Orthocarbonates, Esters, and Derivatives

Orthocarbonates, esters, and derivatives Patent:

Spiroorthocarbonates Containing Epoxy Groups C.C. Chappelow etal, US Patent 6,653,486 (November 25, 2003) Assignee: Curators of the University of Missouri Utility: Photopolymerization Agents

Reaction

c

CI

<-'

OH COsMe

<

C02Me

.-^V «—'

C02Me

'

2

ii ^

/-v/ ^—'

iii I OH

Note 1

°o<:X3a» i^.ocxjo i- Lithium hydride, N,N-dimethylformamide ii- Lithium aluminum hydride, THF iii- p-Toluenesulfonic acid, tetraethylorthocarbonate, toluene iv- CH2CI2, m-chloroperbenzoic acid, sodium bicarbonate

438

ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

Experimental 1. Dimethyl 3-cyclopentene-l,l-dicarboxylate Dimethyl malonate (200 mmol) was dissolved in 300 ml DMF, cooled to 0 °C, and lithium hydride (500 mmol) added in one portion. To the cooled mixture was slowly added cis-l,4-dichloro-2-butene (228mmol) and the mixture stirred 72 hours. Thereafter, the mixture was diluted with 500 ml 20% diethyl ether/hexanes then poured into 350 ml cold water. After washing with 300 apiece water and brine, the product was isolated in 50% yield, mp = 63.4°C. ^H-NMR and IR data supplied. 2. l,l-Bis(hydroxymethyl)-3-Cyclopentene Lithium aluminum hydride (175 mmol) was added to 235 ml THF, cooled to 0°C, the product from Step 1 dissolved in 58 ml THF added, and the reaction stirred 4 hours. The reaction was quenched with the sequential addition of 6 ml water, 6 ml 3 M aqueous NaOH, and 17.5 ml water. The resulting cake was washed with 250 ml refluxing THF. The product was isolated in 86.2% yield as white needles, mp = 81.2 °C. ^H-NMR and IR data supplied. 3. 7,9,17,18-Tetraoxatrispiro[4.2.2.4.2.2]nonadeca-2,13-diene To the product from Step 2 (115.5 mmol) dissolved in 370 ml toluene was added p-toluenesulfonic acid (0.2 g) and tetraethylorthocarbonate (57.8 mmol) and the mixture refluxed until 12.5 ml ethyl alcohol was collected in a Dean-Stark apparatus. The mixture refluxed two hours and stirred at 102 °C overnight. The mixture was neutralized with 1 ml TEA, the product purified by flash chromatography on silica with CH2Cl2/hexanes, 2:1, and the product isolated as white crystals in 62% yield, mp = 174.5 °C. ^H-NMR and IR data supplied. 4. 6,24-Dioxatrispiro[bicycle][3.1.0]hexane-3,5'-l,3-dioxane-2'2"-l,3-dioxane-5"3'"bicyclo[3.1.0[hexane] The product from Step 3 (16.27 mmol) was dissolved in 215 ml CH2CI2, 113 ml 0.5 M aqueous NaHC03 added, the mixture stirred vigorously at ambient temperature, and MCPA (35.8 mmol) added over several portions. The reaction stirred overnight and was monitored using TLC on silica gel using CH2Cl2/diethyl ether, 1:1. The two phases were separated, washed twice with 150 ml 1 M NaOH, twice with 100 ml water, and the solvent removed to provide an off white solid. The product was purified by flash chromatography on silica gel using CH2Cl2/diethyl ether, 95:5, and isolated as white crystals in 75% yield, mp = 256.5 °C. ^H-NMR and IR data supplied.

ORTHOCARBONATES, ESTERS, AND DERIVATIVES

439

Derivatives Derivatives

Melting Points CC)

-0 o - ^ p d-^o o -o o

184.7

67.4

O

Y ">

93.2 n—f

-O O-

Notes 1. An alternative method for preparing spiroorthocarbonates entails transesterifying 1,2-acetoxymethyl ethylene with tetraethylortho-carbonate derivatives (1). Similar preparations are discussed (2,3). 2. Photoinitiation conditions and methods using spiroorthocarbonates are described (4). 3. A method for preparing 5,5-diethyl-19-oxadispiro [l,3-dioxane-2,2'-l,3-dioxane -5^4''-bicyclo [4.1 .OJheptane] was also provided by the author as illustrated in Eq.l: HO

Eq.l

HO

Intermediate

oOCoXoVC

IV

-<

440

ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY i- 4-Dimethylaminopyridine, toluene, thiophosphene ii- Dibutyltin oxide, toluene iii- Toluene iv- m-Chloroperbenzoic acid, sodium bicarbonate, CH2CI2

References 1. 2. 3. 4.

M.S. Cohen etal, US Patent 4,891,436 (January 2, 1990) K. Mizutani etal, US Patent 4,849,529 (July 18, 1989) P. Mues etal, US Patent 4,851,550 (July 25, 1989) J.D. Oxman etal, US Patent 5,998,495 (December 7, 1999)

441

ORTHOCARBONATES, ESTERS, AND DERIVATIVES

Patent:

Assignee: Utility:

Substituted Sprioalkylamino and Alkoxy Heterocyclics, Processes for Their Preparation, and Their Use as Pesticides and Fungicides W. Schaper etal, US Patent 5,859,009 (January 12, 1999) Hoechst Schering AgrEvo GmbH Pesticides and Fungicides

Reaction

oOo OH

OH

—'V_o'^N—/

Notes 1,2,3 —^ ^ O ^—'

3C)0°'

01

i- p-Toluenesulfonic acid, toluene ii- Sodium borohydride, ethyl alcohol iii- 4,5-Dichloro-6-ethylpyrimidine, sodium hydride, THF Experimental 1. 3,3-Diethyl-l,5-dioxaspiro[5.5]undecan-9-one Cyclohexane-1,4-dione (0.27 mmol), 2,2-diethylpropane-1,3-diol (0.27 mmol) and p-toluenesulfonic acid (0.36 g) were dissolved in 200 ml toluene and heated on a water bath. After the mixture had cooled to ambient temperature, water was removed, the organic phase was washed with aqueous NaHCOg, dried and the solvent removed. The residue was purified by flash chromatography using EtOAc/petroleum ether, 1:4, and the product isolated in 47% yield. 2. 3,3-Diethyl-l,5-dioxaspiro[5.5]undecan-9-ol To the product from Step 1 (57.4 mmol) dissolved in 200 ml ethyl alcohol was added NaBH4 (21.5 mmol) and the mixture stirred at ambient temperature 1 hour then stirred at 40 °C 15 hours. Thereafter, 5 ml acetone was added and the mixture stirred 30 minutes. The solution was concentrated in vacuo, the product extracted with diethyl ether, washed with aqueous NH4CI, dried, and the product isolated in 90% yield. 3. 5-Chloro-4-(3,3-diethyl-l,5-dioxaspiro[5.5]undec-9-yloxy)-6-ethylpyrimidine The product from Step 2 (8.8 mmol) was added to a suspension of NaH (13.2 mmol) in 20 ml THF and the mixture refluxed 2 hours. The reaction was cooled to 35 °C, 4,5dichloro-6-ethylpyrimidine (8.9 mmol) dissolved in 3 ml THF added, and the reaction

442

ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

refluxed 2 hours. Thereafter, 3 ml isopropyl alcohol were added, the mixture stirred 30 minutes, and then poured into a 1:1 mixture of diethyl ether and aqueous NH4CL The mixture was purified by chromatography with silica gel using petroleum ether/EtOAc, 3:2, and the product isolated in 60.3% yield.

Derivatives

Ri

R2

Methoxymethyl Methoxymethyl Ethyl Ethyl

Methoxide Methoxide Chloro Chloro

Ri

R2

Ethyl Ethyl Methoxymethyl Methoxymethyl

Chloro Chloro Methoxide Methoxide

X 0 NH NH NH

X NH NH NH 0

R3

R4

Ethyl Methyl Methyl Hydrogen

Ethyl Methyl Phenyl Methoxide

Mp (°C) 46^7 112-114 Oil Oil

R3

R4

Mp CC)

Methyl Hydrogen Methyl Hydrogen

Methyl t-Butyl Methyl n-Butyl

62-63 94-95 107-108 Oil

ORTHOCARBONATES, ESTERS, AND DERIVATIVES

443

Notes 1. The author also converted the product from Step 1 into 3,3-diethyl-l,5-dioxaspiro[5.5]undecan-9-amine (I) as illustrated in Eq. 1:

(I) i- Raney nickel, ammonia, methyl alcohol 2. l,4-Dioxaspiro[4.5]dec-8-ylamino and -8-yloxy pyrimidines were also prepared by the author using cyclohexane-l,4-dione ethylene monoketal. 3. Spiroepoxide derivatives of cyclohexane-l,4-dione ethylene monoketal have been prepared (1,2,3) as illustrated below in Eq. 2:

i- 1-Hexylidene triphenylphosphonium chloride ii- m-Chloroperbenzoic acid 4. In a subsequent investigation by the author, other Step 3 products were prepared and are illustrated, (I), (3). OMe MeO^ J^ ^A

K!

J.

'r^^ I i r

A

IJ

References 1. A. Maercker, Organic Reactions, 14, 270 (1965) 2. H.E. Simmons etal. Organic Reactions, 20, 1 (1973) 3. W. Schaper etal, US Patent 6,596,727 (July 22, 2003)

B

NH NH

444

Patent:

Assignee: Utility:

ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

Synthesis of Spiro Orthoesters, Spiro Orthocarbonates, and Intermediates R. Seemayer etaU US Patent 6,613,918 (September 2, 2003) Bioavailability Systems, LLC. Polymer Precursor for Drug Delivery Devices

Reaction OSiMe2t-Bu

0SiMe2t-Bu

Note 1

OEt

111

Note 2

OEt

OEt OEt

i- N,N-Dimethylformamide, t-butyldimethylsilyl chloride, imidazole ii- Triethyloxonium hexafluoroplatiminate, CH2CI2 iii- THF, tetrabutylammonium fluoride Experimental 1. 4-DimethyI-t-butylsiloxy-7H-furo[3,2-g][l]benzopyran-7-one (General method for preparing silyl-protected Bergaptol) Bergaptol (50mmol) was dissolved in 100 ml DMF containing imidazole (73.4 mmol) and t-butyldimethylsilyl chloride (72.8 mmol), stirred at ambient temperature 4 hours, then quenched with 500 ml EtOAc. The organic phase was washed 8 times with 100 ml brine, mixed with n-heptane, concentrated, and a yellow solid isolated. The solid was washed 3 times with 100ml heptane and the product isolated in 82% yield. ^H- and ^^C-NMR data supplied. 2. 4-Dimethyl-t-butylsiloxy-7H-furo[3,2-g][l]benzopyran-7-diethylorthoester (General method for preparing bergaptol orthoesters) The product from Step 1 (10 mmol) was mixed with 20 ml I M (C2H5)30PF6 dissolved in CH2CI2 and stirred 16 hours at ambient temperature. Thereafter the mixture was cooled with ice water, added to sodium ethoxide (2 eq), and stirred for 30 minutes. It was then poured into 300 ml EtOAc/NEtj, 95:5, and the organic phase concentrated to approximately 20 ml. The product was purified by chromatography with alumina using NEtg/EtOAc/heptane, 5:10:85, and isolated as an oil in 70% yield.

ORTHOCARBONATES, ESTERS, AND DERIVATIVES

445

3. 4-Hydroxyl-7H-furo[3,2-g][l]benzopyran-7-diethylorthoester (General de-silylation procedure) The product from Step 2 (1.27 mmol) was dissolved in 6 ml THF, chilled with ice water, and 1.4 ml 1 M BU4NF dissolved in THF added. After stirring 30 minutes at 0°C the mixture was poured into 20 ml EtOAc and then rinsed with 10 ml I M HCl and 20 ml brine. The solvent was removed and the residue purified by chromatography using hexane/EtOAc, 2:1, and the product isolated in 88% yield.

Notes 1 When bergaptol was orthoesterified in Step 2 using (C2H5)30)BF4 and t-butyldimethylsilyl chloride, product yields varied from 10% to 30%. The author suggests the low yields were the result of attack of the protecting group by trace fluoride or borontetrafluoro anions. 2. The product of Step 2 was converted into spiroorthoesters by the author as illustrated in Eq. 1:

0SiMe2-t-Bu

0^0. Eq.l

OH OH

OH

0SiMe2-t-Bu Step 2 Product OSiMe2-t-Bu

i- Potassium carbonate, THF ii- Pyridine tosylate, THF 3. The preparation of 7-methoxycoumarin orthoesters- and spiro orthospiroester derivatives is provided (1). 4. Methods for preparing orthoesters using lactones (2) or spiroorthocarbonates (3) with boron trifluoride are discussed.

446

ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY

References 1. J.W. Harris, US Patent 6,248,776 (June 19, 2001), US Patent 6,162,479 (December 19, 2000), and US Patent 6,124,477 (December 30, 1997). 2. K. Alster, US Patent 4,990,631 (February 15, 1991) 3. M.S. Cohen etal, US Patent 4,891,436 (January 2, 1990)