SYNTHESIS – Page 17 – All About Drugs

[3 + 2] Cycloaddition of Acetylenes with Azides to give 1,4-Disubstituted 1,2,3- Triazoles in a Modular Flow Reactor

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Oct 282014

[3 + 2] Cycloaddition of Acetylenes with Azides to give 1,4-Disubstituted 1,2,3- Triazoles in a Modular Flow Reactor

C.D. Smith, I.R. Baxendale, S. Lanners, J.J. Hayward, S.C. Smith and S.V. Ley, Org. Biomol. Chem. 2007, 5, 1559-1561.

http://pubs.rsc.org/en/content/articlelanding/2007/ob/b702995k#!divAbstract

The cycloaddition of acetylenes with azides to give the corresponding 1,4-disubstituted 1,2,3-triazoles is reported using immobilised reagents and scavengers in pre-packed glass tubes in a modular flow reactor.

Continuous flow chemistry: a discovery tool for new chemical reactivity patterns

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Sep 212014

Continuous flow chemistry: a discovery tool for new chemical reactivity patterns

Jan Hartwig,^a Jan B. Metternich,^b Nikzad Nikbin,^b Andreas Kirschning^a and Steven V. Ley*^b

*Corresponding authors

^aInstitut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany

^bInnovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, UK

E-mail: svl1000@cam.ac.uk

Org. Biomol. Chem., 2014,12, 3611-3615

DOI: 10.1039/C4OB00662C

Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up.

An automated flow-based synthesis of imatinib: the API of gleevec

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Sep 162014

An automated flow-based synthesis of imatinib: the API of gleevec

M.D. Hopkin, I.R. Baxendale, S.V. Ley, J.C.S. Chem. Commun.2010, 46, 2450-2452.

http://pubs.rsc.org/en/Content/ArticleLanding/2010/CC/c001550d#!divAbstract

A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation.

An in-linesolvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates.

Graphical abstract: A flow-based synthesis of Imatinib: the API of Gleevec

see supp info

http://www.rsc.org/suppdata/cc/c0/c001550d/c001550d.pdf

The flow synthesis of heterocycles for natural products and medicinal chemistry applications

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Sep 142014

The flow synthesis of heterocycles for natural products and medicinal chemistry applications

http://link.springer.com/article/10.1007%2Fs11030-010-9282-1

M. Baumann, I.R. Baxendale, S.V. Ley, Mol. Div. 2011, 15, 613-630.

This article represents an overview of recent research from the Innovative Technology Centre in the field of flow chemistry which was presented at the FROST2 meeting in Budapest in October 2009. After a short introduction of this rapidly expanding field, we discuss some of our results with a main focus on the synthesis of heterocyclic compounds which we use in various natural product and medicinal chemistry programmes.

Synthesis of (-)-hennoxazole A: integrating batch and flow chemistry methods

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Sep 142014

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Synthesis of (-)-hennoxazole A: integrating batch and flow chemistry methods

A. Fernández, Z.G. Levine, M. Baumann, S. Sulzer-Mossé, C. Sparr, S. Schläger, A. Metzger, I.R. Baxendale, S.V. Ley,Synlett, 2013, 24, 514-518.

A new total synthesis of (–)-hennoxazole A is reported. The synthetic approach is based on the preparation of three similarly sized fragments resulting in a fast and convergent assembly of the natural product. The three key reactions of the synthesis include a highly stereoselective 1,5-anti aldol coupling, a gold-catalyzed alkoxycyclization reaction, and a stereocontrolled diene cross-metathesis. The synthesis involves integrated batch and flow chemistry methods leading to the natural product in 16 steps longest linear sequence and 2.8% overall yield.

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https://www.thieme-connect.de/DOI/DOI?10.1055/s-0032-1318109

Continuous flow-processing of organometallic reagents using an advanced peristaltic pumping system and the telescoped flow synthesis of (E/Z)-tamoxifen

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Sep 142014

Continuous flow-processing of organometallic reagents using an advanced peristaltic pumping system and the telescoped flow synthesis of (E/Z)-tamoxifen

P.R.D. Murray, D.L. Browne, J.C. Pastre, C. Butters, D. Guthrie, S.V. Ley, Org. Proc. Res. Dev. 2013, 17, 1192-1208.

A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.

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http://pubs.acs.org/doi/abs/10.1021/op4001548

6,7-methylenedioxy-4-phenylcoumarin

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Aug 262014

6,7-methylenedioxy-4-phenylcoumarin

8-Phenyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one

6H-1,3-Dioxolo[4,5-g][1]benzopyran-6-one, 8-phenyl-

Molecular Formula: C₁₆H₁₀O₄

Molecular Weight: 266.2482

Coumarins are naturally occurring molecules that are found in plants that have numerous uses in the medical field because of its biological activity. The wide varieties of its uses include antibiotics, anticoagulants, and sometimes even used in the perfume industry.

