AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Sep 202017
 

 

Catalyst-free multi-component cascade C-H-functionalization in water using molecular oxygen: an approach to 1,3-oxazines

Green Chem., 2017, 19,4036-4042
DOI: 10.1039/C7GC01494E, Communication
Mohit L. Deb, Choitanya D. Pegu, Paran J. Borpatra, Prakash J. Saikia, Pranjal K. Baruah
Synthesis of 1,3-oxazines via catalyst free C-H functionalization using molecular oxygen in water.

Catalyst-free multi-component cascade C–H-functionalization in water using molecular oxygen: an approach to 1,3-oxazines

 Author affiliations

Abstract

Herein, catalyst-free 3-component reactions of naphthols, aldehydes, and tetrahydroisoquinolines to synthesize 1,3-oxazines is reported. The reaction is performed in H2O in the presence of O2 as the sole oxidant at 100 °C, which proceeds through the formation of 1-aminoalkyl-2-naphthols followed by selective α-C–H functionalization of tert-amine.

15-phenyl-7a,12,13,15-tetrahydronaphtho[1′,2′:5,6][1,3]oxazino[2,3- a]isoquinoline (4a):1

White solid; Yield 61 %, 221 mg;

1H NMR (500 MHz, CDCl3): δ 7.79-7.77 (m, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.43-7.41 (m, 1H), 7.33-7.28 (m, 8H), 7.24-7.19 (m, 3H), 7.11 (d, J = 8.9 Hz, 1H), 5.65 (s, 1H), 5.44 (s, 1H), 3.40-3.26 (m, 2H), 3.12-3.09 (m, 1H), 2.90- 2.86 (m, 1H);

13C NMR (125 MHz, CDCl3): δ 151.9, 142.3, 135.0, 133.0, 132.4, 129.3, 129.1, 128.9, 128.8 (2C), 128.7, 128.6, 128.2, 127.4, 126.5, 126.2, 123.1, 122.7, 118.9, 110.9, 82.2, 62.6, 45.4, 29.4;

HRMS (ESI) exact mass calculated for C26H21NO [M+H]+ : 364.1701; found: 364.1705.

The representative procedure for the synthesis of 4a is as follows: 2-naphthol (1a, 144 mg, 1 mmol), benzaldehyde (2a, 106 mg, 1 mmol), tetrahydroisoquinoline (3, 133 mg, 1 mmol) and water (1.5 mL) were added in a round-bottom flask equipped with a magnetic stirring bar and a reflux condenser. The whole apparatus was efficiently flushed with oxygen gas and then connected to a balloon filled with oxygen. After vigorous stirring at 100 oC for 12 h, water was removed under vacuum and purified the reaction mixture by column chromatography (100-200 mesh silica gel, hexane-ethyl acetate) to obtain the product 4a as white solid. The other 1,3-oxazines were synthesized and purified by following the procedure described above

str4

STR7str6

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Sep 162017
 

 

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC02211E, Paper
F. A. Kucherov, K. I. Galkin, E. G. Gordeev, V. P. Ananikov
Efficient one-pot synthesis of tricyclic compounds from biobased 5-hydroxymethylfurfural (HMF) is described using a [4 + 2] cycloaddition reaction.

Efficient route for the construction of polycyclic systems from bioderived HMF

 Author affiliations

Abstract

The first synthesis of tricyclic compounds from biobased 5-hydroxymethylfurfural (HMF) is described. The Diels–Alder reaction was used to implement the transition from HMF to a non-planar framework, which possessed structural cores of naturally occurring biologically active compounds and building blocks of advanced materials. A one-pot, three-step sustainable synthesis in water was developed starting directly from HMF. The reduction of HMF led to 2,5-bis(hydroxymethyl)furan (BHMF), which could be readily involved in the Diels–Alder cycloaddition reaction with HMF-derived maleimide, followed by hydrogenation of the double bond. The described transformation was diastereoselective and proceeded with a good overall yield. The applicability of the chosen approach for the synthesis of analogous structures containing amine functionality on the side chain was demonstrated. To produce the target compounds, only platform chemicals were used with carbohydrate biomass as the single carbon source.

Endo-4,7-bis(hydroxymethyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione (endo-4,7-bis(hydroxymethyl)norcantharimid-5-ene), 3

1H NMR (DMSO-d6) = 10.82 (s, 1H), 6.37 (s, 2H), 5.11 (t, 2H, J = 5.7 Hz), 3.97 (dd, 2H, J = 5.7 Hz, 12.8 Hz), 3.84 (dd, 2H, J = 5.7 Hz, 12.8 Hz), 3.44 (s, 2H);

13C NMR (DMSO-d6) = 176.9, 136.0, 92.1, 59.8, 48.8 ppm.

m/z HRMS (ESI) Calcd. for C10H11NO5 [M+Na]: 248.0529. Found 248.0536.

