Hydrazine with phthalimides

The 5-(aminomethyl)thiophene-2-acetic acid isomer 76 was prepared by chloromethylation in position 2 of thiophene followed by nucleophilic displacement with phthalimide to afford 81, and a second chloromethylation in position 5 to give 82 (Scheme 23). Subsequent reaction with cyanide gave 83, the hydolysis of which afforded the phthalide-protected amino acid 84 which was coupled to H-Ala-Ile-Gly-OMe using propanephosphoric anhydride, followed by hydrazine N-deprotection)110 ... 

The complex formed between diethyl azodicarboxylate and triphenylphosphine is a very useful reagent for condensation reactions. The reaction of alcohols with phthalimides, in the presence of diethyl azodicarboxylate and triphenylphosphine, resulted in the formation of the corresponding AT-alkylphthalimide in good yield. The reaction proceeds stereospecifically with complete inversion, as shown by conversion of (5 )-(+)-2-octanol to )-2-octylamine, isolated by treatment of the initially formed phthalimide with hydrazine hydrate. Condensation between alcohols and other active-hydrogen compounds using the same reagents has also been described (Scheme 1). Phosphorylation of alcohols by initial activation... 

A second non-selective addition of vinyl Grignard to 661 produces a mixture of alcohols 662 and 665. The hydroxyl center is inverted with phthalimide under Mitsunobu conditions, after which the phthaloyl group is cleaved with hydrazine and the resulting amine acylated to give 664 and 667 (separable by HPLC). Compound 667 is then debenzylated, the acetonide group is hydrolyzed, and the olefin is ozonolyzed to give 668 as a crystalline solid. Likewise, 664 is converted to 669. By a parallel sequence of reactions, 660 is transformed to 670 and 671. Ozonolysis as the last step is a critical feature of these syntheses, because the A-acetyl-hexosamines are generated very cleanly, and such compounds are notoriously difficult to purify. 

Reaction of iodonitrocalix[4]arenes with phthalimide in the presence of Cu(I)20 followed by treatment with hydrazine and cone. HCI provides an easy route into calix[4]arenes carrying both nitro and amino groups at the upper rim. In this way l,2-diiodo-3,4-dinitrocalix[4]arene 2b was converted to the corresponding aminonitro-calix[4]arene 4 in 58% yield. 

Although, in this specific case, attachment of the arms is reversible, activated esters can also be used for covalently bound graft polymer arms. Therefore, amine-capped polymers are required as arms. Lowe and coworkers decided to use amino-PEG, which could be prepared in a two-step reaction [17]. In the first step, commercially available methoxy-PEG was capped with phthalimide subsequent cleavage with hydrazine yielded the amino-PEG (Scheme 11). The resulting primary amine was used to aminolyze the activated PFP-ester of the PFPA main chain to result in linear-g-linear graft-copolymers. 

The independent preparation of potassium phthabmide (from a solution of phthalimide in absolute ethanol and potassium hydroxide in 75 per cent, ethanol) may be avoided in many cases by boiling phthalimide with the halide in the presence of anhydrous potassium carbonate. The N-substituted phthalimide (I) is frequently cleav with difficulty this is often facilitated by reaction with hydrazine hydrate to give an intermediate product, which is easily decomposed by hydrochloric acid to 3deld the insoluble hydrazide of phthaUc acid (II) and the primary amine (III) ... 

Benzylatnine. Warm an alcoholic suspension of 118-5 g. of finely-powdered benzyl phthalimide with 25 g. of 100 per cent, hydrazine hydrate (CAUTION corrosive liquid) a white, gelatinous precipitate is produced rapidly. Decompose the latter (when its formation appears complete) by heating with excess of hydrochloric acid on a steam bath. Collect the phthalyl hydrazide which separates by suction filtration, and wash it with a little water. Concentrate the filtrate by distillation to remove alcohol, cool, filter from the small amount of precipitated phthalyl hydrazide, render alkaline with excess of sodium hydroxide solution, and extract the liberated benzylamine with ether. Dry the ethereal solution with potassium hydroxide pellets, remove the solvent (compare Fig. //, 13, 4) on a water bath and finally distil the residue. Collect the benzylamine at 185-187° the 3ueld is 50 g. 

