AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Jul 172017
 

Revisiting the deoxydehydration of glycerol towards allyl alcohol under continuous-flow conditions

Green Chem., 2017, 19,3006-3013
DOI: 10.1039/C7GC00657H, Paper
Nelly Ntumba Tshibalonza, Jean-Christophe M. Monbaliu
Highly selective flash deoxydehydration of glycerol towards allyl alcohol under continuous-flow conditions.

Green Chemistry

Revisiting the deoxydehydration of glycerol towards allyl alcohol under continuous-flow conditions

Abstract

The deoxydehydration (DODH) of glycerol towards allyl alcohol was revisited under continuous-flow conditions combining a microfluidic reactor setup and a unique reactive dynamic feed solution approach. Short reaction times, high yield and excellent selectivity were achieved at high temperature and moderate pressure in the presence of formic acid, triethyl orthoformate, or a combination of both. Triethyl orthoformate appeared as a superior reagent for the DODH of glycerol, with shorter reaction times, lower reaction temperatures and more robust conditions. In-line IR spectroscopy and computations provided different perspectives on the unique reactivity of glycerol O,O,O-orthoesters.

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Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

 FLOW CHEMISTRY, flow synthesis  Comments Off on Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene
Jun 052017
 

 

 

Abstract Image

The first continuous flow synthesis of C8–C16 alkane fuel precursors from biobased platform molecules is reported. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) was found to be a recyclable and highly efficient organic base catalyst for the aldol condensation of furfural with carbonyl compounds, and the selectivity of mono- or difuryl product can be easily regulated by adjusting the molar ratio of substrates. By means of flow technique, a shorter reaction time, satisfactory output, and continuous preparation are achieved under the present procedure, representing a significant advance over the corresponding batch reaction conditions.

Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

Tao Shen, Jingjing Tang, Chenglun Tang, Jinglan Wu, Linfeng Wang, Chenjie Zhu*§ , and Hanjie Ying§
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
National Engineering Technique Research Center for Biotechnology, Nanjing 211816, China
§Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing 211816, China
State Key Laboratory of Motor Vehicle Biofuel Technology, Nanyang 473000, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00141

 

*E-mail: zhucj@njtech.edu.cn. Phone/Fax: +86 25 58139389.
1-(furan-2-yl)-2-methylpent-1-en-3-one
1a
3-pentanone (100 mmol, 8.6 g) and furfural (100 mmol, 9.6 g) were diluted with MeOH-H2O to 40 mL in stream 1, catalyst TBD (10 mmol, 1.39 g) were diluted with MeOH-H2O (v/v = 1/1) to 40 mL in stream 2, the two streams was purged in a 0.2 mL/min speed into slit plate mixer and at the 353 K passed tubing reactor. Finally, the product was extracted with EtOAc and water, the obtained organic layer was evaporated and purified by silica gel flash chromatography (25:1 hexane-EtOAc) to provide the analytically pure product for further characterization, the aqueous phase was collected and reused.According to the general procedure afforded 14.92 g (91%) of product 1a, isolated as pale yellow oil;
1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 1.4 Hz, 1H), 7.29 (s, 1H), 6.71 (d, J = 3.5 Hz, 1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H), 2.71 (q, J = 7.3 Hz, 2H), 2.05 (s, 3H), 1.04 (t, J = 7.3 Hz, 3H).
13C NMR (100 MHz, CD3OD) δ 203.5, 153.0, 145.8, 133.8, 126.8, 116.6, 113.3, 31.1, 13.2, 9.2.
STR1 STR2 str3
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Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

 FLOW CHEMISTRY, flow synthesis, phase 1  Comments Off on Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement
Jan 212017
 

STR1

Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03123D, Paper
Maurice A. Marsini, Frederic G. Buono, Jon C. Lorenz, Bing-Shiou Yang, Jonathan T. Reeves, Kanwar Sidhu, Max Sarvestani, Zhulin Tan, Yongda Zhang, Ning Li, Heewon Lee, Jason Brazzillo, Laurence J. Nummy, J. C. Chung, Irungu K. Luvaga, Bikshandarkoil A. Narayanan, Xudong Wei, Jinhua J. Song, Frank Roschangar, Nathan K. Yee, Chris H. Senanayake
A convergent and robust synthesis of a developmental CCR1 antagonist is described using continuous flow technology

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03123D?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity.

Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

*Corresponding authors
aDepartment of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, USA
E-mail: maurice.marsini@boehringer-ingelheim.com
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03123D

 

Capture STR0 STR1

 

STR0 STR1

1-(4-fluorophenyl)-N-(1-(2-(methylsulfonyl)pyridin-4-yl)cyclopropyl)-1H-pyrazolo[3,4- c]pyridine-4-carboxamide

1-(4-fluorophenyl)-N-(1-(2-(methylsulfonyl)pyridin-4-yl)cyclopropyl)-1H-pyrazolo[3,4- c]pyridine-4-carboxamide

m.p. = 140-144 °C;

1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 9.43 (s, 1H), 8.95 (s, 1H), 8.70 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.93 (s, J1 = 8.8 Hz, J2 = 4.7 Hz, 1H), 7.82 (s, 1H), 7.54 (d, J = 4.1 Hz, 1H), 7.49 (t, J = 8.7 Hz, 1H), 3.29 (s, 3H), 1.61 (bs, 4H);

13C NMR (100 MHz, CDCl3) δ 166.1, 162.7, 160.3, 158.4, 156.9, 150.6, 139.2, 138.2, 135.8, 135.6, 125.4 (d, JC-F = 8.8 Hz), 123.3, 121.9, 117.2 (d, JC-F = 23.1 Hz), 116.4, 40.2, 34.9, 20.9;

HRMS: calcd for C22H19FN5O3S [M + H+ ]: 452.1187. Found: 452.1189.

 

STR1

 

STR2

 

 

Capture

 

STR0

//////////BI-638683, BI 638683, CCR1 antagonist, 295298-26-8, US2012270870, Boehringer Ingelheim Pharmaceuticals, phase 1

CS(=O)(=O)c1nccc(c1)C2(CC2)NC(=O)c5cncc3c5cnn3c4ccc(F)cc4

SCHEMBL1670702.png

Molecular Formula: C22H18FN5O3S
Molecular Weight: 451.476 g/mol

CCR1 antagonist

cas 295298-26-8

US2012270870

maybe BI-638683, not sure

In September 2010, a randomized, double-blind, placebo-controlled, phase I study (NCT01195688; 1279.1; 2010-021187-15) was initiated in healthy male volunteers (expected n = 64) in Germany, to assess the safety, pharmacokinetics and pharmacodynamics of BI-638683. The study was completed in December 2010 . In June 2014, data were presented at the EULAR 2014 Annual Meeting in Paris, France. A dose of 75-mg showed maximal inhibition of mRNA expression of the four-CC chemokine receptor type-I dependent marker genes. chemokine ligand -2  and Peroxisome proliferator-activated receptor gamma-mRNAs by doses of 300 mg and higher, and for Ras-related protein rab-7b mRNA by doses of 500 mg and higher

Boehringer Ingelheim was developing BI-638683, a CCR1 antagonist, for the potential oral treatment of rheumatoid arthritis. A phase I trial was completed in December 2010 . Phase I data was presented in June 2014

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011049917&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Inventors Brian Nicholas Cook, Daniel Kuzmich, Can Mao, Hossein Razavi
Applicant Boehringer Ingelheim International Gmbh

Chemotactic Cytokine Receptor 1 (CCRl) belongs to a large family (>20) of chemotactic cytokine (chemokine) receptors that interact with specific chemokines (>50) to mediate leukocyte trafficking, granule exocytosis, gene transcription, mitogenic effects and apoptosis. Chemokines are best known for their ability to mediate basal and inflammatory leukocyte trafficking. The binding of at least three chemokines (MIP-1 alpha/CCL3, MCP3/CCL7 and RANTES/CCL5) to CCRl is responsible for the trafficking of monocytes, macrophages and THl cells to inflamed tissues of rheumatoid arthritis (RA) and multiple sclerosis (MS) patients (Trebst et al. (2001) American J of Pathology 159 p. 1701). Macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage chemoattractant protein 3 (MCP-3) and regulated on activation, normal T-cell expressed and secreted (RANTES) are all found in the CNS of MS patients, while MIP-1 alpha and RANTES are found in the CNS in the experimental autoimmune encephalomyelitis (EAE) model of MS (Review: Gerard

and Rollins (2001) Nature Immunology). Macrophages and Thl cells in the inflamed synovia of RA patients are major producers of MIP-1 alpha and RANTES, which continuously recruit leukocytes to the synovial tissues of RA patients to propagate chronic inflammation (Volin et al. (1998) Clin. Immunol. Immunopathology; Koch et al. (1994) J. Clin. Investigation; Conlon et al. (1995) Eur. J. Immunology). Antagonizing the interactions between CCR1 and its chemokine ligands is hypothesized to block chemotaxis of monocytes, macrophages and Thl cells to inflamed tissues and thereby ameliorate the chronic inflammation associated with autoimmune diseases such as RA and MS.

Evidence for the role of CCR1 in the development and progression of chronic inflammation associated with experimental autoimmune encephalitis (EAE), a model of multiple sclerosis, is based on both genetic deletion and small molecule antagonists of CCR1. CCR1 deficient mice were shown to exhibit reduced susceptibility (55% vs. 100%) and reduced severity (1.2 vs. 2.5) of active EAE (Rottman et al. (2000) Eur. J. Immunology). Furthermore, administration of small molecule antagonist of CCR1, with moderate affinity (K; = 120 nM) for rat CCR1, was shown to delay the onset and reduce the severity of EAE when administered intravenously (Liang et al. (2000) /. Biol. Chemistry). Treatment of mice with antibodies specific for the CCR1 ligand MIP- 1 alpha have also been shown to be effective in preventing development of acute and relapsing EAE by reducing the numbers of T cells and macrophages recruited to the CNS (Karpus et al. (1995) /. Immunology; Karpus and Kennedy (1997) /. Leukocyte Biology). Thus, at least one CCR1 ligand has been demonstrated to recruit leukocytes to the CNS and propagate chronic inflammation in EAE, providing further in vivo validation for the role of CCR1 in EAE and MS.

