2-amino-4-bromo-5-fluorobenzoic acid

spectroscopy Comments Off

Oct 092018

Image result for 2-amino-4-bromo-5-fluorobenzoic acid

2-amino-4-bromo-5-fluorobenzoic acid as a white to off-white crystalline solid

1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J=9.6 Hz, 1H), 7.21-6.5 (m, 3H), 3.8- 3.3 (br s, 1H).

13C NMR (100 MHz, DMSO-d6) δ 170.5, 149.6, 147.6, 147.3, 120.4, 118.1, 118.0, 109.2, 109.0, 99.5.

mp >250 °C. IR (neat) 3494, 3351, 3053, 3038, 1521, 774 cm-1;

HRMS (ESI) m/z: calcd for C7H5BrFNO2 [M+H]+ 233.9560, found 233.9551.

Org. Lett., 2018, 20 (13), pp 3736–3740

DOI: 10.1021/acs.orglett.8b01218

1H NMR AND 13C NMR PREDICT

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1-(4-Cyanophenyl)piperazine

spectroscopy Comments Off

Sep 142018

1-(4-Cyanophenyl)piperazine

1-(4-Cyanophenyl)piperazine (1a).1 Isolated as a mixture of mono (1a) and di (3) arylated products ~9:1. Conversion: quantitative. Peaks attributed to 1a: 1H NMR (400 MHz, CD3Cl) δH 7.47 (m, 2H, arH), 6.83 (m, 2H, ar-H), 3.26 (m, 4H, pip-H), 2.99 (m, 4H, pip-H), 1.69 (br s, 1H, NH). Peaks attributed to 3: 7.52 (d, J = 9.0 Hz, 4H, ar-H), 6.88 (d, J = 9.0 Hz, 4H, ar-H), 3.29 (s, 8H, pip-H).

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00090

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https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00090/suppl_file/op8b00090_si_001.pdf

Process Development of Febuxostat Using Palladium- and Copper-Catalyzed C–H Arylation

MANUFACTURING, organic chemistry, spectroscopy, SYNTHESIS Comments Off

Sep 112018

There is significant interest in the development of process routes for active pharmaceutical ingredients using C–H arylation methodology. An efficient and practical synthetic route for febuxostat (1), which is the first non-purine-type xanthine oxidase inhibitor, was established via palladium- and copper-catalyzed C–H arylation of thiazole with aryl bromide. The catalyst loading was reduced to 0.1 mol % for the intermolecular C–H arylation, and a three-step synthesis produced febuxostat in 89% overall yield with excellent selectivity

Process Development of Febuxostat Using Palladium- and Copper-Catalyzed C–H Arylation

Masato Komiyama*

, Hideyoshi Tsuchiya, Mitsuru Teramoto, Naoki Yajima, Masayuki Kurokawa, Kunio Minamizono, Naoki Tsuchiya, Yoshiaki Kato, Yoshinori Sato, and Masahiko Dohi

Active Pharmaceutical Ingredient Technology Section, Pharmaceutical Preparation Department, Teijin Pharma Limited, 2-1 Hinode-cho, Iwakuni-shi, Yamaguchi 740-8511, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00164

*E-mail: m.komiyama@teijin.co.jp.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00164

1 (22.5 g, 98%) as a whitish solid. ¹H NMR (400 MHz, CDCl₃): δ 8.20 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 3.91 (d, J = 6.6 Hz, 2H), 2.80 (s, 3H), 2.23–2.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H).

//////FEBUXOSTAT

“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

Ethyl 4, 6-dichloro-1H-indole-2-carboxylate

organic chemistry, spectroscopy, SYNTHESIS Comments Off

Aug 282018

Ethyl 4, 6-dichloro-1H-indole-2-carboxylate

ethyl 4,6-dichloro-1H-indole-2-carboxylate (1a) (2.70 kg, 99.5%).

Mp 187–188 °C; HRMS (ESI) m/z [M – H]⁻ calcd for C₁₁H₈NO₂Cl₂ 255.9927, found 255.9930;

¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 4.43–4.30 (q, 2H), 1.34 (d, 3H);

¹³C NMR (151 MHz, CDCl₃) δ 161.69, 137.08, 131.00, 128.45, 128.37, 125.31, 121.26, 110.52, 107.07, 61.56, 14.32;

IR (cm^–1) 3314.3, 2987.6, 1700.2, 1615.8, 1566.2, 1523.7, 1487.2, 1323.3, 1247.2, 1072.4, 840.1, 770.2.

