Mass spectra of substituted uracils

The mechanisms for the major fragmentations obtained with selected substituted uracils are discussed. Interpretation of data was facilitated by use of metastable peaks, high-resolution data, and low-voltage spectra. The major fragmentation obtained with N-alkyl substituted uracils, when the alkyl group contains 2 or more carbons, is due to cleavage of the alkyl substituent. This cleavage is accompanied by a rearrangement of 1 or 2 hydrogens from the alkyl group to the uracil ring. Possible mechanisms for the rearrangements are discussed. It was found that the molecular ion of 1- and 3-alkyl substituted uracils (where the alkyl group has 2 or more carbons) does not undergo the expected ‘retro Diels-Alder Reaction’. Instead, the odd-electron ion formed by loss of the alkyl substituent with a single hydrogen rearrangement undergoes this reaction (loses HNCO). Since it is formed as a secondary reaction product, the relative abundance of the ‘retro Diels-Alder’ fragment is low compared to what is obtained in the spectra of the simple uracils. The ‘retro Diels-Alder Reaction’ can be used to differentiate between 2- and 4-thiouracils, and between 1- and 3-methyl and phenyl substituted uracils. It was found that 1- and 3-alkyl substituted uracils (alkyl group of 2 or more carbons) can be differentiated by the mass of the M-alkyl fragment since the 3-substituted compounds give predominantly a double hydrogen rearrangement and the 1-substituted compound gives mainly a single hydrogen rearrangement. In addition the intensity of the molecular ion, relative to the M-alkyl ion, is considerably stronger in the 1-substituted uracils.     

Phosphates D'énols: XI—Étude en Spectrométrie de Masse des Dérivés Diméthyliques

The mass spectrometric study of a series of enolic phosphates of type A leades to fragmentation patterns influenced by the nature of the substituents (R, R′ and R″). It is generally observed that a simple or double hydrogen rearrangement occurs with the loss of the enolic groups. When R and R′ are alkyl groups, the migrating groups are the hydrogen atoms on the alkyl group at position 1. When there is no alkyl group at position 1, the hydrogen atoms of the alkyl group at position 2 induce the rearrangement process. Finally, if R, R′ and R″ are hydrogen atoms, the loss of the enolic chain occurs without any rearrangement.     

Nucleophilic 1,2-Shifts of Carboxamide Groups in the Benzil-Benzilic Acid Type Rearrangement of 4-Aryl-2,3-dioxobutyramides and of Quinisatine

4-Aryl-2,3-dioxobutyramide hydrates 1 , undergo the benzil-benzilic acid rearrangement to form (substituted) benzyltartronate monoamides 2 . For compound 1a (Ar = Ph), it is demonstrated by isotopic labelling that the reaction occurs exclusively by migration of the CONH₂ group. Kinetic measurements with 1a-c and with the cyclic amide quinisatine 6 show that the rearrangement of the carboxamide group, proceeding via an alkali-catalysed step, can reach a plateau in the k_obs./[OH^?] diagram (cf. the Fig.), due to complete formation of a mono-anion, and a further increase of rate attributable to the rearrangement of a bis-anion. Comparisons suggest that rearrangements involving an amide group are slower than those involving an ester group, and that, for this effect (as for others), the pre-equilibrium deprotonation of the hydrate is more important than a specific migration tendency.     

DFT study on the reaction mechanism and regioselectivity for the [1,2]-anionic rearrangement of 2-benzyloxypyridine derivatives

The reaction mechanism of the [1,2]-anionic rearrangement of 2-benzyloxypyridines has been investigated using DFT calculations. Calculated results indicate that: the deprotonation step is relatively fast and the rearrangement step is the rate-determining step; electron-donating group on the benzene ring decreases the activation energy of the rearrangement, which correlates with an increase in reaction yield, while electron-withdrawing groups show the opposite effect. The rearrangement is calculated to proceed by way of an oxirane-like transition state that had previously been postulated as a transient intermediate. Furthermore, the mechanism for the rearrangement of 2-(benzyloxy)nicotinonitrile was discussed. The quick formation of the five membered ring intermediate leads to the predominant formation of 2-phenylfuro[2,3-b]pyridin-3-amine. The calculation results indicate the possibilities of derivatizing the starting pyridyl ether as well as facilitating the rearrangement reaction by adding an appropriate electron-donating group on the benzene ring or electron-withdrawing group on the pyridine ring for future studies.     