In vivo validation of CCR1 in the development and propagation of chronic inflammation associated with RA is also significant. For example, administration of a CCR1 antagonist in the collagen induced arthritis model (CIA) in DBA/1 mice has been shown to be effective in reducing synovial inflammation and joint destruction (Plater-Zyberk et al. (1997) Immunology Letters). Another publication described potent antagonists of murine CCR1 that reduced severity (58%) in LPS-accelerated collagen-induced arthritis (CIA), when administered orally {Biorganic and Medicinal Chemistry Letters 15, 2005, 5160-5164). Published results from a Phase lb clinical trial with an oral CCRl antagonist demonstrated a trend toward clinical improvement in the absence of adverse side effects (Haringman et al. (2003) Ann. Rheum. Dis.). One third of the patients achieved a 20% improvement in rheumatoid arthritis signs and symptoms (ACR20) on day 18 and CCRl positive cells were reduced by 70% in the synovia of the treated patients, with significant reduction in specific cell types including 50% reduction in CD4+ T cells, 50% reduction in CD8+ T cells and 34% reduction in macrophages.

Studies such as those cited above support a role for CCRl in MS and RA and provide a therapeutic rationale for the development of CCRl antagonists.

STR1

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[3 + 2] Dipolar Cycloadditions in Flow Reactors

 FLOW CHEMISTRY, flow synthesis  Comments Off on [3 + 2] Dipolar Cycloadditions in Flow Reactors
Jan 092017
 

Image result for FLOW CHEMISTRY

FLOW CHEMISTRY ILLUSTRATION

Flow chemistry is also known as continuous flow or plug flow chemistry. It involves a chemical reaction run in a continuous flow stream.  The process offers potential for the efficient manufacture of chemical products. Recent breakthroughs using Vapourtec systems are in production of Tamoxifen (Breast Cancer) and Artemisinin (Malaria).

Reactants are first pumped into a mixing device. Flow continues through a temperature controlled reactor until the reaction is complete. The reactor can be a simple pipe, tube or complex micro-structured device. The mixing device and reactor are maintained at the temperature to promote the desired reaction. The reactants may also be exposed to an electrical flux or a photon flux to promote an electrochemical or photochemical reaction.

Click here for examples of flow chemistry performed in Vapourtec systems

 

[3 + 2] Dipolar Cycloadditions in Flow Reactors

 

The [3 + 2] dipolar cycloaddition of unstabilized azomethine ylides can be used to construct susbstituted pyrrolidines, which can be useful building blocks in pharmaceutical and natural product synthesis. A common experimental procedure involves in situ generation of the intermediate ylide in the presence of the dipolarophile; however, this technique can produce a significant exotherm when reactive dipolarophiles (e.g., acrylates, maleimides) are employed. Now Fray and co-workers at Pfizer describe efforts to conduct this chemistry using continuous flow technology, which is often beneficial when applied to systems involving highly energetic intermediates ( Tetrahedron Lett.2010, 51, 1026−1029).

The authors provide a description and schematic for the flow apparatus used and optimized the system for flow-rate/residence time, temperature, and pressure. It was found that the residence times could be reduced to 15 min if a higher operating temperature (100 °C) was used. The best conditions were then applied to a series of substrates, but it was determined that differences in reactivity required adjustment of parameters to achieve optimal results. For comparison, the authors also conducted the reaction in typical batch mode and found the yield to be higher. Nonetheless, the flow process was demonstrated to be capable of processing 30 g substrate within 1 h of operation (87% isolated yield after chromatography).

str1

To demonstrate the viability of performing the cycloaddition in flow on a reasonable scale, the Vapourtec™ R2+/R4 was equipped with four heated reaction loops (total volume 40 ml) so that we could react compound 1 with ethyl acrylate under the previously optimised conditions (0.5 M overall in MeCN, 70 C, 10 min). From a reaction on 30 g scale, we obtained compound 3a in 87% yield, after chromatography in only 1 h.

(e) Srihari, P.; Yaragorla, S. R.; Basu, D.; Chandrasekhar, S. Synthesis 2006, 2646. 12. An attractive alternative has been described for generating the azomethine ylide via decarboxylation, for example, N-benzylglycine, paraformaldehyde, toluene, reflux, see: Joucla, M.; Mortier, J. Bull. Soc. Chim. Fr 1988, 579; Rodriguez Sarmiento, R. M.; Wirz, B.; Iding, H. Tetrahedron: Asymmetry 2003, 14, 1547.

[3+2] Dipolar cycloadditions of an unstabilised azomethine ylide under continuous flow conditions

  • Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom

Abstract

The [3+2] dipolar cycloaddition reactions of the unstabilised azomethine ylide precursor benzyl(methoxymethyl)(trimethylsilylmethyl)amine with 12 electron-deficient alkenes in the presence of catalytic trifluoroacetic acid are examined under continuous flow conditions (20–100 °C, 10–60 min residence time). The more reactive and hazardous alkenes such as ethyl acrylate, N-methylmaleimide and (E)-2-nitrostyrene afford substituted N-benzylpyrrolidine products in 77–83% yields, whereas less reactive dipolarophiles such as (E)-crotononitrile and ethyl methacrylate give lower yields (59–63%). Under optimised conditions, the reaction with ethyl acrylate is scaled up to afford ethyl N-benzylpyrrolidine-3-carboxylate (30 g, 87%) in 1 h.

Under continuous flow conditions an azomethine ylide precursor reacts with 12 electron-deficient alkenes to give the corresponding pyrrolidines. The most reactive and therefore hazardous dipolarophiles give the best yields.

image

MORE INSIGHT………..

The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a dipolarophile to form a five-membered ring. The earliest 1,3-dipolar cycloadditions were described in the late 19th century to the early 20th century, following the discovery of 1,3-dipoles. Mechanistic investigation and synthetic application were established in the 1960s, primarily through the work of Rolf Huisgen.[1]Hence, the reaction is sometimes referred to as the Huisgen cycloaddition (this term is often used to specifically describe the 1,3-dipolar cycloaddition between an organic azide and an alkyne to generate 1,2,3-triazole). Currently, 1,3-dipolar cycloaddition is an important route to the regio- and stereoselective synthesis of five-membered heterocycles and their ring-opened acyclic derivatives.

Example of 1,3-dipolar cycloaddition.tif

Mechanistic overview

There were originally two proposals that describe the mechanism of the 1,3-dipolar cycloaddition: first, the concerted pericyclic cycloaddition mechanism, proposed by Rolf Huisgen;[2] and second, the stepwise mechanism involving a diradical intermediate, proposed by Firestone.[3] After much debate, the former proposal is now generally accepted[4]—the 1,3-dipole reacts with the dipolarophile in a concerted, often asynchronous, and symmetry-allowed π4s + π2s fashion through a thermal six-electron Huckel aromatic transition state. Although, there are few examples of stepwise mechanism of the catalyst free 1,3-dipolar cycloaddition reactions for thiocarbonyl ylides,[5] and nitrile oxides[6]

The generic mechanism of a 1,3-dipolar cycloaddition between a dipole and a dipolarophile to give a five-membered heterocycle, via a six-electron transition state. Note that the red curly arrows are conventionally used to denote the reaction process but do not necessarily represent the actual flow of electrons.

Pericyclic mechanism

Huisgen investigated a series of cycloadditions between the 1,3-dipolar diazo compounds and various dipolarophilic alkenes.[2] The following observations support the concerted pericyclic mechanism, and refute the stepwise diradical or the stepwise polar pathway.

  • Substituent effects: Different substituents on the dipole do not exhibit a large effect on the cycloaddition rate, suggesting that the reaction does not involve a charge-separated intermediate.
  • Solvent effects: Solvent polarity has little effect on the cycloaddition rate, in line with the pericyclic mechanism where polarity does not change much in going from the reactants to the transition state.
  • Stereochemistry: 1,3-dipolar cycloadditions are always stereospecific with respect to the dipolarophile (i.e., cis-alkenes giving syn-products), supporting the concerted pericyclic mechanism in which two sigma bonds are formed simultaneously.
  • Thermodynamic parameters: 1,3-dipolar cycloadditions have an unusually large negative entropy of activation similar to that of the Diels-Alder reaction, suggesting that the transition state is highly ordered, which is a signature of concerted pericyclic reactions.

1,3-Dipole

Structure and nomenclature of all second-row 1,3-dipoles consisting of carbon, nitrogen and oxygen centers. The dipoles are categorized as allyl-type or propargyl/allenyl-type based on the geometry of the central atom.

A 1,3-dipole is an organic molecule that can be represented as either an allyl-type or a propargyl/allenyl-type zwitterionic octet/sextet structures. Both types of 1,3-dipoles share four electrons in the π-system over three atoms. The allyl-type is bent whereas the propargyl/allenyl-type is linear in geometry. There are a total of 18 second-row 1,3-dipoles (see structures in the thumbnail on the right).[7]1,3-Dipoles containing higher-row elements such as sulfur or phosphorus are also known, but are utilized less routinely.

Resonance structures can be drawn to delocalize both negative and positive charges onto any terminus of a 1,3-dipole (see the scheme below). A more accurate method to describe the electronic distribution on a 1,3-dipole is to assign the major resonance contributor based on experimental or theoretical data, such as dipole moment measurements[8] or computations.[9] For example, diazomethane bears the largest negative character at the terminal nitrogen atom, while hydrazoic acid bears the largest negative character at the internal nitrogen atom.