STR7

str4 str6

1H NMR PREDICT

 

str4

str4 str6

13C NMR PREDICT

 

str4 str6

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O=C1NC(=O)[C@H]3[C@@H]1[C@]2(C=C[C@]3(CO)O2)CO

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Sep 072017
 

Metal-free oxidative cyclization of 2-aminobenzothiazoles and cyclic ketones enabled by the combination of elemental sulfur and oxygen

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC02014G, Communication
Yanjun Xie, Xiangui Chen, Zhen Wang, Huawen Huang, Bing Yi, Guo-Jun Deng
Aerobic cyclization of 2-aminobenzothiazoles and cyclic ketones enabled by the combination of elemental sulfur and oxygen under metal-free conditions.

Metal-free oxidative cyclization of 2-aminobenzothiazoles and cyclic ketones enabled by the combination of elemental sulfur and oxygen

 

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C7GC02014G?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Abstract

Metal-free oxidative cyclization for the one-pot synthesis of benzo[d]imidazo[2,1-b]thiazoles from 2-aminobenzothiazoles and cyclic ketones is described. Elemental sulfur combined with molecular oxygen as the benign co-oxidant was found to be unique and highly effective to promote this transformation without the aid of any metal salts. Various cyclic ketones smoothly reacted with 2-aminobenzothiazoles to give functional benzo[d]imidazo[2,1-b]thiazoles in good to very high yields, which thereby demonstrated the synthetic convergence of this methodology.

Graphical abstract: Metal-free oxidative cyclization of 2-aminobenzothiazoles and cyclic ketones enabled by the combination of elemental sulfur and oxygen
7,8,9,10-Tetrahydrobenzo[d]benzo[4,5]imidazo[2,1-b]thiazole (3a)
White solid; yield: 39.2 mg (86%), mp 140-142 °C.
STR1
1H NMR (400 MHz, CDCl3, ppm) δ 7.67-7.62 (m, 2H), 7.38 (t, J = 7.76 Hz, 1H), 7.27 (t, J = 7.68 Hz, 1H), 3.07-3.04 (m, 2H), 2.77-2.74 (m, 2H), 2.00-1.95 (m, 2H), 1.92-1.86 (m, 2H);
13C NMR (100 MHz, CDCl3, ppm) δ 145.1, 142.4, 132.9, 129.7, 125.5, 123.9, 123.5, 121.8, 111.9, 24.8, 22.8, 22.7, 21.8;
MS (EI) m/z (%) 228, 200 (100), 160, 108, 51;
HRMS calcd. for: C13H13N2S + (M+H)+ 229.07940, found 229.07941.
 STR2
str3
PREDICT
STR1
STR2
cas 325766-28-7
C13 H12 N2 S, 228.31,  Benzimidazo[2,​1-​b]​benzothiazole, 7,​8,​9,​10-​tetrahydro-

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C1CCCc2c1nc3sc4ccccc4n23

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Sep 012017
 

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str0

Route to Benzimidazol-2-ones via Decarbonylative Ring Contraction of Quinoxalinediones: Application to the Synthesis of Flibanserin, A Drug for Treating Hypoactive Sexual Desire Disorder in Women and Marine Natural Product Hunanamycin Analogue

 Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
 Academy of Scientific and Innovative Research (AcSIR), New Delhi 110 025, India
ACS Omega, 2017, 2 (8), pp 5137–5141
DOI: 10.1021/acsomega.7b00819
*E-mail: ds.reddy@ncl.res.in. Phone: +91-20-2590 2445 (D.S.R.).

ACS AuthorChoice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

INTRODUCTION

Benzimidazol-2-ones 1 are an important class of heterocycles and a privileged scaffold in medicinal chemistry. They consist of cyclic urea fused with the aromatic backbone, which can potentially interact in a biological system by various noncovalent interactions such as hydrogen bonding and π stacking. Benzimidazolone derivatives exhibit a wide range of biological activities, and they are useful in treating various diseases including cancer, type II diabetes, central nervous system disorders, pain management, and infectious disease.1 Selected compounds embedded with a benzimidazol-2-one moiety along with their use are captured in Figure 1. It is worth mentioning that oxatomide drug with a benzimidazol-2-one core was approved for marketing a few years ago.2a Very recently, US Food and Drug Administration approved a new drug called flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in females, which contains benzimidazol-2- one motif.2b

CONCLUSIONS

We have developed a mild and new protocol for the synthesis of benzimidazol-2-ones from quinoxalinediones through decarbonylation. The present methodology can be an addition to the toolbox to prepare benzimidazolones, and it will be useful in medicinal chemistry, particularly, late-stage functionalization of natural products, drug scaffolds, or an intermediate containing quinoxaline-2,3-diones. As direct application of this method, we have successfully developed a new route for the synthesis of recently approved drug flibanserin and a urea analogue of antibiotic natural product hunanamycin A. Later application demonstrates the utility of the present method in late-stage functionalization

 

Synthesis of 1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1,3-dihydro-2Hbenzo[d]imidazol-2-one (Flibanserin)

Flibanserin hydrochloride as white solid.

