(4-(3-(methylsulfinyl)phenyl)-l-propyl-l,2,3,6- tetrahydropyridine)

Example 7 - Preparation Of Compound 7 (4-(3-(methylsulfinyl)phenyl)-l-propyl-l,2,3,6- tetrahydropyridine)

4-(3-(methylsulfinyl)phenyl)-1-propyl- 1 ,2,3,6-tetrahydropyridin-1-ium chloride Sulfuric acid (42.23g, 0.43 lmol, leq) was added to a mixture of 4-hydroxy-4-(3- (methylsulfonyl)phenyl)-l-propylpiperidin-l-ium chloride (130g, 0.431 mo, leq) and toluene (650mL) at room temperature. The resulting two-phase solution was refluxed for lhour and HPLC showed that the product reached 95% area. The reaction mixture was cooled down to 20°C and the toluene phase was decanted to give viscous residue that was diluted with water (600mL) and neutralized with 2N NaOH to pH~4.2. Hydrogen peroxide (50%, 32.21g, 0.474mol, l.leq) was added dropwise to the water phase and the mixture was stirred at 60°C for lh after which the product reached 96% area (HPLC).

Toluene (600mL) was added to the reaction mixture and made basic first with 25% NaOH (60g) and finally with 10% NaOH up to pH 12. The phases were separated and the water phase was re-extracted with toluene (2xl00mL). The combined toluene phases were washed with 5% sodium sulfite (150mL), brine (150mL) and water (150mL). The toluene phase was then concentrated under vacuum on a rotavapor to give 111.3g oil (HPLC area: 96.6%). Methanol (50mL) was added to the residue and it was filtered and cooled down on ice batch. Dry HC1 in ethyl acetate was added up to pH 1-2 (120mL) and lOOmL of ethyl ether were added to give two phases mixture. The mixture was seeded with the product and precipitation started. The reaction mixture was stirred on ice bath (2-5°C) for additional lh, filtered and washed with 1/3 ethyl acetate/ether mixture (lOOmL) to give 140g of very hygroscopic light yellow solid that was dried on a rotavapor for 2h and stored under nitrogen in deep freeze. The dry 4-(3-(methylsulfinyl)phenyl)-l-propyl-l,2,3,6-tetrahydropyridine-HCl is slightly yellowish solid (94.1g, 79% yield, HPLC (254nm): 96.3% area, 1H-NMR assay: 97.5%).

NMR Identity Analysis of Compound 7

Compound 7: 

The following data in Tables 14 and 15 was determined using a sample of Compound 7, a solvent of CDCb, and the instruments were a Bruker AMX500 and Avance III 800 MHz instrument.

Table 14: Assignment of ¾ NMR"

"Spectra is calibrated by the solvent residual peak (2.5 ppm).

bafter addition of small amount of CeDe

Table 15: Assignment of 13C NMRa*

a Spectra is calibrated by a solvent peak (77.0 ppm)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016003919&recNum=5&docAn=US2015038349&queryString=EN_ALL:nmr%20AND%20PA:(teva%20pharmaceutical)&maxRec=677#H3

3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetrazine

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03494B, Paper

Zheng Fang, Wen-Li Hu, De-Yong Liu, Chu-Yi Yu, Xiang-Guo Hu
A procedure for the synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions has been developed.

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Zheng Fang,a   Wen-Li Hu,a   De-Yong Liu,a  Chu-Yi Yuab and   Xiang-Guo Hu*a  

 

*Corresponding authors

aNational Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P. R. China
E-mail: huxiangg@iccas.ac.cn

bBeijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03494B, http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03494B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

 

An efficient and green procedure for the synthesis of tetrazines has been developed based on an old chemistry reported by Carboni in 1958. Both symmetric and asymmetric 3,6-disubstituted 1,2,4,5-tetrazines can be obtained in moderate to high yields from the corresponding gem-difluoroalkenes under aerobic conditions at room temperature. This work represents a rare example that ambient air is utilized as an oxidant for the synthesis of tetrazines.

