Advances in
Synthetic Organic Chemistry
and Methods Reported in US Patents

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Advances in
Synthetic Organic
Chemistry and Methods
Reported in US Patents
Thomas F. DeRosa

AMSTERDAM • BOSTON • HEIDELBERG • LONDON
NEW YORK • OXFORD • PARIS • SAN DIEGO
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First edition 2006
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Functional Group Contents

(Patent Titles)

Introduction

xvii

Acids and Derivatives

1

Aromatic Carboxylic Acid Derivatives
Azinyloxy, and Phenoxy-Diaryl-Carboxylic Acid Derivatives, Their Preparation and Use
as Mixed ETA/ETB Endothelin Receptor Antagonists
Cinnamic Acid Derivatives
Compounds Derived from Benzoic Acid Esters, Composition Containing Said Compounds
and Use Thereof
1,2-Diarylmethylene Derivatives, Their Methods of Preparation, and Their Uses in
Therapeutics
Geranic Acid Derivatives
Halogenated Cinnamic Acids and Esters Thereof, Processes for the Preparation Thereof
and Halogenated Aryldiazonium Salts
Halogenation Catalyst
Method for Producing Alkoxy Malonic Acid Dinitriles
Phosphonosuccinic Acid Derivatives, Processes for Their Preparation and Medicaments
Containing These Compounds
Preparation of Cyclohexane Carboxylate Derivatives
Water Soluble Fullerenes with Antiviral Activity

Alcohols


1
5
8
12
14
18
20
22
24
26
28
33

36

Butyne Diol Derivatives
1,2-Dithin Antiinfective Agents
Oligiocycloalkanoid Compounds and Methods of Use
Polymers with Controlled Physical State and Bioerodibility
4-Quinolinemethanol Derivatives as Purine Receptor Antagonists
Synthesis of 5-Decenyl Acetate and Other Pheromone Components

Aldols

36
41
44
48
50
53


55

Stereospecific Synthesis of Aldols

55

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FUNCTIONAL GROUP CONTENTS

viii

Aldehydes

58

Process for Selective Catalytic Oxidation of Olefins to Aldehydes, Ketones with Cleavage
of C==C Bonds

Alkenes

58

60

Carbonyl-Containing Compounds

60


Alkynes

62

Diaryl-enynes
DNA-Cleaving Anti-Tumor Agents

62
66

Amides

70

Adamantane Derivatives
o-Anisamide Derivatives
Benzamide Analogues Useful as PARP (ADP-Ribosyltransferase, ADPRT) DNA Repair
Enzyme Inhibitors
Carboxamide Compositions, Methods, and Compositions for Inhibiting PARP Activity
Heterocyclic Amides
Phosphoramide Compounds

Amines

70
73
76
79
82

87

90

Aminophenyl Ketones Derivatives and a Method for the Preparation Thereof
Arylamine Synthesis
Fungicidal Spirocyclic Amines
Method for Producing Propargylamine Compounds
One Pot Process for the Preparation of
1-[2-Methylamino-(4-Methoxyphenyl)-Ethyl]Cyclohexanol
Organic Electroluminescence Device and Phenylenediamine Derivative
Process for Preparing N-Substituted Hydroxylamines and Salts Thereof
Sodium Channel Modulators
Substituted 2-Aminoalkyl 1,4-Diaminobenzene Compounds and Oxidation Dye Precursor
Containing the Same

Aminoacids

90
94
97
101
104
106
110
112
115

117


Aminoindanes
Aminopropylphosphinic Acids
Cyclic Aminoacids and Derivatives Thereof Useful as Pharmaceutical Agents
Isocyanoalkyl, Carbonic Acid Derivatives, Their Conversion into Secondary Amidoalkyl
Carbonic Acid Derivatives by Isocyanide Multicomponent Reactions, as well as these
Secondary Amidoalkyl Carbonic Acid Derivatives
Spirodiamino Acid Scaffold for Combinatorial Synthesis