Direct Trapping of Ketene Intermediate by Internal Nucleophile:A New Approach for the Synthesis of γ-Lactams

The application of Wolff rearrangement of the diazoketones derived from α-amino acids has been well documented.¹ It has been generally observed that if the rearrangement is performed in aqueous solution, homologated acid is the expected products, while if the reaction is run in methanol or ammonia, the corresponding homologated ester or amide will be obtained. In connection with other synthetic work, we unexpectedly observed that the Wolff rearrangement of diazoketone 1 in anhydrous methanol gave exclusively γ-lactam 3 in excellent yield.(Scheme 1) The formation of this intramolecular cyclization product was apparently due to the nucleophilic attack of the intermediate ketene 2 by the tosyl protected amino group. Although the solvent methanol can serve as nucleophile, the exclusive formation of γ-lactam indicates the intermolecular nucleophilic attack of the ketene intermediate 2 by methanol is not effective enough to compete with intramolecular nucleophilic attack by the tosyl protected amino group. This observation aroused our interest in the generality of this reaction and its potential as a novel method for the direct synthesis of γ-lactams. We report here the results of the investigation of Wolff rearrangement of several diazoketones derived from N-tosyl protected α-amino acids and β-amino acids.     

Tandem mass spectrum of a growth hormone secretagogue: Amide bond cleavage and resultant gas-phase rearrangement

Compound 1 [N-[1(R)-[(1,2-dihydro-1-methylsulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide](MW 528) is an orally-active growth hormone secretagogue (GHS). As part of a continual effort to analyze the ESI/MS and MSn data of novel drugs, the ESI/MS and MS/MS data of protonated 1 (m/z 529) are analyzed and reported here. The analyses reveal that under low-energy collision-induced dissociation (CID) in an ion trap or a quadrupole collision cell, protonated 1 undergoes a gas-phase rearrangement to form protonated 3 (m/z 357) which competes with the y- and b-type product ions during the amide bond cleavages of protonated 1. It is proposed that when the b-type ion is formed by cleavage of the piperidine amide bond, piperidine (a neutral species) and the b-ion (a cation) form an ion-neutral complex. In this complex, piperidine functions as a nucleophile to attack the benzylic carbon of the b-ion, and the protonated ether group in the b-ion acts as a leaving group, which results in the migration of the benzylic group to the piperidine amine to form protonated 3. Protonated 2 (an analog of 1) was studied under the same experimental conditions. The results show that protonated 2 undergoes a similar rearrangement to form protonated 3. While this rearrangement is a relatively minor fragmentation process for protonated 1, it is a predominant process for protonated 2. This phenomenon is explained in terms of the proposed ion-neutral-complex mechanism.     

Entropy-driven rearrangement of the water network at the hydrated amide group of the trans-formanilide-water cluster in the gas phase

Photoionization-induced rearrangement of the water network in the trans-formanilide 1:4 cluster, FA-(H(2)O)(4), has been investigated by using IR-photodissociation spectroscopy and quantum chemical calculations. The IR spectrum of FA-(H(2)O)(4) in the S(0) state shows that the observed cluster has a cyclic hydrogen-bonded structure where the CO group and the NH group of FA are bridged with four water molecules, consistent with the reported structure [E. G. Robertson, Chem. Phys. Lett., 2000, 325, 299]. However, the corresponding cyclic hydrogen-bonded structure in the D(0) state of [FA-(H(2)O)(4)](+) is a minor product arising from photoionization via the S(1)-S(0) origin of FA-(H(2)O)(4). The dominant product has an extended H-bonded structure, where the intermolecular hydrogen bond between the hydrogen of the OH group of a water molecule and the CO group is dissociated. This is the first observation of a photoionization-induced rearrangement of the water network in [FA-(H(2)O)(4)](+). Through DFT calculations, we conclude that the rearrangement occurs due to entropic effects.     

Hydroxy-beta-thiolactams to oxazole-2-thiones. A novel DMSO-promoted oxidation

3-Aryl-3-hydroxy-1-methylazetidine-2-thiones react with HCl in DMSO to give 3-methyl-5-aryloxazole-2-thiones. Substituent effects correlate with rate effects on hydrolyses of acetals of benzaldehyde. An (17)O labeling experiment indicates that the oxygen atom of the product is derived from the hydroxyl group. Trifluoroacetic anhydride/DMSO in CH2Cl2 can also promote the reaction. Mechanisms involving a Grob-type fragmentation of an activated substrate, followed by recyclization, or a cyclopropylcarbinyl type of rearrangement can account for this oxidative rearrangement.     