Calculated major resonance structures of diazomethane and hydrazoic acid (doi = 10.1021/ja00475a007)

Consequently, this ambivalence means that the termini of a 1,3-dipole can be treated as both nucleophilic and electrophilic at the same time. The extent of nucleophilicity and electrophilicity at each terminus can be evaluated using the frontier molecular orbitals, which can be obtained computationally. In general, the atom that carries the largest orbital coefficient in the HOMO acts as the nucleophile, whereas that in the LUMO acts as the electrophile. The most nucleophilic atom is usually, but not always, the most electron-rich atom.[10][11][12] In 1,3-dipolar cycloadditions, identity of the dipole-dipolarophile pair determines whether the HOMO or the LUMO character of the 1,3-dipole will dominate (see discussion on frontier molecular orbitals below).

Dipolarophile

The most commonly used dipolarophiles are alkenes and alkynes. Heteroatom-containing dipolarophiles such as carbonyls and imines can also undergo 1,3-dipolar cycloaddition. Other examples of dipolarophiles include fullerenes and nanotubes, which can undergo 1,3-dipolar cycloaddition with azomethine ylide in the Prato reaction.

Solvent effects

1,3-dipolar cycloadditions experience very little solvent effect because both the reactants and the transition states are generally non-polar. For example, the rate of reaction between phenyl diazomethane and ethyl acrylate or norbornene (see scheme below) changes only slightly upon varying solvents from cyclohexane to methanol.[13]

Effect of solvent polarity on 1,3-dipolar cycloaddition reactions(doi:10.3987/S(N)-1978-01-0109.)

Lack of solvent effects in 1,3-dipolar cycloaddition is clearly demonstrated in the reaction between enamines and dimethyl diazomalonate (see scheme below).[14] The polar reaction, N-cyclopentenyl pyrrolidine nucleophilic addition to the diazo compound, proceeds 1,500 times faster in polar DMSO than in non-polar decalin. On the other hand, a close analog of this reaction, N-cyclohexenyl pyrrolidine 1,3-dipolar cycloaddition to dimethyl diazomalonate, is sped up only 41-fold in DMSO relative to decalin.

Rate of polar nucleophilic addition reaction versus 1,3-dipolar cycloaddition in decalin and in DMSO (doi:10.1016/S0040-4039(00)70991-9)

Frontier molecular orbital theory

Orbital overlaps in types I, II and III 1,3-dipolar cycloaddition.

1,3-Dipolar cycloadditions are pericyclic reactions, which obey the Dewar-Zimmerman rules and the Woodward–Hoffmann rules. In the Dewar-Zimmerman treatment, the reaction proceeds through a 5-center, zero-node, 6-electron Huckel transition state for this particular molecular orbital diagram. However, each orbital can be randomly assigned a sign to arrive at the same result. In the Woodward–Hoffmann treatment, frontier molecular orbitals (FMO) of the 1,3-dipole and the dipolarophile overlap in the symmetry-allowed π4s + π2s manner. Such orbital overlap can be achieved in three ways: type I, II and III.[15] The dominant pathway is the one which possesses the smallest HOMO-LUMO energy gap.

Type I

The dipole has a high-lying HOMO which overlaps with LUMO of the dipolarophile. A dipole of this class is referred to as a HOMO-controlled dipole or a nucleophilic dipole, which includes azomethine ylide, carbonyl ylide, nitrile ylide, azomethine imine, carbonyl imine and diazoalkane. These dipoles add to electrophilic alkenes readily. Electron-withdrawing groups (EWG) on the dipolarophile would accelerate the reaction by lowering the LUMO, while electron-donating groups (EDG) would decelerate the reaction by raising the HOMO. For example, the reactivity scale of diazomethane against a series of dipolarophiles is shown in the scheme below. Diazomethane reacts with the electron-poor ethyl acrylate more than a million times faster than the electron rich butyl vinyl ether.[16]

This type resembles the normal-electron-demand Diels-Alder reaction, in which the diene HOMO combines with the dienophile LUMO.

doi:10.1016/S0040-4039(01)92781-9

Type II

HOMO of the dipole can pair with LUMO of the dipolarophile; alternatively, HOMO of the dipolarophile can pair with LUMO of the dipole. This two-way interaction arises because the energy gap in either direction is similar. A dipole of this class is referred to as a HOMO-LUMO-controlled dipole or an ambiphilic dipole, which includes nitrile imide, nitrone, carbonyl oxide, nitrile oxide, and azide. Any substituent on the dipolarophile would accelerate the reaction by lowering the energy gap between the two interacting orbitals; i.e., an EWG would lower the LUMO while an EDG would raise the HOMO. For example, azides react with various electron-rich and electron-poor dipolarophile with similar reactivities (see reactivity scale below).[17]

doi:10.1021/ja01016a011

Type III

The dipole has a low-lying LUMO which overlaps with HOMO of the dipolarophile (indicated by red dashed lines in the diagram). A dipole of this class is referred to as a LUMO-controlled dipole or an electrophilic dipole, which includes nitrous oxide and ozone. EWGs on the dipolarophile decelerate the reaction, while EDGs accelerate the reaction. For example, ozone reacts with the electron-rich 2-methylpropene about 100,000 times faster than the electron-poor tetrachloroethene (see reactivity scale below).[18]

This type resembles the inverse electron-demand Diels-Alder reaction, in which the diene LUMO combines with the dienophile HOMO.

doi:10.1021/ja01016a011

Reactivity

Concerted processes such as the 1,3-cycloaddition require a highly ordered transition state (high negative entropy of activation) and only moderate enthalpy requirements. Using competition reaction experiments, relative rates of addition for different cycloaddition reactions have been found to offer general findings on factors in reactivity.

  • Conjugation, especially with aromatic groups, increases the rate of reaction by stabilization of the transition state. During the transition, the two sigma bonds are being formed at different rates, which may generate partial charges in the transition state that can be stabilized by charge distribution into conjugated substituents.
  • More polarizable dipolarophiles are more reactive because diffuse electron clouds are better suited to initiate the flow of electrons.
  • Dipolarophiles with high angular strain are more reactive due to increased energy of the ground state.
  • Increased steric hindrance in the transition state as a result of unhindered reactants dramatically lowers the reaction rate.
  • Hetero-dipolarophiles add more slowly, if at all, compared to C,C-diapolarophiles due to a lower gain in sigma bond energy to offset the loss of a pi bond during the transition state.
  • Isomerism of the dipolarophile affects reaction rate due to sterics. trans-isomers are more reactive (trans-stilbene will add diphenyl(nitrile imide) 27 times faster than cis-stilbene) because during the reaction, the 120° bond angle shrinks to 109°, bringing eclipsing cis-substituents towards each other for increased steric clash.
See Huisgen reference doi:10.1002/anie.196306331.

Stereospecificity

1,3-dipolar cycloadditions usually result in retention of configuration with respect to both the 1,3-dipole and the dipolarophile. Such high degree of stereospecificity is a strong support for the concerted over the stepwise reaction mechanisms. As mentioned before, there are many examples that show that the reactions were stepwise, thus, presenting partial or no stereospecificity.

With respect to dipolarophile

cis-Substituents on the dipolarophilic alkene end up cis, and trans-substituents end up trans in the resulting five-membered cyclic compound (see scheme below).[19]

doi:10.3987/S-1978-01-0147

With respect to dipole

Generally, the stereochemistry of the dipole is not of major concern because only few dipoles could form stereogenic centers, and resonance structures allow bond rotation which scrambles the stereochemistry. However, the study of azomethine ylides has verified that cycloaddition is also stereospecific with respect to the dipole component. Diastereopure azomethine ylides are generated via electrocyclic ring opening of aziridines, and then rapidly trapped with strong dipolarophiles before bond rotation can take place (see scheme below).[20][21] If weaker dipolarophiles are used, bonds in the dipole have the chance to rotate, resulting in impaired cycloaddition stereospecificity.

These results altogether confirm that 1,3-dipolar cycloaddition is stereospecific, giving retention of both the 1,3-dipole and the dipolarophile.

doi:10.1021/ja00983a052

Diastereoselectivity

When two or more chiral centers are generated during the reaction, diastereomeric transition states and products can be obtained. In the Diels-Alder cycloaddition, the endodiastereoselectivity due to secondary orbital interactions is usually observed. In 1,3-dipolar cycloadditions, however, there are two forces that influence the diastereoselectivity: the attractive π-interaction (resembling secondary orbital interactions in the Diels-Alder cycloaddition) and the repulsive steric interaction. Unfortunately, these two forces often cancel each other, causing poor diastereoselection in 1,3-dipolar cycloaddition.

