Heck–Matsuda Reaction in Flow

Abstract Image

Product 3 was obtained as a mixture of diastereomers (58:42). The NMR data are consistent with literature precedent.20a

Major diastereomer: 1H NMR (300 MHz, CDCl3) δ (ppm) 7.25-7.28 (m, 2H), 7.14-7.17 (m, 2H), 5.14 (dd, 1H, J = 2.5, 5.8 Hz), 4.29 (t, 1H, J = 8.3 Hz), 3.79 (dd, 1H, J = 6.9, 8.4 Hz), 3.54-3.62 (m, 1H), 3.38 (s, 3H), 2.32 (dd, 1H, J = 7.7, 12.9 Hz), 2.04 (ddd, 1H, J = 5.1, 9.3, 13.1 Hz);

Minor diastereomer: 1H NMR (300 MHz, CDCl3) δ 7.25-7.28 (m, 4H), 5.16 (d, 1H, J = 4.4 Hz), 4.17 (t, 1H, J = 8.1 Hz), 3.72 (dd, 1H, J = 8.5, 9.7 Hz), 3.42 (s, 3H), 3.32-3.36 (m, 1H), 2.59 (ddd, 1H, J = 5.5, 10.3, 13.7 Hz), 1.91 (ddd, 1H, J = 2.4, 7.7, 10.2 Hz);

13C NMR (75 MHz, CDCl3) δ (ppm) 141.4, 140.0, 132.4, 132.3, 129.1, 128.7, 128.7, 128.5, 105.7, 105.4, 73.7, 73.0, 54.9, 54.7, 43.6, 42.1, 41.4, 41.1.

(20) (a) Oliveira, C. C.; Angnes, R. A.; Correia, C. R. D. J. Org. Chem. 2013, 78, 4373. (b) Oliveira, C. C.; Pfaltz, A.; Correia, C. R. D. Angew. Chem. Int. Ed. 2015, 54, 14036.

The optimization of a palladium-catalyzed Heck–Matsuda reaction using an optimization algorithm is presented. We modified and implemented the Nelder–Mead method in order to perform constrained optimizations in a multidimensional space. We illustrated the power of our modified algorithm through the optimization of a multivariable reaction involving the arylation of a deactivated olefin with an arenediazonium salt. The great flexibility of our optimization method allows to fine-tune experimental conditions according to three different objective functions: maximum yield, highest throughput, and lowest production cost. The beneficial properties of flow reactors associated with the power of intelligent algorithms for the fine-tuning of experimental parameters allowed the reaction to proceed in astonishingly simple conditions unable to promote the coupling through traditional batch chemistry.

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Multicomponent-Multicatalyst Reactions (MC)2R: Efficient Dibenzazepine Synthesis

Multicomponent-Multicatalyst Reactions (MC)2R: Efficient Dibenzazepine Synthesis
Jennifer Tsoung, Jane Panteleev, Matthias Tesch, and Mark Lautens

Org. Lett. 2014, 16, 110-113. DOI:10.1021/ol4030925 .

http://pubs.acs.org/doi/abs/10.1021/ol4030925

A RhI/Pd0 catalyst system was applied to the multicomponent synthesis of aza-dibenzazepines from vinylpyridines, arylboronic acids, and amines in a domino process with no intermediate isolation or purification.

5-(p-tolyl)-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepine (4a)

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1H NMR
(400 MHz, CDCl3) δ 8.66 (d, J = 1.1 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.43 – 7.38 (m, 1H), 7.38 – 7.29
(m, 3H), 6.98 (d, J = 8.4 Hz, 2H), 6.57 – 6.51 (m, 2H), 3.33 – 3.21 (m, 2H), 3.09 – 2.99 (m, 2H), 2.26 (s,
3H);

13C NMR (101 MHz, CDCl3) δ 161.7 (q, J = 1.3 Hz), 145.8, 143.6, 143.4 (q, J = 4.0 Hz), 139.7,
139.5, 134.9 (q, J = 3.5 Hz), 130.3, 130.0, 129.9, 128.9, 128.2, 127.7, 125.3 (q, J = 33.1 Hz), 123.4 (q, J =
272.5 Hz), 114.0 (2), 35.9, 29.0, 20.4;

19F NMR (377 MHz, CDCl3) δ -62.0;

IR (NaCl, neat): 3063, 3028,
2926, 2862, 1616, 1506, 1489, 1456, 1435, 1429, 1410, 1339, 1319, 1296, 1267, 1240, 1207, 1165, 1128,
1086, 1036, 978, 947, 930, 910, 895, 808, 772, 756, 737, 721, 704, 687, 664, 646, 627 cm-1;

HRMS (ESI):
calcd for C21H18F3N2 (M+H)+: 355.1422; found. 355.1419.

