AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Nov 232017
 

 

Catalytic C-H amination at its limits: challenges and solutions

Org. Chem. Front., 2017, 4,2500-2521
DOI: 10.1039/C7QO00547D, Review Article
Damien Hazelard, Pierre-Antoine Nocquet, Philippe Compain
Pushing C-H amination to its limits fosters innovative synthetic solutions and offers a deeper understanding of the reaction mechanism and scope.

Catalytic C–H amination at its limits: challenges and solutions

 

Abstract

Catalytic C–H amination reactions enable direct functionalization of non-activated C(sp3)–H bonds with high levels of regio-, chemo- and stereoselectivity. As a powerful tool to unlock the potential of inert C–H bonds, C–H amination chemistry has been applied to the preparation of synthetically challenging targets since major simplification of synthetic sequences are expected from this approach. Pushing C–H amination to its limits has led to a deeper understanding of the reaction mechanism and scope. In this review, we present a description of the specific challenges facing catalytic C–H amination in the synthesis of natural products and related compounds, as well as innovative tactics created to overcome them. By identifying and discussing the major insights gained and strategies designed, we hope that this review will stimulate further progress in C–H amination chemistry and beyond.

Conclusion Since the seminal works of Du Bois in the early 2000s, the pace of discovery in the field of metal-catalysed C–H amination has been breath-taking. Not surprisingly, this synthetic tool has been applied to the total synthesis of many compounds of interest, given the high prevalence of the amino group in natural products and synthetic pharmaceuticals.67 Chemist’s confidence in the high potential of the C–H amination methodology to unlock inert C–H bonds has been demonstrated by its application to more and more challenging substrates. This has been a powerful drive for progress in the field. New valuable insights have been gained allowing, for example, a better regiochemical control via stereoelectronic and/or conformational effects. Innovative strategies have been discovered to direct the insertion event in substrates bearing a large degree of attendant functionality. Solutions have spanned from the elegant exploitation of kinetic isotope effects to the tactical use of protecting groups with different sizes or electronic characteristics. Systematic exploration of different catalytic systems has been also performed leading to the opening of new possibilities in C–H amination technology. Manganese-based catalysts have thus given rise to nitrenoids that overcome the low reactivity of primary aliphatic C–H bonds without interfering with weaker secondary/tertiary C–H bonds. Despite these impressive achievements, much remains to be done. Counterintuitive selectivity and unexplained reactivity should serve as a reminder that further studies are highly needed to understand in depth catalytic C–H amination chemistry. Many challenges remain on the way, from basic to applied research. A clear mechanistic view based on definitive evidence concerning the details of the C–N bond forming process would undoubtedly facilitate the rational design of efficient catalytic systems leading to higher regio-, chemio- and stereoselectivity. In particular, the quest for site-selective C–H amination through catalyst control has to be pursued.10d,e In this context, the development of efficient intermolecular C–H amination process still represents a major challenge and upcoming advancements are expected to increase the impact of this technology in organic synthesis. Future progress made in the field of catalytic C–H amination chemistry might also lead to industrial-scale applications in the next decade. It is likely that total synthesis of synthetically challenging targets related to natural products will continue to be a powerful driving force towards this goal.

STR1 STR2

/////////////

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This 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

Follow amcrasto on Twitter

Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK

Join me on twitterFollow amcrasto on Twitter
Join me on google plus Googleplus

 amcrasto@gmail.com

Share

Gram-Scale Synthesis of Amines Bearing a gem-Difluorocyclopropane Moiety

 organic chemistry, spectroscopy, SYNTHESIS  Comments Off on Gram-Scale Synthesis of Amines Bearing a gem-Difluorocyclopropane Moiety
Nov 102017
 
Image result for ukraine flag animated

Image result for National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine

Ukraine

original image

 

Abstract

The synthesis of monocyclic, spirocyclic and fused bicyclic secondary amines bearing a gem-difluorocyclopropane moiety via difluorocyclopropanation of unsaturated N-Boc derivatives using the trifluoromethyl(trimethyl)silane/sodium iodide [CF3SiMe3-NaI] system is described. The relative order of the substrate reactivity is established. It is shown that for the reactive alkenes the standard reaction conditions can be used, whereas for the substrates with low reactivity, slow addition of the Ruppert–Prakash reagent is necessary.

