(R)-(−)-2-[(5-oxido-5-phenyl-5λ4-isoquino[4,3-c][2,1]benzothiazin- 12-yl)amino]benzonitrile (4).



Copper-catalyzed cross-coupling between (S)-S-methyl-S-phenylsulfoximine (1) and 2-iodobenzonitrile (2) resulted in the discovery of an unprecedented one-pot triple arylation sequence to give (R)-(−)-2-[(5-oxido-5-phenyl-5λ4-isoquino[4,3-c][2,1]benzothiazin- 12-yl)amino]benzonitrile (4). Here, we describe the synthesis of the title compound (R)-4 and the elucidation of its structure by means of various techniques.

Molbank 2014, 2014(3), M834; doi:10.3390/M834

http://www.mdpi.com/1422-8599/2014/3/M834

(R)-(−)-2-[(5-Oxido-5-phenyl-5λ⁴-isoquino[4,3-c][2,1]benzothiazin-12-yl)amino]benzonitrile

Marcus Frings, Iuliana Atodiresei and Carsten Bolm * 

* Author to whom correspondence should be addressed; E-Mail: carsten.bolm@oc.rwth-aachen.de;

Fax: +29-241-80-92-391. http://bolm.oc.rwth-aachen.de/

Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany

 Carsten Bolm

   Dr. rer. nat., Professor of Organic Chemistry

Institut für Organische Chemie
RWTH Aachen University
Landoltweg 1
D-52074 Aachen, Germany 

Tel.: + 49 241-80 94 675
FAX : + 49 241-80 92 391 

e-mail: Carsten.Bolm@oc.RWTH-Aachen.de

http://bolm.oc.rwth-aachen.de/

The combined organic phases were dried with

MgSO4 and filtered. After evaporation of solvents, the oily residue was subjected to column

chromatography (SiO2, n-pentane/EtOAc = 2/1). Product (R)-4 was isolated as a yellow solid.

Additionally, sulfoximine (S)-3 was separately obtained as a yellow oil (61% yield, 0.899 g, 3.51 mmol).

Yield: 23% (0.616 g, 1.34 mmol); mp = 211–212 °C (racemate: 263–265 °C); [α] = −57.7 (c = 0.6 g,

100 mL−1, CHCl3); 1H NMR (600 MHz, CDCl3): δ = 7.11 (ddd, J = 8.2 Hz, 7.1 Hz, 1.2 Hz, 1H, Ar-H),

7.25 (dd, J = 8.0 Hz, 1.1 Hz, 1H, Ar-H), 7.27 (td, J = 7.6 Hz, 1.0 Hz, 1H, Ar-H), 7.42–7.50 (m, 3H,

Ar-H), 7.50–7.58 (m, 3H, Ar-H), 7.70 (dd, J = 7.8 Hz, 1.5 Hz, 1H, Ar-H), 7.78 (ddd, J = 8.8 Hz, 7.5

Hz, 1.6 Hz, 1H, Ar-H), 7.87–7.90 (m, 2H, Ar-H), 8.07 (dd, J = 7.6 Hz, 1.6 Hz, 1H, Ar-H), 8.19–8.24

(m, 2H, Ar-H and NH), 8.50 (dd, J = 8.1 Hz, 1.5 Hz, 1H, Ar-H), 8.81 (d, J = 8.4 Hz, 1H, Ar-H) ppm;

13C NMR (150 MHz, CDCl3): δ = 103.4 (C), 105.5 (Ar-C), 116.9 (Ar-C), 117.5 (C), 118.4 (Ar-C),

120.3 (Ar-CH), 121.8 (Ar-CH), 122.3 (Ar-CH), 123.6 (Ar-CH), 123.8 (Ar-CH), 124.8 (Ar-CH), 125.9

(Ar-CH), 127.6 (Ar-CH), 127.7 (2 Ar-CH), 129.0 (2 Ar-CH), 132.0 (2 Ar-CH), 132.4 (Ar-CH), 132.5