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Jennifer Tsoung

Jennifer Tsoung

Jennifer Tsoung

PhD graduate, organic chemistry

Department of Chemistry, University of Toronto

Experience

PhD

University of Toronto

September 2010 – October 2015 (5 years 2 months)

Research Intern

Kyoto University

June 2014 – August 2014 (3 months)Kyoto, Japan

Methodology project in asymmetric phase-transfer catalyzed alkylations.

Co-op student

Angiotech

May 2009 – August 2009 (4 months)Vancouver, Canada Area

Formulation chemistry

Co-op student

Boehringer Ingelheim

January 2008 – August 2008 (8 months)Montreal, Canada Area

On two hit-to-lead teams working to synthesize analogues of hit compounds for HIV research.

Publications

Diastereoselective Friedel−Crafts Alkylation of Hydronaphthalenes(Link)

The Journal of Organic Chemistry

September 27, 2011

An efficient and versatile synthesis of chiral tetralins has been developed using both inter- and intramolecular Friedel-Crafts alkylation as a key step. The readily available hydronaphthalene substrates were prepared via a highly enantioselective metal-catalyzed ring opening of meso-oxabicyclic alkenes followed by hydrogenation. A wide variety of complex tetracyclic compounds have been isolated…more

One-Pot Synthesis of Chiral Dihydrobenzofuran Framework via Rh/Pd Catlaysis

Organic Letters

October 12, 2012

A one-pot synthesis of the chiral dihydrobenzofuran framework is described. The method utilizes Rh-catalyzed asymmetric ring opening (ARO) and Pd-catalyzed C-O coupling to furnish the product in excellent enantioselectivity without isolation of intermediates. Systematic metal-ligand studies were carried out to investigate the compatibility of each catalytic system using product enantiopurity as an…more

Rh/Pd Catalysis with Chiral and Achiral Ligands: Domino Synthesis of Aza-Dihydrodibenzoxepines(Link)

Angew. Chem. Int. Ed

July 19, 2013

A game of dominoes: A synthetic route to aza-dihydrodibenzoxepines is described, through the combination of a Rh-catalyzed arylation and a Pd-catalyzed C-O coupling in a single pot. For the first time, the ability to incorporate a chiral and an achiral ligand in a two-component, two-metal transformation is achieved, giving the products in moderate to good yields, with excellent enantioselectivities.

Multicomponent-multicatalyst reactions (MC)(2)R: efficient dibenzazepine synthesis.

Organic Letters

January 13, 2014

A Rh(I)/Pd(0) catalyst system was applied to the multicomponent synthesis of aza-dibenzazepines from vinylpyridines, arylboronic acids, and amines in a domino process with no intermediate isolation or purification.

Formation of substituted oxa- and azarhodacyclobutanes.

Chemistry – A European Journal

December 6, 2013

The preparation of substituted oxa- and azarhodacyclobutanes is reported. After exchange of ethylene with a variety of unsymmetrically and symmetrically substituted alkenes, the corresponding rhodium-olefin complexes were oxidized with H2O2 and PhINTs (Ts=p-toluenesulfonyl) to yield the substituted oxa- and azarhodacyclobutanes, respectively. Oxarhodacyclobutanes could be prepared with excellent…more

Women in Chemistry group, 2015

Lautens Research Group :: Group Pictures

Mark Lautens , O.C.

University Professor
J. Bryan Jones Distinguished Professor
AstraZeneca Professor of Organic Chemistry
NSERC/Merck-Frosst Industrial Research Chair


Department of Chemistry
Davenport Chemical Laboratories
80 St. George St.
University of Toronto
Toronto, Ontario
M5S 3H6

Tel: (416) 978-6083
Fax: (416) 946-8185
E-Mail: mlautens@chem.utoronto.ca

Curriculum Vitae

Personal

Place and Date of Birth Hamilton, Ontario, Canada July 9, 1959

Education

Harvard University NSERC PDF with D. A. Evans 1985 – 1987
University of Wisconsin-Madison Ph.D. with B. M. Trost 1985
University of Guelph B.Sc. – Distinction 1981

Academic Positions

J. Bryan Jones Distinguished Professor University of Toronto 2013 – 2018
University Professor University of Toronto 2012 – present
NSERC/Merck Frosst Industrial Research Chair NSERC/Merck Frosst 2003 – 2013
AstraZeneca Professor of Organic Synthesis University of Toronto 1998 – present
Professor University of Toronto 1995 – 1998
Associate Professor University of Toronto 1992 – 1995
Assistant Professor University of Toronto 1987 – 1992