Examples of substrate-controlled diastereoselective 1,3-dipolar cycloadditions are shown below. First is the reaction between benzonitrile N-benzylide and methyl acrylate. In the transition state, the phenyl and the methyl ester groups stack to give the cis-substitution as the exclusive final pyrroline product. This favorable π-interaction offsets the steric repulsion between the phenyl and the methyl ester groups.[22] Second is the reaction between nitrone and dihydrofuran. The exo-selectivity is achieved to minimize steric repulsion.[23] Last is the intramolecular azomethine ylide reaction with alkene. The diastereoselectivity is controlled by the formation of a less strained cisfused ring system.[24]

doi:10.1021/ja00731a056

Directed 1,3-dipolar cycloaddition

Trajectory of the cycloaddition can be controlled to achieve a diastereoselective reaction. For example, metals can chelate to the dipolarophile and the incoming dipole and direct the cycloaddition selectively on one face. The example below shows addition of nitrile oxide to an enantiomerically pure allyl alcohol in the presence of a magnesium ion. The most stable conformation of the alkene places the hydroxyl group above the plane of the alkene. The magnesium then chelates to the hydroxyl group and the oxygen atom of nitrile oxide. The cycloaddition thus comes from the top face selectively.[25]

Directed dipolar cycloaddition.tif

Such diastereodirection has been applied in the synthesis of epothilones.[26]

Use of directed cycloaddition in Epothilones synthesis.tif

Regioselectivity

For asymmetric dipole-dipolarophile pairs, two regioisomeric products are possible. Both electronic/stereoelectronic and steric factors contribute to the regioselectivity of 1,3-dipolar cycloadditions.[27]

Electronic/Stereoelectronic effect

The dominant electronic interaction is the combination between the largest HOMO orbital and the largest LUMO orbital. Therefore, regioselectivity is governed by the atoms that bear the largest orbital HOMO and LUMO coefficients.[28][29]

For example, consider the cycloaddition of diazomethane to three dipolarophiles: methyl acrylate, styrene or methyl cinnamate. The carbon of diazomethane bears the largest HOMO orbital, while the terminal olefinic carbons of methyl acrylate and styrene bear the largest LUMO orbital. Hence, cycloaddition gives the substitution at the C-3 position regioselectively. For methyl cinnamate, the two substituents (Ph v.s. COOMe) compete at withdrawing electrons from the alkene. The carboxyl is the better electron-withdrawing group, causing the β-carbon to be most electrophilic. Thus, cycloaddition yields the carboxyl group on C-3 and the phenyl group on C-4 regioselectively.

doi:10.1021/ja00444a013 and doi:10.1021/ja00436a062

Steric effect

Steric effects can either cooperate or compete with the aforementioned electronic effects. Sometimes steric effects completely outweighs the electronic preference, giving the opposite regioisomer exclusively.[30]

For example, diazomethane generally adds to methyl acrylate to give 3-carboxyl pyrazoline. However, by putting more steric demands into the system, we start to observe the isomeric 4-carboxyl pyrazolines. The ratio of these two regioisomers depends on the steric demands. At the extreme, increasing the size from hydrogen to t-butyl shifts the regioselectivity from 100% 3-carboxyl to 100% 4-carboxyl substitution.[31][32]

ISBN 0-471-08364-X. and Koszinowski, J. (1980) (Ph.D. Thesis)

Synthetic Applications

1,3-dipolar cycloadditions are important routes toward the synthesis of many important 5-membered heterocycles such as triazoles, furans, isoxazoles, pyrrolidines, and others. Additionally, some cycloadducts can be cleaved to reveal the linear skeleton, providing another route toward the synthesis of aliphatic compounds. These reactions are tremendously useful also because they are stereospecific, diastereoselective and regioselective. Several examples are provided below.

Nitrile oxides

1,3-dipolar cycloaddition with nitrile oxides is a widely used masked-aldol reaction. Cycloaddition between a nitrile oxide and an alkene yields the cyclic isoxazoline product, whereas the reaction with an alkyne yields the isoxazole. Both isoxazolines and isoxazoles can be cleaved by hydrogenation to reveal aldol-type β-hydroxycarbonyl or Claisen-type β-dicarbonyl products, respectively.

Nitrile oxide-alkyne cycloaddition followed by hydrogenation was utilized in the synthesis of Miyakolide as illustrated in the figure below.[33]

Application of nitrile oxide in the synthesis of miyakolide.tif

Carbonyl ylides

1,3-dipolar cycloaddition reactions have emerged as powerful tools in the synthesis of complex cyclic scaffolds and molecules for medicinal, biological, and mechanistic studies. Among them, [3+2] cycloaddition reactions involving carbonyl ylides have extensively been employed to generate oxygen-containing five-membered cyclic molecules.[34]

Preparation of Carbonyl Ylides for 1,3-Dipolar Cycloaddition Reactions

Ylides are regarded as positively charged heteroatoms connected to negatively charged carbon atoms, which include ylides of sulfonium, thiocarbonyl, oxonium, nitrogen, and carbonyl.[35] Several methods exist for generating carbonyl ylides, which are necessary intermediates for generating oxygen-containing five-membered ring structures, for [3+2] cycloaddition reactions.

Synthesis of Carbonyl Ylides from Diazomethane Derivatives by Photocatalysis

One of the earliest examples of carbonyl ylide synthesis involves photocatalysis.[36] Photolysis of diazotetrakis(trifluoromethyl)cyclopentadiene* (DTTC) in the presence of tetramethylurea can generate the carbonyl ylide by an intermolecular nucleophilic attack and subsequent aromatization of the DTTC moiety.[36] This was isolated and characterized by X-ray crystallography due to the stability imparted by aromaticity, electron withdrawing trifluoromethyl groups, and the electron donating dimethylamine groups. Stable carbonyl ylide dipoles can then be used in [3+2] cycloaddition reactions with dipolarophiles.

Scheme 1. Photolysis of DTTC in the presence of tetramethylurea. Modified from Janulis, E. P.; Arduengo, A. J. J. Am. Chem. Soc. 1983, 105, 5929.

Another early example of carbonyl ylide synthesis by photocatalysis was reported by Olah et al.[37] Dideuteriodiazomethane was photolysed in the presence of formaldehyde to generate the dideuterioformaldehyde carbonyl ylide.

Scheme 2. Photolysis of Dideuteriodiazomethane with formaldehyde. Modified from Prakash, G. K. S.; Ellis, R. W.; Felberg, J. D.; Olah, G. A. J Am Chem Soc 1986, 108, 1341.
Synthesis of Carbonyl Ylides from Hydroxypyrones via Proton Transfer

Carbonyl ylides can be synthesized by acid catalysis of hydroxy-3-pyrones in the absence of a metal catalyst.[38] An initial tautomerization occurs, followed by elimination of the leaving group to aromatize the pyrone ring and to generate the carbonyl ylide. A cycloaddition reaction with a dipolarophile lastly forms the oxacycle. This approach is less widely employed due to its limited utility and requirement for pyrone skeletons.

Scheme 3. Acid-Catalyzed Synthesis of Carbonyl Ylides from Hydroxy-3-Pyrones. Modified from Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun. 1982, 1056.

5-hydroxy-4-pyrones can also be used to synthesize carbonyl ylides via an intramolecular hydrogen transfer.[39] After hydrogen transfer, the carbonyl ylide can then react with dipolarophiles to form oxygen-containing rings.

Scheme 4. Intramolecular Hydrogen Transfer-Mediated Synthesis of Carbonyl Ylides from 5-Hydroxy-4-Pyrones. Modified from Garst, M. E.; McBride, B. J.; Douglass III, J. G. Tetrahedron Lett. 1983, 24, 1675.
Synthesis of α-Halocarbonyl Ylides from Dihalocarbenes

Dihalocarbenes have also been employed to generate carbonyl ylides. The electron withdrawing nature of dihalocarbenes has been exploited by Landgrebe and coworkers for this purpose.[40][41][42] Both phenyl(bromodichloromethyl)mercury and phenyl(tribromomethyl)mercury have been converted to dichlorocarbenes and dibromocarbenes, respectively. The carbonyl ylide can be generated upon reaction of the dihalocarbenes with ketones or aldehydes. However, the synthesis of α-halocarbonyl ylides can also undesirably lead to the loss of carbon monoxide and the generation of the deoxygenation product.

Scheme 5. α-Halocarbonyl Ylide Synthesis via Dihalocarbene Intermediates. Modified from Padwa, A.; Hornbuckle, S. F. Chem Rev 1991, 91, 263.
Synthesis of Carbonyl Ylides from Diazomethane Derivatives by Metal Catalysis

A universal approach for generating carbonyl ylides involves metal catalysis of α-diazocarbonyl compounds, generally in the presence of dicopper or dirhodium catalysts.[43] After release of nitrogen gas and conversion to the metallocarbene, an intermolecular reaction with a carbonyl group can generate the carbonyl ylide. Subsequent cycloaddition reaction with an alkene or alkyne dipolarophile can afford oxygen-containing five-membered rings. Popular catalysts that give modest yields towards synthesizing oxacycles include Rh2(OAc)4 and Cu(acac)2.[44][45]

Scheme 6. Metal-Catalyzed Synthesis of Carbonyl Ylides. Reproduced from Hodgson, D. M.; Bruckl, T.; Glen, R.; Labande, A. H.; Selden, D. A.; Dossetter, A. G.; Redgrave, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5450.

Mechanism of the 1,3-Dipolar Cycloaddition Reaction Mediated by Metal Catalysis of Diazocarbonyl Compounds

The universality and extensive use of 1,3-dipolar cycloaddition reactions mediated by metal catalysis of diazocarbonyl molecules, for synthesizing oxygen-containing five-membered rings, has spurred significant interest into its mechanism. Several groups have investigated the mechanism to expand the scope of synthetic molecules with respect to regio- and stereo-selectivity. However, due to the high turn over frequencies of these reactions, the intermediates and mechanism remains elusive. The generally accepted mechanism, developed by characterization of stable ruthenium-carbenoid complexes[46] and rhodium metallocarbenes,[47] involves an initial formation of a metal-carbenoid complex from the diazo compound. Elimination of nitrogen gas then affords a metallocarbene. An intramolecular nucleophilic attack by the carbonyl oxygen regenerates the metal catalyst and forms the carbonyl ylide. The carbonyl ylide can then react with an alkene or alkyne, such as dimethyl acetylenedicarboxylate (DMAD) to generate the oxacycle.

Scheme 7. Accepted Mechanism of the 1,3-Dipolar Cycloaddition Reaction Mediated by Metal Catalysis (Example Dirhodium Catalyst) of Diazocarbonyl Compounds. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.