(Ar-C), 132.8 (Ar-CH), 133.9 (Ar-CH), 141.7 (Ar-C), 144.0 (Ar-C), 144.2 (Ar-C), 148.0 (C), 153.2

(C) ppm; 1

H NMR [600 MHz, (CD3)2SO]: δ = 6.98 (ddd, J = 8.2 Hz, 7.2 Hz, 1.1 Hz, 1H, Ar-H), 7.11

(dd, J = 8.1 Hz, 0.8 Hz, 1H, Ar-H), 7.40 (ddd, J = 8.6 Hz, 7.2 Hz, 1.6 Hz, 1H, Ar-H), 7.53 (td, J = 7.7 Hz,

1.0 Hz, 1H, Ar-H), 7.56–7.60 (m, 2H, Ar-H), 7.60–7.64 (m, 1H, Ar-H), 7.67–7.73 (m, 2H, Ar-H), 7.80

(d, J = 8.0 Hz, 1H, Ar-H), 7.84–7.88 (m, 3H, Ar-H), 8.04 (dd, J = 7.8 Hz, 1.4 Hz, 1H, Ar-H), 8.12 (dd,

J = 7.7 Hz, 1.8 Hz, 1H, Ar-H), 8.18 (dd, J = 8.1 Hz, 1.5 Hz, 1H, Ar-H), 8.68 (dd, J = 7.5 Hz, 1.7 Hz,

1H, Ar-H), 10.51 (s, 1H, NH) ppm; 

13C NMR [150 MHz, (CD3)2SO]: δ = 103.5 (C), 110.2 (Ar-C),

117.0 (Ar-C), 117.4 (C), 118.0 (Ar-C), 119.7 (Ar-CH), 122.6 (Ar-CH), 123.6 (Ar-CH), 124.5 (Ar-CH),

125.6 (Ar-CH), 126.2 (Ar-CH), 127.1 (2 Ar-CH), 127.3 (Ar-CH), 127.4 (Ar-CH), 129.3 (2 Ar-CH), 

131.7 (Ar-C), 131.8 (Ar-CH), 132.2 (Ar-CH), 133.0 (Ar-CH), 133.1 (Ar-CH), 133.9 (Ar-CH), 141.9

(Ar-C), 143.7 (Ar-C), 144.0 (Ar-C), 147.4 (C), 155.6 (C) ppm; 

IR (ATR): ν = 3640, 3258, 2324, 2221,

2020, 1980, 1936, 1601, 1572, 1546, 1515, 1484, 1459, 1422, 1376, 1333, 1277, 1241, 1206, 1149,

1092, 1038, 1009, 976, 844, 794, 754, 720, 681 cm−1; EI-MS: m/z (%) = 458 (100) [M]+, 410 (15), 381(22), 357 (9), 333 (62), 102 (6), 77 (12), 51 (10); CI-MS: m/z (%) = 499 (3) [M+C3H5]+, 487 (16)[M+C2H5]+

, 459 (100) [M+H]+, 358 (7); ESI-MS: m/z (%) = 939 (9) [2M+Na]+, 497 (8) [M+K]+, 481(24) [M+Na]+, 459 (42) [M+H]+, 358 (100); ESI-HRMS: m/z calcd for C28H19N4OS: 459.12741; found

459.12793 with ∆ = 1.14 ppm; anal. calcd for C28H18N4OS (458.54): C, 73.34; H, 3.96; N, 12.22;

found C, 73.44; H, 4.09; N, 12.30; HPLC: tr = 16.8 min [major], tr = 25.2 min [minor] (Chiralpak AD-H,

0.6 mL min−1, n-heptane/isopropanol = 60/40, λ = 230 nm, 20 °C); >99% ee.

Crystallographic data were collected with a Bruker Kappa APEX II CCD-diffractometer with

monochromatic Mo–Kα radiation (λ = 0.71073 Å) and a CCD detector. The structure was solved by

direct methods using SHELXS-97 and refined against F2 on all data by full-matrix least-squares

methods using SHELXL-97 [13,14]. 

Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany

GERMANY....