1H NMR (400MHz ,DMSO-d6)  11.06 (s, 1 H), 10.93 (br. s., 1 H), 7.54 – 7.41 (t, J = 7.9 Hz, 1 H), 7.36 – 7.22 (m, 3 H), 7.15 (d, J = 7.6 Hz, 1 H), 7.09 – 7.01 (m, 3 H), 4.30 (t, J = 6.7 Hz, 2 H), 4.01 (d, J = 11.6 Hz, 2 H), 3.75 (d, J = 10.4 Hz, 2 H), 3.54 – 3.43 (d, J = 4.2 Hz 2 H), 3.31 – 3.10 (m, 4 H);

HRMS (ESI): m/z calculated for C20H22ON4F3[M+H]+ 391.1740 found 391.1743;

str0STR1

Figure

Scheme 4. Synthesis of Flibanserin through Ring Contraction

The same methodology was applied for the synthesis of flibanserin, also known as “female viagra”, which is the first approved medication for treating HSDD in women and is classified as a multifunctional serotonin agonist antagonist.(14, 15) Our synthesis of flibanserin commenced with 1-benzyl-1,4-dihydroquinoxaline-2,3-dione 36,(16) which was reacted with known chloride 37(17) under the basic condition in DMF to give the desired product 38 in good yield. Compound 38 was subjected for the decarbonylative cyclization under the optimized condition to afford the product 39 in 59% yield. Finally, the benzyl group was deprotected using trifluoromethanesulfonic acid in toluene under microwave irradiation,(8b, 18) which gave flibanserin in excellent yield (Scheme 4). The final product was isolated as HCl salt, and all of the spectral data are in agreement with the published data.(15c)

Image result for Rahul D. Shingare

Rahul D. Shingare completed his M.Sc  (Chemistry) from Fergusson College,  Pune  in 2008. He worked as a research associate in Ranbaxy and Lupin New drug discovery center, Gurgaon and Pune respectively until 2012 and currently pursuing his doctoral research in NCL – Pune from 2012.

Current Research Interests: Antibacterial Natural Product Hunanamycin A: Total Synthesis, SAR and Related Chemistry.

e-mail: rd.shingare@ncl.res.in

 

 

 

 

 

 

 

Akshay Kulkarni completed his M.Sc. from Ferguson College, Pune University in the year 2015 and joined our group as a Project Assistant in the month of October, 2015.

Current research interest: Synthesis of silicon incorporated biologically active antimalerial compounds.

e-mail : as.kulkarni@ncl.res.in

Image result for Rahul D. Shingare

 

Dr.D. Srinivasa Reddy
Organic Chemistry Division
CSIR-National Chemical Laboratory

  1. 14.

    StahlS. M. Mechanism of action of Flibanserin, A multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder CNS Spectrums 2015201 DOI: 10.1017/s1092852914000832

  2. 15.

    See, previous synthesis of Flibanserin:

    (a) BiettiG.BorsiniF.TurconiM.GiraldoE.BignottiM. For treatment of central nervous system disorders. U.S. Patent 5,576,318, 1996.

    (b) MohanR. D.ReddyP. K.;ReddyB. V. Process for the preparation of Flibanserin involving novel intermediates. WO2010128516 A2,2010.

    (c) YangF.WuC.LiZ.TianG.WuJ.ZhuF.ZhangJ.HeY.ShenJ. A Facile route of synthesis for making Flibanserin Org. Process Res. Dev. 2016201576 DOI: 10.1021/acs.oprd.6b00108

  3. 16.

    JarrarA. A.FataftahZ. A. Photolysis of some quinoxaline-1,4-dioxides Tetrahedron 1977332127 DOI: 10.1016/0040-4020(77)80326-8

  4. 17.

    XueongX. Preparation method of Flibanserin. CN104926734 A, 2015.

  5. 18.

    RomboutsF.FrankenD.Martínez-LamencaC.BraekenM.ZavattaroC.ChenJ.TrabancoA. A.Microwave-assisted N-debenzylation of amides with triflic acid Tetrahedron Lett. 2010514815 DOI: 10.1016/j.tetlet.2010.07.022

 

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Ecocatalyzed Suzuki cross coupling of heteroaryl compounds

 spectroscopy, SYNTHESIS  Comments Off on Ecocatalyzed Suzuki cross coupling of heteroaryl compounds
Jul 302017
 

Ecocatalyzed Suzuki cross coupling of heteroaryl compounds

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC01672G, Paper
Guillaume Clave, Franck Pelissier, Stephane Campidelli, Claude Grison
A bio-based EcoPd was developed for the Suzuki cross coupling of heteroaryl compounds.