Gram-Scale Synthesis of Amines Bearing a gem-Difluorocyclopropane Moiety

Authors., Pavel S. Nosik,

DOI: 10.1002/adsc.201700857

Pavel S. Nosik,a.b Andrii O. Gerasov,a Rodion O. Boiko,a Eduard Rusanov,b Sergey V. Ryabukhin,c Oleksandr O. Grygorenko,c * Dmitriy M. Volochnyukb

a Spectrum Info Ltd., Life Chemicals Inc., Murmanska Street 5, Kyiv 02094, Ukraine

b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine

c National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine

Image result for National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine

* Corresponding author. E-mail: gregor@univ.kiev.ua.

 

Oleksandr Grygorenko at National Taras Shevchenko University of Kyiv

Oleksandr Grygorenko

Ph D
Professor (Associate)
National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine
National Taras Shevchenko University of Kyiv

Image result for Dmitriy M. Volochnyuk

Dmitriy M. Volochnyuk

Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine

Dmitriy M. Volochnyuk was born in 1980 in Irpen, Kyiv region, Ukraine. He graduated from Kyiv State Taras Shevchenko University in 2002 and was awarded his M.S. degree in chemistry. He received his Ph.D. in organic chemistry in 2005 from the Institute of Organic Chemistry, National Academy of Sciences of Ukraine under the supervision of Dr. A. Kostyuk for research on the chemistry of enamines. At present, he divides his time between the Institute of Organic Chemisty, as Deputy Head of Organophosphorus Department and Senior Researcher, and Enamine Ltd (Kyiv, Ukraine), as Director of Chemistry. His main scientific interests are related to fluoroorganic, organophosphorus, heterocyclic and combinatorial chemistry, and multistep organic synthesis. He is a coauthor of more than 80 papers

institute-of-organic-chemstry-nanu

 

  • Given that the incorporation of small fluorinated fragments in drug-like molecules continues to rise, this has created an onus on the synthetic community to provide robust, scalable routes to these molecules of interest. Grygorenko and co-workers have reported on a synthesis of amines featuring a gem-difluorocyclopropane moiety using the readily available Ruppert–Prakash reagent ( Adv. Synth. Catal. 201710.1002/adsc.201700857).
  • Evaluating a series of olefins under the standard reaction conditions in refluxing THF indicated that only the most reactive olefins (gem-disubstituted) provided good yields of the desired cyclopropane, while other solvents proved to be ineffective. Conducting a control experiment omitting the substrate demonstrated that the key issue herein was competitive decomposition of the TMSCF3 to a series of gaseous byproducts under the reaction conditions.
  • Whereas continuous flow provides a potential to mitigate against this, the current report demonstrated that slow addition of the reagent to the reaction mixture also provided a practical solution to this problem.
  • Employing this approach enabled not only excellent conversions and yields to be realized but also allowed reactivity trends to be identified. In general, gem-disubstituted are the most reactive with the trend correlating with steric hindrance.
  • For other classes of olefins, electronics are the major factor with the ability of the substituents to stabilize a positive charge in the transition state consistent with a nonsynchronous formation of the two sigma bonds in the cycloaddition the key consideration. The removal of the Boc-protecting group under standard acidic conditions provided the amines as their hydrochloride salts.
  • Eduard Rusanov at Institute of Organic Chemistry National Academy of Sciences of Ukraine
  • Eduard Rusanov

    PhD
    Head of Crystallographic Lab./Director of the crystallographic facility Nat. Acad. of Sci. Ukraine ‘Single Mjlecule Crystallography’ at IOC
    Institute of Organic Chemistry… · DEPARTMENT OF PHYSICOCHEMICAL INVESTIGATIONS

STR2STR1

tert-Butyl 1,1-difluoro-6-azaspiro[2.5]octane-6-carboxylate (10a):

