobenzo[b]thiophen-3(2H)-one (VIIc) with semicarbazide. With triphenylphosphine the diazo-ketone gives the expected adduct, which on brief boiling with methanol suffers elimination of hydrocyanic acid to provide 2-(triphenylphosphoranylidene-hydrazono)benzo[b]thiophen-3(2H)-one (VIIIb). The potassium salt of 2-(cyanohydrazono)indane-1,3-dione (IIb) is obtained by an analogous reaction of potassium cyanide with 2-diazo-2′-(methoxycarbonyl)-acetophenone, the triphenylphosphine adduct of which, however, did not cyclise. It is suggested that these cyclisations proceed by nucleophilic attack at the terminal nitrogen atom of the diazo-function rather than by deprotonation of the diazo-carbon atom.

Struktur und reaktivität aliphatischer diazoverbindungen—XI. Untersuchungen zum mechanismus der elektrochemischen oxydation aliphatischer diazoverbindungen, Teil 2

In continuation of the polarographic, oscillopolarographic and coulometric studies described in Part 1, the electrochemical oxidations of 1-diazo-2.3.4.5-tetraphenylcyclopentadiene (A), p-phenyl-diphenyldiazomethane (B), diphenyldiazomethane (C), p-nitro-diphenyldiazomethane (D), p-nitrophenylmethyl-diazomethane (E), p-nitrophenyl-diazomethane (F), 9-diazofluorence (G), phenyl-benzoyl-diazomethane (H) and p-nitrophenyl-benzoyl-diazomethane (J) have been investigated in LiClO 4/acetonitrile solution by measurements at a rotating platinum ring-disk electrode and by recording the Kalousek polarograms. In comparison with the reversible anodic wave of diphenylpicrylhydrazyle at +0.69 V(sce) the electrochemically initiated chain reaction of the aromatic substituted diazomethane derivatives B to G causes a considerable degradation of the shielding efficiency S of the ring-disk electrode. This is an example for the fact that, in addition to the collection efficiency N, the value of S can also be used as criterion of the mechanism of an electrode reaction. Because the lifetime of the primary electrochemical products is diminished by irreversible reactions, a degradation of the collection efficiency N has also been observed. The graduation of the stability of the diazonium radical ions II following from the values of N is confirmed by the quotients i cath/ i anod of the Kalousek polarograms and can be explained qualitatively by mesomeric and inductive effects of the substituents bonded to the diazo carbon atom. Current/potential curves of diphenyl-diazomethane, measured at the rotating platinum ring-disk electrode and at the rotating disk electrode using a Kalousek commutator, are discussed.

The mechanism of the conversion of o-nitrobenzoyldiazomethane to N-hydroxyisatin

The acid-catalyzed conversion of o-nitrobenzoyldiazomethane (I) to N-hydroxyisatin (V) has been studied by following the fate of the diazo carbon atom in I which was labelled with C 14. Degradation of V showed that all the C 14 was in the C 2-position, thus establishing that a Wolff-type rearrangement of I (via a ketene intermediate) was not involved in the formation of V. A mechanism for the rearrangement of I to V, differing in important details from the mechanism previously proposed by Moore, 3 has been advanced.