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Sunday, 21 September 2014

Metal-free coupling of saturated heterocyclic sulfonylhydrazones with boronic acids


 Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, U.K.
 Neusentis Chemistry, Pfizer Worldwide Research and Development, The Portway Building, Granta Park, Cambridge, CB21 6GS, U.K.
J. Org. Chem.201479 (1), pp 328–338
DOI: 10.1021/jo402526z

The coupling of aromatic moieties with saturated heterocyclic partners is currently an area of significant interest for the pharmaceutical industry. Herein, we present a procedure for the metal-free coupling of 4-, 5-, and 6-membered saturated heterocyclic p-methoxyphenyl (PMP) sulfonylhydrazones with aryl and heteroaromatic boronic acids. This procedure enables a simple, two-step synthesis of a range of functionalized sp2–sp3 linked bicyclic building blocks, including oxetanes, piperidines, and azetidines, from their parent ketones.

Saturday, 13 September 2014

Flow chemistry syntheses of natural products

J.C. Pastre, D.L. Browne, S.V. Ley, Chem. Soc. Rev. 201342, 8801-9198.
The development and application of continuous flow chemistry methods for synthesis is a rapidly growing area of research. In particular, natural products provide demanding challenges to this developing technology. This review highlights successes in the area with an emphasis on new opportunities and technological advances.

Tuesday, 9 September 2014

Benzocoumarin Family Complete

Benzocoumarin Family Complete

Benzo[g]coumarins most suitable for applications as photonic materials
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 Benzene-fused coumarins, benzocoumarins, constitute a promising family of photonic materials due to the extended nature of their π-electron system. Among four possible subfamilies of benzocoumarins


Bispirooxindole Derivatives

Bispirooxindole Derivatives

Regio- and stereoselective synthesis of bispirooxindole derivatives via a three-component 1,3-dipolar cycloaddition
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An efficient synthesis of spirooxindole derivatives is highly valued due to the pronounced biological activities of this class of compounds.

Sunday, 31 August 2014

7,7-dichlorobicyclo[4.1.0]heptane (7,7-dichloronorcarane

7,7-dichlorobicyclo[4.1.0]heptane (7,7-dichloronorcarane

reacts to
7,7-Dichlorobicyclo[4.1.0]heptane+Hydrogen chloride

Synthesis of 7,7-dichlorobicyclo[4.1.0]heptane (7,7-dichloronorcarane) from cyclohexene

Reaction type:addition to alkenes, elimination, cycloaddition
Substance classes:alkene, carbene, chloroalkane
Techniques:stirring with magnetic stir bar, adding dropwise with an addition funnel, distilling under reduced pressure, evaporating with rotary evaporator, shaking out, extracting, filtering, use of an ice cooling bath, heating with oil bath

Instruction (batch scale 100 mmol)
100 mL three neck round bottom flask, reflux condenser, addition funnel with pressure
balance, heatable magnetic stirrer, magnetic stir bar, thermometer for inside of the flask,
separating funnel, destillation apparatus, rotary evaporator, oil bath, ice bath, vacuum pump
cyclohexene (bp 83 °C) 8.21 g (10.1 mL, 100 mmol)
chloroform (bp 61 °C) 48.0 g (32.7 mL, 400 mmol)
sodium hydroxide 16.0 g (400 mmol)
tri-n-propylamine (bp 156 °C) 0.14 g (0.19 mL, 1.0 mmol)
water 16 mL
ethanol (bp 78 °C) 1 mL
n-pentane (bp 36 °C) 120 mL
sodium sulfate for drying about 5 g
sodium chloride about 18 g
Into a 100 mL three neck round bottom flask equipped with a reflux condenser addition
funnel, thermometer for measuring the inside temperature and magnetic stir bar, 8.21 g
(10.1 mL, 100 mmol) cyclohexene 0.14 g (0.19 mL, 1.0 mmol) tri-n-propylamine, 48.0 g
(32.7 mL, 400 mmol) chloroform and 1 mL ethanol is added. The mixture is cooled to 0 °C
with an ice bath, then under stirring and further cooling in the ice bath a solution of 16.0 g
(400 mmol) sodium hydroxide in 16 mL water is added through an addition funnel. The
mixture should be stirred vigourously during the next 20 minutes at 0 °C. After this time the
mixture is further stirred during 1 hour at room temperature and 3 hours at 50 °C.
Work up
Chloroform is evaporated with a rotary evaporator, then the residue is transferred with about
50 mL water and 30 mL n-pentane into a separating funnel. The organic phase is separated,
the aqueous phase is further extracted three times with 30 mL pentane. If an emulsion is
formed the aqueous phase is saturated with NaCl. The combined organic phases are dried over
sodium sulfate. The solution is filtered from sodium sulfate and the solvent is evaporated with
a rotary evaporator, yielding a nearly colourless liquid as crude product. The crude yield is
14.6 g. The crude product is distilled under reduced pressure.
Yield: 13.6 g (82.3 mmol, 82%), colourless liquid; bp 77 °C (11 hPa)