Yield: 66.7 g (91%) (Method A); off-white crystalline powder: mp 46–48 8C;

1H NMR (CDCl3 , 400 MHz): d= 3.57–3.42 (m, 2H), 3.40–3.27 (m, 2H), 1.66–1.47 (m, 4H), 1.44 (s, J=2.3 Hz, 9H), 1.08 (t, J=8.3 Hz, 2H);

13C NMR (CDCl3, 101 MHz): d=154.2, 115.4 (t, J=288.1 Hz), 79.3, 42.8, 28.4, 28.1, 26.8 (t, J=10.0 Hz), 21.0 (t, J=10.1 Hz);

19F NMR (CDCl3 , 376 MHz): d=@140.6;

MS (EI): m/z= 247 (M+ ), 192 (M+@t-Bu), 174 (M+@t-BuO), 147 (M+@Boc), 127 (M+@Boc@HF);

Anal. calcd. for C12H19F2NO2 : C 58.29, H 7.74, N 5.66; found: C 58.49, H 8.02, N 5.30.

//////////////

Follow amcrasto on Twitter

Share

Benzisoxazole: a privileged scaffold for medicinal chemistry

 new drugs, organic chemistry, SYNTHESIS, Uncategorized  Comments Off on Benzisoxazole: a privileged scaffold for medicinal chemistry
Nov 082017
 

 

Med. Chem. Commun., 2017, Advance Article
DOI: 10.1039/C7MD00449D, Review Article
K. P. Rakesh, C. S. Shantharam, M. B. Sridhara, H. M. Manukumar, Hua-Li Qin
The benzisoxazole analogs represent one of the privileged structures in medicinal chemistry and there has been an increasing number of studies on benzisoxazole-containing compounds.

Benzisoxazole: a privileged scaffold for medicinal chemistry

 

Abstract

The benzisoxazole analogs represent one of the privileged structures in medicinal chemistry and there has been an increasing number of studies on benzisoxazole-containing compounds. The unique benzisoxazole scaffold also exhibits an impressive potential as antimicrobial, anticancer, anti-inflammatory, anti-glycation agents and so on. This review examines the state of the art in medicinal chemistry as it relates to the comprehensive and general summary of the different benzisoxazole analogs, their use as starting building blocks of multifarious architectures on scales sufficient to drive human drug trials. The number of reports describing benzisoxazole-containing highly active compounds leads to the expectation that this scaffold will further emerge as a potential candidate in the field of drug discovery.

Hua-Li Qin

Dr. Hua-Li Qin Ph. D 2009
qinhuali@bu.edu

Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan, PR China

  • Wuhan University of Technology

Hua-Li joined the Panek group in 2005.

C. S. Shantharam at Pooja Bhagavat Memorial Mahajana P.G Centre

C. S. Shantharam

M.Sc., Ph.D
Assistant professor
Pooja Bhagavat Memorial Mahaja… , Mysore · Department of Chemistry
Department of Chemistry, Pooja Bhagavath Memorial Mahajana Education Centre, Mysuru-570016, India
Image result for Department of Chemistry, Pooja Bhagavat Memorial Mahajana Education Centre, Mysore-570016, India
Image result for Department of Chemistry, Pooja Bhagavat Memorial Mahajana Education Centre, Mysore-570016, India

Hua-Li Qin

 

Manukumar H M at University of Mysore

Manukumar H M

Master of Science
Research Scholar

 

////////////Benzisoxazole, scaffold, medicinal chemistry

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This 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

Share

Metal-free synthesis of polysubstituted pyrroles using surfactants in aqueous medium

 organic chemistry, SYNTHESIS  Comments Off on Metal-free synthesis of polysubstituted pyrroles using surfactants in aqueous medium
Nov 072017
 

 

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC01874F, Communication
Amrendra Kumar, Ramanand, Narender Tadigoppula
An efficient and metal-free method has been developed for the synthesis of polysubstituted pyrrole derivatives with combination of sodium dodecyl sulphate (SDS) and Triton X-100 surfactants using water as a solvent at room temperature in 2-6 h and under microwave conditions (10 min) with good to excellent yields.