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00144

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00144

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00144/suppl_file/op8b00144_si_001.pdf

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Copper-catalyzed pyrrole synthesis from 3,6-dihydro-1,2-oxazines

organic chemistry, spectroscopy, SYNTHESIS Comments Off

Jul 262018

Copper-catalyzed pyrrole synthesis from 3,6-dihydro-1,2-oxazines

Naoki Yasukawa,^a Marina Kuwata,^a Takuya Imai,^a Yasunari Monguchi,^a Hironao Sajiki*^a and Yoshinari Sawama*^a

Author affiliations

*Corresponding authors

^aLaboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
E-mail: sajiki@gifu-pu.ac.jp, sawama@gifu-pu.ac.jp
Fax: +81-58-230-8109

Abstract

Highly-functionalized pyrroles could be effectively synthesized from 3,6-dihydro-1,2-oxazines using a heterogeneous copper on carbon (Cu/C) under neat heating conditions. Furthermore, the in situ formation of 3,6-dihydro-1,2-oxazines via the hetero Diels–Alder reaction between nitroso dienophiles and 1,3-dienes and the following Cu/C-catalyzed pyrrole synthesis also provided the corresponding pyrrole derivatives in a one-pot manner.

Brown solid; M. p. 107–108 o C;

IR (ATR) cm-1 : 3064, 2923, 2851, 1687, 1596, 1562, 1541, 1498, 1488, 1459, 1451, 1422, 1390, 1343, 1319, 1256, 1187, 1098, 1073, 1053, 1037, 1009;

1 H NMR (500 MHz, CDCl3): δ 7.37–7.28 (m, 5H), 7.17 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.95 (dd, J = 2.0, 3.0 Hz, 1H), 6.45 (dd, J = 2.0, 3.0 Hz, 1H), 6.37 (dd, J = 3.0, 3.0 Hz, 1H);

13C NMR (125 MHz, CDCl3): δ 140.19, 132.52, 131.85, 131.19, 129.65, 129.14, 126.84, 125.69, 124.83, 120.24, 110.97, 109.38;

ESI-HRMS m/z: 298.0231([M+H+ ]); Calcd for C16H13NBr: 298.0226.

//////////3,6-dihydro-1,2-oxazines

A borrowing hydrogen methodology: palladium-catalyzed dehydrative N-benzylation of 2-aminopyridines in water

organic chemistry, spectroscopy, SYNTHESIS Comments Off

Jul 042018

Graphical abstract: A borrowing hydrogen methodology: palladium-catalyzed dehydrative N-benzylation of 2-aminopyridines in water

A borrowing hydrogen methodology: palladium-catalyzed dehydrative N-benzylation of 2-aminopyridines in water

Hidemasa Hikawa,*^a Hirokazu Imamura,^a Shoko Kikkawa^a and Isao Azumaya*^a

Author affiliations

*Corresponding authors

^aFaculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Japan
E-mail: hidemasa.hikawa@phar.toho-u.ac.jp, isao.azumaya@phar.toho-u.ac.jp

Image result for Hidemasa Hikawa Toho University

Isao Azumaya

Abstract

We demonstrate a greener borrowing hydrogen methodology using the π-benzylpalladium system, which offers an efficient and environmentally friendly dehydrative N-monobenzylation of 2-aminopyridines with benzylic alcohols in the absence of base. The crossover experiment using benzyl-α,α-d₂ alcohol and 3-methylbenzyl alcohol afforded H/D scrambled products, suggesting that the dehydrative N-benzylation in our catalytic system involves a borrowing hydrogen pathway. KIE experiments show that C–H bond cleavage at the benzylic position of benzyl alcohol is involved in the rate-determining step (KIE = 2.9). This simple base-free protocol can be achieved under mild conditions in an atom-economic process, affording the desired products in moderate to excellent yields.

N-Benzylpyridin-2-amine 3a 1 Yield 165 mg (90%) as a white solid; mp 90-91 C; IR (KBr) (cm-1) 3226, 3029, 1600, 1575; 1H NMR (400 MHz, CDCl3):  4.50 (d, J=5.7 Hz, 2H), 4.95 (brs, 1H), 6.36 (dt, J=8.5, 0.9 Hz, 1H), 6.58 (ddd, J=7.1, 5.0, 0.9 Hz, 1H), 7.23-7.36 (m, 4H), 7.39 (dd, J=8.7, 7.1, 1.8 Hz, 1H), 8.09 (ddd, J=5.0, 1.8, 0.9 Hz, 2H); 13C-NMR (100 MHz, CDCl3): 46.3, 106.8, 113.1, 127.2, 127.4, 128.6, 137.5, 139.2, 148.2, 158.6; MS (FAB): m/z 185 [M+H]+ .