Operating scheme

Operating schemeOperating scheme


Batch scale:0.01 mol0.1 mol1 molCyclohexene

two-necked flask 10 mLtwo-necked flask 10 mLreflux condenserreflux condenser
heatable magnetic stirrer with magnetic stir barheatable magnetic stirrer with magnetic stir barthermometerthermometer
graduated pipettegraduated pipetteseparating funnelseparating funnel
microdistillation apparatusmicrodistillation apparatusrotary evaporatorrotary evaporator
oil bathoil bathice bathice bath
vacuum pumpvacuum pump


pure product chromatogram

GC: pure productcolumnSE-54, L= 25 m, ID 0.32 mm, DF 0.25 µm (Macherey & Nagel)inletGerstel KAS, injector: 250°C, split injection 1:20, 0.15 µLcarrier gasN2, pre-column pressure 62 kPa, 1.04 mL/minoven80 °C (1 min), 10 °C/min --> 250 °C (30 min)detectorFID, 275 °Cintegrationpercent concentration calculated from relative peak area


1H-NMR: 7,7-Dichlorobicyclo[4.1.0]heptane
500 MHz, CDCl3
delta [ppm]mult.atomsassignment
1.12-1.36m4 HC4-H, C5-H
1.61-1.71m4 HC3-H, C6-H
1.88-1.98m2 HC1-H, C2-H
7.26s1 HCHCl3


3C-NMR: 7,7-Dichlorobicyclo[4.1.0]heptane
125 MHz, CDCl3
delta [ppm]assignment
18.9C4, C5
20.2C3, C6
25.8C2, C1

IR: 7,7-Dichlorobicyclo[4.1.0]heptane
[Film, T%, cm-1]
2944, 2855aliph. C-H valence
796C-Cl valence


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Sunday, 24 August 2014

ENDO EXO STORY.......cis-norborene-5,6-endo-dicarboxylic anhydride

ENDO EXO STORY.......cis-norborene-5,6-endo-dicarboxylic anhydride


You will react cyclopentadiene with maleic anhydride to form the Diels-Alder product below. This Diels-Alder reaction produces almost solely the endo isomer upon reaction at ambient temperature.


The preference for endo–stereochemistry is “observed” in most Diels-Alder reactions. The fact that the more hindered endo product is formed puzzled scientists until Woodward, Hoffmann, and Fukui used molecular orbital theory to explain that overlap of the p orbitals on the substituents on the dienophile with p orbitals on the diene is favorable, helping to bring the two molecules together.

Hoffmann and Fukui shared the 1981 Nobel Prize in chemistry for their molecular orbital explanation of this and other organic reactions. In the illustration below, notice the favorable overlap (matching light or dark lobes) of the diene and the substituent on the dienophile in the formation of the endo product:


Oftentimes, even though the endo product is formed initially, an exo isomer will be isolated from a Diels-Alder reaction. This occurs because the exo isomer, having less steric strain than the Endo , is more stable, and because the Diels-Alder reaction is often reversible under the reaction conditions. In a reversible reaction, the product is formed, reverts to starting material, and forms again many times before being isolated.

The more stable the product, the less likely it will be to revert to the starting material. The isolation of an exo product from a Diels-Alder reaction is an example of an important concept: thermodynamic vs kinetic control of product composition. The first formed product in a reaction is called the kinetic product. If the reaction is not reversible under the conditions used, the kinetic product will be isolated. However, if the first formed product is not the most stable product and the reaction is reversible under the conditions used, then the most stable product, called the thermodynamic product, will often be isolated.