Fragmentation of tunichrome Sp-1 is dominated by an unusual gas-phase intramolecular rearrangement

Tunichrome Sp-1 is a modified pentapeptide from the ascidian Styela plicata, having the structure H-DOPA-DOPA-Gly-Pro-dcDeltaDOPA (where DOPA = 3,4-dihydroxyphenylalanine and dcDeltaDOPA = decarboxy-(E)-alpha,beta-dehydro-DOPA). The tandem mass spectrum of the peptide is dominated by a number of abundant fragment ions that involve a gas-phase rearrangement where the dcDeltaDOPA group becomes covalently attached to the N-terminus. The high degree of rearrangement in Sp-1 compared with a related octapeptide, plicatamide, allowed for detailed multiple mass spectrometric (MS(n)) (up to n = 6) experiments, and hence permitted a detailed assessment of the origin and routes to the formation of the various rearrangement ions. Analyses on both a triple-quadrupole and a quadrupole time-of-flight mass spectrometer were made to ascertain whether the gas-phase rearrangements observed for tunichrome Sp-1 were unique to an ion trap mass spectrometer (i.e. the hypothesis being that perhaps the extended trapping times were required to facilitate this unusual gas-phase rearrangement). Interestingly, analyses on both the triple-quadrupole and quadruple time-of-flight mass spectrometers revealed an identical phenomenon, with the rearrangement fragment ions present at approximately the same abundance as the non-rearranged a-, b- and y-type sequence ions. We suggest that the smaller size of tunichrome Sp-1 compared with plicatamide facilitates the transfer of the dcDeltaDOPA group in this gas-phase rearrangement. This rearrangement was not observed for peptide analogs of tunichrome Sp-1 that did not contain the dcDeltaDOPA at the C-terminus, confirming that the presence of dcDeltaDOPA is critical for the rearrangement.     

Isomerization and fragmentation reactions of gaseous dimethyl phenylarsane radical cations and methyl phenylarsenium cations. A study by tandem mass spectrometry and density functional theory calculations

The unimolecular reactions of the radical cation of dimethyl phenylarsane, C6H5As(CH3)2, 1*+ and of the methyl phenylarsenium cation, C6H5As+CH3, 2+, in the gas phase were investigated using deuterium labeling and methods of tandem mass spectrometry. Additionally, the rearrangement and fragmentation processes were analyzed by density functional theory (DFT) calculations at the level UBHLYP/6- 311+G(2d,p)//UBHLYP/5-31+G(d). The molecular ion 1*+ decomposes by loss of a .CH3 radical from the As atom without any rearrangement, in contrast to the behavior of the phenylarsane radical cation. In particular, no positional exchange of the H atoms of the CH3 group and at the phenyl ring is observed. The results of DFT calculations show that a rearrangement of 1*+ by reductive elimination of As and shift of the CH3 group is indeed obstructed by a large activation barrier. The MIKE spectrum of 2+ shows that this arsenium cation fragments by losses of H2 and AsH. The fragmentation of the trideuteromethyl derivative 2-d3+ proves that all H atoms of the neutral fragments originate specifically from the methyl ligand. Identical fragmentation behavior is observed for metastable m-tolyl arsenium cation, m-CH3C6H4As+H, 2tol+. The loss of AsH generates ions C7H7+ which requires rearrangement in 2+ and bond formation between the phenyl and methyl ligands prior to fragmentation. The DFT calculations confirm that the precursor of this fragmentation is the benzyl methylarsenium cation 2bzl+, and that 2bzl+ is also the precursor ion fo the elimination of H2. The analysis of the pathways for rearrangements of 2+ to the key intermediate 2bzl+ by DFT calculations show that the preferred route corresponds to a 1,2-H shift of a H atom from the CH3 ligand to the As atom and a shift of the phenyl group in the reverse direction. The expected rearrangement by a reductive elimination of the As atom, which is observed for the phenylarsenium cation and for halogeno phenyl arsenium cations, requires much more activation enthalpy.     

Decomposition of 1-(2-thienyl)alkylalkanones under electron-impact

The major fragmentation paths of the 1-(2-thienyl)alkylalkanones ionized by electron impact are delineated by means of isotopically labeled molecules, metastable ion peaks and low ionization voltage data. A prominent process is cleavage of the bond beta to the carbonyl group with the concurrent rearrangement of a hydrogen atom. Another important process is cleavage alpha to the carbonyl group to produce the thienoylium ion analogous to the benzoylium ion. As expected, the data show that increasing the chain length by two methylene groups increases the total ion current. The bulk of this increase is found in the increased ion current of the rearrangement ion with the remainder being associated with alkyl fragments and oxygenated ion species.     

