Vilsmeier Reagent Research Articles

Design and synthesis of ring C opened analogues of α-santonin as potential anticancer agents

Here we describe ring opening reaction of a novel halo triene derivative viz., (3S, 5aS)-8-chloro-3a, 4, 5, 5a-tetrahydro-3, 5a, 9-trimethylnaphtho [1, 2-b] furan-2(3H)-one of α-santonin upon nucleophillic attack with alcohols. Halo-triene was synthesized from α-santonin upon reaction with vilsmeier reagent. The synthesized compounds from ring opening reaction were evaluated for anticancer activity against a panel of four human cancer cell lines (A-549, THP-1, HCT-15, and IMR-13). Most of the compounds exhibited promising anticancer activity against all cancer cells in vitro; however compound. 3d with benzyl substitution showed most potent anticancer activity with an IC50 value of 0.3, 0.51, 0.6 and 0.23 μM against A-549, THP-1, HCT-116 and IMR-13 cell lines respectively.

Intensification of a highly exothermic chlorination reaction using a combined experimental and simulation approach for fast operating conditions prediction

Process intensification and micro-structured reactor design can be relevant means to improve the safety of a process involving hazardous substances. This work deals with the intensification of a chlorination reaction usually performed in batch mode, using thionyl chloride (SOCl2) to chlorinate a sterically hindered carboxylic acid dissolved in dimethylacetamide (DMAC). This chlorination reaction involves the exothermic formation of a species called Vilsmeier reagent, resulting from a reaction between SOCl2 and DMAC. In order to intensify this process, a reaction scheme with kinetic and thermal data is identified in the first place. This model is then used to suggest how the chlorination reaction could be carried out in a continuous mode and under which optimal operating conditions it should be operated. Tests are then conducted using a lab-scale microreactor providing good mixing and heat exchange, resulting in better performances than the batch process, within seconds of residence time. Further tests are performed at larger scale using a pilot-scale microreactor, designed to achieve the same yield and quality performances as the lab-scale microreactor with a higher throughput, as long as residence time, ratio between reactants and temperature remain constant.

Michael Franz Lappert. 31 December 1928 — 28 March 2014

Michael Lappert was one of the giants of twentieth-century organometallic chemistry. His research, carried out over six decades and leading to about 800 publications, had a profound and influential effect on the field, and his contributions covered almost every block of the Periodic Table. His early reputation was established by his extensive studies in boron chemistry exemplified by the reports of BCl 4 − , BN cyclobutadiene analogues, triborylamines, BCl 3 -catalysed ortho -Claisen rearrangements and evidence for restricted rotation about the B–N bond in aminoboranes. He had a lifelong interest in amides, including those of carbon, and especially electron-rich olefins, which remarkably were the ready source of numerous transition-metal carbene complexes. The last could also be obtained directly from the Vilsmeier reagent. He was the first to show that a carbene complex may act as an initiator of olefin metathesis. Later interests concerned the syntheses of new types of compound from all blocks of the Periodic Table driven by his imaginative use of new types of ligand (either sterically crowded or having no β-hydrogen atoms, often including SiMe 3 or Bu t substituents to confer lipophilicity). The use of CH n SiMe (3− n ) ( n = 0, 1 or 2) to stabilize transition-metal alkyl compounds was a major advance, because at the time stable homoleptic (a term he introduced) transition-metal alkyl compounds were unknown. He showed that the −CH(SiMe 3 ) 2 ligand could stabilize both low-coordinate transition metal and lanthanide compounds. Similarly, carbene analogues of the Main Group 14 elements germanium, tin and lead were obtained. Surprisingly in the solid state, these species were weakly dimerized (for example R 2 Sn=SnR 2 ), and unexpectedly exhibited a pyramidalized geometry at the heavy element. The latter had very significant bonding implications, because it differed fundamentally from the well-known planar structure of the corresponding alkenes. The first persistent or stable paramagnetic heavier Main Group element species MR 2 (M = P or As) and MR 3 (M = Ge or Sn) were also obtained while parallel work using −N(SiMe 3 ) 2 resulted in the corresponding Main Group amido derivatives. Other lipophilic ligands, such as β-diketiminates, were also widely used, as were bulky aryloxo and thiolato ligands, to obtain stable low-coordinate Main Group species. The first examples of d- and f-block species containing bridging alkyl groups were described. Those who worked with him cited his vast knowledge and supportive low-key advisory style, which ensured a contented and productive laboratory atmosphere. In addition to his scientific work, he was deeply interested in opera, literature and the theatre, about which he could talk knowledgeably.