However, it is uncertain whether the metallocarbene intermediate generates the carbonyl ylide. In some cases, metallocarbenes can also react directly with dipolarophiles.[48] In these cases, the metallocarbene, such as the dirhodium(II)tetracarboxylate carbene, is stabilized through hyperconjugative metal enolate-type interactions.[49][50][51][52]Subsequent 1,3-dipolar cycloaddition reaction occurs through a transient metal-complexed carbonyl ylide. Therefore, a persistent metallocarbene can influence the stereoselectivity and regioselectivity of the 1,3-dipolar cycloaddition reaction based on the stereochemistry and size of the metal ligands.

The dirhodium(II)tetracarboxylate metallocarbene stabilized by πC-Rh→πC=O hyperconjugation. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.

The mechanism of the 1,3-dipolar cycloaddition reaction between the carbonyl ylide dipole and alkynyl or alkenyl dipolarophiles has been extensively investigated with respect to regioselectivity and stereoselectivity. As symmetric dipolarophiles have one orientation for cycloaddition, only one regioisomer, but multiple stereoisomers can be obtained.[52] On the contrary, unsymmetric dipolarophiles can have multiple regioisomers and stereoisomers. These regioisomers and stereoisomers may be predicted based on frontier molecular orbital (FMO) theory, steric interactions, and stereoelectronic interactions.[53][54]

Scheme 9. Products of the 1,3-Dipolar Cycloaddition Reaction Between Carbonyl Ylide Dipoles and Alkenyl or Alkynyl Dipolarophiles. Modified from M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.
Regioselectivity of the 1,3-Dipolar Cycloaddition Reaction Mediated by Metal Catalysis of Diazocarbonyl Compounds

Regioselectivity of 1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkynyl or alkenyl dipolarophiles is essential for generating molecules with defined regiochemistry. FMO theory and analysis of the HOMO-LUMO energy gaps between the dipole and dipolarophile can rationalize and predict the regioselectivity of experimental outcomes.[55][56] The HOMOs and LUMOs can belong to either the dipole or dipolarophile, for which HOMOdipole-LUMOdipolarophile or HOMOdipolarophile-LUMOdipole interactions can exist. Overlap of the orbitals with the largest coefficients can ultimately rationalize and predict results.

Scheme 10. Diagram of the Molecular Orbital Interactions of HOMOdipole-LUMOdipolarophile or HOMOdipolarophile-LUMOdipole Between a Carbonyl Ylide Dipole and Alkenyl Dipolarophile.

The archetypal regioselectivity of the 1,3-dipolar cycloaddition reaction mediated by carbonyl ylide dipoles has been examined by Padwa and coworkers.[54][57] Using a Rh2(OAc)4catalyst in benzene, diazodione underwent a 1,3-dipolar cycloaddition reaction with methyl propiolate and methyl propargyl ether. The reaction with methyl propiolate affords two regioisomers with the major resulting from the HOMOdipole-LUMOdipolarophile interaction, which has the largest coefficients on the carbon proximal to the carbonyl group of the carbonyl ylide and on the methyl propiolate terminal alkyne carbon. The reaction with methyl propargyl ether affords one regioisomer resulting from the HOMOdipolarophile-LUMOdipole interaction, which has largest coefficients on the carbon distal to the carbonyl group of the carbonyl ylide and on the methyl propargyl ether terminal alkyne carbon.

Scheme 11. Regioselectivity and Molecular Orbital Interactions of the 1,3-Dipolar Cycloaddition Reaction Between a Diazodione and Methyl Propiolate or Methyl Propargyl Ether. Modified from Padwa, A.; Weingarten, M. D. Chem Rev 1996, 96, 223.

Regioselectivities of 1,3-dipolar cycloaddition reactions mediated by metal catalysis of diazocarbonyl compounds may also be influenced by the metal through formation of stable metallocarbenes.[48][58] Stabilization of the metallocarbene, via metal enolate-type interactions, will prevent the formation of carbonyl ylides, resulting in a direct reaction between the metallocarbene dipole and an alkynyl or alkenyl dipolarophile (see image of The dirhodium(II)tetracarboxylate metallocarbene stabilized by πC-Rh→πC=O hyperconjugation.). In this situation, the metal ligands will influence the regioselectivity and stereoselectivity of the 1,3-dipolar cycloaddition reaction.

Stereoselectivity and Asymmetric Induction of the 1,3-Dipolar Cycloaddition Reaction Mediated by Metal Catalysis of Diazocarbonyl Compounds

The stereoselectivity of 1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkenyl dipolarophiles has also been closely examined. For alkynyl dipolarophiles, stereoselectivity is not an issue as relatively planar sp2 carbons are formed, while regioselectivity must be considered (see image of the Products of the 1,3-Dipolar Cycloaddition Reaction Between Carbonyl Ylide Dipoles and Alkenyl or Alkynyl Dipolarophiles). However, for alkenyl dipolarophiles, both regioselectivity and stereoselectivity must be considered as sp3 carbons are generated in the product species.

1,3-dipolar cycloaddition reactions between carbonyl ylide dipoles and alkenyl dipolarophiles can generate diastereomeric products.[52] The exo product is characterized with dipolarophile substituents being cis to the ether bridge of the oxacycle. The endo product is characterized with the dipolarophile substituents being trans to the ether bridge of the oxacycle. Both products can be generated through pericyclic transitions states involving concerted synchronous or concerted asynchronous processes.

One early example conferred stereoselectivity in terms of endo and exo products with metal catalysts and Lewis acids.[59] Reactions with just the metal catalyst Rh2(OAc)4 prefer the exo product while reactions with the additional Lewis acid Yb(OTf)3 prefer the endo product. The endo selectivity observed for Lewis acid cycloaddition reactions is attributed to the optimized orbital overlap of the carbonyl π systems between the dipolarophile coordinated by Yb(Otf)3 (LUMO) and the dipole (HOMO). After many investigations, two primary approaches for influencing the stereoselectivity of carbonyl ylide cycloadditions have been developed that exploit the chirality of metal catalysts and Lewis acids.[52]

Facial Selectivity of the 1,3-Dipolar Cycloaddition Reaction using a Metal Catalyst and Lewis Acid
Rationale for the Endo Selectivity of the 1,3-Dipolar Cycloaddition Reaction with a Lewis Acid

The first approach employs chiral metal catalysts to modulate the endo and exo stereoselectivity. The chiral catalysts, in particular Rh2[(S)-DOSP]4 and Rh2[(S)-BPTV]4 can induce modest asymmetric induction and was used to synthesize the antifungal agent pseudolaric acid A.[60] This is a result of the chiral metal catalyst remaining associated with the carbonyl ylide during the cycloaddition, which confers facial selectivity. However, the exact mechanisms are not yet fully understood.

Asymmetric Induction of the 1,3-Dipolar Cycloaddition Reaction with Chiral Metal Catalysts

The second approach employs a chiral Lewis acid catalyst to induce facial stereoselectivity after the generation of the carbonyl ylide using an achiral metal catalyst.[61] The chiral Lewis acid catalyst is believed to coordinate to the dipolarophile, which lowers the LUMO of the dipolarophile while also leading to enantioselectivity.

Asymmetric Induction of the 1,3-Dipolar Cycloaddition Reaction with Chiral Lewis Acid Catalysts

Azomethine ylides

1,3-Dipolar cycloaddition between an azomethine ylide and an alkene furnishes an azacyclic structure, such as pyrrolidine. This strategy has been applied to the synthesis of spirotryprostatin A.[62]

Application of azomethine ylide in the synthesis of spirotryprostatin.tif

Ozone

Ozonolysis is a very important organic reaction. Alkenes and alkynes can be cleaved by ozonolysis to give aldehyde, ketone or carboxylic acid products.

Biological Applications

The 1,3-dipolar cycloaddition between organic azides and terminal alkynes (i.e., the Huisgen cycloaddition) has been widely utilized for bioconjugation.

Copper catalysis

The Huisgen reaction generally does not proceed readily under mild conditions. Meldal et al. and Sharpless et al. independently developed a copper(I)-catalyzed version of the Huisgen reaction, CuAAC (for Copper-catalyzed Azide-Alkyne Cycloaddition), which proceeds very readily in mild, including physiological, conditions (neutral pH, room temperature and aqueous solution).[63][64] This reaction is also bioorthogonal: azides and alkynes are both generally absent from biological systems and therefore these functionalities can be chemoselectively reacted even in the cellular context. They also do not react with other functional groups found in Nature, so they do not perturb biological systems. The reaction is so versatile that it is termed the “Click” chemistry. Although copper(I) is toxic, many protective ligands have been developed to both reduce cytotoxicity and improve rate of CuAAC, allowing it to be used in in vivo studies.[65]

Copper catalyzed AAC.tif

For example, Bertozzi et al. reported the metabolic incorporation of azide-functionalized sugars into the glycan of the cell membrane, and subsequent labeling with fluorophore-alkyne conjugate. The now fluorescently labeled cell membrane can be imaged under the microscope.[66]

Metabolic labeling with GlcNAz and click chemistry.tif

Strain-promoted cycloaddition

To avoid toxicity of copper(I), Bertozzi et al. developed the Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC) between organic azide and strained cyclooctyne. The angle distortion of the cyclooctyne helps to speed up the reaction, enabling it to be used in physiological conditions without the need for the catalyst.[67]

Strained promoted AAC.tif

For instance, Ting et al. introduced an azido functionality onto specific proteins on the cell surface using a ligase enzyme. The azide-tagged protein is then labeled with cyclooctyne-fluorophore conjugate to yield a fluorescently labeled protein.[68]

Enzyme-mediated labeling with azidooctanoic acid and SPAAC.tif
CLIP

Computational Studies of 1,3-Dipolar [3 + 2]-Cycloaddition Reactions of Fullerene-C60 with Nitrones