Synthesis of highly substituted ureas and thioureas through 1,3-diaza-Claisen rearrangements

Isocyanates and isothiocyanates that are not activated by an electron withdrawing group react with azanorbornenes in benzene at reflux to afford ureas and thioureas through the corresponding 1,3-diaza-Claisen rearrangements. At higher temperatures, a triazinone byproduct is observed. Isocyanates and isothiocyanates that are activated by an electron-withdrawing group react at room temperature to give the corresponding ureas and thioureas. The reactions of the activated isocyanates and isothiocyanates are also accompanied by the formation of isoureas and isothioureas. Interestingly, while benzoyl isocyanate reacts with N-benzyl azanorbornene at room temperature to give a 2:1 mixture of urea to isourea, in benzene at reflux the only product observed is the urea. A crossover experiment rules out the possibility that the products are formed through a retro-Diels-Alder, [4+2] cycloaddition sequence instead of a 1,3-diaza-Claisen rearrangement. Competition experiments between isocyanates and isothiocyanates with limiting azanorbornene indicate that isothiocyanates react faster to give the rearrangement product. Since isocyanates are shown to be more electrophilic, these data are consistent with a fast addition step and a rate-determining rearrangement step.     

The aza-

The inclusion of a C-2 trialkylsilyl substituent into allylic amine precursors allows the base-induced aza-[2,3]-Wittig sigmatropic rearrangement to proceed in excellent yield and diastereoselectivity. The rearrangement precursors require a carbonyl-based nitrogen protecting group that must be stable to the excess of strong base required for the reaction. The N-Boc and N-benzoyl group are very good at stabilizing the product anion and initiating deprotonation. The migrating groups (G) need to stabilize the intial anion by resonance and require G-CH(3)() pK(a) > 22 in order for the initial anion to be reactive enough for rearrangement. Products 7, 20b-d,f,g, and 23 are formed with high (10-20:1) anti diastereoselectivity. Product 23 containing the morpholine amide group is useful for preparing other carbonyl derivatives.     

An unusual rearrangement of Zofenopril,a new ACE inhibitor drug: mass spectrometric and conformational studies

Zofenopril (1) is a new ACE inhibitor, used in therapy for hypertension and post-myocardial infarction. The protonated quasi-molecular ion (m/z 430) of 1, obtained under positive electrospray ionization conditions, loses a benzoic acid molecule (m/z 308), which in turn decomposes via loss of CO (m/z 280) when low-energy collisional-induced dissociation (CID) and in-source experiments are performed. This rearrangement is the main fragmentation process and can be observed both in-source and in the product ion tandem mass spectra, using either an ion trap or a triple quadrupole instrument. Other known diastereoisomers of 1, an impurity with an acetyl in the place of the benzoyl group (2) and an impurity with two propanoyl chains in series (3), give the same rearrangement. On the other hand, the mass spectra of the methyl ester (4) and an impurity with two proline moieties (5) do not show this unusual fragmentation. Time-resolved CID spectra of 1 show that the rearrangement occurs after about 2 ms, a time scale comparable to those of the other non-rearrangement cleavages. These experiments suggest a conformation in the gas phase for 1 in which the benzoyl group is close to the hydroxyl of the carboxylic acid group, from which the rearrangement could readily occur. Since compounds 4 and 5 do not show the same behaviour, the presence of a carboxylic acid in the proline ring seems to play a crucial role in the rearrangement, probably due to an intramolecular hydrogen bond. To confirm this hypothesis, deuterium exchanges in mass spectrometric experiments and a conformational analysis via computational methods were performed.     

Studies of rearrangement reactions of protonated and lithium cationized 2-pyrimidinyloxy-N-arylbenzylamine derivatives by MALDI-FT-ICR mass spectrometry

The rearrangement reactions of protonated and lithium-cationized 2-pyrimidinyloxy-N-arylbenzylamine derivatives were studied by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and infrared multiphoton dissociation mass spectrometry (IRMPD). Our results show that three kinds of rearrangement reactions occur in IRMPD processes. First, nearly all protonated 2-pyrimidinyloxy-N-arylbenzylamine derivatives undergo Pathway A to form the K ion series. It is proposed that this rearrangement (migration of a substituted benzyl group) proceeds by way of a gas-phase intramolecular S(N)2 reaction. Second, a gas phase intramolecular S(N)Ar type rearrangement mechanism is proposed to explain the formation of the F ion series from protonated and lithium-cationized 5 (or 6). This skeletal rearrangement reaction competes with the S(N)2 reaction of the Pathway A, which produces the K ion series, in IRMPD of protonated 5 and 6. Third, the formation pathway of the W ion series is explained by a gas phase Cope type rearrangement mechanism.     