Synthesis of 4-Ynamides and Cyclization by the Vilsmeier Reagent to Dihydrofuran-2(3H)-ones.

The room-temperature nucleophilic addition of vinyl azides to propargylic alcohols under BF3·Et2O catalysis provides an efficient synthesis of 4-ynamides. The procedure is operationally convenient, shows broad substrate scope, and is viable for the synthesis of multifunctional 4-ynamides. Further, a Vilsmeier intramolecular cyclization of 4-ynamides into dihydrofuran-2(3H)-ones has also been discovered, which represents the first report of alkynes being used as the nucleophiles in Vilsmeier-type reactions.

ChemInform Abstract: Vilsmeier Reagent Initialed Sequential One‐Pot Multicomponent Synthesis of N,O‐Disubstituted Glycolamides as Dipeptidyl Peptidase 4 Inhibitors.

AbstractAll compounds have been screened on their DPP‐4 inhibitory activity (disc diffusion method, 1.0 μM).

ChemInform Abstract: The Vilsmeier—Haack Formylation of 2,3‐Dihydro‐4H‐1,3‐benzoxazin‐4‐ones and Isomeric 1,2‐Dihydro‐4H‐3,1‐benzoxazin‐4‐ones: An Effective Approach to Functionalized 2H‐/4H‐Chromenes and Tetrahydroacridines.

AbstractIt is demonstrated, that 1,3‐benzoxazin‐4‐ones react with Vilsmeier reagent to give chromene derivatives in generally good yields.

Vilsmeier reagent initialed sequential one-pot multicomponent synthesis of N,O-disubstituted glycolamides as dipeptidyl peptidase 4 inhibitors

A series of N,O-disubstituted glycolamide derivatives have been successfully synthesized through Vilsmeier reagent initialed sequential one-pot multicomponent procedure from α-chloro N-arylacetamides with formamide/PBr3 and acid chloride. The three-step synthesis involved Vilsmeier formyloxylation reaction, decarbonylation, and esterification. The strategy was also applicable to α-chloro N-(naphthalenyl)acetamide to prepare the corresponding N,O-disubstituted glycolamide products. All of N,O-disubstituted glycolamides were evaluated against dipeptidyl peptidase 4 inhibitory activity. Based on the inhibitory results, several of O-furan-2-carbonyl and O-quinoline-8-sulfonyl N-aryl glycolamide compounds possessed the better effective inhibition of dipeptidyl peptidase 4.

The Vilsmeier–Haack formylation of 2,3-dihydro-4H-1,3-benzoxazin-4-ones and isomeric 1,2-dihydro-4H-3,1-benzoxazin-4-ones: an effective approach to functionalized 2H-/4H-chromenes and tetrahydroacridines

We found that 1,3- and isomeric 3,1-benzoxazin-4-ones react with the Vilsmeier reagent in vastly different ways. Thus, either 2H- or 4H-chromenes were obtained in good yields when 1,3-benzoxazin-4-ones were reacted at 75–80 °C, while the formylation of 3,1-benzoxazines at ambient temperature leads to acridine-9-one or 9-chloroacridine derivatives, depending on the amount of Vilsmeier reagent and the nature of substrate.

ChemInform Abstract: A Practical and Mild Chlorination of Fused Heterocyclic N‐Oxides.

AbstractThe Vilsmeier reagent is employed as both activating agent and nucleophilic chloride source for the regioselective chlorination of quinoline‐ and isoquinoline‐N‐oxides.

ChemInform Abstract: Three Questionable Cases in the Chemistry of Quinoxalines and Benzodiazepines in the Way of the Syntheses of Benzimidazoles.

AbstractThe reaction of (I) with Vilsmeier reagent to give (III), the reaction of (V) with aqueous NaOH to give (VI), and the reaction of (X) with o‐phenylenediamine to give (XI) are studied and earlier reports are revised.

Synthesis of Vildagliptin Utilizing Continuous Flow and Batch Technologies

The preparation and utilization of the Vilsmeier reagent (VR) is well-known in the literature with its usefulness and scope being frequently demonstrated in organic synthesis. However, it is an irritant and has a high thermal energy of decomposition; consequently, these factors lead to operational issues on larger scale which suggests approaches whereby the reagent is not isolated. Herein, we report the in-line formation and instantaneous consumption of VR utilizing both conventional batch and flow technologies. The approach is demonstrated by way of the synthesis of Vildagliptin, thereby mitigating potential safety and hygiene hazards.

