Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones

Graphical abstract: Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones


An environmentally benign decarboxylative cyclization in water has been developed to synthesize 4-quinolones from readily available isatoic anhydrides and 1,3-dicarbonyl compounds. Isatins are also compatible for the reaction to generate 4-quinolones in the presence of TBHP in DMSO. This protocol provides excellent yields under mild conditions for a broad scope of 4-quinolones, and has good functional group tolerance. Only un-harmful carbon dioxide and water are released in this procedure. Moreover, the newly synthesized products have also been selected for anti-malarial examination against the chloroquine drug-sensitive Plasmodium falciparum 3D7 strain. 3u is found to display excellent anti-malarial activity with an IC50 value of 33 nM.

Eco-friendly decarboxylative cyclization in water: practical access to the anti-malarial 4-quinolones

 Author affiliations!divAbstract

ethyl 2-(4-(benzyloxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (3u) White solid, m.p. 288-289 oC;

1H NMR (600 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.72 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.52 (td, J = 8.5, 1.7 Hz, 1H), 7.43 – 7.35 (m, 4H), 7.29 – 7.21 (m, 4H), 7.10 (td, J = 7.5, 0.5 Hz, 1H), 5.17 (s, 2H), 3.91 (q, J = 7.1 Hz, 2H), 2.00 (s, 1H), 0.83 (t, J = 7.1 Hz, 3H) ppm;

13C NMR (150 MHz, DMSO-d6) δ 174.1, 166.2, 156.2, 148.0, 139.8, 137.2, 132.8, 132.0, 130.5, 129.4, 128.7, 128.2, 127.6, 125.5, 125.2, 124.3, 123.6, 120.9, 118.9, 116.4, 115.8, 113.5, 70.2, 60.2, 14.0 ppm;

HRMS (ESI) calcd for [C25H21NO4+H]+ 400.1471, found 400.1463.


A Convenient and “Greener” Synthesis of Methyl Nitroacetate

Abstract Image

Methyl Nitroacetate (2)

Warning: Although no incidents occurred, the intermediates generated, as well as the end product, are energetic and should be handled as if they are explosive materials. It is essential that all reactions be conducted behind a blast shield and that proper protective equipment, including a face shield, be worn at all times during the operation.

A new procedure for the synthesis and isolation of methyl nitroacetate is described. The previously published method required drying the explosive dipotassium salt of nitroacetic acid in a vacuum desiccator, followed by grinding this material into a fine powder with a mortar and pestle prior to esterification. To obtain the desired product, benzene was employed as the extraction solvent, sodium sulfate was used as the drying agent, and two distillations were required. The new procedure eliminates drying and grinding of the explosive dipotassium salt, employs ethyl acetate or dichloromethane as the extraction solvent, eliminates the need for a drying agent, and requires a single distillation to furnish the end product in high yield and purity.


clear colorless liquid, bp 65 °C (3.9 Torr).

1H NMR (400 MHz; CDCl3) δ 5.18 (s, 2H), 3.87 (s, 3H);

13C NMR (100 MHz, CDCl3) δ 162.5, 76.2, 53.6;

IR (neat): 3041, 2967, 1751, 1557;

Tdec= 251 °C (onset), 272 °C (peak).


Energetics Technology Branch, Energetic Materials Science Branch, U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00093


*E-mail: Phone: 410-278-0235., *E-mail: Phone: 410-278-8608.


NMR predict

str1 str2


Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03494B, Paper
Zheng Fang, Wen-Li Hu, De-Yong Liu, Chu-Yi Yu, Xiang-Guo Hu
A procedure for the synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions has been developed.