Reversible 1,4 migration of a silyl group from oxygen to carbon: an unexpected route to α-trialkylsilyl ketoximes

Anions generated from trialkylsilyl ethers of methyl ketoximes (1) undergo anionic rearrangement with 1,4 migration of the silyl group. After protonation, the resulting α-trialkylsilyl ketoximes (2), suffer thermal rearrangement with 1,4 migration of the silyl group from carbon to oxygen.     

Die Dienol-Benzol-Umlagerung von Allyldienolen: aromatische [1,2]-, [3,3]- und [3,4]-sigmatropische Umlagerungen

The dienol-benzene rearrangement of syn and anti-4-allyl-4-methylcyclohexa-2,5-dien-1-ol (syn and anti 15) occurs by formation of a benzonium ion intermediate in p-toluene-sulphonic acid in ether below 0° and leads to a mixture of 2-, 3- and 4-allyltoluenes in the ratio 54:10:36. By the introduction of ¹⁴C-, D- and methyl labelled dienols it is shown that only the allyl group migrates and that this rearrangement is an intramolecular, one-step process. The formation of 2-allyltoluene occurs with retention, whereas the 3- and 4-allyltoluenes are formed by inversion of the carbon skeleton of the migrating allyl group. These rearrangements can be therefore classified as suprafacial, aromatic sigmatropic reactions of the order [1,2], [3,3] and [3,4]. The transition state can be postulated as representing a positively charged complex consisting of interacting allyl and tolyl radicals. The interaction of the two parts is controlled by the symmetry of the highest occupied π-orbitals (ψ₃ for toluene and ψ₂ for the allyl group) in agreement with the Woodward-Hoffmann rules. The better “distribution” of the charge in the transition state of these reactions in comparison to the ground state is chiefly responsible for the CoPE-like [3,3] sigmatropic reaction occurring at low temperatures. In general, sigmatropic reactions in charged systems are faster. The rearrangement of syn and anti 2-allyl-2-methylcyclohexa-3,5-dien-1-ol (syn and anti 28) gives results similar to those obtained with the para-allyldienols. The thermal rearrangement of 15 and 28 gives 3-allyltoluene by a [3,3] sigmatropic Cope rearrangement followed by elimination of water.     

A novel rearrangement of 1-(2-aminoaryl)imidazoles

6-Ethyl-2,4-bis(1H-imidazol-1-yl)pyrimidin-5-amine was found to undergo a novel rearrangement in the presence of acetic anhydride. The structure of the rearrangement product was deduced using a combination of one- and two-dimensional nmr methods. Confirmation of the structure was obtained by unambiguous synthesis of a reduced analog and establishment of the identity of this material with material prepared by reduction of the rearrangement product. Examination of three related cases indicated that the rearrangement process is significant only when both positions adjacent to the aryl amino group are substituted.     

Magnetic and Spectroscopic Studies on the Complexes of 9-Oxo-10-Acridinemetanophosphonic Ion with Cu (II) Co (II)and Ni (II)

Abstract

Three complexes of 9-oxo-10-acridinemetanophosphonlc ion (PMA⁼ see figure) have been synthesised. The meta1:ligand ratio in the complexes is equal 1:1 and their formulas are (CUPMA) ₂,×5H₂O,NiPMA×4H₂O and CoPMA×4H₂O. The structure of the complexes has been investigated by the IR,FIR, Raman spectroscopy, UV-VIS spectroscopy, magnetic measurements and EPR spectroscopy. The physical properties of the complexes obtained are characteristic for inorganic polymers. The lowering of the ν(P-Q) stretching frequency by about cm^?, in the spectra of the complexes as compared to that of the free ligand suggests that the phosphonlc group takes part in coordination. Data from the EPR spectrum indicate that Cu(II)may form the dimeric, water bridged or even more complicated polymeric structures.     

MOLECULAR POLARIZATION INDUCTION IN CONCERTED MECHANISM OF ALKOXY MIGRATION

The rearrangement of α-substituted phenyl-α, α′-dimethoxypropanones (R1) was recently proved to he an [1, 3] siqmatropic migration of methoxy group by study of LFER, solvent effect, crossover experiment, and by other means. The rearrangement catalysed by trace of totuenesulfonic acid gave a negligible value of the Hammett reaction constant. Further experimental results show that the electronic effect of substituent on the aromatic ring for the rearrangement in neutral medium is much greater (Table 1). We propose sigmatropic migration