Awards & Honors

University of Toronto Alumni Faculty Award University of Toronto 2016
CIC Catalysis Award CSC 2016
Officer of the Order of Canada Governor General 2014
Killam Research Fellowship Canada Council for the Arts 2013-2015
CIC Medal Chemical Institute of Canada 2013
Fellow of the Royal Society of UK Royal Society of Chemistry 2011
Pedler Award Royal Society of Chemistry 2011
Senior Scientist Award Alexander von Humboldt Foundation
Berlin, Aachen and Gottingen
2009-2014
Visiting Professor University of Berlin 2009
Visiting Professor Université de Marseilles 2008
ICIQ Summer School ICIQ Tarragona, Spain 2008
Attilio Corbella Summer School Professor Italian Chemical Society 2007
Arthur C. Cope Scholar Award American Chemical Society 2006
Alfred Bader Award Canadian Society for Chemistry 2006
R. U. Lemieux Award Canadian Society for Chemistry 2004
Solvias Prize Solvias AG 2002
Fellow of the Royal Society of Canada Royal Society of Canada 2001

Areas of Research Interest and Expertise

  • new synthetic methods
  • metal catalyzed cycloaddition and annulation reactions
  • asymmetric catalysis with focus on rhodium, nickel and palladium catalysts
  • cyclopropane synthesis and reactions
  • hydrometallation reactions
  • reactions of organosilicon and organotin compounds
  • fragmentation reactions
  • new routes to medicinally/biologically interesting compounds
  • heterocycle synthesis using metal catalysts

///////Multicomponent, Multicatalyst Reactions,  (MC)2R,  Dibenzazepine Synthesis, Mark Lautens, University of Toronto , Toronto, Ontario, Jennifer Tsoung

Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis

Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC01600F, Paper
Li Chen, Jinmo Zhao, Sivaram Pradhan, Bruce E. Brinson, Gustavo E. Scuseria, Z. Conrad Zhang, Michael S. Wong
The nonselective nature of glucose pyrolysis chemistry can be controlled by preventing the sugar ring from opening and fragmenting.

Ring-locking enables selective anhydrosugar synthesis from carbohydrate pyrolysis

*Corresponding authors
aDepartment of Chemical and Biomolecular Engineering, Rice University, Houston, USA
E-mail: mswong@rice.edu
bDepartment of Chemistry, Rice University, Houston, USA
cDalian National Laboratory of Clean Energy, Dalian Institute of Chemical Physics, Dalian, China
E-mail: zczhang@dicp.ac.cn
dDepartment of Civil and Environmental Engineering, Rice University, Houston, USA
eDepartment of Materials Science and NanoEngineering, Rice University, Houston, USA
Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC01600F

The selective production of platform chemicals from thermal conversion of biomass-derived carbohydrates is challenging. As precursors to natural products and drug molecules, anhydrosugars are difficult to synthesize from simple carbohydrates in large quantities without side products, due to various competing pathways during pyrolysis. Here we demonstrate that the nonselective chemistry of carbohydrate pyrolysis is substantially improved by alkoxy or phenoxy substitution at the anomeric carbon of glucose prior to thermal treatment. Through this ring-locking step, we found that the selectivity to 1,6-anhydro-β-D-glucopyranose (levoglucosan, LGA) increased from 2% to greater than 90% after fast pyrolysis of the resulting sugar at 600 °C. DFT analysis indicated that LGA formation becomes the dominant reaction pathway when the substituent group inhibits the pyranose ring from opening and fragmenting into non-anhydrosugar products. LGA forms selectively when the activation barrier for ring-opening is significantly increased over that for 1,6-elimination, with both barriers affected by the substituent type and anomeric position. These findings introduce the ring-locking concept to sugar pyrolysis chemistry and suggest a chemical-thermal treatment approach for upgrading simple and complex carbohydrates.

////////Ring-locking ,  selective anhydrosugar, carbohydrate pyrolysis, synthesis

N-Butylpyrrolidinone as a dipolar aprotic solvent for organic synthesis

N-Butylpyrrolidinone as a dipolar aprotic solvent for organic synthesis

Green Chem., 2016, 18,3990-3996
DOI: 10.1039/C6GC00932H, Paper
James Sherwood, Helen L. Parker, Kristof Moonen, Thomas J. Farmer, Andrew J. Hunt
N-Butylpyrrolidinone (NBP) has been demonstrated as a suitable safer replacement solvent for N-Methylpyrrolidinone (NMP) in selected organic syntheses.