/////////////borrowing hydrogen methodology, palladium-catalyzed, dehydrative N-benzylation, 2-aminopyridines,

SNS-Ligands for Ru-Catalyzed Homogeneous Hydrogenation and Dehydrogenation Reactions

organic chemistry, spectroscopy Comments Off

Jul 042018

A detailed study of literature-known and novel S-containing pincer-type ligands for ruthenium-catalyzed homogeneous hydrogenation and dehydrogenation reactions was carried out. The scope and limitations of these catalysts were carefully investigated, and it was shown that simple bench-stable SNS–Ru complexes can be used to facilitate the hydrogenation of a variety of different substrates at a maximum H₂ pressure of 20 bar under operationally simple, easy to scale up, glovebox-free conditions by using starting materials and reagents that do not require any special purification prior to use. It was also shown that such complexes can be used to catalyze the dehydrogenative coupling of alcohols and amines to get amides as well as for the dehydrogenative dimerization of alcohols to esters.

SNS-Ligands for Ru-Catalyzed Homogeneous Hydrogenation and Dehydrogenation Reactions

Johannes Schörgenhumer^†, Axel Zimmermann*^‡, and Mario Waser*^†

^†Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstr. 69, 4040 Linz, Austria

^‡Patheon Austria, part of Thermo Fisher Scientific, St. Peterstr. 25, 4020 Linz, Austria

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00142

*E-mail: mario.waser@jku.at. Tel: +4373224685411. Fax: +437322468545402., *E-mail: axel.zimmermann@patheon.com.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00142

Complex IIb:

Method A was applied, using 180 mg of ligand 11b (1.09 mmol) and 993 mg of 27 (1.04 mmol) to give the complex IIb as yellow powder in 83% yield. The complex was isolated as mixture of three isomers.

1 H-NMR (CDCl3, 300 MHz, 298 K), δ / ppm: 7.75-7.50 (m, 10H), 7.41-7.25 (m, 16H), 5.05 (bs, 1H), 3.73-2.9 (m, 9H), 2.71-2.41 (m, 3H), 1.89-1.71 (m, 1H), 1.64-1.54 (m, 12H);

31P-NMR (CDCl3, 121 MHz, 298 K), δ / ppm: 50.6 (59%), 49.0 (24%), 47.6 (17%);

13C NMR (75 MHz, CDCl3, 298 K): δ / ppm = 137.1 (d, J = 39.5 Hz), 134.6 (d, J = 10.0 Hz), 129.3, 127.8 (d, J = 8.9 Hz), 49.0, 42.2, 17.7;

HRMS (ESI+): m/z calcd for C24H30ClNPRuS2 [M – Cl]+: 564.0284; found: 564.0272.

1 H-NMR (CDCl3, 300 MHz, 298 K), δ / ppm: 7.75-7.50 (m, 10H), 7.41-7.25 (m, 16H), 5.05 (bs, 1H), 3.73-2.9 (m, 9H), 2.71-2.41 (m, 3H), 1.89-1.71 (m, 1H), 1.64-1.54 (m, 12H);

31P-NMR (CDCl3, 121 MHz, 298 K), δ / ppm: 50.6 (59%), 49.0 (24%), 47.6 (17%);

13C NMR (75 MHz, CDCl3, 298 K): δ / ppm = 137.1 (d, J = 39.5 Hz), 134.6 (d, J = 10.0 Hz), 129.3, 127.8 (d, J = 8.9 Hz), 49.0, 42.2, 17.7;

///////////////SNS-Ligands, Ru-Catalyzed, Homogeneous Hydrogenation, Dehydrogenation Reactions

tert-butyl (N-[3-[(3S,4R)-3-amino-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]-4-fluorophenyl]acetamide)

ANTHONY CRASTO, spectroscopy, SYNTHESIS Comments Off

Apr 272018

tert-butyl (N-[3-[(3S,4R)-3-amino-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]-4-fluorophenyl]acetamide)

1H-NMR (500 MHz, DMSO-d6): 1.31 (s, 9H), 2.02 (s, 3H), 3.21 (m, 1H), 3.88 (m, 1H), 3.94 (m, 1H), 4.03 (m, 1H), 4.13 (m, 1H), 4.74 (m, 1H), 5.07 (m, 1H), 7.08 (m, 1H), 7.43 (bs, 1H), 7.63 (m, 1H), 7.67 (m, 1H), 10.03 (s, 1H) .

13C-NMR (125 MHz, DMSO-d6): 24.3, 28.5, 60.8, 65.1, 72.6, 78.1, 78.9, 105.8, 116.4, 119.7, 120.8, 127.2, 136.2, 155.2, 156.4, 168.7.

19F-NMR (470.6 MHz, DMSO-d6): -164.77, -117.26.