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Zheng Fang,a   Wen-Li Hu,a   De-Yong Liu,a  Chu-Yi Yuab and   Xiang-Guo Hu*a  
*Corresponding authors
aNational Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P. R. China
bBeijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03494B,!divAbstract

An efficient and green procedure for the synthesis of tetrazines has been developed based on an old chemistry reported by Carboni in 1958. Both symmetric and asymmetric 3,6-disubstituted 1,2,4,5-tetrazines can be obtained in moderate to high yields from the corresponding gem-difluoroalkenes under aerobic conditions at room temperature. This work represents a rare example that ambient air is utilized as an oxidant for the synthesis of tetrazines.
Synthesis of symmetric 3,6-dialkyl-1,2,4,5−tetrazine(3a−3h)
To a solution of 1,1−difluoroalkenes (1a, 50 mg, 0.27 mmol) in N,N-dimethylformide (DMF,5 mL) was added hydrazine (80%, 35 mg, 1.35 mmol). After stirring at room temperature for 4−6 hours, saturated ammonium chloride (20 mL) was added and the reaction mixture was extracted with dichloromethane (10 mL×3). The organic layer was combined, dried with anhydrous sodium sulfate. The solvent was concentrated and the crude product was dissolved in a suspension of Ethyl Acetate(5 mL) and 10% potassium carbonate solution(wt%, 5 mL) and stirred at room temperature for 24h under air atomerspere until the organic layer turned into amaranth obviously. The organic layer was collected, dried with anhydrous sodium sulfate. The crude product was purified by flash column chromatography[silica gel(#100–200), toluene] to afford the pure 1,2,4,5−tetrazines(3a−3h).
3,6−bis([1,1’−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine (3a).
(41 mg, 83%).
purple solid; m.p. 200−202°C;
IR(KBr) nmax/cm−1 2924, 2850, 1488, 1451, 1432, 1388, 851, 750;
1 H NMR (400 MHz, CDCl3) 7.55−7.33 (m, 18H), 4.65 (s, 4H).
13C NMR (100 MHz, CDCl3) δ 169.2, 140.6, 140.4, 134.8, 129.7, 128.8, 127.6, 127.4, 127.1, 40.9;
HRMS (ESI): calcd. for C28H22N4 [M+H]+ 415.19172, found 415.19124.

///////tetrazines,  gem-difluoroalkenes, aerobic conditions, room temperature

Endogenous water-triggered and ultrasound accelerated synthesis of 1,5-disubstituted tetrazoles via a solvent and catalyst-free Ugi-azide reaction


Endogenous water-triggered and ultrasound accelerated synthesis of 1,5-disubstituted tetrazoles via a solvent and catalyst-free Ugi-azide reaction

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03324E, Communication
Shrikant G. Pharande, Alma Rosa Corrales Escobosa, Rocio Gamez-Montano
An ultrasound accelerated, environmentally benign Ugi-azide based method was developed for the synthesis of 1,5-disubstituted tetrazoles under solvent and catalyst-free conditions.

Endogenous water-triggered and ultrasound accelerated synthesis of 1,5-disubstituted tetrazoles via a solvent and catalyst-free Ugi-azide reaction

 *Corresponding authors
aDepartamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato, México
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03324E,!divAbstract

A novel, sustainable, endogenous water-triggered, environmentally friendly, high substrate scope, efficient, solvent-free and catalyst-free Ugi-azide based method for the synthesis of 1,5-disubstituted tetrazoles is described.
Shrikant Pharande