Richard Tia*, Jacob Amevor and Evans Adei

Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

*Corresponding Author:
Richard Tia
Department of Chemistry
Kwame Nkrumah University of Science and Technology
Kumasi, Ghana
Tel: 00233(0) 243574146
E-mail: richtiagh@yahoo.com

Received date: May 12, 2014; Accepted date: Septem

Image result for [3 + 2] Dipolar Cycloadditions

References

  1. Jump up^ Huisgen, Rolf (1963). “1.3-Dipolare Cycloadditionen Ruckschau und Ausblick.” (abstract). Angewandte Chemie. 75: 604–637. doi:10.1002/ange.19630751304.
  2. ^ Jump up to:a b Huisgen, Rolf (November 1963). “Kinetics and Mechanism of 1,3-Dipolar Cycloadditions”. Angewandte Chemie International Edition. 2 (11): 633–645. doi:10.1002/anie.196306331.
  3. Jump up^ Fireston, R (1968). “Mechanism of 1,3-dipolar cycloadditions”. Journal of Organic Chemistry. 33: 2285–2290. doi:10.1021/jo01270a023.
  4. Jump up^ Huisgen, Rolf (1976). “1,3-Dipolar cycloadditions. 76. Concerted nature of 1,3-dipolar cycloadditions and the question of diradical intermediates”. Journal of Organic Chemistry. 41: 403–419. doi:10.1021/jo00865a001.
  5. Jump up^ Mloston, G.; Langhals, E.; Huisgen, Rolf (1986). “First Two-Step 1,2-Dipolar Cycloadditons: Nonstereospecificity”. J. Am. Chem. Soc. 108: 6401–66402. doi:10.1021/ja00280a053.
  6. Jump up^ Seyyed Amir, Siadati (2015). “An example of a stepwise mechanism for the catalyst-free 1,3-dipolar cycloaddition between a nitrile oxide and an electron rich alkene”. Tetrahedron Letters. 56: 4857–4863. doi:10.1016/j.tetlet.2015.06.048.
  7. Jump up^ Huisgen, Rolf (1963). “1,3-Dipolar Cycloadditions. Past and Future”. Angewandte Chemie International Edition. 2: 565–598. doi:10.1002/anie.196305651.
  8. Jump up^ Cox, A; Thomas, L; Sheridan, J (1958). “Microwave Spectra of Diazomethane and its Deutero Derivatives”. Nature. 181 (4614): 1000–1001. doi:10.1038/1811000a0.
  9. Jump up^ Hilberty, P; Leforestier, C (1978). “Expansion of molecular orbital wave functions into valence bond wave functions. A simplified procedure.”. Journal of the American Chemical Society. 100: 2012–2017. doi:10.1021/ja00475a007.
  10. Jump up^ McGarrity, J.F.; Patai, Saul (1978). “Basicity, acidity and hydrogen bonding”. Diazonium and Diazo Groups. 1: 179–230. doi:10.1002/9780470771549.ch6.
  11. Jump up^ Berner, Daniel; McGarrity, John (1979). “Direct observation of the methyldiazonium ion in fluorosulfuric acid”. Journal of the American Chemical Society. 101: 3135–3136. doi:10.1021/ja00505a059.
  12. Jump up^ Muller, Eugen; Rundel, Wolfgans (1956). “Untersuchungen an Diazomethanen, VI. Mitteil.: Umsetzung von Diazoäthan mit Methyllithium”. Chemische Berichte. 89: 1065–1071. doi:10.1002/cber.19560890436.
  13. Jump up^ Geittner, Jochen; Huisgen, Rolph; Reissig, Hans-Ulrich (1978). “Solvent Dependence of Cycloaddition Rates of Phenyldiazomethane and Activation Parameters”. Heterocycles. 11: 109–120. doi:10.3987/S(N)-1978-01-0109.
  14. Jump up^ Huisgen, Rolph; Reissig, Hans-Ulrich; Huber, Helmut; Voss, Sabine (1979). “α-Diazocarbonyl compounds and enamines – a dichotomy of reaction paths”. Tetrahedron Letters. 20: 2987–2990. doi:10.1016/S0040-4039(00)70991-9.
  15. Jump up^ Sustmann, R (1974). “Orbital energy control of cycloaddition reactivity”. Pure and Applied Chemistry. 40: 569–593. doi:10.1351/pac197440040569.
  16. Jump up^ Geittner, Jochen; Huisgen, Rolf (1977). “Kinetics of 1,3-dipolar cycloaddition reactions of diazomethane; A correlation with homo-lumo energies”. Tetrahedron Letters. 18: 881–884. doi:10.1016/S0040-4039(01)92781-9.
  17. Jump up^ Huisgen, Rolf; Szeimies, Gunter; Mobius, Leander (1967). “K1.3-Dipolare Cycloadditionen, XXXII. Kinetik der Additionen organischer Azide an CC-Mehrfachbindungen”. Chemische Berichte. 100: 2494–2507. doi:10.1002/cber.19671000806.
  18. Jump up^ Williamson, D. G.; Cvetanovic, R. J. (1968). “Rates of ozone-olefin reactions in carbon tetrachloride solutions”. Journal of the American Chemical Society. 90: 3668–3672. doi:10.1021/ja01016a011.
  19. Jump up^ Bihlmaier, Werner; Geittner, Jochen; Huisgen, Rolf; ReissigP, Hans-Ulrich (1978). “The Stereospecificity of Diazomethane Cycloadditions”. Heterocycles. 10: 147–152. doi:10.3987/S-1978-01-0147.
  20. Jump up^ Huisgen, Rolf; Scheer, Wolfgang; Huber, Helmut (1967). “Stereospecific Conversion of cis-trans Isomeric Aziridines to Open-Chain Azomethine Ylides”. Journal of the American Chemical Society. 89: 1753–1755. doi:10.1021/ja00983a052.
  21. Jump up^ Dahmen, Alexander; Hamberger, Helmut; Huisgen, Rolf; Markowski, Volker (1971). “Conrotatory ring opening of cyanostilbene oxides to carbonyl ylides”. Journal of the Chemical Society D: Chemical Communications: 1192–1194. doi:10.1039/C29710001192.
  22. Jump up^ Padwa, Albert; Smolanoff, Joel (1971). “Photocycloaddition of arylazirenes with electron-deficient olefins”. Journal of the American Chemical Society. 93: 548–550. doi:10.1021/ja00731a056.
  23. Jump up^ Iwashita, Takashi; Kusumi, Takenori; Kakisawa, Hiroshi (1979). “A Synthesis of dl-isoretronecanol”. Chemistry Letters: 1337–1340. doi:10.1246/cl.1979.1337.
  24. Jump up^ Wang, Chia-Lin; Ripka, William; Confalone, Pat (1984). “A short and stereospecific synthesis of (±)-α-lycorane”. Tetrahedron Letters. 25: 4613–4616. doi:10.1016/S0040-4039(01)91213-4.
  25. Jump up^ Kanemasa, Shuji (2002). “Metal-Assisted Stereocontrol of 1,3-Dipolar Cycloaddition Reactions”. Synthesis Letters. 2002: 1371–1387. doi:10.1055/s-2002-33506.
  26. Jump up^ Bode, Jeffrey; Carreira, Erick (2011). “Stereoselective Syntheses of Epothilones A and B via Directed Nitrile Oxide Cycloaddition.”. Journal of the American Chemical Society. 123 (15): 3611–3612. doi:10.1021/ja0155635. PMID 11472140.
  27. Jump up^ Vsevolod V. Rostovtsev; Luke G. Green; Valery V. Fokin; K. Barry Sharpless (2002). “A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective Ligation of Azides and Terminal Alkynes”. Angewandte Chemie International Edition. 41 (14): 2596–22599. doi:10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4. PMID 12203546.
  28. Jump up^ Caramella, Pierluigi; Houk, K.N. (1976). “Geometries of nitrilium betaines. The clarification of apparently anomalous reactions of 1,3-dipoles”. Journal of the American Chemical Society. 98: 6397–6399. doi:10.1021/ja00436a062.
  29. Jump up^ Caramella, Pierluigi; Gandour, Ruth W.; Hall, Janet A.; Deville, Cynthia G.; Houk, K. N. (1977). “A derivation of the shapes and energies of the molecular orbitals of 1,3-dipoles. Geometry optimizations of these species by MINDO/2 and MINDO/3”. Journal of the American Chemical Society. 99: 385–392. doi:10.1021/ja00444a013.
  30. Jump up^ Huisgen, Rolf (November 1963). “Kinetics and Mechanism of 1,3-Dipolar Cycloadditions” (abstract). Angewandte Chemie International Edition. 2 (11): 633–645. doi:10.1002/anie.196306331.
  31. Jump up^ Padwa, Albert (1983). 1,3-Dipolar Cycloaddition Chemistry. General Heterocyclic Chemistry Series. 1. United States of America: Wiley-Interscience. pp. 141–145. ISBN 0-471-08364-X.
  32. Jump up^ Koszinowski, J. (1980). thesis (Ph.D. Thesis).
  33. Jump up^ Evans, David; Ripin, David; Halstead, David; Campos, Kevin (1999). “Synthesis and Absolute Stereochemical Assignment of (+)-Miyakolide”. Journal of the American Chemical Society. 121: 6816–6826. doi:10.1021/ja990789h.
  34. Jump up^ Synthetic Reactions of M=C and M=N Bonds: Ylide Formation, Rearrangement, and 1,3-Dipolar Cycloaddition; Hiyama, T. W., J., Ed.; Elsevier, 2007; Vol. 11.
  35. Jump up^ Padwa, A.; Hornbuckle, S. F. Ylide Formation from the Reaction of Carbenes and Carbenoids with Heteroatom Lone Pairs Chem Rev 1991, 91, 263.
  36. ^ Jump up to:a b Janulis, E. P.; Arduengo, A. J. Structure of an Electronically Stabilized Carbonyl Ylide J Am Chem Soc 1983, 105, 5929.
  37. Jump up^ Prakash, G. K. S.; Ellis, R. W.; Felberg, J. D.; Olah, G. A. Formaldehyde 0-Methylide, [CH2=O+-CH2: The Parent Carbonyl Ylide] J Am Chem Soc 1986, 108, 1341.