The rice flavor compound.......2-Acetyl-1-pyrroline

• 
  
  
  
  2-acetyl-4,5-dihydro-3H-pyrrole
  
  US4522838
  
  2-Acetyl-1-pyrroline, abbreviated 2AP, with the IUPAC name 1-(3,4-dihydro-2H-pyrrol-5-yl)ethanone, is an aroma compound and flavor that gives white bread, jasmine rice and basmati rice, the spice pandan (Pandanus amaryllifolius), and bread flowers (Vallaris glabra) their customary smell.^[1] 2-Acetyl-1-pyrroline and its structural homolog, 6-acetyl-2,3,4,5-tetrahydropyridine of similar smell, can be formed by Maillard reactions during heating of food such as the baking of bread dough. Both compounds have odor thresholds below 0.06 ng/l.^[2]
  A pyrroline that is 1-pyrroline in which the hydrogen at position 2 is replaced by an acetyl group. It is an aroma and flavour compound present in jasmine rice and basmati rice. It is responsible for the 'popcorn' aroma in a large variety of cereal and food products. It is one of the key odourants of the crust of bread and considered to be responsible for the cracker-like odour properties. In bread, it is primarily generated during baking but amounts are influenced by ingredient composition and fermentation conditions.
  

  Structure and properties

  2-Acetyl-1-pyrroline is a substituted pyrroline and a cyclic imine as well as a ketone.
  
   
  The analogous 2-acetyl-1-pyrroline 6 has a similar potent cracker-like flavor and is considered as the most important flavor component of cooked rice. It has been identified and isolated from different varieties of cooked rice [R.G. Buttery, L.C. Ling, B.O. Juliano, Chem. Ind., 958 (1982); R.G. Buttery, L.C. Ling, B.O. Juliano, J.G. Turnbaugh, J. Agric. Food Chem., vol.31, 823 (1983); R.G. Buttery, L.C. Ling, T.R. Mon, J. Agric. Food Chem., vol.34, 112 (1986)] and the crust of wheat and rye bread [P. Schieberle, W. Grosch, J. Agric. Food Chem., vol.35, 252 (1987); P. Schieberle, w. Grosch, Z. Lebensm. Unters Forsch., vol. 180, 474 (1985)]. It is remarkable that 2-acetyl-1-pyrroline 6 has been found in pandam leaves (Pandanus amaryllifolius Roxb.)[R.G. Buttery, B.O. Juliano, L.C. Ling, Chem. Ind., 478 (1983)]. This fact explains that it has long been the practice in India and other parts of Asia to use leaves of Pandanus species in the cooking of common rices to impart a resemblance of the aroma of the more costly scented rice.
• [0007]
  U.S. Pat. 4,522,838 discloses the sole known synthetic route to 2-acetyl-1-pyrroline.
• [0008]
  The synthesis entails hydrogenation of 2-acetylpyrrole 4 with rhodium on alumina, followed by oxidation of the resulting aminoalcohol 5 by means of an excess of silver carbonate (absorbed on celite) in benzene.
  

  

  
  2-Acetyl-1-pyrroline 6 has been used in flavoring foods, particularly in imparting a scented rice flavor to foods. The drawback of this synthesis of the rice flavor component 6 is the use of the very expensive reagents, the low overall yield of 10%, the use of toxic chemicals (e.g. benzene) and the virtually inaccessibility of the compound on a larger scale. Indeed, according to the patented procedure mentioned above, 2-acetyl-1-pyrroline 6 was isolated and purified by preparative gas chromatography, which entails at best subgram quantities.
  