The NMR spectrum of cis-5-norbornene-2,3-endo-dicarboxylic anhydride is given below:

Cis-Norbornene-5,6-endo-dicarboxylic anhydride 
Cyclopentadiene was previously prepared through the cracking of dicyclopentadiene and kept under cold conditions.  In a 25 mL Erlenmeyer flask, maleic anhydride (1.02 g, 10.4 mmol) and ethyl acetate (4.0 mL) were combined, swirled, and slightly heated until completely dissolved.  To the mixture, ligroin (4 mL) was added and mixed thoroughly until dissolved.  Finally, cyclopentadiene (1 mL, 11.9 mmol) was added to the mixture and mixed extensively.  The reaction was cooled to room temperature and placed into an ice bath until crystallized.  The crystals were isolated through filtration in a Hirsch funnel.  The product had the following properties: 0.47 g (27.6% yield) mp: 163-164 °C (lit: 164 °C).  1H NMR (CDCl3, 300 MHz) δ: 6.30 (dd, J=1.8 Hz, 2H), 3.57 (dd, J=7.0 Hz, 2H), 3.45 (m, 2H), 1.78 (dt, J=9.0,1.8 Hz, 1H), 1.59 (m, 1H) ppm.  13C NMR (CDCl3, 75Hz) δ: 171.3, 135.5, 52.7, 47.1, 46.1 ppm.  IR 2982 (m), 1840 (s), 1767 (s), 1089 (m) cm-1.

Reaction Mechanism The scheme below depicts the concerted mechanism of the Diels-Alder reaction of cyclopentadiene and maleic anhydride to formcis-Norbornene-5,6-endo-dicarboxylic anhydride.

diels-alder reaction

Results and Discussion 
When combining the reagents, a cloudy mixture was produced and problems arose in the attempt to completely dissolve the mixture.  After heating for about 10 minutes and magnetically stirring, tiny solids still remained. The undissolved solids were removed form the hot solution by filtration and once they cooled, white crystals began to form. Regarding the specific reaction between cyclopentadiene and maleic anhydride, the endo isomer, the kinetic product, was formed because the experiment was directed under mild conditions.   The exo isomer is the thermodynamic product because it is more stable.3
A total of 0.47 g of the product was collected; a yield of 27.6%. The melting point was in the range of 163-164 °C which indicates the absence of impurities because the known melting point of the product is 164 °C.
Cis-Norbornene-5-6-endo-dicarboxylic anhydride

The 1H NMR spectrum of the product revealed a peak in the alkene range at 6.30 ppm, H-2 and H-3 (Figure 1).  In addition, it exhibited two peaks at 3.57 and 3.45 ppm because of the proximity of H-1, H-4, H-5, and H-6 to an electronegative atom, oxygen.  Finally, two peaks at 1.78 and 1.59 ppm corresponded to the sp3 hydrogens, Hb and Ha, respectively.  Impurities that appeared included ethyl acetate at 4.03, 2.03, and 1.31 ppm as well as acetone at 2.16 ppm.
Regarding the 13C NMR, a peak appeared at 171.3 ppm, accounting for the presence of two carbonyl functional groups, represented by C-7 and C-8 in Figure 1.  The alkene carbons, C-2 and C-3, exhibited a peak at 135.5 ppm, while the sp3 carbons close to oxygen, C-5 and C-6, displayed a peak at 52.7 ppm.  Finally, peaks at 46.1 and 47.1 ppm accounted for the sp3 carbons, C-1 and C-4, and C-9.  Impurities of ethyl acetate appeared at 46.6, 25.8, and 21.0 ppm accompanied with acetone at 30.9 ppm.
The IR spectrum revealed a peak at 2982 cm-1 representing the C-H stretches.  A peak at 1840 cm-1 accounted for the carbonyl functional group, while a peak at 1767 cm-1 accounted for the alkene bond.  A peak at 1089 cm-1 represented the carbon-oxygen functional group.
In order to distinguish between the two possible isomers, properties such as melting point and spectroscopy data were analyzed.  The exo product possessed a melting point in the range of 140-145 °C which is significantly lower than the endo product.  The observed melting point in this experiment supported the production of the endo isomer. 
The 1H NMR spectum exhibited a doublet of doublets at 3.57 ppm for the endo isomer.  The exo isomer would possess a triplet around 3.50 ppm due to the difference in dihedral angle between the hydrogen molecules of H-1 and H-4, and H-5 and H-6 (Figure 1).  A peak at 3.00 ppm would appear in the exo isomer spectra as opposed to a peak at 3.60 ppm as shown in the observed endo product.3 This is because of the interaction and coupling with the H-5 and H-6, as displayed in Figure 1.

Through the Diels-Alder reaction, 27.6% yield of cis-Norbornene-5,6-endo-dicarboxylic anhydride was produced. The distinction of the presence of the endo isomer was proven by analyzing physical properties of both possible isomers.
Martin, J.; Hill, R.; Chem Rev, 196161, 537-562.
2 Pavia, L; Lampman, G; Kriz, G; Engel, R. A Small Scale Approach to Organic Laboratory   Techniques, 2011, 400-409.
3 Myers, K.; Rosark, J. Diels-Alder Synthesis, 2004, 259-265.


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