Shrikant Pharande

Doctoral student

Research experience

  • Apr 2014–Jun 2014, Research chemist
    TCG Lifesciences · pune
  • Mar 2012–Dec 2013, project assistant
    CSIR – National Chemical Laboratory, Pune · Organic Chemistry Division (NCL)
N-((1-(tert-butyl)-1H-tetrazol-5-yl)(4-chlorophenyl)methyl)aniline (4a)
Based on GP, 100 mg 4-Chlorobenzaldehyde (0.71 mmol), 0.065 cm3 aniline (0.71 mmol), 0.080 cm3 ter. Butyl isocyanide (0.71 mmol), and 0.093 cm3 TMS-azide (0.71 mmol) were reacted together to afford 237 mg (97%) as a white solid.
Melting range 144-145oC,
Rf = 0.45 (Hexane-AcOEt = 7/3 V/V),
1H NMR (500 MHz, CDCl3) δ 7.34 – 7.29 (m, 4H), 7.18 – 7.13 (m, 2H), 6.79 – 6.75 (m, 1H), 6.65 (d, J = 7.6 Hz, 2H), 6.11 (d, J = 6.2 Hz, 1H), 4.78 (d, J = 5.6 Hz, 1H), 1.71 (s, 9H);
13C NMR (126 MHz, CDCl3) δ 155.03, 145.54, 136.81, 134.71, 129.62, 129.43, 129.19, 119.64, 114.42, 61.95, 53.93, 30.29;
FT-IR (ATR) νmax/cm-1 3330.5, 3052.5, 2940.9, 1603.6, 1284.1;
HRMS (ESI+): m/z calcd. for C18H20ClN5 + 342.1480, found 342.1474


Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material


Abstract Image

Efficient continuous Grignard and lithiation processes were developed to produce one of the key regulatory starting materials for the production of edivoxetine hydrochoride. For the Grignard process, organometallic reagent formation, Bouveault formylation, reduction, and workup steps were run in continuous stirred tank reactors (CSTRs). The lithiation utilized a hybrid approach where plug flow reactors (PFRs) were used for the metal halogen exchange and Bouveault formylation steps, while the reduction and workup steps were performed in CSTRs. Relative to traditional batch processing, both approaches offer significant advantages. Both processes were high-yielding and produced the product in high purity. The two main processes were directly compared from a number of perspectives including reagent and operational safety, fouling potential, process footprint, need for manual operation, and product yield and purity.

Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
D&M Continuous Solutions, LLC, Greenwood, Indiana 46143, United States
Org. Process Res. Dev., Article ASAP

//////////Flow Grignard,  Lithiation, Screening Tools,  Development, Continuous Processes,  Benzyl Alcohol, Starting Material

Day 10 of the 2016 Doodle Fruit Games! Find out more at


Green Chem., 2016, Advance Article

DOI: 10.1039/C5GC02977E, Communication

Ryosuke Matake, Yusuke Adachi, Hiroshi Matsubara

A convenient preparation of vinyl ethers from alcohols with calcium carbide was developed. This protocol is an alternative to the Favorskii-Reppe reaction without any high pressure device.

Vinyl ethers are important and useful synthetic building blocks. Using a test tube with a screw cap, a convenient preparation of vinyl ethers from alcohols with calcium carbide under superbasic catalytic conditions (KOH/DMSO) was developed. The vinylation of primary and secondary alcohols was successfully achieved, affording the desired products in good yields. The gram-scale preparation of a vinyl ether was also demonstrated. In this reaction, calcium carbide acts as an acetylene source, constituting a safer alternative to acetylene gas.

 F. de Nanteuil, E. Serrano, D. Perrotta and J. Waser, J. Am. Chem. Soc., 2014, 136, 6239.


1H NMR PREDICT using nmrdb , signals may vary , use your discretion to understand sequence



Synthesis of vinyl ethers of alcohols using calcium carbide under superbasic catalytic conditions (KOH/DMSO)