Anthracenones

117
120
122

125
128

132

10-Substituted 1,8-Dihydroxy-9(10H) Anthracenone Pharmaceuticals

Aza and Diaza Bi- and Tricyclics

132

136

Bi- and Tri-Cyclic Aza Compounds and Their Uses
Certain Tricyclic Substituted Diazabicyclo[3.2.1]octane Derivatives
Dopamine Transporter Imaging Agent


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136
141
144


FUNCTIONAL GROUP CONTENTS

ix

N-Alkyl and N-Acyl Derivatives of 3,7-Diazabicyclo-[3.3.1] Nonanes and Selected Salts
Thereof as Multiclass Antirrhythmic Agents
Process for the Manufacture of Tropenol

Aza Benzazolium Salts

147
150

153

Aza-Benzazolium Containing Cyanine Dyes

Aza-Dihydroquinoxaline

153

156


8-Aza, 6-Aza and 6,8-Diazo-1,4-dihydroquinoxaline-2,3-diones and the Use Thereof as
Antagonists for the Glycine/NMDA Receptor

Aza-Indolyls

156

159

Aza-Indolyl Derivatives for Treating Obesity

Aza-Oxindoles

159

162

Substitued Aza-Oxindole Derivatives

162

Azides

165

Stereoselective Ring Opening Reactions

Aziridines/Diazirines


165

170

Diazirine Derivatives of Aromatic Heterocyclic Compounds
Preparation of N-Arylmethyl Aziridine Derivatives 1,4,7,10-Tetraazacyclododecane
Derivatives Obtained Therefrom and N-Arylethyl-ethanolamine Sulfonate Esters as
Intermediates
Process for Producing Aziridine Compounds

170

173
176

Benzodiazopines

178

Benzodiazepines

178

Benzoxazoles

182

Benzoxazoles

182


Benzopyrans

186

Benzopyran Derivatives

186

Benzothiophenes

190

Pentacyclic Compounds, Intermediates, Processes, Compositions, and Methods

Benzotriazole

190

195

Method of Synthesizing t-Amido-Substituted 2-(2-Hydroxyphenyl)benzotriazole
Compounds in a One-Step Process

Carbamates/Ureas

195

199


Herbicidal Sulfonylureas, Their Preparation and Use
Process for the Preparation of Aminocarbonyl Derivatives of Geneseroline Having
Selective Brain Anticholinesterase Activity

Catalysis

199
202

205

Highly Reactive Form of Copper and Reagents Thereof
Lewis Acid Catalyst Composition

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205
208


FUNCTIONAL GROUP CONTENTS

x

Cumulenes

Aromatic Allene Compounds of the Formula CH2 ==CH-O n -R- A
R is an Aromatic Group and Preparation Thereof
Preparation of Unsaturated Ketones
(S)-4-Amino-Hepta-5,6-Dienoic Acid and Intermediates Thereof


211
m

in Which

Cyanohydrins

211
214
217

220

Method for the Stereoselective Production of Substituted Cyclohexylanhydrins

Cyclodextrane/Dextrane

220

223

Conjugation of Biomolecules Using Diels-Adler Cycloaddition
Nohr-McDonald Elimination Reaction

Cyclopentadiene

223
227


230

Cyclopentadienyl Derivatives and Process for Their Preparation

Cyclopropanes

230

233

Aryl Phenylcyclopropyl Sulfide Derivatives and Their Use as Cell Adhesion Inhibiting
Anti-Inflammatory and Immune Suppressive Agents
Cyclic Compounds Having a Cycloalkylene Chain
2-Hydroxymethylcyclopropylidene-Methylpurines and -Pyrimidines as Antiviral Agents
Process of Producing Cyclopropanecarboxylate Compounds
Process for the Preparation of Methylenecyclopropane
Synthesis of Cyclopropaneacetylene by a One Pot Process

