1-(2-Methoxy-4-nitrophenyl)-4-(p-tolyl)-1H-1,2,3-triazole

1-(2-Methoxy-4-nitrophenyl)-4-(p-tolyl)-1H-1,2,3-triazole (3a), (Table 2, entry 1):
Using method A described above with 2-methoxy-4-nitroaniline
(1a). After purification by flash column
chromatography (25% AcOEt/hexanes, Rf = 0.45), 359 mg
of 3a (79%) were obtained as a yellow solid. Mp > 190 °C;

1H-NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.16 (d, J = 8.8
Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.26 (d, J =
7.8 Hz, 2H), 4.08 (s, 3H) 2.41 (s, 3H) ppm;

13C{1H} NMR (100 MHz, CDCl3) δ 150.6,
148.1, 148.0, 138.6, 131.1, 129.7, 127.3, 125.9, 125.1, 121.1, 116.8, 108.0, 57.0,
21.4 ppm; HRMS (EI) calcd. for C16H13NO3 310.1066 [M+]; found 310.1060.

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00292

Handling Hazards Using Continuous Flow Chemistry: Synthesis of N1-Aryl-[1,2,3]-triazoles from Anilines via Telescoped Three-Step Diazotization, Azidodediazotization, and [3 + 2] Dipolar Cycloaddition Processes

Matthieu Teci†, Michael Tilley†, Michael A. McGuire*‡, and Michael G. Organ*†§

† Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario M3J1P3, Canada

‡ GlaxoSmithKline Pharmaceuticals Inc., 709 Swedeland Road, P.O. Box 1539, UMW 2810, King of Prussia, Pennsylvania 19406, United States

§ Centre for Catalysis Research and Innovation (CCRI) and Department of Chemistry, University of Ottawa, Ottawa, Ontario K1N6N5, Canada

Org. Process Res. Dev., Article ASAP

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00292

Michael G. Organ Professor of Chemistry, York University, Toronto, Canada

Webpage: http://www.yorku.ca/organ/ Education: B. Sc. (Honours) in Biology (1986) from the University of Guelph; M. Sc. in Botany (1988) from the University of Guelph; Ph.D. in Chemistry (1992) from the University of Guelph. Professional Career: 1992-1994 NSERC Post-Doctoral Fellow with Barry Trost at Stanford University; 1994-1997 Faculty member at IUPUI in Indianapolis; 1997-present Faculty member at York University in Toronto. Awards and Honours: Author Profile in Angewandte Chemie, November 2013; Appointed to the Editorial Board of Chemistry, A European Journal, November 2013; NSERC Accelerator Award, April 2013; Agilent Labs Fellow, October 2011; Japan Society for the Promotion of Science (JSPS) Fellow, May 2010; Naeja Pharmaceuticals Lecturer, University of Alberta, March 2008; Merck-Frosst Canadian Academic Development Program Fellow, December 2007; International Xerox Foundation Fellow, July 2007; E.T.S. Walton Visitor Award (Ireland), May 2002; 1999 Premier's Research Excellence Award. Research Interests: Synthetic efficiency, catalysis, flow chemistry, sustainable manufacturing.

Department of Chemistry, York University

4700 Keele Street, Toronto, Ontario, Canada M3J 1P3

Phone: 416-736-5313. Facsimile: 416-736-5936. E-mail: organ@yorku.ca

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2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinolone (R)-7

1H NMR (500 MHz, CDCl3): δ 7.82 (br s, 1H), 7.28-7.34 (m, 2H), 7.22-7.24 (m, 1H), 3.87 (m, 1H), 3.56 (m, 1H), 3.32 (m, 1H), 3.00-3.03 (m, 2H), 2.46-2.74 (m, 3H), 1.65-2.05 (m, 5H);

13C NMR (100 MHz, CDCl3): δ 137.6, 130.4, 129.2, 127.9, 124.1, 55.9, 54.5, 27.3, 25.2, 22.9, 20.3, 17.1;

Enantiomeric excess was determined by SFC: Chiralpak OD-3, 4.6 mm x 150 mm, particle size: 3 μm, temperature: 30 ºC, A: CO2, B: ethanol with 0.2% of isobutylamine, isocratic: A/B: 95/5, v/v, flow rate 3.0 mL/min.

HRMS (ESI) [M+H]+ m/z calcd for [C13H18N]+ is 188.1361 found 188.1429.