Metal-free synthesis of polysubstituted pyrroles using surfactants in aqueous medium

Image result for Narender Tadigoppula

Dr. Narender Tadigoppula

Principal Scientist
Medicinal & Process Chemistry
Central Drug Research Institute
India

Dr. Narender Tadigoppula is currently principal scientist in the department of medicine chemistry central drug research institute. He published more than 30 research articles. His major major research activities are identification of biologically active lead molecules through activity guided fraction and isolation work on the medicinal plants, marine organisms and microorganisms for metabolic diseases (hyperglycemia, dyslipidemia), parasitic diseases (leishmania and malaria), cancer etc., and chemical transformation of natural products of biological importance to improve their potency. We synthesize these biologically active lead molecules and their analogues in our laboratory. We have identified several lead molecules from the Indian medicinal plants for various disease areas as described below and further work is in progress to develop natural products based drugs.

Abstract

An efficient and metal-free method has been developed for the synthesis of polysubstituted pyrrole derivatives via intermolecular cycloaddition of substituted 1-phenyl-2-(phenylamino)-ethan-1-one/1-phenyl-2-(phenylamino)-propan-1-ones/2-((4-methoxyphenyl)amino)-1-(thiophen-2-yl)ethan-1-one/1-(furan-2-yl)-2-((4-methoxyphenyl)amino)ethan-1-one/1-(benzofuran-3-yl)-2-((4-methoxyphenyl)amino)ethan-1-one and dialkyl acetylene dicarboxylate/ethylbutynoate in the presence of a combination of sodium dodecyl sulphate (SDS) and Triton X-100 surfactants using water as a solvent at room temperature in 2–6 h under microwave conditions (10 min) with good to excellent yields.

Diethyl-1-(4-methoxyphenyl)-4-(p-tolyl)-1H-pyrrole 2,3dicarboxylate

STR1

white solid, yield 77%, mp 128-130 ;

1H NMR (400 MHz, CDCl3) δ 7.38(d, J = 8.2,2H), 7.31 (d, J = 7.9, 2H), 7.21 (d, J = 7.12, 2H), 6.99-6.96 (m, 3H), 4.31 (q, J = 7.2 Hz, 2H), 4.12 (q, J = 7.6Hz, 2H), 3.88 (s, 3H), 2.38 (s, 3H), 1.31 (t, J = 7.9Hz, 3H), 1.19 (t, J = 7.5Hz, 3H) ;

13C NMR (100 MHz, CDCl3) δ 166.3, 159.9, 149.0, 148.8, 136.7, 132.6, 130.3, 129.2, 127.6, 125.8, 124.5, 123.4, 121.5, 118.3, 110.5, 110.2, 61.2, 60.7, 56.0, 21.1, 14.0, 13.9.

IR (KBr) ṽ (cm-1): 2981.9, 1717.9, 1514.1, 1419.2, 1381.3, 1245.0, 1175.9, 1226.7, 1043.6, 835.7, 755.3, 663.

HRESIMS: m/zcalcd for [M+H]+ C24H26NO5 408.1805 found 408.1845.

STR1 STR2

 

/////////////

O=C(OCC)c2c(c(cn2c1ccc(OC)cc1)c3ccc(C)cc3)C(=O)OCC

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This 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

Share

Total synthesis of (-)-aritasone via the ultra-high pressure hetero-Diels-Alder dimerisation of (-)-pinocarvone

 organic chemistry, spectroscopy, SYNTHESIS  Comments Off on Total synthesis of (-)-aritasone via the ultra-high pressure hetero-Diels-Alder dimerisation of (-)-pinocarvone
Oct 102017
 

STR1

Total synthesis of (-)-aritasone via the ultra-high pressure hetero-Diels-Alder dimerisation of (-)-pinocarvone