Dentrimer

233
236
240
245
247
249

251

Dentrimeric Fullerene Derivatives, Process for Their Preparation, and Use

as Neurprotectants
Starburst Conjugates

Enamines

251
255

258

Use of Enamines as Light Protection Agents

Enaminones

258

261

Phenyl-Substituted Cyclic Enaminones

Ethers

261

265

Diaryl Ether Condensation Reactions
Preparation and Use of Ionic Liquids in Microwave-Assisted Chemical Transformations
Wurster’s Crown Ligands


Formazan

265
268
270

272

Formazan Metal Complexes

272

Furazancarboxylic Acid Derivatives
Hydroxymethylfurazancarboxylic acid derivatives

Furanones

275
275

278

Furanone Derivatives

278

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FUNCTIONAL GROUP CONTENTS


xi

Guanidines

280

Cyclic Guanidine Derivatives and Their Use as Pesticides

Guanines

280

283

Substituted O6 -Benzyl-8-Aza-Guanines

Hydrazine

283

286

Diacylhydrazine Derivatives
Method for Synthesizing Hydrazodicarbonamide

Imidazole

286
290


292

Method for Preparing Cycloheptimidazoles
Substituted Imidazole Compounds

Imidazolidine

292
295

299

Cis-Imidazolines
Spiroimidazolidine Derivatives, Their Preparation, Their use and Pharmaceutical
Preparations Formed Therefrom

Imidazolone

299
302

307

Fungicidal 2-Imidazolin-5-ones and Imidazoline-5-thiones

Imidazoltriazionones

307


311

2-Phenyl Substituted Imidazotriazinones as Phosphodiesterase Inhibitors

Imide Derivatives

311

315

Photocleavable Agents and Conjugates for the Detection and Isolation of Biomolecules
Process for the Preparation of Alkyl 4[2-(Phthalimido)ethoxy]-Acetoacetate

Iminocarboxylic Acid Methyl Amides
Preparation of -Methoxyiminocarboxylic Acid Methylamides and Intermediates Therefore

Indoles

315
320

322
322

326

Process for the Preparation of Indole Derivatives and Intermediates of the Process
Synthetic Compounds for Treatment of Inflammation
Tetrahydro- -Carbolines


Indoline

326
331
333

337

Amination Process

337

Isocoumarins

341

Process for Preparing Isocoumarins

341

Isoxazolines

345

Method for Producing Isoxazoline-3-yl-acyl Benzene

Ketones

345


349

Acetoacetic Acid Derivatives, Process for Their Preparation and Their Use
Methods for Making Substituted Phenylketoenols

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349
352


FUNCTIONAL GROUP CONTENTS

xii

Process for Preparing 3-Hydroxymethyl-4-(Aryl or Heterocyclic)-Cyclopentanones
Process for Preparing Trifluoromethyl Ketones
Process for the Preparation of High Purity Alkyladamanantyl Esters

Lactams

355
360
362

364

Anticonvulsant and Anxiolytic Lactam and Thiolactam Derivatives
-Lactams as Antiproliferative Agents
-Lactam-like Chaperone Inhibitors

N-Thiolated -Lactam Antibiotics
Process for Preparing -Lactam Compounds
6-(Spirocyclopropyl)-Penicillanic Acid-4,4-Dioxides

Lactones

364
367
371
373
376
379

382

Benzylidene- -Butryolactones, Process for Their Preparation and Their Use as UV
Absorbers
Ring-Opened Azlactone Initiators for Nitroxide-Mediated Polymerization

Macocyclic Rings

382
385

388

-Diketone Compounds, -Diketone Compounds Coordinated to Metal, Method
of Organic Synthesis with These, and Catalyst
1,4-Dioxacylcycloalkane-2-one and 1,4-Dioxacylcycloalkene-2-one
Synthesis of Macrocyclic Tetraamido-N Ligands