Synthesis of Enantioenriched 2‐Alkyl Piperidine Derivatives through
Asymmetric Reduction of Pyridinium Salts
Bo Qu,* Hari P. R. Mangunuru, Xudong Wei, Keith R. Fandrick, Jean-Nicolas Desrosiers, Joshua D.
Sieber, Dmitry Kurouski, Nizar Haddad, Lalith P. Samankumara, Heewon Lee, Jolaine Savoie, Shengli
Ma, Nelu Grinberg, Max Sarvestani, Nathan K. Yee, Jinhua J. Song and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road,
Ridgefield, CT 06877 USA
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2-chloro-5-(((E)-2-(((E)-2,2,2-trifluoroethylidene)hydrazono)imidazolidin-1-yl)methyl)pyridi ne

2-chloro-5-(((E)-2-(((E)-2,2,2-trifluoroethylidene)hydrazono)imidazolidin-1-yl)methyl)pyridi ne (5):

white solid, mp 114–115 o C;

1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.2 Hz, 1H), 7.68 (q, J = 8.0, Hz, 1H), 7.48 (q, J = 4.5 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 5.88 (s, 1H), 4.50 (s, 2H), 3.55 (t, J = 7.8 Hz, 2H), 3.46 – 3.40 (m, 2H); 19F NMR (376 MHz, CDCl3) δ –66.13 (d, J = 4.5 Hz);

13C NMR (100 MHz, CDCl3) δ 165.04, 150.86, 149.32, 134.55 (q, JC-F = 35.63 Hz), 131.37, 124.45, 121.27 (q, JC-F = 268.16 Hz) 46.83, 45.14, 40.68;

IR (KBr) ν 2884.47, 1638.83, 1568.03, 1515.93, 1338.41, 1266.40, 1115.71, 1020.69, 896.58, 739.17, 593.14 cm-1 ;

HRMS (ESI) found: m/z 306.0726, [M+H]+ calcd. for C11H12ClF3N5 + 306.0728.




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(E)-1,3-bis(2,6-diisopropylphenyl)-2-((2,2,2-trifluoroethylidene)hydrazono)imidazolidine

(E)-1,3-bis(2,6-diisopropylphenyl)-2-((2,2,2-trifluoroethylidene)hydrazono)imidazolidine :

white solid; mp 133–134 o C;

1 H NMR (600 MHz, CDCl3) δ 7.28 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 7.04 (d, J = 7.5 Hz, 2H), 6.85 (q, J = 4.2 Hz, 1H), 3.78 (s, 4H), 3.12 – 3.03 (m, 4H), 1.24 (t, J = 6.9 Hz, 12H), 1.16 (d, J = 6.6 Hz, 6H), 1.05 (d, J = 6.6 Hz, 6H);

19F NMR (565 MHz, CDCl3) δ –66.51 (d, J = 3.7 Hz);


13C NMR (150 MHz, CDCl3) δ 160.08, 147.72, 145.49, 137.54, 134.30, 133.60 (q, JC-F = 23.60 Hz), 129.10, 127.97, 124.29, 123.83, 121.17 (q, JC-F = 179.01 Hz), 51.45, 49.07, 29.21, 28.95, 24.71, 24.40, 24.02, 22.92;

IR (KBr) ν 2987.56, 1534, 1491, 1463, 1325, 1267, 934, 894 cm-1 ;

HRMS (ESI) found: m/z 501.3204, [M+H]+ calcd. for C29H40F3N4 + 501.3200.




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Methyl (2RS,4RS)-4-hydroxy-4-isopropyl-1,2,3,4-tetrahydronaphthalene-2-carboxylate

.

Stereoselective synthesis of tricyclic compounds by intramolecular palladium-catalyzed addition of aryl iodides to carbonyl groups

Freie Universität Berlin, Institut für Chemie und Biochemie, Takustrasse 3, D-14195 Berlin, Germany

 Corresponding author email     hreissig@chemie.fu-berlin.de

This article is part of the Thematic Series "Organometallic chemistry" and is dedicated to the memory of Professor Peter Hofmann.

Guest Editor: B. F. Straub

Beilstein J. Org. Chem. 2016, 12, 1236–1242.

doi:10.3762/bjoc.12.118

Jakub Saadi, Christoph Bentz, Kai Redies, Dieter Lentz, Reinhold Zimmer, Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2016, 12, 1236–1242. published 16 Jun 2016

Abstract

Starting from γ-ketoesters with an o-iodobenzyl group we studied a palladium-catalyzed cyclization process that stereoselectively led to bi- and tricyclic compounds in moderate to excellent yields. Four X-ray crystal structure analyses unequivocally defined the structure of crucial cyclization products. The relative configuration of the precursor compounds is essentially transferred to that of the products and the formed hydroxy group in the newly generated cyclohexane ring is consistently in trans-arrangement with respect to the methoxycarbonyl group. A transition-state model is proposed to explain the observed stereochemical outcome. This palladium-catalyzed Barbier-type reaction requires a reduction of palladium(II) back to palladium(0) which is apparently achieved by the present triethylamine.