Ecocatalyzed Suzuki cross coupling of heteroaryl compounds

 

Abstract

A bio-based EcoPd was developed for the Suzuki cross coupling of heteroaryl compounds. Based on the ability of Eichhornia crassipes to bioconcentrate Pd in its roots, we addressed the transformation of plant-derived Pd metals to green catalysts. The methodology is based on eco-friendly procedures. It allowed the preparation of a wide range of heterocyclic biaryl and heterocyclic–heterocyclic biaryl compounds, with a low Pd catalyst loading. EcoPd was found to have the ideal microstructure to promote complex Suzuki reactions without ligands or additives. For the first time, post-reaction solution was treated by rhizofiltration. The resulting EcoPd has been reused with the same performance. This work has established the ecocatalysis concept as a powerful strategy for Pd sustainability, with the development of homogeneous catalysts that are easily recycled and reused.

str4 str5 str6

2-Bromothiophene (20 g, 125 mmol), Phenyl boronic acid (16.8 g, 138 mmol), potassium carbonate (20.7 g, 150 mmol) and EcoPd1 (113 mg, 125 µmol of Pd, 13.3 mg of Pd, EcoPd1 at 11.7 wt% of Pd) were suspended into degassed glycerol (200 mL). The mixture was stirred at 120°C for 4h thanks to an oil bath under an argon atmosphere. The reaction was checked for completion by TLC (cyclohexane) and GCMS analysis after a short extraction of the organic material: 10 µL of the crude were added into a 1 mL microtube containing a mixture of water and AcOEt (800 µL, 1:1, v/v) ; the microtube was vortexed before using the organic layer to perform analysis. Deionised water (500 mL) and AcOEt (500 mL) were added into the flask and the mixture filtered through fritted glass to isolate black Pd for recycling. The organic layer was further washed by deionised water (500 mL x 3) before drying over Na2SO4. The organic layer was filtered and concentrated under vacuum. The residue was then purified by chromatography on a silica gel column (250 g) with pure cyclohexane as the mobile phase, giving the desired coupled compound as a white powder (18 g, 112.5 mmol, yield 90%) Rf = 0.7 (cyclohexane).

1H NMR (300 MHz, CDCl3):  = 7.10- 7.13 (m, 2H), 7.44-7.26 (m, 5H), 7.38-7.33 (m, 1H).

13C NMR (75.5 MHz, CDCl3):  = 123.0, 124.8, 125.9, 127.4, 128.0, 128.8, 134.4, 144.4.

MS (EI): m/z = 160 (M+ , 100%), 128 (21%), 115 (54%), 89 (17%) calcd for C10H8S: 159.99.

 

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Catalytic carbonyl hydrosilylations via a titanocene borohydride-PMHS reagent system

 spectroscopy, SYNTHESIS  Comments Off on Catalytic carbonyl hydrosilylations via a titanocene borohydride-PMHS reagent system
Jul 142017
 

 

DOI: 10.1039/C7CY01088E, Paper
Godfred D. Fianu, Kyle C. Schipper, Robert A. Flowers II
Catalytic amounts of titanocene(III) borohydride, generated under mild conditions from commercially available titanocene dichloride, in concert with a stoichiometric hydride source is shown to effectively reduce aldehydes and ketones to their respective alcohols in aprotic media.
  • Catalysis Science & Technology

Catalytic carbonyl hydrosilylations viaa titanocene borohydride–PMHS reagent system

 Author affiliations

Abstract

Reduction of a wide range of aldehydes and ketones with catalytic amounts of titanocene borohydride in concert with a stoichiometric poly(methylhydrosiloxane) (PMHS) reductant is reported. Preliminary mechanistic studies demonstrate that the reaction is mediated by a reactive titanocene(III) complex, whose oxidation state remains constant throughout the reaction.

Godfred Fianu

Godfred Fianu

Robert A Flowers

Robert A Flowers

Danser Distinguished Faculty Chair in Chemistry and Deputy Provost for Faculty Affairs
Lehigh University
Bethlehem, United States
Phenyl methanol (2-c)
Phenyl methanol (2-c) was prepared from benzaldehyde (1-c) by the procedure outlined
in GP1. NMR analysis showed 100% conversion in 1 hour. 86% isolated yield of alcohol
product was obtained after complete workup.
1H NMR (400 MHz, CDCl3) δ 7.37 – 7.26 (m,5H), 4.59 (s, 2H), 2.99 (s, 1H).
13C NMR (101 MHz, CDCl3) δ 140.92, 128.56, 127.60, 127.07,77.52, 77.20, 76.88, 65.04.
STR1 STR2

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Dr. Vinayak Pagar( GUEST BLOGGER) Development of a Povarov Reaction/Carbene Generation Sequence for Alkenyldiazocarbonyl Compounds

 cancer, new drugs, spectroscopy, SYNTHESIS  Comments Off on Dr. Vinayak Pagar( GUEST BLOGGER) Development of a Povarov Reaction/Carbene Generation Sequence for Alkenyldiazocarbonyl Compounds
Apr 282017
 

Discussing my paper……..