 

 

Synthesis of symmetric 3,6-dialkyl-1,2,4,5−tetrazine(3a−3h)

 

To a solution of 1,1−difluoroalkenes (1a, 50 mg, 0.27 mmol) in N,N-dimethylformide (DMF,5 mL) was added hydrazine (80%, 35 mg, 1.35 mmol). After stirring at room temperature for 4−6 hours, saturated ammonium chloride (20 mL) was added and the reaction mixture was extracted with dichloromethane (10 mL×3). The organic layer was combined, dried with anhydrous sodium sulfate. The solvent was concentrated and the crude product was dissolved in a suspension of Ethyl Acetate(5 mL) and 10% potassium carbonate solution(wt%, 5 mL) and stirred at room temperature for 24h under air atomerspere until the organic layer turned into amaranth obviously. The organic layer was collected, dried with anhydrous sodium sulfate. The crude product was purified by flash column chromatography[silica gel(#100–200), toluene] to afford the pure 1,2,4,5−tetrazines(3a−3h).

 

3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine (3a).

 

(41 mg, 83%).

 

purple solid; m.p. 200−202°C;

 

IR(KBr) nmax/cm−1 2924, 2850, 1488, 1451, 1432, 1388, 851, 750;

 

1 H NMR (400 MHz, CDCl3) 7.55−7.33 (m, 18H), 4.65 (s, 4H).

 

13C NMR (100 MHz, CDCl3) δ 169.2, 140.6, 140.4, 134.8, 129.7, 128.8, 127.6, 127.4, 127.1, 40.9;

 

HRMS (ESI): calcd. for C28H22N4 [M+H]+ 415.19172, found 415.19124.

 

 

 

///////tetrazines,  gem-difluoroalkenes, aerobic conditions, room temperature

2,2′-(1-(tert-Butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic Acid

2,2′-(1-(tert-Butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic Acid

    

2,2′-(1-(tert-Butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic Acid 

as a white solid. Mp: 162–163 °C, % purity: 94.09% (HPLC);

 

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.38 (s, 9H), 2.10–2.18 (m, 2H), 2.28–2.32 (m, 2H), 2.49–2.50 (m, 2H, merged with DMSO peak), 2.97–3.03 (m, 2H), 3.33–3.40 (m, 2H), 12.23 (bs, 2H); ¹H NMR (CD₃OD, 400 MHz) δ: 1.46 (s, 9H), 2.26 (ddd, J₁ = 2.8 Hz, J₂ = 9.2 Hz, J₃ = 16.0 Hz, 2H), 2.43 (dd, J₁ = 5.2 Hz, J₂ = 16.0 Hz, 2H), 2.69 (m, 2H), 3.16 (dd, J₁ = 5.2 Hz, J₂ = 10.8 Hz, 2H), 3.49–3.54 (m, 2H);

 

¹³C NMR (DMSO-d₆, 100 MHz) δ: 28.49, 32.97, 36.49, 37.31, 50.10, 50.20, 78.67, 154.05, 173.96;

 

IR (KBr): ν = 871, 933, 1143, 1166, 1292, 1411, 1689, 1708, 2881, 2929, 2980, 3001 cm^–1;

 

TOFMS: [C₁₃H₂₁NO₆ – H⁺]: calculated 286.1296, found 286.1031(100%).

HPLC conditions were as follows for compound ; Agilent 1100 series, column: YMC J’SPHERE C18 (150 mm X 4.6 mm) 4µm with mobile phases A (0.05% TFA in water) and B (acetonitrile). Detection was at 210 nm, flow was set at 1.0 mL/min, and the temperature was 30 °C (Run time: 45 min). Gradient: 0 min, A = 90%, B = 10%; 5.0 min, A = 90%, B = 10%; 25 min, A = 0%, B = 100%; 30 min, A = 0%, B = 100%, 35 min, A = 90%, B = 10%; 45 min, A = 90%, B = 10%.