For our systematic studies on samarium diiodide promoted cyclizations leading to benzannulated medium-sized rings [1-4] we required starting materials such as alkenyl-substituted compounds B (Scheme 1). Obvious precursors for B are aryl iodides A that smoothly undergo palladium-catalyzed coupling reactions to provide the desired products. However, in one case [A: R¹–R² = (CH₂)₄] typical Heck reaction conditions employing styrene as olefin component not only led to the desired styrene derivative B but mainly to the cyclized product C. If the reaction was performed without the olefin it provided only the tertiary alcohol C in reasonable yield [5]. Similar C–C bond forming reactions of aryl halides that involve an insertion of the intermediate aryl palladium species into a carbonyl group are relatively rare (see discussion below). Therefore this serendipitous discovery led us to investigate the reaction in more detail.

Scheme 1: Planned Heck reaction of A to compound B and serendipitous discovery of the palladium-catalyzed cyclization to products C.

Conclusion

We have found new examples of intramolecular palladium-catalyzed nucleophilic additions of aryl iodides to alkyl ketones. These additions proceed in the presence of only 2–5 mol % Pd(PPh₃)₄ and afford bi- and tricyclic compounds with excellent stereoselectivity and in moderate to very good efficacy. The low mass balance observed in several cases may be due to subsequent reactions such as simple de-iodination of the precursor compounds or elimination of water in the products. However, in general none of these byproducts has been isolated. For compound 2 the bulky isopropyl group slows down the addition to the carbonyl group and an enolate arylation was observed instead as major reaction pathway. Although the scope of the discovered aryl iodide addition to carbonyl groups may be limited it is attractive since only low catalyst loadings are required and interesting products are formed with high stereoselectivity.

Methyl (2RS,4RS)-4-hydroxy-4-isopropyl-1,2,3,4-tetrahydronaphthalene-2-carboxylate

Methyl (2RS,4RS)-4-hydroxy-4-isopropyl-1,2,3,4-tetrahydronaphthalene-2-carboxylate (8): According to the GP1: compound 2 (200 mg, 0.535 mmol), Pd(PPh3)4 (30 mg, 27 µmol), NEt3 (18 mg, 1.78 mmol), DMF (4 mL), 90 °C, 3 d. Column chromatography (silica gel, hexanes/ethyl acetate 4:1 to 1:1) provided 14 mg (11%) of 8, 33 mg (25%) of 9 and 82 mg (62%) of 10 as colorless oils. 

1H NMR (CDCl3, 500 MHz): δ = 0.60, 1.13 (2 d, J = 6.9 Hz, 2 × 3 H, CHMe2), 1.84 (dd, J = 13.9, 12.3 Hz, 1 H, 3-H), 1.95 (s, 1 H, OH), 2.17 (ddd, J = 13.9, 2.7, 2.4 Hz, 1 H, 3-H), 2.47 (sept, J = 6.9 Hz, 1 H, CHMe2), 2.81 (dd, J = 14.5, 12.7 Hz, 1 H, 1-H), 2.88 (dddd, J = 12.7, 12.3, 2.7, 2.6 Hz, 1 H, 2-H), 2.98 (ddd, J = 14.5, 2.6, 2.4 Hz, 1 H, 1-H), 3.73 (s, 3 H, CO2Me), 7.10-7.25, 7.48-7.49 (2 m, 3 H, 1 H, Ar) ppm. 

13C NMR (CDCl3, 126 MHz): δ = 16.3, 18.6 (2 q, CHMe2), 33.2, 33.3 (2 t, C-1, C-3), 36.6 (d, C-2), 37.9 (d, CHMe2), 75.0 (s, C-4), 125.8, 127.2, 127.5, 129.2, 135.9, 140.4 (4 d, 2 s, Ar), 51.9, 176.1 (q, s, CO2Me) ppm. 

IR (neat): ν̃= 3490 (br, O-H), 3060-2845 (=C-H, C-H), 1735 (C=O) cm-1 . 

MS (EI = 70 eV): m/z (%) = 248 (1) [M]+ , 217 (4), 242 (6), 205 (100), 173 (32), 145 (62). 

EA: C15H20O3 (248.3) calcd. (%): C 72.55, H 8.12; found (%): C 72.47, H 7.75. 

/////////1,2-addition,  aryl iodides,  ketones,  nucleophilic addition,  palladium catalysis, 

MALVANI FOOD, MAHARASHTRA, INDIA

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