N-Butylpyrrolidinone as a dipolar aprotic solvent for organic synthesis

*Corresponding authors
aGreen Chemistry Centre of Excellence, Department of Chemistry, University of York, UK
E-mail: andrew.hunt@york.ac.uk
bEastman Chemical Company, Pantserschipstraat 207 – B-9000, Gent, Belgium
Green Chem., 2016,18, 3990-3996

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC00932H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract
DOI: 10.1039/C6GC00932H

Dipolar aprotic solvents such as N-methylpyrrolidinone (or 1-methyl-2-pyrrolidone (NMP)) are under increasing pressure from environmental regulation. NMP is a known reproductive toxin and has been placed on the EU “Substances of Very High Concern” list. Accordingly there is an urgent need for non-toxic alternatives to the dipolar aprotic solvents. N-Butylpyrrolidinone, although structurally similar to NMP, is not mutagenic or reprotoxic, yet retains many of the characteristics of a dipolar aprotic solvent. This work introduces N-butylpyrrolidinone as a new solvent for cross-coupling reactions and other syntheses typically requiring a conventional dipolar aprotic solvent.
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//////////////N-Butylpyrrolidinone, dipolar aprotic solvent, organic synthesis

Mechanisms and reactivity differences of proline-mediated catalysis in water and organic solvents

Catal. Sci. Technol., 2016, 6,3378-3385
DOI: 10.1039/C6CY00033A, Paper
Gang Yang, Lijun Zhou
Several key issues regarding the mechanisms of proline catalysis are unravelled by first-principles calculations that can guide future catalyst design.

Mechanisms and reactivity differences of proline-mediated catalysis in water and organic solvents

Gang Yang*a and   Lijun Zhoua  
*Corresponding authors
aCollege of Resource and Environment & Chongqing Key Laboratory of Soil Multi-scale Interfacial Process, Southwest University, Chongqing, PR China
E-mail: theobiochem@gmail.com
Fax: +86 023 68250444
Tel: +86 023 68251545
Catal. Sci. Technol., 2016,6, 3378-3385

DOI: 10.1039/C6CY00033A

Proline is an efficient and versatile catalyst for organic reactions while a number of issues remain controversial. Here, ab initio and density functional calculations were used to unravel a few key issues of catalytic mechanisms in water and organic solvents. Zwitterionic proline that predominates in water and DMSO is assumed to be the active conformation for catalysis, and reactivity differences in two solvents are revealed. Meanwhile, an abundance of experimental observations can be finely interpreted by the present computational results, including those seemingly contradictory. Although bearing lower activation barriers than that in DMSO, the production of enamines and further aldol products in water will be blocked at an early stage (J. Am. Chem. Soc., 2006, 128, 734) because the reaction in water is significantly driven towards acetyl formation that is kinetically and thermodynamically preferred. Due to significant promotion of the rate-determining proton transfer step, aldol reactions in organic solvents can be obviously initiated by the addition of some water (Angew. Chem., Int. Ed., 2004, 43, 1983). In order to show catalytic effects in water (an obviously environmentally benign solvent), proline has to be structurally modified so that canonical structures can be the principal (or sole) conformations, which is in line with the analyses of all proline-based catalysts available in water (e.g., J. Am. Chem. Soc., 2006, 128, 734, Catal. Commun., 2012, 26, 6). Thus, the present results provide insightful clues to mechanisms of proline-mediated catalysis as well as future design of more efficient catalysts.
//////Mechanisms,  reactivity,  differences,  proline-mediated catalysis, water ,  organic solvents

Intensified biocatalytic production of enantiomerically pure halophenylalanines from acrylic acids using ammonium carbamate as the ammonia source

Catal. Sci. Technol., 2016, Advance Article
DOI: 10.1039/C6CY00855K, Communication
Nicholas J. Weise, Syed T. Ahmed, Fabio Parmeggiani, Elina Siirola, Ahir Pushpanath, Ursula Schell, Nicholas J. Turner
An industrial-scale method employing a phenylalanine ammonia lyase enzyme

Intensified biocatalytic production of enantiomerically pure halophenylalanines from acrylic acids using ammonium carbamate as the ammonia source

*Corresponding authors
aManchester Institute of Biotechnology & School of Chemistry, University of Manchester, 131 Princess Street, Manchester, UK
E-mail: nicholas.turner@manchester.ac.uk
bJohnson Matthey Catalysts and Chiral Technologies, 28 Cambridge Science Park, Milton Road, Cambridge, UK
Catal. Sci. Technol., 2016, Advance Article

DOI: 10.1039/C6CY00855K

SEE

An intensified, industrially-relevant strategy for the production of enantiopure halophenylalanines has been developed using the novel combination of a cyanobacterial phenylalanine ammonia lyase (PAL) and ammonium carbamate reaction buffer. The process boasts STYs up to >200 g L−1 d−1, ees ≥ 98% and simplified catalyst/reaction buffer preparation and work up.

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///////Intensified,  biocatalytic production, enantiomerically pure,  halophenylalanines,  acrylic acids,  ammonium carbamate, ammonia source