SYNTHESIS

Synthesis of 6,7-methylenedioxy-4-phenylcoumarin from sesamol and ethyl phenylpropiolate using a Pd(OAc)2 catalyst to illustrate coumarin synthesis. This procedure is simple and easy and can be applied to the synthesis of other coumarins that have electron-rich phenol groups. The reaction is conducted by stirring a solution of Pd(OAc)2, sesamol and ethyl phenylpropiolate in trifluoroacetic acid at room temperature (15-20 degrees C) under atmospheric conditions.

STEP 1

phenyl acetylene is the starting material

Ethyl Phenylpropiolate:

Phenylacetylene (500 mg, 4.896 mmol, 1 equivalent) was added to a round bottom flask and flushed with nitrogen. A septum and balloon of nitrogen was then attached and 3-4mL of THF was added by syringe. The flask was cool to -78^oC in a dry ice and acetone bath. Next, n-butyllithium (2.36 mL, 1.2 equivalent) was added to the solution and allowed to warm to 0^oC for 1 hour. The solution was cooled to -78^oC again for 15 minutes, and then ethyl chloroformate (0.702 mL, 7.344 mmol, 1.5 equivalent) was added dropwise by syringe and allowed to warm again to 0^oC. The reaction mixture was then quenched by adding 10mL of saturated aqueous NaHCO₃ and allowed to stir for 15 minutes. The resulting substance Ethyl Phenylpropiolate was a yellowish-orange liquid.

¹H NMR (200 MHz, CDCl₃) δ 7.60-7.26 (m, 5H),

4.38 (m, 2H), -O CH2 CH3

1.44 (m, 3H); -O CH2 CH3

IR (neat, NaCl)

3551.4, 3399.9, 3958.2, 2934.4, 2872.2, 2236.4, 2211.6, 1744.0, 1709.5 cm^-1

The conversion of phenylacetylene to ethyl phenylpropiolate was made apparent by the comparison of IR spectras. The phenylacetylene reference IR spectra found on the Spectral Database of Organic Compounds shows a strong peak at about 3300 that the IR of the intermediate lacks. Also the intermediate’s IR contains strong peaks at 3000 and 2230 which are both absent from the starting material’s IR spectrum. Both of these changes indicate a successful conversion of phenylacetylene to the intermediate ethyl phenylpropiolate.

STEP 2

This specific reaction will result in a ring closure and addition of the ethyl phenylpropiolate aided by the palladium acetate catalyst. The palladium catalyst allows for the addition of an ester to a phenol resulting in a ring closure and product coumarin derivative.

6,7-methylenedioxy-4-phenylcoumarin:

Sesamol (0.075g, 0.5167mmol, 0.9 equivalent) and ethyl phenylpropiolate (102mg, 0.57405 mmol,1 equivalent) and Palladium acetate (Pd(OAc)₂)(0.00394g, 3mol%) were added to a 1 dram vial and cooled to 0^oC in an ice water bath. Trifluoroacetic acid (0.5mL) was added to the vial, then the vial was capped and the reaction allowed to proceed overnight. The resulting solid was a brown, sticky, crystalline (0.387 mmol, 67 %yield).

¹H NMR (300 MHz, CDCl₃)

δ 7.55-7.38 (m, 5H),

6.90 (s, 1H),

6.83 (s, 1H),

6.24 (s, 1H),

6.05 (s, 2H); CH2 SANDWICHED BETWEEN 2 OXYGEN ATOMS

IR (DCM, NaCl)

3553.8, 3401.9, 2958.2, 2872.2, 2236.3, 2211.4, 1744.4, 1717.4 cm^-1

References

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

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Aug 242014

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.

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.

Conclusion
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, 1961, 61, 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.
link
http://orgspectroscopyint.blogspot.in/2014/08/cis-norborene-56-endo-dicarboxylic.html

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Catalyst-free sulfonylation of activated alkenes for highly efficient synthesis of mono-substituted ethyl sulfones in water

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Aug 102014

Catalyst-free sulfonylation of activated alkenes for highly efficient synthesis of mono-substituted ethyl sulfones in water

Green Chem., 2014, Advance Article
DOI: 10.1039/C4GC00932K, Communication

Yu Yang,^a Lin Tang,^a Sheng Zhang,^a Xuefeng Guo,^a Zhenggen Zha^a and Zhiyong Wang*^a

Corresponding authors

Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry & Collaborative Innovation Center of Suzhou Nano Science and Technology, University of Science and Technology of China, Hefei, P. R. China
E-mail: zwang3@ustc.edu.cn;
Fax: (+86) 551-360-3185

Green Chem., 2014, Advance Article

DOI: 10.1039/C4GC00932K

A catalyst-free sulfonylation of activated alkenes developed under mild conditions in water.

http://pubs.rsc.org/en/Content/ArticleLanding/2014/GC/C4GC00932K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

A catalyst-free sulfonylation reaction of activated alkenes with sulfonyl hydrazides was efficiently developed under mild and environmentally benign conditions, in water without any ligand or additive. The reaction gave a range of structurally diverse mono-substituted ethyl sulfones with excellent yields, in which the by-product was nitrogen.