Metal-catalyzed cycloadditions of alkenyldiazo reagents are useful tools to access carbo- and heterocycles.[1] These diazo compounds are chemically sensitive toward both Brønsted orLewis acids. Their reported cycloadditions rely heavily on the formation of metal carbenes to initiate regio- and stereoselective [3+n] cycloadditions (n=2–4) with suitable dipolarophiles.[2–4] A noncarbene route was postulated for a few copper-catalyzed cycloadditions of these diazo species, but they resulted in complete diazo decomposition.[3a, 4a, 5] oyle and co-workers reported[4a] a [3+2] cycloaddition of the alkenylrhodium carbene A with imines to give dihydropyrroles (Scheme 1a). We proposed a cycloaddition the tetrahydroquinoline derivatives 3 and 3’, as well as the tetrahydro-1H-benzo[b]azepine species 4. Access to these frameworks are valuable

Access to these frameworks are valuable for the preparation of several bioactive molecules including 2-phenyl-2,3-
dihydroquinolone,[8a] L-689,560,[8b] torcetrapib,[8c] martinellic acid,[8d] OPC-31260,[8e] OPC-51803,[8f] and tetraperalone A (Figure 1).[8g] Their specific biological functions have been well documented.[8]

str2

Spectral data for ethyl 2-diazo-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-4-yl) acetate (2a)

Yellow Semi-Solid;

IR (KBr, cm-1 ): 3542 (m), 2117 (s), 3015 (s), 1737 (s), 1564 (s), 1334 (m), 1137 (s), 817 (s);

1H NMR (600 MHz, CDCl3): δ 7.41 (d, J = 7.3 Hz, 2 H), 7.36 ~ 7.33 (m, 2 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.07 (d, J = 7.6 Hz, 1 H), 7.04 (t, J = 7.6 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H) 4.56 (dd, J = 11.0, 2.3 Hz, 1H ), 4.25 (q, J = 7.1 Hz, 2H ), 4.21 (dd, J = 11.0, 5.3 Hz, 1H ), 4.01 (s, 1H) 2.36 ~ 2.33 (m, 1H), 2.00 (dd, J = 11.8, 2.3 Hz, 1H ), 1.28 (t, J = 7.1 Hz, 3H);

13C NMR (150 MHz, CDCl3): δ 167.2, 145.3, 142.9, 128.6, 128.0, 127.8, 126.5, 126.4, 118.8, 117.9, 114.4, 60.9, 59.5, 56.2, 36.8, 32.6, 14.4.

HRMS calcd for C19H19N3O2: 321.1477; found: 321.1483.

Development of a Povarov Reaction/Carbene Generation Sequence for Alkenyldiazocarbonyl Compounds

Authors, Appaso Mahadev Jadhav, Vinayak Vishnu Pagar, and Rai-Shung Liu*, DOI: 10.1002/anie.201205692

 We thank the National Science Council, Taiwan, for financial support of this work., [*] A. M. Jadhav, V. V. Pagar, Prof. Dr. R.-S. Liu

Department of Chemistry, National Tsing Hua University
Hsinchu (30013) (Taiwan)
E-mail: rsliu@mx.nthu.edu.tw

Abstract

original image

Rings aplenty: A HOTf-catalyzed (Tf=trifluoromethanesulfonyl) Povarov reaction of alkenyldiazo species has been developed and delivers diazo-containing cycloadducts stereoselectively (see scheme). The resulting cycloadducts provide access to six- and seven-membered azacycles through the generation of metal carbenes as well as the functionalization of diazo group.

[1] Selected reviews: a) M. P. Doyle,M. A. McKervy, T. Ye, Modern Catalytic Methods for Organic Synthesis with Diazo Compounds,  Wiley, New York, 1998; b) A. Padwa, M. D. Weingarten, Chem. Rev. 1996, 96, 223; c) H. M. L. Davies, J. R. Denton, Chem. Soc. Rev. 2009, 38, 3061; d) M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010, 110, 704; e) H. M. L. Davies, D. Morton, Chem. Soc. Rev. 2011, 40, 1857; f) Z. Zhang, J. Wang, Tetrahedron
2008, 64, 6577.
[2] Selected examples for carbocyclic cycloadducts, see: a) L. Deng, A. J. Giessert, O. O. Gerlitz, X. Dai, S. T. Diver, H. M. L. Davies, J. Am. Chem. Soc. 2005, 127, 1342; b) H. M. L. Davies, Adv. Cycloaddit. 1999, 5, 119; c) H. M. L. Davies, B. Xing, N. Kong, D. G. Stafford, J. Am. Chem. Soc. 2001, 123, 7461; d) H. M. L. Davies, T. J. Clark, H. D. Smith, J. Org. Chem. 1991, 56, 3819; e) Y. Liu, K. Bakshi, P. Zavalij, M. P. Doyle, Org. Lett. 2010, 12, 4304; f) J. P. Olson, H. M. L. Davies, Org. Lett. 2008, 10, 573.
[3] For oxacyclic cycloadducts, see: a) X. Xu, W.-H. Hu, P. Y. Zavalij, M. P. Doyle, Angew. Chem. 2011, 123, 11348; Angew. Chem. Int. Ed. 2011, 50, 11152; b) M. P. Doyle, W. Hu, D. J. Timmons, Org. Lett. 2001, 3, 3741.