A Convenient Synthesis of N,N-Dimethylformamidines from Sulfonamides

N,N-Dimethylformamidines were synthesized from sulfonamides using the Vilsmeier reagent as a cleavage activator. The reactions were performed under mild conditions achieving good to excellent yields. The chemistry presented can also be used as a deprotection strategy when amines or anilines are protected with sulfonyl groups, such as the tosyl group.

ChemInform Abstract: Formation of Azolo[1,2,4]triazinium Salts by Reaction of Heterocyclic‐Substituted 1‐Azo‐naphthalen‐2‐ols with Strong Acids.

AbstractPolycyclic azolo[1,2,4]triazinium salts are obtained by reaction of heterocyclic‐substituted 1‐azo‐naphth‐2‐ols with the Vilsmeier reagent or with strong acids.

A practical and mild chlorination of fused heterocyclic N-oxides

Fused azine N-oxides were selectively chlorinated at C2 in moderate to excellent yields, employing Vilsmeier reagent as both the activating agent and the nucleophilic chloride source. Remarkable features of the method include simple operation, mild reaction conditions, a wide substrate scope, and the use of only stoichiometric amount of POCl3. The potential extension of this method to a one-pot oxidation/chlorination sequence that obviates the need for isolation of the N-oxide intermediates is also validated.

ChemInform Abstract: The Synthesis of New Heterocycles Using 2‐(4‐Chloro‐1,3‐dihydro‐3,3,7‐trimethyl‐2H‐indol‐2‐ylidene) Propanedial.

4-Chloro-2,3,3,7-tetramethyl-3H-indole (an indolenine) was produced by the reaction of 5-chloro-2-methylphenylhydrazine hydrochloride with 3-methylbutan-2-one via Fischer reaction. Exposure of the indolenine to the Vilsmeier reagent at 50°C produced a β-diformyl compound, 2-(4-chloro-1,3-dihydro-3,3,7-trimethyl-2H-indol-2-ylidene)propanedial. This dialdehyde was reacted with arylhydrazines, acetamidinium chloride, urea, thiourea, guanidinium chloride, and cyanoacetamide to give various 5-membered and 6-membered heterocyclic products, each carrying a 4-chloro-3,3,7-trimethyl-3H-indol-2-yl unit as a substituent, in excellent yields.

The reactions of 3-ethoxycarbonylmethylene-3,4-dihydroquinoxalin-2(1H)-one and its derivatives in the synthesis of benzodiazepines and benzimidazoles: reinvestigation, structural reassignment, and new insight

The reaction of 3-ethoxycarbonylmethylene-3,4-dihydroquinoxalin-2(1H)-one with the Vilsmeier reagent, the treatment of 3-(3,4-dihydroquinoxalin-2(1H)-on-3-yl)-1,2-dihydro-1,5-benzodiazepin-2(1H)-one hydrochloride with 10% sodium hydroxide and 3-benzimidazoylquinoxalin-2(1H)-one with both 1,2-phenylenediamine dihydrochloride, and the reactions of 1,2-phenylenediamine have been reinvestigated and the structures of these reaction products have been revised. It has been shown that in all the three cases other regioisomers of products have been formed as distinct from the literature data. The mechanisms to explain the formation of the products are suggested.

Michael Lappert (1928-2014).