  38. Jump up^ Sammes, P. G.; Street, L. J. Intra molecular Cyclo additions with Oxido pyrylium Ylides J. Chem. Soc., Chem. Commun. 1982, 1056.
  39. Jump up^ Garst, M. E.; McBride, B. J.; Douglass III, J. G. Intramolecular cycloadditions with 2-(ω-alkenyl)-5-hydroxy-4-pyrones Tetrahedron Lett. 1983, 24, 1675.
  40. Jump up^ Gisch, J. F.; Landgrebe, J. A. Dichlorocarbene from flash vacuum pyrolysis of trimethyl(trichloromethyl)silane. Possible observation of 1,1-dichloro-3-phenylcarbonyl ylide J Org Chem 1985, 50, 2050.
  41. Jump up^ Huan, Z. W.; Landgrebe, J. A.; Peterson, K. Dibromocarbonyl ylides: Deoxygenation of aldehydes and ketones by dibromocarbene J Org Chem 1983, 48, 4519.
  42. Jump up^ Martin, C. W.; Lund, P. R.; Rapp, E.; Landgrebe, J. A. Halogenated carbonyl ylides in the reactions of mercurial dihalocarbene precursors with substituted benzaldehydes J Org Chem 1978, 43, 1071.
  43. Jump up^ Hodgson, D. M.; Bruckl, T.; Glen, R.; Labande, A. H.; Selden, D. A.; Dossetter, A. G.; Redgrave, A. J. Catalytic enantioselective intermolecular cycloadditions of 2-diazo-3,6-diketoester-derived carbonyl ylides with alkene dipolarophiles Proceedings of the National Academy of Sciences of the United States of America 2004, 101, 5450.
  44. Jump up^ Padwa, A.; Hertzog, D. L.; Nadler, W. R. Intramolecular Cycloaddition of Isomunchnone Dipoles to Heteroaromatic π-Systems J Org Chem 1994, 59, 7072.
  45. Jump up^ Hamaguchi, M.; Ibata, T. New Type of Mesoionic System. 1,3-Dipolar Cycloaddition of Isomunchnon With Ethylenic Compounds Chem Lett 1975, 499.
  46. Jump up^ Park, S. B.; Sakata, N.; Nishiyama, H. Aryloxycarbonylcarbene Complexes of Bis(oxazolinyl)pyridineruthenium as Active Intermediates in Asymmetric Catalytic Cyclopropanations Chem-Eur J 1996, 2, 303.
  47. Jump up^ Snyder, J. P.; Padwa, A.; Stengel, T.; Arduengo, A. J., 3rd; Jockisch, A.; Kim, H. J. A Stable Dirhodium Tetracarboxylate Carbenoid: Crystal Structure, Bonding Analysis, and Catalysis J Am Chem Soc 2001, 123, 11318.
  48. ^ Jump up to:a b Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Catalytic enantioselective rearrangements and cycloadditions involving ylides from diazo compounds Chem Soc Rev 2001, 30, 50.
  49. Jump up^ Yoshikai, N.; Nakamura, E. Theoretical Studies on Diastereo- and Enantioselective Rhodium-Catalyzed Cyclization of Diazo Compound via Intramolecular C[BOND]H Bond Insertion Adv Synth Catal 2003, 345, 1159.
  50. Jump up^ Nakamura, E.; Yoshikai, N.; Yamanaka, M. Mechanism of C−H Bond Activation/C−C Bond Formation Reaction between Diazo Compound and Alkane Catalyzed by Dirhodium Tetracarboxylate J Am Chem Soc 2002, 124, 7181.
  51. Jump up^ Costantino, G.; Rovito, R.; Macchiarulo, A.; Pellicciari, R. Structure of metal–carbenoid intermediates derived from the dirhodium(II)tetracarboxylate mediated decomposition of α-diazocarbonyl compounds: a DFT study J Mol Struc-Theochem 2002, 581, 111.
  52. ^ Jump up to:a b c d M. Hodgson, D.; H. Labande, A.; Muthusamy, S. In Organic Reactions; John Wiley & Sons, Inc.: 2004.
  53. Jump up^ Suga, H.; Ebiura, Y.; Fukushima, K.; Kakehi, A.; Baba, T. Efficient Catalytic Effects of Lewis Acids in the 1,3-Dipolar Cycloaddition Reactions of Carbonyl Ylides with Imines J Org Chem 2005, 70, 10782.
  54. ^ Jump up to:a b Padwa, A.; Fryxell, G. E.; Zhi, L. Tandem cyclization-cycloaddition reaction of rhodium carbenoids. Scope and mechanistic details of the process J Am Chem Soc 1990, 112, 3100.
  55. Jump up^ Houk, K. N.; Sims, J.; Duke, R. E.; Strozier, R. W.; George, J. K. Frontier molecular orbitals of 1,3 dipoles and dipolarophiles J Am Chem Soc 1973, 95, 7287.
  56. Jump up^ Houk, K. N.; Rondan, N. G.; Santiago, C.; Gallo, C. J.; Gandour, R. W.; Griffin, G. W. Theoretical studies of the structures and reactions of substituted carbonyl ylides J Am Chem Soc 1980, 102, 1504.
  57. Jump up^ Padwa, A.; Weingarten, M. D. Cascade Processes of Metallo Carbenoids Chem Rev 1996, 96, 223.
  58. Jump up^ Padwa, A.; Austin, D. J.; Hornbuckle, Ligand-Induced Selectivity in the Rhodium(II)-Catalyzed Reactions of α-Diazo Carbonyl Compounds S. F. J Org Chem 1996, 61, 63.
  59. Jump up^ Suga, H.; Kakehi, A.; Ito, S.; Inoue, K.; Ishida, H.; Ibata, T. Stereocontrol in a Ytterbium Triflate-Catalyzed 1,3-Dipolar Cycloaddition Reaction of Carbonyl Ylide with N-Substituted Maleimides and Dimethyl Fumarate B Chem Soc Jpn 2001, 74, 1115.
  60. Jump up^ Geng, Z.; Chen, B.; Chiu, P. Total Synthesis of Pseudolaric Acid A Angewandte Chemie 2006, 45, 6197.
  61. Jump up^ Suga, H.; Inoue, K.; Inoue, S.; Kakehi, A.; Shiro, M. Chiral 2,6-Bis(oxazolinyl)pyridine−Rare Earth Metal Complexes as Catalysts for Highly Enantioselective 1,3-Dipolar Cycloaddition Reactions of 2-Benzopyrylium-4-olates J Org Chem 2005, 70, 47.
  62. Jump up^ Onishi, Tomoyuki; Sebahar, Paul; Williams, Robert (2003). “Concise, Asymmetric Total Synthesis of Spirotryprostatin A”. Organic Letters. 5: 3135–3137. doi:10.1021/ol0351910. PMID 12917000.
  63. Jump up^ Tornoe, Christian; Christensen, Caspar; Meldal, Morten (2002). “Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides”. Journal of Organic Chemistry. 67 (9): 3057–3064. doi:10.1021/jo011148j. PMID 11975567.
  64. Jump up^ Rostovtsev, Vsevolod; Green, Luke; Fokin, Valery; Sharpless, Barry K. (2002). “A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective Ligation of Azides and Terminal Alkynes”. Angewandte Chemie International Edition. 41: 2596–2599. doi:10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4. PMID 12203546.
  65. Jump up^ Besanceney-Webler, Christen; Jiang, Hao; Zheng, Tianqing; Feng, Lei; Soriano del Amo, David; Wang, Wei; Klivansky, Liana M.; Marlow, Florence L.; Liu, Yi; Wu, Peng (2011). “Increasing the Efficacy of Bioorthogonal Click Reactions for Bioconjugation: A Comparative Study”. Angewandte Chemie International Edition. 50: 8051–8056. doi:10.1002/anie.201101817. PMC 3465470Freely accessible. PMID 21761519.
  66. Jump up^ Breidenbach, Mark; Gallagher, Jennifer; King, David; Smart, Brian; Wu, Peng; Bertozzi, Carolyn (2010). “Targeted metabolic labeling of yeast N-glycans with unnatural sugars”. Proceedings of the National Academy of Sciences of the United States of America. 107 (9): 3988–3993. doi:10.1073/pnas.0911247107. PMC 2840165Freely accessible. PMID 20142501.
  67. Jump up^ Agard, Nicholas; Prescher, Jennifer; Bertozzi, Carolyn (2004). “A Strain-Promoted [3 + 2] Azide−Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems”. Journal of the American Chemical Society. 46: 15046–15047. doi:10.1021/ja044996f. PMID 15547999.
  68. Jump up^ Fernandez-Suarez, Marta; Baruah, Hemanta; Martinez-Hernandez, Laura; Xie, Kathleen; Baskin, Jeremy; Bertozzi, Carolyn; Ting, Alice (2007). “Redirecting lipoic acid ligase for cell surface protein labeling with small-molecule probes”. Nature Biotechnology. 25: 1483–1487. doi:10.1038/nbt1355. PMC 2654346Freely accessible. PMID 18059260

 

///////////////[3 + 2] Dipolar Cycloadditions,  Flow Reactors

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Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

 FLOW CHEMISTRY, flow synthesis  Comments Off on Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions
Jan 022017
 

Abstract Image

Over the last 20 years organic carbamates have found numerous applications in pesticides, fungicides, herbicides, dyes, pharmaceuticals, cosmetics, and as protecting groups and intermediates for polyurethane synthesis. Recently, in order to avoid phosgene-based synthesis of carbamates, many environmentally benign and alternative pathways have been investigated. However, few examples of carbamoylation of aniline in continuous-flow apparatus have been reported. In this work, we report a high-yielding, dimethyl carbonate (DMC)-mediated carbamoylation of aniline in a fixed-bed continuously fed reactor employing basic zinc carbonate as catalyst. Several variables of the system have been investigated (i.e. molar ratio of reagents , flow rate, and reaction temperature) to optimize the operating conditions of the system.