[4] For azacyclic cycloadducts, see selected reviews: a) M. P. Doyle, M. Yan, W. Hu, L. Gronenberg, J. Am. Chem. Soc. 2003, 125, 4692; b) J. Barluenga, G. Lonzi, L. Riesgo, L. A. Lpez, M. Tomas, J. Am. Chem. Soc. 2010, 132, 13200; c) M. Yan, N. Jacobsen, W. Hu, L. S. Gronenberg, M. P. Doyle, J. T. Colyer, D. Bykowski, Angew. Chem. 2004, 116, 6881; Angew. Chem. Int. Ed. 2004, 43, 6713; d) X.Wang, X. Xu, P. Zavalij, M. P. Doyle, J. Am.
Chem. Soc. 2011, 133, 16402; e) Y. Lian, H. M. L. Davies, J. Am. Chem. Soc. 2010, 132, 440; f) X. Xu, M. O. Ratnikov, P. Y. Zavalij, M. P. Doyle, Org. Lett. 2011, 13, 6122; g) V. V. Pagar, A. M. Jadhav, R.-S. Liu, J. Am. Chem. Soc. 2011, 133, 20728; h) R. P. Reddy, H. M. L. Davies, J. Am. Chem. Soc. 2007, 129, 10312.

[5] Y. Qian, X. Xu, X.Wang, P. Zavalij,W. Hu, M. P. Doyle, Angew. Chem. 2012, 124, 6002; Angew. Chem. Int. Ed. 2012, 51, 5900.
[6] Povarov reactions refer to the formal [4+2] cycloadditions of Naryl imines with enol ethers or enamines. See reviews: a) L. S. Povarov, Russ. Chem. Rev. 1967, 36, 656; b) V. V. Kouznetsov, Tetrahedron 2009, 65, 2721; c) D. Bello, R. Ramn, R. Lavilla, Curr. Org. Chem. 2010, 14, 332; d) M. A. McCarrick, Y. D. Wu, K. N. Houk, J. Org. Chem. 1993, 58, 3330; e) A. Whiting, C. M. Windsor, Tetrahedron 1998, 54, 6035.

[7] For Povarov reactions catalyzed by Brønsted acids, see selected examples: a) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobson, Science 2010, 327, 986; b) T. Akiyama, H. Morita, K. Fuchibe, J. Am. Chem. Soc. 2006, 128, 13070; c) H. Liu, G. Dagousset, G. Masson, P. Retailleau, J. Zhu, J. Am. Chem. Soc. 2009, 131, 4598; d) G. Dagousset, J. Zhu, G. Masson, J. Am. Chem. Soc. 2011, 133, 14804; e) H. Ishitani, S. Kobayashi, Tetrahedron Lett. 1996, 37, 7357; f) G. Bergonzini, L. Gramigna, A. Mazzanti, M. Fochi, L. Bernardi, A. Ricci, Chem. Commun.
2010, 46, 327; g) L. He, M. Bekkaye, P. Retailleau, G. Masson, Org. Lett. 2012, 14, 3158.

[8] a) Y. Xia, Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Tachibana, S.-C. Kuo, E. Hamel, T. Hackl, K.-H. Lee, J. Med. Chem. 1998, 41, 1155; b) R.W. Carling, P. D. Leeson, A. M. Moseley, J. D. Smith, K. Saywell, M. D. Trickelbank, J. A. Kemp, G. R. Marshall, A. C. Foster, S. Grimwood, Bioorg. Med. Chem. Lett. 1993, 3, 65;
c) D. B. Damon, R. W. Dugger, R.W. Scott, U.S. Patent 6,689,897, 2004; d) D. A. Powell, R. A. Batey, Org. Lett. 2002, 4, 2913; e) A. Matsuhisa, K. Kikuchi, K. Sakamoto, T. Yatsu, A. Tanaka, Chem. Pharm. Bull. 1999, 47, 329; f) M. Y. Christopher, E. A. Christine, D. M. Ashworth, J. Barnett, A. J. Baxter, J. D. Broadbridge, R. J. Franklin, S. L. Hampton, P. Hudson, J. A. Horton, P. D. Jenkins, A. M. Penson, G. R.W. Pitt, P. Rivire,
P. A. Robson, D. P. Rooker, G. Semple, A. Sheppard, R. M.Haigh, M. B. Roe, J. Med. Chem. 2008, 51, 8124; g) C. Li, X. Li, R. Hong, Org. Lett. 2009, 11, 4036.