 

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00399

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00399

 

/////////

3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine

3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03494B, Paper

Zheng Fang, Wen-Li Hu, De-Yong Liu, Chu-Yi Yu, Xiang-Guo Hu
A procedure for the synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions has been developed.

An efficient and green procedure for the synthesis of tetrazines has been developed based on an old chemistry reported by Carboni in 1958. Both symmetric and asymmetric 3,6-disubstituted 1,2,4,5-tetrazines can be obtained in moderate to high yields from the corresponding gem-difluoroalkenes under aerobic conditions at room temperature. This work represents a rare example that ambient air is utilized as an oxidant for the synthesis of tetrazines.

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Zheng Fang,^a   Wen-Li Hu,^a   De-Yong Liu,^a  Chu-Yi Yu^ab and   Xiang-Guo Hu*^a  

Hide Affiliations

*

Corresponding authors

^a

National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P. R. China
 E-mail: huxiangg@iccas.ac.cn

^b

Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03494B

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03494B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine (3a). (41 mg, 83%). purple solid;

m.p. 200−202°C;

IR(KBr) nmax/cm−1 2924, 2850, 1488, 1451, 1432, 1388, 851, 750;

1 H NMR (400 MHz, CDCl3) 7.55−7.33 (m, 18H), 4.65 (s, 4H).

 13C NMR (100 MHz, CDCl3) δ 169.2, 140.6, 140.4, 134.8, 129.7, 128.8, 127.6, 127.4, 127.1, 40.9;

HRMS (ESI): calcd. for C28H22N4 [M+H]+ 415.19172, found 415.19124.



///////

2,6-diphenyl-5-methylpyrimidinone

Metal-free radical C-H methylation of pyrimidinones and pyridinones with dicumyl peroxide

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03355E, Communication

Pei-Zhi Zhang, Jian-An Li, Ling Zhang, Adedamola Shoberu, Jian-Ping Zou, Wei Zhang
A method for free radical methylation of pyrimidinones and pyridinones with dicumyl peroxide under metal-free conditions is introduced. A 50 g-scale reaction could be performed safely. The product was separated by crystallization and the byproducts were recovery by distillation

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03355E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Metal-free radical C–H methylation of pyrimidinones and pyridinones with dicumyl peroxide

Pei-Zhi Zhang,^a   Jian-An Li,^a   Ling Zhang,^a  Adedamola Shoberu,^a   Jian-Ping Zou*^a and  Wei Zhang*^b  

*

Corresponding authors

^a

Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow University, 199 Renai Street, Suzhou, China
 E-mail: jpzou@suda.edu.cn

^b

Centre for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, USA
 E-mail: wei2.zhang@umb.edu

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03355E

A new method for free radical methylation of pyrimidinones and pyridinones with dicumyl peroxide (DCP) under metal-free conditions is introduced. A 50 g-scale reaction could be performed safely at the desired concentration. The reaction solvent and DCP derivative were readily recovered by distillation. The product was purified by crystallization to minimize the amount of waste.


2,6-diphenyl-5-methylpyrimidinone

Colorless solid, mp 258−260 °C, 73% yield (191 mg).

1H NMR (400 MHz, DMSO-d6): δ 12.85 (s, 1H), 8.17 (d, J = 7.1 Hz, 2H), 7.68 (d, J = 6.6 Hz, 2H), 7.53 (dd, J = 14.3, 6.8 Hz, 6H), 2.10 (s, 3H).

13C NMR (101 MHz, CDCl3): δ 161.15, 152.97, 138.68, 132.26, 131.62, 129.11, 129.02, 128.86, 128.15, 127.45, 119.09, 12.65.

 HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C17H15N2O 263.1184, found 263.1194.





///////////

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

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

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

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.




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

(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.




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

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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