  

  • 
  B.3. Synthesis of 2-Acetyl-1-pyrroline 6
  • [0021]
    The rice flavor compound 6 was prepared in exactly the same way as described in detail for the synthesis of the bread flavor component 3 (see A.3.). Compound 6 was obtained as a clear light-yellow oil (purity ⋟ 96%) which darkened rapidly on standing at room temperature in neat form (yield 40%). Compound 6 was characterized by the usual spectrometric methods (¹H NMR,¹³C NMR, IR, MS). It should be stressed that, contrary to compound 3, the rice flavor component 6 exclusively occurs as the imine form. The compound is preferably kept in dilute solution (pentane, dichloromethane) at -20°C. After an inital decantation from a small amount of dark viscous liquid (one week at -20°C), the clear solution is stable for several months at -20°C (up to now, we observed a good stability over a period of two years).
  http://www.google.com/patents/EP0436481A1?cl=en 
  
   
  
  
  
  
  
  
  
  
  
  

  References

  1. S. Wongpornchai, T. Sriseadka, S. Choonvisase (2003). "Identification and quantitation of the rice aroma compound, 2-acetyl-1-pyrroline, in bread flowers (Vallaris glabra Ktze)". J. Agric. Food. Chem. 51 (2): 457–462. doi:10.1021/jf025856x. PMID 12517110.
  2. T. J. Harrison, G. R. Dake (2005). "An expeditious, high-yielding construction of the food aroma compounds 6-acetyl-1,2,3,4-tetrahydropyridine and 2-acetyl-1-pyrroline". J. Org. Chem. 70 (26): 10872–10874. doi:10.1021/jo051940a. PMID 16356012.

  
  http://pubs.acs.org/doi/pdf/10.1021/jf00118a036
  
  

  Yang DongSik, Lee Kyu‐Seong, Kays StanleyJ (2010) Characterization and discrimination of premium‐quality, waxy, and black‐pigmented rice based on odor‐active compounds Journal of the science of food and agriculture 90, 2595-2601 [Agricola:IND44456134] [show Abstract]

  Wongpornchai S, Sriseadka T, Choonvisase S (2003) Identification and quantitation of the rice aroma compound, 2-acetyl-1-pyrroline, in bread flowers (Vallaris glabra Ktze). Journal of agricultural and food chemistry 51, 457-462 [PubMed:12517110] [show Abstract]

  Costello PJ, Henschke PA (2002) Mousy off-flavor of wine: precursors and biosynthesis of the causative N-heterocycles 2-ethyltetrahydropyridine, 2-acetyltetrahydropyridine, and 2-acetyl-1-pyrroline by Lactobacillus hilgardii DSM 20176. Journal of agricultural and food chemistry 50, 7079-7087 [PubMed:12428963] [show Abstract]

  Maraval I, Sen K, Agrebi A, Menut C, Morere A, Boulanger R, Gay F, Mestres C, Gunata Z (2010) Quantification of 2-acetyl-1-pyrroline in rice by stable isotope dilution assay through headspace solid-phase microextraction coupled to gas chromatography-tandem mass spectrometry. Analytica chimica acta 675, 148-155 [PubMed:20800726] [show Abstract]

  Arikit S, Yoshihashi T, Wanchana S, Uyen TT, Huong NT, Wongpornchai S, Vanavichit A (2011) Deficiency in the amino aldehyde dehydrogenase encoded by GmAMADH2, the homologue of rice Os2AP, enhances 2-acetyl-1-pyrroline biosynthesis in soybeans (Glycine max L.). Plant biotechnology journal 9, 75-87 [PubMed:20497370] [show Abstract]

  Poonlaphdecha J, Maraval I, Roques S, Audebert A, Boulanger R, Bry X, Gunata Z (2012) Effect of timing and duration of salt treatment during growth of a fragrant rice variety on yield and 2-acetyl-1-pyrroline, proline, and GABA Levels. Journal of agricultural and food chemistry 60, 3824-3830 [PubMed:22404867] [show Abstract]

  Harrison TJ, Dake GR (2005) An expeditious, high-yielding construction of the food aroma compounds 6-acetyl-1,2,3,4-tetrahydropyridine and 2-acetyl-1-pyrroline. The Journal of organic chemistry 70, 10872-10874 [PubMed:16356012] [show Abstract]