*Corresponding authors

aDepartment of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Japan

Green Chem., 2016, Advance Article

DOI: 10.1039/C5GC02977E


Iron bis(oxazoline) complexes in asymmetric catalysis


Iron bis(oxazoline) complexes in asymmetric catalysis

Asymmetric reactions catalyzed by iron complexes have attracted considerable attention because iron is a ubiquitous, inexpensive, and environmentally benign metal. Various chiral iron complexes can be prepared from bis(oxazoline) ligands and be used in asymmetric reactions. This overview charts the development and application of chiral iron bis(oxazoline) and pyridine-2,6-bis(oxazoline) catalysts through their most prominent and innovative uses in asymmetric catalysis, especially in Lewis acid and oxidation catalysis.
Catal. Sci. Technol., 2015, Advance Article
DOI: 10.1039/C5CY01357G, Minireview
Thierry Ollevier
Asymmetric reactions catalyzed by iron complexes have attracted considerable attention because iron is a ubiquitous, inexpensive, and environmentally benign metal. This overview charts the development and application of chiral iron bis(oxazoline) and pyridine-2,6-bis(oxazoline) catalysts through their most prominent and innovative uses in asymmetric catalysis, especially in Lewis acid and oxidation catalysis.


Iron bis(oxazoline) complexes in asymmetric catalysis
Thierry Olleviera

aDépartement de chimie, Pavillon Alexandre-Vachon, Université Laval, 1045 avenue de la Médecine, Québec (Qc) G1V 0A6, Canada
Catal. Sci. Technol., 2015, Advance Article
DOI: 10.1039/C5CY01357G!divAbstract






Bisoxazoline ligand

In chemistry, bis(oxazoline) ligands (often abbreviated BOX ligands) are a class of privileged chiral ligands containing two oxazoline rings. They are typically C2‑symmetric and exist in a wide variety of forms; with structures based around CH2 or pyridine linkers being particularly common (often generalised BOX and PyBOX respectively). The coordination complexes of bis(oxazoline) ligands are used extensively in asymmetric catalysis.

BOX and PyBOX.png


Further information: Synthesis of oxazoline rings

The synthesis of oxazoline rings is well established and in general proceeded via the cyclisation of a 2‑amino alcohol with any of a number of suitable functional groups. In the case of bis(oxazoline)s, synthesis is most conveniently achieved by using bi-functional starting materials; as this allows both rings to be produced at once. Of the materials suitable, dicarboxylic or dinitrile compounds are the most commonly available and hence the majority bis(oxazoline) ligands are produced from these materials.

BOX and PyBOX general synthesis.png

Part of the success of the BOX and PyBOX motifs lies in their convenient one step synthesis from malononitrile and dipicolinic acid, which are commercially available at low expense. Chirality is introduced with the amino alcohols, as these are prepared from amino acids and hence are chiral (e.g. valinol).

The advantages C2-symmetry

The left hand structure has a C2‑rotational axis whereas the right hand structure is asymmetric. Arrows indicate the theoretical attack trajectories of reagents, identical colours lead to identical transition states (and hence products) with red arrows being disfavoured due to steric repulsion.

In bis(oxazoline) complexes the metal is held close to the stereogenic centres, which will strongly influence the enantioselectivity of any process taking place there. However the C2‑symmetry of the ligand is also important in controlling this enantioselectivity.

While the presence of any symmetry element within a ligand intended for asymmetric induction might appear counterintuitive, asymmetric induction only requires that the ligand be chiral (i.e. have no improper rotation axis); it does not have to be asymmetric (i.e. devoid of any symmetry element). C2‑symmetry actually improves the enantioselectivity of the complex by reducing the number of transition states with a unique geometry. Steric/kinetic factors then usually favour the formation of a single product.[1] The benefits of C2‑symmetry in bis(oxazoline) ligands have been reviewed in depth[2]

In general, for methylene bridged BOX ligands the stereochemical outcome is consistent with a twisted square planar intermediate that was proposed based on related crystal structures.[3][4] The substituent at the oxazoline’s 4-position blocks one enantiotopic face of the substrate, leading to enantioselectivity. This is demonstrated in the following aldol-type reaction,[5] but is applicable to a wide variety of reactions such as Mannich-type reactions,[6] ene reaction,[7] Michael addition,[8] Nazarov cyclization,[9] and hetero-Diels-Alder reaction.[10]