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Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

Department of Environmental Sciences, Informatics and Statistics, Ca’ Foscari University of Venice, Dorsoduro 2137, 30123 Venezia, Italia
Org. Process Res. Dev., 2013, 17 (4), pp 679–683
*Tel.: (+39) 041 234 8642. Fax: (+39) 041 234 8620. E-mail: tundop@unive.it.

PIETRO TUNDO

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PIETRO R. TUNDO is Professor of Organic Chemistry at Ca’ Foscari University of Venice (Italy).
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).
He is Member of the Bureau of IUPAC.

P: Tundo is author of about 300 scientific publications, 40 patents and many books.
His scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry, heteropolyacids, and finally safe alternatives to harmful chemicals.
He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731). He founded and was Chairman (2004-2016) of the Working Party on “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

Founder of the IUPAC International Conferences Series on Green Chemistry, he was awarded by American Chemical Society on 1983 (Kendall Award, with Janos Fendler), and by Federchimica (Italian association of chemical industries) on 1997 (An Intelligent Future).

P. Tundo coordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia, Italy) sponsored by the EU, UNESCO and NATO.
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).

He is holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731) and author of about 260 scientific publications and 30 patents.

Scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry and finally, heteropolyacids.

He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and presently is Chairman of Working Party of “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

Founder of the IUPAC International Conferences Series on Green Chemistry, he was awarded by American Chemical Society on 1983 (Kendall Award, with Janos Fendler), and by Federchimica (Italian association of chemical industries) on 1997 (An Intelligent Future).

P. Tundo co-ordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia), the latter sponsored by the EU, UNESCO and NATO.

Contact:

Professor of Organic Chemistry
Ca’ Foscari University of Venice
IUPAC Bureau Member
Tel. +39 041 2348642
Mob. +39 349 3486191
E-mail: tundop@unive.it

Phone 041 234 8642 / Lab .: 041 234 8669
E-mail tundop@unive.it
green.chemistry@unive.it – 6th IUPAC Conference on Green Chemistry
unescochair@unive.it – TUNDO Pietro
Fax 041 234 8620
Web www.unive.it/persone/tundop

////////Carbamoylation of Aniline, Dimethyl Carbonate, Continuous-Flow Conditions, flow synthesis

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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Enantioselective Borohydride Reduction of Ketones Catalyzed by Optically Active Cobalt Complexes

 FLOW CHEMISTRY, flow synthesis  Comments Off on Enantioselective Borohydride Reduction of Ketones Catalyzed by Optically Active Cobalt Complexes
Nov 282016
 

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Homogeneous Enantioselective Catalysis in a Continuous-Flow Microreactor: Highly Enantioselective Borohydride Reduction of Ketones Catalyzed by Optically Active Cobalt Complexes

Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Hitachi Research Laboratory, Hitachi, Ltd., 832-2 Horiguchi, Hitachinaka, Ibaraki 312-0034, Japan
§ Hitachi Plant Technologies, Ltd., 603 Kandatsu-machi, Tsuchiura, Ibaraki 300-0013, Japan
Org. Process Res. Dev., 2012, 16 (6), pp 1235–1240
DOI: 10.1021/op300061k

Abstract

Abstract Image

Highly enantioselective homogeneous catalysis under continuous-flow conditions was established for the cobalt-catalyzed borohydride reduction of tetralone derivatives. A microreactor allowed higher reaction temperature with the residence time of 12 min than the corresponding batch system to maintain enantioselectivity as well as reactivity. The present system was directly applied to gram-scale synthesis to afford the reduced product with 92% ee.

////////////Homogeneous Enantioselective Catalysis,  Continuous-Flow Microreactor, Highly Enantioselective Borohydride, Reduction of Ketones Catalyzed,  Optically Active Cobalt Complexes

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Continuous-Flow Diazotization

 FLOW CHEMISTRY, flow synthesis  Comments Off on Continuous-Flow Diazotization
Nov 242016
 

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Characterization Data of Compound 7

Mp: 118–120 °C. MS (M + H+): 314.
HRMS (ESI) m/z: Calcd for C16H15N3NaO4, (M + Na+): 336.0960. Found: 336.0899.
IR (KBr) ν/cm–1: 3447, 3339, 1717, 1714, 1699, 1594.
1H NMR (CDCl3, 400 MHz) δ/ppm: 8.50 (s, 1H, Ar–H), 7.88 (d, J = 8.8 Hz, 1H, Ar–H), 7.76 (d, J = 7.6 Hz, 1H, Ar–H), 7.60 (d, J = 8.0 Hz, 1H, Ar–H), 7.54 (t, J = 7.2 Hz, 1H, Ar–H), 7.41 (t, J = 7.2 Hz, 1H, Ar–H), 6.71 (d, J = 9.2 Hz, 1H, Ar–H), 6.28 (br s, 2H, −NH2), 3.91 (s, 3H, −CH3), 3.89 (s, 3H, −CH3).
13C NMR (CDCl3, 100 MHz) δ/ppm: 168.2, 168.0, 152.9, 151.6, 143.4, 131.7, 131.2, 129.4, 128.8, 128.0, 126.3, 118.9, 117.1, 109.8, 52.3, 51.9.

 

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Continuous-Flow Diazotization for Efficient Synthesis of Methyl 2-(Chlorosulfonyl)benzoate: An Example of Inhibiting Parallel Side Reactions

National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00238
Publication Date (Web): November 17, 2016
Copyright © 2016 American Chemical Society
*Tel.: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.

Abstract

Abstract Image

An expeditious process for the highly efficient synthesis of methyl 2-(chlorosulfonyl)benzoate was described, which involved the continuous-flow diazotization of methyl 2-aminobenzoate in a three-inlet flow reactor via a cross joint followed by chlorosulfonylation in the tandem tank reactor. The side reaction such as hydrolysis was decreased eminently from this continuous-flow process even at a high concentration of hydrochloric acid. The mass flow rate of methyl 2-aminobenzoate was 4.58 kg/h, corresponding to an 18.45 kg/h throughput of diazonium salt solution. The potential of inhibiting parallel side reactions by conducting in a flow reactor was successfully demonstrated in this method.

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Reformatsky and Blaise Reactions in Flow as a Tool for Drug Discovery. One Pot Diversity Oriented Synthesis of Valuable Intermediates and Heterocycles

 FLOW CHEMISTRY, flow synthesis  Comments Off on Reformatsky and Blaise Reactions in Flow as a Tool for Drug Discovery. One Pot Diversity Oriented Synthesis of Valuable Intermediates and Heterocycles
Oct 232016
 

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Compound 3aa was obtained as pale yellow oil (163 mg, 92% yield).MS (ESI): mass calcd. for C12H16O3, 208.1099; m/z found, 209.1102 [M+H] + .

1H NMR (CHLOROFORM-d, 400MHz): δ = 7.45 (d, J=7.7 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.21-7.27 (m, 1H), 4.37 (s, 1H), 4.00-4.18 (m, 2H), 2.97 (d, J=15.9 Hz, 1H), 2.79 (d, J=15.9 Hz, 1H), 1.55 (s, 3H), 1.08-1.18 ppm (m, 3H).

13C NMR (CHLOROFORM-d, 101MHz): δ = 173.1, 147.3, 128.6, 127.3, 124.9, 73.2, 61.4, 46.9, 31.1, 14.4 ppm

 

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The application of Reformatsky and Blaise reactions for the preparation of a diverse set of valuable intermediates and heterocycles in a one-pot protocol is described. To achieve this goal, a novel green activation protocol for zinc in flow conditions has been developed to introduce this metal efficiently into -bromoacetates. The organozinc compounds were added to a diverse set of ketones and nitriles to obtain a wide range of functional groups and heterocyclic systems in a one pot procedure.

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC02619B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Reformatsky and Blaise Reactions in Flow as a Tool for Drug Discovery. One Pot Diversity Oriented Synthesis of Valuable Intermediates and Heterocycles.

Green Chem., 2016, Accepted Manuscript

DOI: 10.1039/C6GC02619B

////////////Reformatsky, Blaise Reactions ,  Flow chemistry,  Drug Discovery. One Pot,  Diversity Oriented Synthesis, Valuable Intermediates,  Heterocycles.

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Scalable Flow Chemistry : A Flexible Tool for the Research, Developments and Production of Pharmaceuticals, Fine & Speciality Chemicals

 FLOW CHEMISTRY, flow synthesis  Comments Off on Scalable Flow Chemistry : A Flexible Tool for the Research, Developments and Production of Pharmaceuticals, Fine & Speciality Chemicals
Oct 072016
 

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Scalable Flow Chemistry : A Flexible Tool for the Research, Developments and Production of Pharmaceuticals, Fine & Speciality Chemicals
– Dr. Charlotte Wiles, Chief Executive Officer, Chemtrix BV, Netherlands

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A PRESENTATION

 

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///////Scalable Flow Chemistry,  A Flexible Tool,  Research, Developments,  Production,  Pharmaceuticals, Fine ,  Speciality Chemicals, Charlotte Wiles, Chief Executive Officer, Chemtrix BV, Netherlands

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