  Adams A, De Kimpe N (2006) Chemistry of 2-acetyl-1-pyrroline, 6-acetyl-1,2,3,4-tetrahydropyridine, 2-acetyl-2-thiazoline, and 5-acetyl-2,3-dihydro-4H-thiazine: extraordinary Maillard flavor compounds. Chemical reviews 106, 2299-2319 [PubMed:16771451]

A Method to Identify Best Available Technologies (BAT) for Hydrogenation Reactors in the Pharmaceutical Industry

J. Flow Chem. 2012, 2(3), 77–82

http://www.akademiai.com/content/8652651g3378x686/?p=ab7c1bc4cd7740e1855623297649f542&pi=3

http://www.akademiai.com/content/8652651g3378x686/fulltext.pdf

Journal of Flow Chemistry
Publisher	Akadémiai Kiadó
ISSN	2062-249X (Print) 2063-0212 (Online)
Subject	Flow Chemistry
Issue	Volume 2, Number 3/September 2012
Pages	77-82
DOI	10.1556/JFC-D-12-00014

Authors

Tuong Doan¹, Petr Stavárek¹, Claude Bellefon^{1 * Author for correspondence: claude.debellefon@lgpc.cpe.fr}

¹CNRS, CPE Lyon University of Lyon Villeurbanne France

Abstract

A methodology that may be applied to help in the choice of a continuous reactor is proposed. In this methodology, the chemistry is first described through the use of eight simple criteria (rate, thermicity, deactivation, solubility, conversion, selectivity, viscosity, and catalyst). Then, each reactor type is also analyzed from their capability to answer each of these criteria. A final score is presented using “spider diagrams.” Lower surfaces indicate the best reactor choice. The methodology is exemplified with a model substrate nitrobenzene and a target pharmaceutical intermediate, N-methyl-4-nitrobenzenemethanesulphonamide, and for three different continuous reactors, i.e., stirred tank, fixed bed, and an advanced microstructured reactor. Comparison with the traditional batch reactor is also provided.

lyon france...........

 

 

 

Important Industrial Procedures Revisited in Flow: Very Efficient Oxidation and N-Alkylation Reactions with High Atom-Economy

http://www.akademiai.com/content/u87p126856085276/?p=2f48c96a10a64882aeb5c47c657a10b7&pi=4

Journal	Journal of Flow Chemistry
Publisher	Akadémiai Kiadó
ISSN	2062-249X (Print) 2063-0212 (Online)
Subject	Flow Chemistry
Issue	Volume 3, Number 2/June 2013
Pages	51-58
DOI	10.1556/JFC-D-12-00025

Authors

Gellért Sipos¹, Viktor Gyollai¹, Tamás Sipőcz¹, György Dormán¹, László Kocsis¹ , Richard V. Jones¹, Ferenc Darvas¹

¹ThalesNano Zahony u. 7 1031 Budapest Hungary

László Kocsis holds a Masters degree in Bioorganic Chemistry from the Eötvös Lóránd University in Budapest, Hungary (2001) and a PhD in Organic Chemistry from the Eötvös Lóránd University in Budapest, Hungary (2008). In 2004 he began working as a research chemist at the Reanal Finechemical Company in Budapest, Hungary. He became the Head of the R&D laboratory in 2007 and a manager of production in 2008. In 2011 he joined ThalesNano Inc. as Head of Chemistry. He has experience in organic chemistry, with emphasis on sythesis of amino acid derivatives and peptides, focusing mainly on the following subjects: structure – relationship studies in opiod peptides, methodological studies in the internal solubilization of the sekf-aggregating peptides, industrial scale sythesis of protected amino acid derivatives, and peptides, heterogeneous catalysis, reactions under continuous flow conditions. He is the co-author of 10 pulications and a member of the European Peptide Society.