About author( Me)

Dr. Vinayak Pagar

Dr. Vinayak Pagar

Postdoctoral Research Fellow at The Ohio State University

Vinayak Vishnu Pagar was born in Nasik, Maharashtra (India) in 1983. He obtained his BSc and MSc degrees in chemistry from the University of Pune (India) in 2004 and 2006, respectively. From 2006–2010, he worked as Research Associate in pharmaceutical companies like Jubilant Chemsys Ltd. and Ranbaxy Laboratories Ltd. (India). In 2010, he joined the group of Professor Rai-Shung Liu to pursue his PhD degree in National Tsing Hua University (Taiwan) and completed it in 2014. Subsequently, he worked as a postdoctoral fellow in the same group for one year. Currently, he is working as a Research Scientist at The Ohio State University, Columbus, Ohio USA. His research focused on the development of new organic reactions by using transition-metal catalysis such Gold, Silver, Rhodium, Zinc, Cobalt, Nickel and Copper metals which enables mild, diastereoselective, enantioselective and efficient transformations of variety of readily available substrates to wide range of synthetically useful nitrogen and oxygen containing heterocyclic products which are medicinally important. He published his research in a very high impact factor international Journals includes  J. Am. Chem. Soc.,  Angew. Chem. Int. Ed.,  J. Org. Chem.,  Chem- A. Eur. Journal,  Org. Biomol. Chem., and Synform (Literature Coverage).

Dr. Vinayak Pagar

Postdoctoral Researcher

Department of Chemistry and Biochemistry

The Ohio State University

100 West 18th Avenue

Columbus, Ohio 43210 USA

vinayak.pagar@gmail.com

/////////Vinayak Pagar, Postdoctoral Research Fellow, The Ohio State University, blog, Povarov Reaction, Carbene Generation Sequence,  Alkenyldiazocarbonyl Compounds

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Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

 spectroscopy, SYNTHESIS  Comments Off on Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile
Apr 222017
 

Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

 Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC00602K, Communication
Katharina J. Hock, Robin Spitzner, Rene M. Koenigs
Applications of diazo acetonitrile in cyclopropa(e)nation reactions are realized in a slow-release protocol with bench-stable reagents. Cyclopropyl nitriles are obtained in one step in good diastereoselectivity on a gram-scale providing an efficient entry into this class of fragrances and drug-like molecules.
STR1
STR2
trans-2-phenylcyclopropane-1-carbonitrile
colorless solid (46 mg, 81%);
m.p. = 29°C;
1 H-NMR (600 MHz, CDCl3): δ = 7.34 – 7.30 (m, 2H), 7.28 – 7.24 (m, 1H), 7.12 – 7.08 (m, 2H), 2.63 (ddd, J = 9.2, 6.7, 4.7 Hz, 1H), 1.62 (dt, J = 9.2, 5.4 Hz, 1H), 1.55 (ddd, J = 8.7, 5.5, 4.8 Hz, 1H), 1.45 (ddd, J = 8.8, 6.7, 5.3 Hz, 1H);
13C-NMR (151 MHz, CDCl3): δ = 137.55, 128.76, 127.41, 126.31, 121.05, 24.90, 15.24, 6.63;
HRMS (ESI): m/z calc. for [C10H9NNa]: 166.06272, found 166.06276;
IR (KBr): νmax/cm-1 = 3044, 2235, 2098, 1761, 1600, 1461, 1220, 1051, 920, 705.
The analytical data is in correspondence with the literature [2]
STR1 STR2
[2] M. Gao, N. N. Patwardhan, P. R. Carlier, J. Am. Chem. Soc., 2013, 135 (38), 14390–14400

Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

Author affiliations

Abstract

Diazo acetonitrile has long been neglected despite its high value in organic synthesis due to a high risk of explosions. Herein, we report our efforts towards the transient and safe generation of this diazo compound, its applications in iron catalyzed cyclopropanation and cyclopropenation reactions and the gram-scale synthesis of cyclopropyl nitriles.

Graphical abstract: Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile
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(3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine

 spectroscopy  Comments Off on (3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine
Feb 092017
 

STR1

 

(3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine

STR1 STR2

Synthesis of (3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine (10)

off-white solid (53.9 kg, 68.3% yield). 1H NMR (400 MHz, DMSO-d6, δ): 1.20 (d, J = 6.8 Hz, 3 H), 2.52 (m, 1 H), 2.63 (s, 3 H), 3.21 (m, 1 H), 3.44 (m, 1 H), 3.58 (dd, J = 11.6, 3.1 Hz, 1 H), 3.72 (d, J = 11.5 Hz, 1 H), 3.92 (m, 3 H), 4.07 (d, J = 12.4 Hz, 1 H), 6.80 (s, 1 H); Assay (HPLC) 99%; Assay (QNMR) 100%; Chiral purity (HPLC) (R,R)-diastereoisomer 99.6%, (R,S)-diastereoisomer 0.4%.