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Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00069

Catalyst-free and solvent-free hydroboration of aldehydes

ANTHONY CRASTO, spectroscopy, SYNTHESIS Comments Off

Mar 302018

Green Chem., 2018, Advance Article
DOI: 10.1039/C8GC00042E, Communication

Hanna Stachowiak, Joanna Kazmierczak, Krzysztof Kucinski, Grzegorz Hreczycho
For the first time, a general method for catalyst-free and solvent-free hydroboration of various aldehydes has been developed

Catalyst-free and solvent-free hydroboration of aldehydes

Hanna Stachowiak,^a Joanna Kaźmierczak,^a Krzysztof Kuciński^a and Grzegorz Hreczycho*^a

Author affiliations

*Corresponding authors

^aFaculty of Chemistry, Adam Mickiewicz University in Poznań, Umultowska 89b, 61-614 Poznań, Poland
E-mail: g.h@amu.edu.pl

Abstract

A simple catalyst-free and solvent-free method for the hydroboration of various aldehydes bearing a wide array of electron-withdrawing and electron-donating groups was developed. Unlike aldehydes, the addition of boranes to ketones is less efficient and is thus advantageous for the chemoselective reduction of the former ones. It is suggested that the described transformation proceeds with the formation of Lewis acid–base adducts, which facilitates further hydroboration.

4,4,5,5-tetramethyl-2-((4-methylbenzyl)oxy)-1,3,2-dioxaborolane (3b) [1] 4,4,5,5-tetramethyl-2-((4-methylbenzyl)oxy)-1,3,2-dioxaborolane was obtained as colorless oil in 97% yield.

1H NMR (400 MHz, CDCl3) δ (ppm) = 1.29 (s, 12H), 2.36 (s, 3H), 4.91 (s, 2H), 7.17 (d, J = 7.9 Hz, 2H), 7.27-7.30 (m, 2H).

13C NMR (101 MHz, CDCl3) δ (ppm) = 21.3, 24.7, 66.7, 83.0, 127.0, 127.2, 129.1, 129.3, 136.4, 137.1.

11B NMR (128 MHz, CDCl3) δ (ppm) = 22.5.

EA: C14H21BO3 (248.16): calcd.C 67.77; H 8.53; found C 67.66; H 8.47.

11B NMR (128 MHz, CDCl3) δ (ppm) = 22.5.

////////////hydroboration

http://pubs.rsc.org/en/Content/ArticleLanding/2018/GC/C8GC00042E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Concise synthesis of ketoallyl sulfones through an iron-catalyzed sequential four-component assembly

green chemistry, spectroscopy, SYNTHESIS, Uncategorized Comments Off

Mar 092018

Concise synthesis of ketoallyl sulfones through an iron-catalyzed sequential four-component assembly

Green Chem., 2018, 20,973-977
DOI: 10.1039/C7GC03719H, Communication

Fuhong Xiao, Chao Liu, Dahan Wang, Huawen Huang, Guo-Jun Deng
A three starting material four component reaction (3SM-4CR) strategy is described to prepare [small beta]-acyl allylic sulfones from methyl ketones, sodium sulfinates and dimethylacetamide (DMA) in an iron-catalyzed oxidative system.

Concise synthesis of ketoallyl sulfones through an iron-catalyzed sequential four-component assembly

Fuhong Xiao,*^a Chao Liu,^a Dahan Wang,^a Huawen Huang^a and Guo-Jun Deng*^a

Author affiliations

* Corresponding authors

^a Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, Key Laboratory for Green Organic Synthesis and Application of Hunan Province, College of Chemistry, Xiangtan University, Xiangtan 411105, China
E-mail: fhxiao@xtu.edu.cn, gjdeng@xtu.edu.cn

Abstract

A three starting material four component reaction (3SM-4CR) strategy is described to prepare β-acyl allylic sulfones from methyl ketones, sodium sulfinates and dimethylacetamide (DMA) in an iron-catalyzed oxidative system. In this process, DMA was used as a dual synthon to provide two carbons. A broad range of functional groups were tolerated in this reaction system.

1-phenyl-2-(tosylmethyl)prop-2-en-1-one (3ab)

43.2 mg, 72% yield).

1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.68-7.65 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.25 (s, 1H), 6.02 (s, 1H), 4.35 (s, 2H), 2.39 (s, 3H).

13C NMR (100 MHz, CDCl3) δ 194.7, 144.9, 136.1, 135.8, 135.7, 133.9, 132.6, 129.8, 129.6, 128.3, 128.2, 57.7, 21.6.

HRMS calcd. for: C17H17O3S+ [M+H]+ 301.08929, found 301.08908