The Preparation of Giant Ring Compounds

Morpholines

388
392
394
397

399

Lewis Acid-Catalyzed Claisen Rearrangements in the Preparation of Chiral Products

Naphthopyans

399

401

Indeno-fused Photochromic Naphthopyrans

Naphthyridines

401

406

4-Hydroxy-1,8-Naphthyridine-3-Carboxamides as Antiviral Agents

Nitro Derivatives


406

410

Geminal-Dinitro-1,5-Diazocine Derivatives
Methods of Preparing Salts of Dinitromethane
Vicarious Nucleophilic Substitution Using 4-Amino-1,2,4-Triazole, Hydroxylamine
or O-Alkylhydroxylamine to Prepare 1,3-Diamino-2,4,6-Trinitrobenzene or
1,3,5-Triamine-2,4,6-Trinitrobenzene

Nitrones

410
416

418

420

Furan Nitrone Compounds

420

Organometallics

424

Aryl Borates
Boric Ester Synthesis

Method for Producing Monoaryloxy-ansa-Metallocenes
Process for Preparing Bisallylboranes and Non-Aromatic Boronic Acids
Synthetic Molecules That Specifically React with Target Sequences

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424
427
429
432
434


FUNCTIONAL GROUP CONTENTS

xiii

Orthocarbonates, Esters, and Derivatives
Spiroorthocarbonates Containing Epoxy Groups
Substituted Sprioalkylamino and Alkoxy Heterocyclics, Processes for Their Preparation,
and Their Use as Pesticides and Fungicides
Synthesis of Spiro Orthoesters, Spiro Orthocarbonates, and Intermediates

Oxadiazines

437
437
441
444


447

Oxadiazine Derivatives
1,3,4-Oxadiazine Derivatives and Their Use as Pesticides

Oxathiolanes

447
451

454

Antiviral Activity and Resolution of
2-Hydroxylmethyl-5-(5-fluorocytosin-1-yl)-1,3-Oxathiolane
Substituted 1,3-Oxathiolanes with Antiviral Properties

Oxazines

454
458

462

Photochromic Oxazine Compounds and Methods for Their Manufacture

Oxazolidinones

462

465


Process to Prepare Cyclic-Sulfur Fluorine Containing Oxazolidinones

Oxetanes

465

470

Fluorinated Oxetane Derivatives and Production Process Thereof
Process for the Production of 3-Alkyl-3-Hydroxymethyloxetanes

Oxetanones

470
473

475

Oxetanone Derivatives

475

Oximes

478

O-Acyloxime Photoinitiators
Oxime Derivatives and Their Use Thereof as Latent Acids


Oxirane

478
482

484

Diels-Adler Adducts of Epoxybutene and Epoxybutene Derivatives
Process for the Preparation of an Oxirane, Aziridine or Cyclopropane

Phenols

484
486

489

Calixarene Derivatives
Dimeric Arylisoquinoline Alkaloids and Synthesis Method Thereof
Process for Preparing Procyanidin 4 →6 or 4 →8 Oligomers and Their Derivatives

Piperidine

489
493
497

501

N-Acyl Cyclic Amine Derivatives

Opiate Compounds, Methods of Making and Methods of Use
Process for Production of Piperidine Derivatives (Note 1)
Spiropiperidine Derivatives

Piperizines

501
505
509
513

517

Piperazine Derivatives

517

Porphyrins

520

1,3-Dipolar Cycloadditions to Polypyrrolic Macrocycles

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520


FUNCTIONAL GROUP CONTENTS


xiv

Pyrans

522

Synthesis of 3,6-Dialkyl-5,6-Dihydro-4-Hydroxy-Pyran-2-One

Pyrazoles

522

525

Parasiticidal Compounds
Spiropyrazole Compounds

525
529

Pyridine

532

Process for Preparing Tribromomethylsulfonylpyridine
3-Pyridinyl Compounds

Pyridone and Tetrahydropyridone
Pyridone Derivatives, Their Preparation and Their Use as Synthesis Intermediates
Solid Phase Synthesis of Heterocycles


Pyrimidines

532
534

537
537
542

545

N-Heterocyclic Derivatives as NOS Inhibitors

Pyrrols

545

548

7-Azabicyclo[2.2.1]Heptane and Heptene Derivatives as Cholinergic Receptor Ligands
Colormetric Sensor Compositions and Methods

Quinones

548
552

555


Compositions and Methods for Treating Viral Infections
Quinone Compound, Liquid Crystal Composition, and Guest-Host-Type Liquid Crystal
Cell Employing the Same
Polycyclic Aryl and Heteroaryl Substituted 1,4-Quinones Useful for Selective Inhibition of
the Coagulation Cascade
Synthesis of Coenzyme Q10 (Ubiquinone)

Radiolabelled Reagents

555
559
562
566

570

Radioligands and Their Use for Identifying Potassium Channel Modulators
Synthesis of 2 H- and 13 C-Substituted Dithanes
Tritioacetylating Reagents and Processes for Preparation Thereof

Saccharides

570
574
576

578

2-Saccharinylmethyl Heterocyclic Carboxylates Useful as Proteolytic Enzyme Inhibitors
and Compositions and Method of Use Thereof


Sugars

578

583

Heavily Fluorinated Sugar Analogues
Preparation of Thioarabinofuranosyl Compounds and Use Thereof
Process for the Alkaline Oxidative Degradation of Reducing Sugars
Sugar Derivatives of Hydromorphorine, Dihydromorphorine and Dihydroisomorphorine
Compositions Thereof and Uses for Treating or Preventing Pain

Sulfonamides

583
587
591
594

597

Thioaryl Sulfonamide Hydroxamic Acid Compounds

Sulfones

597

602


-Amino- -Sulfonyl Hydroxamic Acid Compounds
Nitromethylthiobenzene Derivatives as Inhibitors of Aldose Reductase

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602
605


FUNCTIONAL GROUP CONTENTS

xv

Process for the Preparation of Ethanesulfonyl-piperidine Derivatives
-Unsaturated Sulfones for Treating Proliferative Disorders

Sulfonylimides

608
612

615

Sulfonylimide Compounds

615

Tetrabenazine

618


Iodine Derivatives of Tetrabenazine

618

Tetracyclines

621

7-Substituted Fused Ring Tetracycline Compounds

Tetrahydrobenzoquinoxaline Diones
Pyrrolyl Tetrahydrobenzoquinoxaline Diones, Their Preparation and Use As Glutamate
Receptor Antagonist

Tetrahydrobenzothiepines

621

624
624

628

Method for the Preparation of Tetrahydrobenzothiepines

Tetrahydroisoquinolines

628


633

Pictet-Spengler Reaction for the Synthesis of Tetrahydroisoquinolines and Related
Heterocyclic Compounds

633

Tetrahydroquinolines

635

Dimeric Compounds

635

Tetrazoles

638

Tetrazolyl-Phenyl Actamide Glucokinase Activators

Thiazoles

638

643

Oxazolo, Thiazolo and Selenazolo [4,5-c]-Quinolin-4-Amines and Analogues Thereof
Tri-Aryl-Substituted-Ethane PDE4 Inhibitors


Thiophenes

643
646

651

3,4-Diaryl Thiopenes and Analogs Thereof Having Use as Anti-inflammatory Agents
Oligiothiophenes and Synthesis Thereof
Polyaryl Antitumor Agents

Triazines

651
655
658

661

Aryloxy- and Arylthio-substituted Pyrimidines and Triazines and Derivatives Thereof
Method of Alkylating Triazine Derivatives

Triazoles

661
665

668

One Step Synthesis of 1,2,3-Triazole Carboxylic Acids

Triazolyl-Tetrazinyl-Aminotriazine Compounds Useful in Pyrotechnic Compositions
and Process Thereof

Trioxolanes

668
671

674

Spiro and Dispiro 1,2,4-Trioxolane Antimalarials

Index

674

677

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Introduction
The first US Patent was issued to inventor John Ruggles on July 13, 1836 for improved
Traction Wheels for locomotive-engines. The Traction Wheels addressed the need for locomotives to efficiently climb ‘inclined plains and hills with heavy loads drawn up to the
same with more facility and economy than heretofore.’ US Patent 130 was the first chemical

invention patent issued on February 16, 1837 to English chemist Webster Flockton. Flockton
had developed a method of preserving wood by treating lumber with ‘the essential oil of
vegetable tar saturated with the oxide of iron.’
This initially small stream of issued patents has become a deluge. In February, 2005,
12,915 US patents were granted; on March 1, 2005, US Patent 6,862,742 issued. Assignees
are not limited to individuals and small and large corporations, but also include academic
institutions and national and international government agencies.
The purpose of this book is to provide academic and industrial chemists with significant
advances in current chemical research in 46 subject areas as reported in the US Patent
literature. This objective is best achieved using four inter-connected components. First,
chemical reactions necessary to achieve the inventor’s stated goal are depicted for
each patent. All structural transformations, reagents, chemical intermediates, as well as
experimental conditions have been supplied. Second, chemical agents have been classified
by both their Functional Group Type and Product Utility. For example, water soluble
fullerenes derivatives are classified as ‘Acids and Derivatives’ under Functional Group Type
and as ‘Pharmaceuticals, Virucides’ under the Product Utility designation. Third, explicit
laboratory procedures for synthesizing targeted compounds, intermediates, and derivatives
have been provided to assist in the preparation, isolation, characterization, and assaying of
chemical agents of interests. Where available, relevant prior art US Patent references are
incorporated throughout the text which are assessable from the US Patent and Trademark
Office database (www.uspto.gov). Finally, individual Reagent, Product, and Name Reaction
indices are incorporated to more efficiently access required information.
Thomas F. DeRosa,
May, 2005

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Acids and Derivatives
Aromatic Carboxylic Acid Derivatives
M. Klaus et al, US Patent 6,610,877 (August 26, 2003)
Assignee: Hoffman-La Roche Inc.
Utility:
Treatment of Photodamaged Skin
Patent:

Reaction

i- Aluminium trichloride, carbon disulfide
ii- Carbon tetrachloride, iron, bromine
iii- t-Butyl lithium,
N,N-dimethylformamide, THF

iv- Diethyl(4-carboethoxybenzyl)
phosphonate, sodium hydride,
dimethylsulphoxide, THF
v- Ethyl alcohol, potassium hydroxide

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ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

2


Experimental
1. 1,1,4,4-Tetramethyl-6-hexyl-1,2,3,4-tetrahydro-naphthalene
6-Hexylbenzene (83 ml) and AlCl3 (1.8 g) were mixed while cooling and 2,5-dichloro-2,5dimethyl-hexane (40 g) dissolved in 300 ml CS2 added dropwise. Thereafter, the mixture
was stirred 2 hours, poured into 6 M HCl in ice, extracted with EtOAc, and the crude
product isolated as a colorless oil, bp = 141–152 C at 0.8 mm Hg.
2. 7-Bromo-1,1,4,4-tetramethyl-6-hexyl-1,2,3,4-tetrahydro-naphthalene
The product from Step 1 (10 g) was dissolved in 100 ml CCl4 followed by the addition of a
spatula full of iron and bromine (6.4 g) and the mixture stirred at 0 C for 3 hours. The mixture
was poured into ice water, extracted with diethyl ether, and purified by column chromatography on silica gel with hexane/EtOAc, 9:1, the product isolated as a pale yellow oil.
3. 2-Formyl-3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene
The product from Step 2 (10 g) was dissolved in 100 ml THF and treated with 40 ml 1.4 M
t-BuLi in pentane and 60 ml DMF and stirred 1 hour at −78 C. The mixture was poured into
ice water acidified with 2 M HCl, extracted with diethyl ether, purified by column chromatography on silica gel using hexane/EtOAc, 19:1, and the product isolated as a yellow oil.
4. Ethyl-p-[(E)-2-(3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl)vinyl]benzoate
Diethyl(4-carboethoxybenzyl)phosphonate (20 g) was dissolved in 50 ml DMSO and
treated with pentane-washed NaH (3.2 g) in 50 ml DMSO at ambient temperature for
2 hours and the product from Step 3 (9 g) dissolved in 50 ml THF added dropwise. The
mixture was heated to 40 C for 3 hours and the product isolated as in Step 3.
5. p-[(E)-2-(3-Hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthyl)vinyl]benzoic acid
The product from Step 4 (8 g) was dissolved in 50 ml ethyl alcohol and treated with
10 g KOH dissolved in 10 ml apiece ethyl alcohol and water. Thereafter 50 ml THF was
added and the mixture heated to 40 C 4 hours, poured into ice water containing 6 M
HCl, extracted with EtOAc, and the crude product re-crystallized using hexane/EtOAc,
mp = 134–136 C.

Derivatives

R1
Pentyl
Octyl

Allyloxy

R2
(2E, 4E, 6E)-3-Methyl-hepta-trienoic acid
E-[(5H-Benzocyclohepten-2-yl)vinyl]benzoic acid
E-Vinylbenzoic acid

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Melting Point ( C)
170–174
183–183
191–192


ACIDS AND DERIVATIVES

3

Notes
1. This is an example of the Horner-Wadsworth-Emmons reaction and is discussed (1)
2. (2E, 4E, 6E)-7-(3-Hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthanen-2-yl)-3methyl-hepta-2,4,6-trienoic acid (II) was also prepared by reacting 2-formyl-3-hexyl5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene
with
ethyl
(E,E)-6-(diethoxyphosphinyl)-3-methyl-2,4-hexdienolate followed by basic hydrolysis illustrated in Eq. 1
as described below by the author.

i- Dimethyl sulfoxide
ii- Potassium hydroxide, ethyl alcohol, THF
Procedure-1, Step 1

Ethyl (2E, 4E, 6E)-7-(3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthanen-2-yl)-3methyl-hepta-2,4,6-trienoate (I)
Pentane-washed NaH (4.1 g) was suspended in 70 ml DMSO and a solution of ethyl
(E,E)-6-(diethoxyphosphinyl)-3-methyl-2,4-hexdienolate (24.5 g) dissolved in 70 ml
DMSO added. The reaction was stirred for 30 minutes at ambient temperature and
2-formyl-3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (11.3 g) dissolved in
70 ml DMSO and 35 ml THF added. The mixture was stirred 2 hours and the product
precipitated in ice water acidified with 6M HCl. The mixture was extracted with EtOAc
and purified by flash chromatography on silica gel with hexane/methyl t-butyl ether, 98:2,
and the product isolated as a pale yellow oil.

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ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

4

Step 2
(2E, 4E, 6E)-7-(3-Hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthanen-2-yl)-3methyl-hepta-2,4,6-trienoic acid (II)
The product from Procedure-1 step 1 (8.5 g) was dissolved in 160 ml EtOH and 30 ml
THF, treated with 12.8 g KOH dissolved in 60 ml water and the mixture stirred for
3 hours at 45 C. The mixture was poured into ice water acidified with 1 M HCl,
extracted with EtOAc, and re-crystallized with hexane/EtOAc forming yellow crystals,
mp = 173–174 C.
3. Alkyne-containing aromatic carboxylic acid derivatives were also prepared by the author
illustrated in Eq. 2:

i- Piperidine, tetrakis(triphenylphosphine)palladium,
copper(I) iodide, triphenylphosphine,
ethynyl-trimethylsilane, tetrabutylammonium fluoride

ii- THF, n-butyl lithium, DMF
iii- Sodium hydride, dimethylsulfoxide, ethyl
4-ethoxyphosphinyl-3-methyl-cronate
iv- Potassium hydroxide, ethyl alcohol, THF
4. The preparation of other 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthanen-2-yl-benzoic
acid derivatives is provided (3).

References
1. J. Boutagy, Chem. Rev. 79, 87 (1974)
2. M. Klaus et al, US Patent 5,700,836 (December 23, 1997)
3. H.-H.Wuest et al, US Patent 4,801,733 (January 31,1989)

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ACIDS AND DERIVATIVES

5

Azinyloxy, and Phenoxy-Diaryl-Carboxylic Acid Derivatives, Their
Preparation and Use as Mixed ETA/ETB Endothelin Receptor
Antagonists
W. Amberg et al, US Patent 6,670,367 (December 30, 2003)
Assignee: Abbott GmbH & Co., KG
Utility:
Treatment of Vasoconstrictive Disorders

Patent:

Reaction


i- 2-(3,4-Dimethoxyphenyl)ethanol, CH2 Cl2 , boron trifluoride
etherate
ii- Dioxane, sodium hydroxide
iii- N,N-dimethylformamide, sodium hydride,
4-methoxy-6-methyl-2-methylsulfonylpyrimidine

Experimental
1. Methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate
Methyl 3,3-diphenyl-2,3-epoxypropionate (27.5 mmol) and 2-(3,4-dimethoxy-phenyl)
ethanol (30.2 mmol) were dissolved in 20 ml CH2 Cl2 at ambient temperature and 5 drops
boron trifluoride etherate added. The mixture was stirred for 2 hours, concentrated, and
the residue isolated in 89% yield and used without further purification.
2. 2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid
The product from Step 1 (27.5 mmol) was dissolved in 110 ml dioxane, 55 ml 1 M NaOH
added, and the mixture stirred at 80 C for 2 hours. Water was added to the mixture and
the aqueous phase extracted twice with diethyl ether. The aqueous phase was acidified
with 1 M HCl, extracted with ether, and the combined organics, dried, and concentrated.

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ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

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The residue was recrystallized from diethyl ether/n-hexane and the product isolated in
87% yield, mp = 133–135 C.
3. 2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(2-(3,4-dimethoxyphenyl)-ethoxy)3,3-diphenylpropionic acid
The product from Step 2 (2.3 mmol) was dissolved in 10 ml N,N-dimethylformamide,

NaH (340 mg, 50% suspension) added, stirred 15 minutes, and 4-methoxy-6-methyl2-methylsulfonylpyrimidine (526 mg) added. The reaction stirred 3 hours at ambient
temperature, water was then added, and the mixture extracted with diethyl ether. The
aqueous phase was acidified with 1 M HCl, extracted with diethyl ether, dried, and
concentrated. The residue was purified by liquid chromatography, and the product isolated
in 52% yield. 1 H-NMR and MS data supplied.

Derivatives

R1
Methyl
Methoxy
Methoxy
Methyl

R2
4-Chlorophenyl
4-Ethoxy-3-methoxy-phenyl
3,4-Methylenedioxyphenyl
Methyl

n
2
2
2
3

Melting Point ( C)
150–152
166–169 (dec)
146–148 (dec)

153–155 (dec)

Notes
1. Other 6-methyl-2-methylsulfonylpyrimidine derivatives were prepared by the author in
the current invention starting from 6-dimethyl-1-methylthiopyrimidine and are described.
2. Other derivatives of the Step 1 reagent have been prepared (1) as illustrated in Eq. 1 were
also prepared by the author.

i- Borontrifluoride etherate, methyl alcohol

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