 

Abstract Image

A Baeyer–Villiger monooxygenase enzyme has been used to manufacture a chiral sulfoxide drug intermediate on a kilogram scale. This paper describes the evolution of the biocatalytic manufacturing process from the initial enzyme screen, development of a kilo lab process, to further optimization for plant scale manufacture. Efficient gas–liquid mass transfer of oxygen is key to obtaining a high yield.

Development and Scale-up of a Biocatalytic Process To Form a Chiral Sulfoxide

The Departments of Pharmaceutical Sciences and Pharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, United Kingdom
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00391
Publication Date (Web): January 4, 2017
Copyright © 2017 American Chemical Society
*Tel: +44 (0)1625-519149. E-mail: william.goundry@astrazeneca.com.
Figure
Examples of biologically active molecules containing a sulfoxide or sulfoximine: esomeprazole (3), aprikalim (4), oxisurane (5), OPC-29030 (6), ZD3638 (7), buthionine sulfoximine (8), and AZD6738 (9).

“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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(±)-trans-ethyl 2-(3,4-difluorophenyl)Cyclopropanecarboxylate

 spectroscopy  Comments Off on (±)-trans-ethyl 2-(3,4-difluorophenyl)Cyclopropanecarboxylate
Feb 092017
 

STR1 STR2 STR3

(±)-trans-ethyl 2-(3,4-difluorophenyl)Cyclopropanecarboxylate

C12H12F2O2

GC-MS (EI) m/z: [M]+ calc. for C12H12F2O2 + : 226.08; found: 226.08.

δH (400 MHz, CDCl3): 1.25 (1H, ddd, 3 J 8.4 Hz, 3 J 6.4 Hz, 2 J 4.5 Hz , 3-H); 1.28 (3H, t 3 J 6.4 Hz CH3Ethyl) 1.57-1.62 (2H, m, 3 J 9.2 Hz, 3 J 5.2 Hz, 2 J 4.5 Hz, 3-H + H2O), 1.84 (1H, ddd, 3 J 8.5 Hz, 3 J 5.3 Hz, 3 J 4.3 Hz , 2-H), 2.47 (1H, ddd, 3 J 9.5 Hz, 3 J 6.4 Hz, 3 J 4.2 Hz , 1-H), 4.17 (2H, q, 3 J 6.3 Hz, CH2Ethyl) 6.81-6.87 (1H, m, 3 J 8.5 Hz, 4 J 7.6 Hz, 4 J 2.4 Hz, 6-H’ ), 6.88 (1H, ddd, 3 J 11.5 Hz, 4 J 7.6 Hz, 4 J 2.2 Hz, 2-H’) 7.06 (1H, dt, 3 J 10.3 Hz, 3 J 8.2 Hz. 5-H’).

δc (400 MHz, CDCl3): 14.27 (CH3Ethyl), 16.84 (3-C) 24.04 (1-C), 25.14 (d, 4 J 1.4, 2-C), 60.71 (CH2Ethyl), 114.74 (d, 2 J 19 Hz, 2-C’), 117.09 (d, 2 J 18 Hz, 5-C’), 122.25 (dd, 3 J 6.1 Hz, 4 J 3.4 Hz, 6- C’), 137.06 (dd, 3 J 6.1 Hz, 4 J 3.4 Hz, 1- C’), 149.2 (dd, 1 J 248 Hz, 2 J 13 Hz, 4-C’) 151.32 (dd, 1 J 249 Hz, 2 J 12.5 Hz, 3-C’) 172.87 (Ccarbonyl).

[ ] 20 a D = -381.9 (c 1.0 in EtOH) for (1R,2R)-3, ee = 95%

Abstract Image

In this study a batch reactor process is compared to a flow chemistry approach for lipase-catalyzed resolution of the cyclopropanecarboxylate ester (±)-3. (1R,2R)-3 is a precursor of the amine (1R,2S)-2 which is a key building block of the API ticagrelor. For both flow and batch operation, the biocatalyst could be recycled several times, whereas in the case of the flow process the reaction time was significantly reduced.

Comparison of a Batch and Flow Approach for the Lipase-Catalyzed Resolution of a Cyclopropanecarboxylate Ester, A Key Building Block for the Synthesis of Ticagrelor

School of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
Chemessentia, SRL – Via G. Bovio, 6-28100 Novara, Italy
§ Institute of Process Research and Development, School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, United Kingdom
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00346
Publication Date (Web): December 22, 2016
Copyright © 2016 American Chemical Society

“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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