Box Stereochemical model

On the other hand, two-point binding on a Lewis acid bearing the meridially tridentate PyBOX ligand would result in a square pyramidal complex. A study using (benzyloxy)acetaldehyde as the electrophile showed that the stereochemical outcome is consistent with the carbonyl oxygen binding equatorially and the ether oxygen binding axially.[11]

PyBox Stereochemical model

Catalytic applications

Metal complexes incorporating bis(oxazoline) ligands are effective for an wide range of asymmetric catalytic transformations and have been the subject of numerous literature reviews.[12][13][14] The neutral character of bis(oxazoline)s makes them well suited to use with noble metals, with copper complexes being particularly common.[13] Their most important and commonly used applications are in carbon–carbon bond forming reactions.

Carbon–carbon bond forming reactions

bis(oxazoline) ligands have been found to be effective for a range of asymmetric cycloaddition reactions, this began with the very first application of BOX ligands in carbenoid cyclopropanations[15] and has been expanded to include 1,3-Dipolar cycloaddition and Diels-Alder reactions. Bisoxazoline ligands have also been found to be effective for Aldol, Michael and Ene reactions, amongst many others

Evans 1997:[16] BOX assisted Aldol reaction

Aggarwal 1998:[17] BOX assisted Diels-Alder reaction resulting in verbenone synthesis. The final conversion with diphenylphosphoryl azide involves a modified Curtius rearrangement

Other reactions

The success of bis(oxazoline) ligands for carbenoid cyclopropanations led to their application for aziridination. Another common reaction is hydrosilylation, which dates back to the first use of PyBOX ligands.[18] Other niche applications include as fluorination catalysts[19] and for Wacker-type cyclisations.[20]

Nishiyama 1989:[18] Enantioselective hydrosilylation


The development of bis(oxazoline) ligands

Oxazoline ligands were first used for asymmetric catalysis in 1984 when Brunner et al. showed a single example, along with a number of Schiff bases, as being effective for enantioselective carbenoid cyclopropanation.[21] Schiff bases were prominent ligands at the time, having been used by Ryōji Noyori during the discovery of asymmetric catalysis in 1968[22] (for which he and William S. Knowles would later be awarded the Nobel Prize in Chemistry). Brunner’s work was influenced by that of Tadatoshi Aratani, who had worked with Noyori,[23] before publishing a number of papers on enantioselective cyclopropanation using Schiff bases.[24][25][26]

In this first usage the oxazoline ligand performed poorly, giving an ee of 4.9% compared to 65.6% from one of the Schiff base ligands. However Brunner reinvestigated oxazoline ligands during research into the monophenylation of diols, leading to the development of chiral pyridine oxazoline ligands, which achieved ee’s of 30.2% in 1986[27] and 45% in 1989.[28] In the same year Pfaltz et al. reported the use of C2‑symmetric semicorrin ligands for enantioselective carbenoid cyclopropanations, achieving impressive results with ee’s of between 92-97%.[29] Reference was made to both Brunner’s and Aratani’s work, however the design of the ligands was also largely based on his earlier work with various macrocycles.[30] A disadvantage of these ligands however, was that they required a multi-step synthesis with a low overall yield of approximately 30%.

C2-symmetric bis(oxazoline) ligands with axial chirality

Brunner’s work led to the development of very first bisoxazolines by Nishiyama et al., who synthesised the first PyBox ligands in 1989. These ligands were used in the hydrosilylation of ketones; achieving ee’s of up to 93%[18] The first BOX ligands where reported a year later by Masamune et al.[15] and were first used in copper catalysed carbenoid cyclopropanation reactions; achieving ee’s of up to 99% with 1% molar loadings. This was a remarkable result for the time and generated significant interest in the BOX motif. As the synthesis of 2-oxazoline rings was already well established at this time (literature reviews in 1949[31] and 1971[32]), research proceeded quickly, with papers from new groups being published within a year.[33][34] and review articles being published by 1996.[35] Today a considerable number of bis(oxazoline) ligands exist; structurally these are still largely based around the classic BOX and PyBOX motifs, however they also include a number of alternative structures, such as axially chiral compounds.[36][37]





  1. Ohta, Tetsuo; Ito, Junji; Hori, Kazushige; Kodama, Hidehiko; Furukawa, Isao (2000). “Lanthanide-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones to alkenes using 3,3′-bis(2-oxazolyl)-1,1′-bi-2-naphthol (BINOL-Box) ligands”. Journal of Organometallic Chemistry 603 (1): 6–12. doi:10.1016/S0022-328X(00)00024-3.


Aza-bis(oxazolines) – New Chiral Ligands for Asymmetric Catalysis

M. Glos, O. Reiser, Org. Lett. 2000, 2, 2045-2048
Web edition:

graphical abstract

Aza-bis(oxazolines) are introduced as chiral ligands for asymmetric catalysis combining the advantages of easy availability of bis(oxazolines) and backbone variability of aza-semicorrins. Especially, the title ligands could be attached to a polymeric support, which allowed the development of easily recoverable copper(I)-catalysts for asymmetric cyclopropanation reactions.








Synthesis of Polymer Bound Azabis(oxazoline) Ligands and their Application in Asymmetric Cyclopropanations

H. Werner, C. I. Herrerí­as, M. Glos, A. Gissibl, J. M. Fraile, I. Pérez, J. A. Mayoral, O. Reiser, Adv. Synth. Catal. 2006, 348, 125-132
Web edition:

graphical abstract

Aza(bisoxazoline) ligands were attached to various polymeric supports and the resulting immobilized ligands were evaluated in copper(I)-catalyzed asymmetric cyclopropanations. The efficiency of these transformations depends greatly on the polymeric support, on the protocol being applied for the immobilization of the ligands, and on the preparation of the catalysts.



Cu(II)-Aza(bisoxazoline)-Catalyzed Asymmetric Benzoylations

A. Gissibl, M. G. Finn, O. Reiser, Org. Lett. 2005, 7, 2325-2328
Web edition:

graphical abstract

Racemic 1,2-diols and a-hydroxy carbonyl compounds can be asymmetrically benzoylated in a kinetic resolution in the presence of various Cu(II)-azabis(oxazoline) catalysts. A novel bisbenzyl substituted aza(bisoxazoline) ligand proved to be especially effective when immobilized on MeOPEG5000, giving 91 – ≥99% ee in 37 – 49% yield for each of five sequential reactions.


The role of binding constant in the efficiency of chiral catalysts immobilized by electrostatic interactions. The case of azabis(oxazoline)-copper complexes

J. M. Fraile, J. I. Garcí­a, C. I. Herrerí­as, A. Mayoral, O. Reiser, A. Socuéllamos, H. Werner, Chem. Eur. J. 2004, 10, 2997-3005
Web edition:

graphical abstract

Azabis(oxazoline)-copper complexes are considerably more stable than the analogous bis(oxazoline)-copper complexes, as shown by theoretical calculations. The enhanced stability allows the efficient immobilization by means of electrostatic interactions with different anionic supports, such as clays and nafion-silica nanocomposites, without the loss of ligand observed with bis(oxazolines). In this way, enantioselectivities around 90% ee are obtained in the cyclopropanation reaction



Improved Synthesis of Aza-bis(oxazoline) Ligands

H. Werner, R. Vicha, A. Gissibl, O. Reiser, J. Org. Chem. 2003, 68, 10166-10168
Web edition:

graphical abstract

A straightforward synthesis of chiral aza-bis(oxazoline) (Azabox) ligands from commercial available aminoalcohols is described. The new protocol allows access to previously reported Azabox ligands in considerably improved yields but also to new derivatives, including non C2-symmetrical ones.


Research Group Prof. Reiser

Prof. Dr.
Oliver Reiser



Phone +941/943-4630
Fax +941/943-4121