Abstract

The atom economy concept is one of the earliest recognition for green and sustainable aspects of organic synthesis. Over the years, novel technologies emerged that made this important feature of reactions into practice. Continuous-flow devices increased the efficiency of the chemical transformations with novel process windows (high T, high p and heterogeneous packed catalysts etc.) and increased safety which turned the attention to reexamine old, industrial processes. Oxidation can be performed under flow catalytic conditions with molecular oxygen; alcohols can be oxidized to carbonyl compounds with high atom economy (AE = 87 %). Using O₂ and 1 % Au/TiO₂, alcohol oxidation in flow was achieved with complete conversion and >90 % yield. N-alkylation is another good example for achieving high atom economy. Under flow catalytic conditions (Raney Ni), amines were successfully reacted with alcohols directly (AE = 91 %) with >90 % conversion and selectivity. In both examples, the effective residence time was less than 1 min. These two examples demonstrate the significant contribution of flow technology to the realization of key principles in green and sustainable chemistry.

ThalesNano Nanotechnology Inc, GraphisoftPark. Záhony u. 7. H-1031 Budapest HUNGARY

budapest hungary

 

 

 

A PdCl2-Based Hydrogenation Catalyst for Glass Microreactors

A PdCl₂-Based Hydrogenation Catalyst for Glass Microreactors

Journal	Journal of Flow Chemistry
Publisher	Akadémiai Kiadó
ISSN	2062-249X (Print) 2063-0212 (Online)
Subject	Flow Chemistry
Issue	Volume 4, Number 3/September 2014
Pages	110-112
DOI	10.1556/JFC-D-13-00036

Clemens R. Horn¹ , Carine Cerato-Noyerie

¹7bis avenue de Valvins Corning European Technology Center F- 77210 Avon France

hornc@corning.com

http://www.akademiai.com/content/622t676074227362/?p=a966d2661bb04f91919c965b3dbff07c&pi=1

Abstract

A convenient and simple PdCl₂-based hydrogenation catalyst has been developed. The liquid, air, and moisture stable precursor is pumped into the reactor where it is temporarily immobilized and reduced on the channel surface into Pd(0), providing a constant high activity for hydrogenation reaction. The catalyst is leached with time, avoiding any kind of clogging problems during long time runs.

7 Bis Avenue de Valvins, 77210 Avon, France

lyon france

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Curtius reaction..........Flow Synthesis

A Modular Flow Reactor for Performing Curtius Rearrangements as a Continuous Flow Process.		Link: 10.1039/b801631n
Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.; Tierney, J. P.
Org. Biomol. Chem. 2008, 6, 1577-1586.
Abstract: The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.

http://pubs.rsc.org/en/Content/ArticleLanding/2008/OB/b801631n#!divAbstract

A modular flow reactor for performing Curtius rearrangements as a continuous flow process

Marcus Baumann,^a   Ian R. Baxendale,^a   Steven V. Ley,*^a  Nikzad Nikbin,^a   Christopher D. Smith^a and   Jason P. Tierney^b  

^a

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
E-mail: svl1000@cam.ac.uk;
Fax: +44 1223 336442 ;
Tel: +44 1223 336398

^b

Neurology Lead Discovery Chemistry, Neurology CEDD, GlaxoSmithKline R and D, New Frontiers Science Park (North), Third Avenue, Harlow, UK

Org. Biomol. Chem., 2008,6, 1577-1586

DOI: 10.1039/B801631N

Azide Monoliths as Convenient Flow Reactors for Efficient Curtius Rearrangement Reactions.		Link: 10.1039/b801634h
Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.
Org. Biomol. Chem. 2008, 6, 1587-1593.
Abstract: The preparation and use of an azide-containing monolithic reactor is described for use in a flow chemistry device and in particular for conducting Curtius rearrangement reactions via acid chloride inputs.

http://pubs.rsc.org/en/Content/ArticleLanding/2008/OB/b801634h#!divAbstract

Azide monoliths as convenient flow reactors for efficient Curtiusrearrangement reactions

Marcus Baumann,^a   Ian R. Baxendale,^a   Steven V. Ley,*^a  Nikzad Nikbin^a and   Christopher D. Smith^a  

^a

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
E-mail: svl1000@cam.ac.uk;
Fax: +44 1223 336442 ;
Tel: +44 1223 336398

Org. Biomol. Chem., 2008,6, 1587-1593

DOI: 10.1039/B801634H