Org. Biomol. Chem., 2017, Advance Article

DOI: 10.1039/C7OB02204B, Paper
Maliha Uroos, Phillip Pitt, Laurence M. Harwood, William Lewis, Alexander J. Blake, Christopher J. Hayes
The total synthesis of aritasone via the proposed biosyntheic hetero-Diels-Alder [4 + 2] cyclodimerisation of pinocarvove, has been achieved under ultra-high pressure (19.9 kbar) conditions

Total synthesis of (−)-aritasone via the ultra-high pressure hetero-Diels–Alder dimerisation of (−)-pinocarvone

 Author affiliations

Christopher Hayes

Abstract

This paper describes a total synthesis of the terpene-derived natural product aritasone via the hetero-Diels–Alder [4 + 2] cyclodimerisation of pinocarvove, which represents the proposed biosyntheic route. The hetero-Diels–Alder dimerisation of pinocarvone did not proceed under standard conditions, and ultra-high pressure (19.9 kbar) was required. As it seems unlikely that these ultra-high pressures are accessible within a plant cell, we suggest that the original biosynthetic hypothesis be reconsidered, and alternatives are discussed.

STR1 STR2
Aritasone (1) A solution of pinocarvone (()-2) (100 mg, 0.66 mmol) in dichloromethane (5 mL) was pressurized to 19.9 kbar for 120 h. The 1H NMR spectrum of the crude reaction mixture showed significant change in the composition as compared to the starting material. The solvent was evaporated and the residue was purified by column chromatography (pentane/Et2O; 25/1) to afford aritasone (1) (20 mg, 40%) as a white solid; mp 101- 103 C; (lit3 mp 105-106 °C); []D 26 26.1 (c 0.40 in CHCl3); (lit3 []D 9 118); max/cm-1 (CHCl3) 2926, 2359, 1722, 1689, 1601, 1467, 1372, 1305, 1152; H (400 MHz; CDCl3, 298 K) 2.67 (2H, app dd, J 4.8, 2.5, H-2a, H-2b), 2.45-2.32 (3H, m, H-7a, H-15a, H-3), 2.15-2.01 (4H, m, H-10, H-12, H-15b, H-16a), 1.91-1.80 (2H, m, H-4, H-16b), 1.66 (1H, ddd, J 13.8, 6.4, 3.4, H-7b), 1.38 (3H, s, CH3), 1.29-1.22 (7H, br s, CH3, H-13a, H-13b, H-8a, H- 8b), 0.90 (3H, s, CH3), 0.80 (3H, s, CH3); C (100 MHz; CDCl3, 298 K) 209.5 (C), 142.9 (C), 112.8 (C), 80.8 (C), 45.2 (CH), 44.3 (CH), 43.7 (CH2), 40.9 (CH), 40.5 (C), 39.4 (CH), 38.3 (C), 33.2 (CH2), 32.7 (CH2), 27.7 (CH3), 27.3 (CH2), 27.3 (CH3), 26.3 (CH3), 22.5 (CH2), 22.1 (CH2), 20.9 (CH3); HRMS m/z (ES+ ) found 301.2162 (M + H) C20H29O2 requires 301.2162 and 323.1981 (M + Na) C20H28O2Na requires 323.1982. These data were consistent to those previously reported, 5, 7 however the value of the specific rotation5 differs significantly from that measured during the original isolation work.3

Christopher Hayes

Contact

Biography

Prof. Christopher Hayes began his academic career here in Nottingham with his B.Sc. in July 1992. Remaining at Nottingham, he completed his Ph.D. studies in organic chemistry, under the supervision of Professor Gerald Pattenden, in September 1995. In January 1996, on a NATO Postdoctoral Fellowship, he moved to the University of California at Berkeley where he worked in the group of Professor Clayton H. Heathcock. In September 1997, he returned to Nottingham as a Lecturer in Organic Chemistry, and has subsequently been promoted to Reader (2003), Associate Professor (2006) and Professor of Organic Chemistry (2011).

Research Summary

Research is centred in main-stream synthetic organic chemistry, focusing on the organic chemistry of biologically active molecules. His current research interests span a number of areas such as (i)… read more

Recent Publications

Share
Follow

Get every new post on this blog delivered to your Inbox.

Join other followers: