Imides from alcohols

Imides (e.g. phthalimide) can be purified by conversion to their potassium salts by reaction in ethanol with ethanolic potassium hydroxide. Hie imides are regenerated when the salts are hydrolysed with dilute acid. Like amides, imides readily crystallise from alcohols and, in some cases (e.g. quinolinic imide), from glacial acetic acid. 

In a complementary approach, Larry Overman of the University of California at Irvine, has developed (J. Org. Chem. 2004,69,8101) a Co catalyst that effects the rearrangement of allylic imidates such as 9 with high . There is no need for the starting allylic alcohols to be perfectly trans, as imidates from cis allylic alcohols do not participate in the rearrangement. 

N-Alkyl amides or imides can also be prepared starting from alcohols by treatment of the latter with equimolar amounts of the amide or imide, Ph3P, and diethyl azodicarboxylate (EtOOCN=NCOOEt) at room temperature (the Mitsunobu reaction, see p. 396).925... 

Another approach to the preparation of iV-alkyl derivatives 26 is the Mitsunobu reaction. The Mitsunobu procedure is now a well-known method for preparing amines from alcohols using acidic imide derivatives as a nitrogen nucleophile < 198IS 1, 19960PP127>. The remarkably high acidity of l,2,4-dithiazolidine-3,5-dione 12 (pA), 2.8) <2000SL1622>... 

It has been found that the results of this new variant of the Mitsunobu procedure are generally comparable with the results of the traditional Mitsunobu reaction both with respect to the yields and enantiomeric excess (ee) of chiral compounds 26. Thus, products prepared from alcohol 86e using both methods had ee 70% and 72%, and from (Tl-methyl lactate 86i 92% and 99%, respectively. However the new variant of the Mitsunobu procedure has a significant synthetic advantage over the traditional procedure imides 26 can be transformed into primary amines under milder conditions in comparison with the deprotection of /V-alkylphthalimides (see Section 6.03.6.1.3). 

Perchloric acid supported on silica is a useful catalyst for carbamoylation of alcohols and phenols under solvent-free conditions (ROH + NaOCN)/ and sulfuric acid on silica catalyzes formation of imides from nitriles and acid anhydrides. ... 

Spiro[5.5]undecan-3-one (33.2 g, 0.2 mol) and 47.5 g ethyl cyanoacetate (0.42 mol) were placed in a 500-mL thick-walled flask. The mixture was cooled to 0°C, and 100 mL ethanol saturated with anhydrous ammonia at 0°C was added. A stopper was wedged and the mixture was stored at 0-5°C for 1 week. The precipitated ammonium salt of the Guareschi imide was filtered, dissolved in boiling water. Altered, and acidified with HCI. The Guareschi imide was filtered, washed with water, and dried. It melted at 230-233°C and 232-233°C after recrystaUization from alcohol-water. l,5-Dicyano-3-azadispiro[5.2.5.2] hexadecane-2,4-dione (24 g) was obtained, in a yield of 40%. 

Lithium [749,750,760-762] and sodium [750,760] organic compounds, lithium alcoholates [752,757,760-762], sodiomalonic diesters [755], complex bases from alkali imides and alcohols or alcoholates [756], phosphines [758,759], and others [751,753,754] have been used as initiators. It was found that with THF as solvent and fluorenyllithium or phenyllithium as initiator, molar mass is independent of initiator and monomer concentration. Relatively low masses of 2600 to 4200 were found. With DMF as solvent, the molecular mass increases with the monomer concentration at low (1.5mmol/L) initiator levels. With cyclopentadienyllithium or cyclopentadienyl sodium at high concentrations (68 mmol/L) and DMF as solvent, the molecular mass increases strongly with the monomer concentration. This is explained on the basis of a polyfunctionality of cyclopentadienyllithium and cyclopentadienyl sodium initiators. This view is supported by ozonolysis of the incorporated initiator, which leads to a decrease in the molar masses only of those polymers that were initiated by cyclopentadienyllithium or cyclopentadienyl sodium [750]. 

Further investigations of oxidations by dimethyl sulphoxide activated by oxalyl chloride have shown the system to be of general use, although allenic and acetylenic alcohols are not oxidized. The same reagent activated by dicyclo-hexylcarbodi-imide has been reported to yield ketones from alcohols in the presence of dithianes/°... 

The addition of dry HCl to a mixture of a nitrile and an alcohol in the absence of water leads to the hydrochloride salt of an imino ester (imino esters are also called imidates and imino ethers). This reaction is called the Pinner synthesisThe salt can be converted to the free imino ester by treatment with a weak base such as sodium bicarbonate, or it can be hydrolyzed with water and an acid catalyst to the corresponding carboxylic ester. If the latter is desired, water may be present from the beginning, in which case aqueous HCl can be used and the need for gaseous HCl is eliminated. Imino esters can also be prepared from nitriles with basic catalysts. ... 

O-Allyl imidate esters undergo [3,3]-sigmatropic rearrangements to /V-allyl amides. Trichloromethyl imidates can be made easily from allylic alcohols by reaction with trichloroacetonitrile. The rearrangement then provides trichloroacetamides of IV-allylamines.260... 

The drug candidate 1 was prepared from chiral cyclopentanol 10 as shown in Scheme 7.3. Reaction of 10 with racemic imidate 17, prepared from the corresponding racemic benzylic alcohol, in the presence of catalytic TfOH furnished a 1 1 mixture of diastereomers 18 and 19 which were only separated from one another by careful and tedious chromatography. Reduction of ester 18 with LiBH4 and subsequent Swern oxidation gave aldehyde 20 in 68% yield. Reductive animation of 20 with (R)-ethyl nipecotate L-tartrate salt 21 and NaBH(OAc)3 and subsequent saponification of the ester moiety yielded drug candidate 1. 

In 1975, van der Baan and Bickelhaupt reported the synthesis of imide 37 from pyridone 34 as an approach to the hetisine alkaloids, using an intramolecular alkylation as the key step (Scheme 1.3) [23]. Beginning with pyridone 34, alkylation with sodium hydride/allyl bromide followed by a thermal [3,3] Claisen rearrangement gave alkene 35. Next, formation of the bromohydrin with A -bi omosuccinimide and subsequent protection of the resulting alcohol as the tetrahydropyranyl (THP) ether produced bromide 36, which was then cyclized in an intramolecular fashion to give tricylic 37. 

Microwave-induced 1,3-dipolar cycloadditions involving azomethine ylides have been widely reported in the literature. Bazureau showed that imidates derived from a-amino esters 120, as potential azomethine ylides, undergo 1,3-dipolar cyclo-additions with imino-alcohols 121 in the absence of solvent under microwave irradiation. This reaction leads to polyfunctionalized 4-yliden-2-imidazolin-5-ones 122 (Scheme 9.36) [87]. 

A series of imidate esters derived from secondary alcohols has been found to react with potassium benzoate or potassium phthalimide to give products of 5 n2 substitution in excellent yields and with clean inversion of stereochemistry. ... 

The method described for the preparation of 4-methoxycarbonyl-2-methyl-1,3-oxazole is that of Cornforth, and is widely applicable to the synthesis of 2-substituted 1,3-oxazole-4-carboxylates. The appropriate imidate hydrochloride required for step A is obtained from the reaction of a nitrile with an alcohol in the presence of hydrochloric add (eq. 1 ). A different synthesis of 2-substituted 1,3-oxazole-4-carboxylates employing rhodium-catalyzed heterocycloaddition of a diazomalonate to a nitrile has been described in Organic Syntheses by Helquist, but appears to be less general than the present route. 

BKC115>. Amides derived from aromatic carboxylic acids and benzotriazole were reported to form 2-aryl-5,6-dihydro-4//-l,3-oxazines with 3-aminopropanol in excellent yields when subjected to microwave irradiation in the presence of SOCI2 <2004JOC811 >. Imidates have often been applied to cyclize 1,3-amino alcohols directly to 5,6-dihydro-l,3-oxazine derivatives <1996ACS922, 2004JHC69, 2004JHC367>. 

OXAZOLINES FROM NITRILES AND AMINO ALCOHOLS, 385-386 OXAZOLINES FROM IMIDATES AND AMINO ALCOHOLS, 388-389 CONVERSION OF ALLYLIC ALCOHOLS TO P-AMINO ALCOHOLS VIA OXAZO-... 

Fmoc-Dhc(Plm)2-OH (200mg, 0.48mmol) was activated in CH2CI2/DMF (1 1 5mL) with /V-hydroxy-norborn-5-ene-2,3-dicarboxy imide (86 mg, 0.48 mmol) and DIPEA (74 pL, 0.48 mmol) at 0°C. After 5min, the mixture was added to H-Ser(tBu)-[Lys(Boc)]4- linked to 4-benzyloxybenzyl alcohol-resin (0.5 g 0.48 mmol g-1). After shaking for 2 h, the solvent was removed by filtration, and the resin washed with CH2C12 and DMF. The Fmoc-protected peptide-resin was treated with a mixture of TEA (5 mL) and thioanisole (0.5 mL) for 1 h. The resin was filtered off and the filtrate was concentrated to dryness. The Fmoc-protected hexapeptide was recrystallized (acetone) at — 20 °C. By lyophilization from tBuOH, a powder was obtained yield 80 mg (87%). 

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