The passing of Michael F. Lappert at the age of 85 on March 28th, 2014 has deprived organometallic chemistry of one of its greatest protagonists. In a research career spanning over six decades, he characterized a vast array of organometallic compounds from all parts of the periodic table. Many were of an unknown type, featuring rare oxidation states, coordination numbers, or bonding. Several were progenitors of new compound classes and were a major influence on subsequent developments.1 1 1 Michael (Mike) Lappert was born in Brno, Czechoslovakia in 1928. In 1939, he came to the UK as a refugee on one of the last Kindertransports, along with his brother Martin (most of his immediate family did not survive the Holocaust). He was educated at Cannock House School, and later at Wilson’s Grammar School. Subsequently, he enrolled at the Northern Polytechnic, and graduated with first-class honors as an external student at the University of London in 1949. He remained there for his PhD (awarded in 1951) working with Professor W. Gerrard on the interaction of alcohols or ethers with boron halides. He became a faculty member at Northern Polytechnic, and in 1959 moved to the University of Manchester Institute of Science and Technology. In 1964, he was recruited as a reader at the University of Sussex by Professor Colin Eaborn. He was appointed professor in 1969, research professor in 1994, and research professor emeritus in 1997. His work yielded over eight hundred journal articles and three books. He advised over one hundred PhD students, and a similar number of postdoctoral fellows. He received many honors, including election to the Royal Society (1979), and honorary doctorates from the Ludwig-Maximilians-Universität München (1980) and the Universidad de Murcia (2013). His early reputation rested on his contributions to boron chemistry. Besides the alkoxides, he also discovered [BCl4]–, BN cyclobutadiene analogues, triborylamines, the BCl3-catalyzed ortho-Claisen rearrangement, and studied for the first time the restricted B–N rotation in aminoboranes (with P. A. Barfield and J. Lee). Work on B–N compounds led to a lifelong interest in amides, including those of carbon, specifically the carbenoid electron-rich olefins, which allowed access to numerous transition-metal carbenes. He also obtained carbene complexes from the Vilsmeier reagent, and was the first to demonstrate that a carbene complex was an initiator in olefin metathesis. By the late 1960s, his interests had extended to the synthesis of new types of compounds from all blocks of the periodic table. The key to his synthetic accomplishments was the use of new ligands, many of which were sterically crowding, had no β-hydrogen atoms, and often included SiMe3 or tBu substituents that conferred lipophilicity. In particular, the use of CH2SiMe3, CH(SiMe3)2, and C(SiMe3)3 ligands to stabilize transition-metal alkyl compounds, described in a 1969 patent, was a major advance. At the time, stable homoleptic (a term he introduced) transition-metal alkyl compounds were unknown. He showed that the CH(SiMe3)2 ligand could stabilize low-coordinate transition-metal and the lanthanide alkyl compounds [Ln{CH(SiMe3)2}3]. In the main group, he showed that it stabilized germanium, tin, and lead carbene analogues (1973). In the solid state, it was shown that these species are weakly dimerized, but had pyramidalized coordination at the carbon-homologue element, for example, the heavier Group 14 element analogue of ethylene R2SnSnR2 (1976). This structure, and the recognition that its bonding differed fundamentally from that in alkenes, was an important turning point in modern main-group chemistry and in our understanding of bonding. He also synthesized the first persistent or stable paramagnetic heavier main-group species MR2 (M=P or As) and MR3 (M=Ge or Sn) using the same ligand. These studies were paralleled by the use of the related N(SiMe3)2 ligand to synthesize the corresponding main-group amido derivatives. Other lipophilic ligands, such as {η5-1,3-(Me3Si)2C5H3}− and the β-diketiminate [{N(SiMe3)CPh}2CH]− were also widely used. In addition, the first d- and f-block species with bridging alkyl groups, such as {Cu(µ-CH2SiMe3)}4 or {LnCp2(µ-Me)}2 were synthesized. He also pioneered the use of bulky aryloxo and thiolato ligands to synthesize stable low-coordinate main-group species. To those who worked with him, his supportive and low-key advising style, combined with his vast chemical knowledge, meant that he had the happy knack of producing a huge volume of interesting results while maintaining a relaxed lab atmosphere. Besides science, he had a deep interest in literature, opera, and the theater, and he could talk knowledgeably about many subjects besides. He was a kind and generous man of great hospitality, one aspect of which was the lavish parties at his home that were hosted originally by his aunt Louise Gross-Lappert and later by his wife Lorna. Visitors were always welcome and treated royally at their home. He was a true gentleman and a great scientist.

ChemInform Abstract: Vilsmeier Reagent: An Efficient Reagent for the Transformation of 2‐Aminobenzamides into Quinazolin‐4(3H)‐one Derivatives.

Abstract Clean and easy preparation of quinazolin-4(3H)-one derivatives using 2-aminobenzamides and Vilsmeier reagent is described. 2-Aminobenzamides were converted into the corresponding quinazolinones under mild and efficient conditions, in good yields without undesirable by-products. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

AB0829 Inhibition of Xanthine Oxidase by 1- [2'-Aminophenyl]-3-[3-(2-CHLORO-6-METHYLQUINOLYL)] Prop-2-Ene-1-One

BackgroundXanthine oxidase (XO) is a ubiquitous cytoplasmic protein that catalyzes the final two steps in purine catabolism. Inhibition of xanthine oxidase is a key element in the treatement of goutObjectivesIn...

Formation of Azolo[1,2,4]triazinium Salts by Reaction of Heterocyclicsubstituted 1-Azo-naphthalen-2-ols with Strong Acids

By reaction of heterocyclic-substituted 1-azo-naphth-2-ols with the Vilsmeier reagent or with strong acids polycyclic azolo[1,2,4]triazinium salts are formed in good yields. The azolo[1,2,4] triazinium salts exhibit similar UV=Vis absorption properties as the starting azo compounds, but in contrast to those the fluorescence appears in the visible range.