In a typical experiment, triethylene glycol was treated with two equivalents of sodium toluenesulfonamide in dry DMF solution. After 6 h at reflux, the solution was distilled and product obtained by a standard work-up procedure. By this procedure, 9 was obtained in about 10% yield. The transformation is illustrated below as Eq. (4.10). Note also that Vogtle and his coworkers have also utilized phthalimide as a source of nitrogen in the preparation of such azacrown precursors as H2N(CH2CH2 0)2CH2CH2NH2 In such reactions, a standard hydrazine cleavage was used to remove the phthaloyl residue. 

The reaction of potassium phthalimide 1 with an alkyl halide 2 leads to formation of a N-alkyl phthalimide 3/ which can be cleaved hydrolytically or by reaction with hydrazine (Ing-Manske variant) to yield a primary amine 5. This route owes its importance as a synthetic method to the fact that primary amines are prepared selectively, not contaminated with secondary or tertiary amines. 

Finally the aminoquinoline bearing a primary amine at the terminal carbon atom of the side chain is itself an effective antimalarial drug. Ring opening of 2-methyltetrahydrofuran by bromine gives the dibromide, 99. The primary halide is sufficiently less hindered so that reaction with potassium phthalimide affords exclusively the product of displacement of that halogen (100). Alkylation of the aminoquinoline with lOO affords the secondary amine, 101. Removal of the phthalimide group by means of hydrazine yields primaquine (102). ... 

The polymeric resin used for Merrifield solid-phase peptide synthesis (Section 26.8) is prepared by treating polystyrene with iV-(hydroxymethyl) phthalimide and trifluoromethanesulfonic acid, followed by reaction with hydrazine. Propose a mechanism for both steps. 

Intermediate D-a-6 must now be converted into a form amenable to the crucial lactamization reaction. To this end, treatment of D-a-6 with hydrazine accomplishes the removal of the phthalimide protecting group and provides D-a-18 (Scheme 5) after acidification with dilute aqueous HC1. It is noteworthy that the acid-labile tert-butyl ester function withstands the latter step. Introduction of the... 

BromoaUylamine has been prepared by heating N-(2-bromo-allyl)-phthalimide with hydrazine in methanol 1 by treatment of 2,3-dibromopropylamine hydrochloride with excess alcoholic potassium hydroxide 6 by treatment of 1,2,3-tribromopropane with alcoholic ammonia at 100° and by the present procedure.7... 

M-Aminophthalimide is available from Fluka AG or may be prepared from phthalimide and hydrazine.2 The quality is important the m.p. should be 199-202° with subsequent resolidification of the melt due to thermal reaction. Reerystallization, if necessary, can be carried out in ethanol. The checkers observed that with one batch of recrystallized material, the solid never really did melt, but seemed to sinter at 200°. 

It is obvious that the primary amines formed in this reaction will be uncontaminated by secondary or tertiary amines (unlike 10-44). The reaction is usually rather slow but can be conveniently speeded by the use of a dipolar aprotic solvent such as DMF or with a crown ether. Hydrolysis of the phthalimide, whether acid or base catalyzed (acid catalysis is used far more frequently), is also usually very slow, and better procedures are generally used. A common one is the Ing-Manske procedure,in which the phthalimide is heated with hydrazine in an exchange... 

The modified procedure involves refluxing the N-substituted phthalimide in alcohol with an equivalent quantity of hydrazine hydrate, followed by removal of the alcohol and heating the residue with hydrochloric acid on a steam bath the phthalyl hydtazide produced is filtered off, leaving the amine hydrochloride in solution. The Gabriel synthesis has beai employed in the preparation of a wide variety of amino compounds, including aliphatic amines and amino acids it provides an unequivocal synthesis of a pure primary amine. 

The enhanced acidity of the NH group in phthalimide permits formation of the anion, which is readily alkylated by alkyl halides or tosylates. The amine can then be liberated by reaction of the substituted phthalimide with hydrazine. 

Bromo-l-phthalimidopentane 3 was obtained in 72-82 g yield by refluxing 92 g of 1,4-dibromopentane 1, 55.5 g of potassium phthalimide 2, and 200 mL dry acetone on a steam bath for 30 h. Compound 3 (30 g) and 42 g 6-methoxy-8-aminoquinoline 4 refluxed at 130-135 °C for 6 h, extracted with benzene to separate insoluble 6-methoxy-8-aminoquinoline hydrobromide, the residue from evaporation of the benzene was refluxed with stirring with 100 mL of an alcoholic solution of 6 g hydrazine hydrate for 4 h, the solution was concentrated, made acidic to Congo red with 8 N hydrochloric acid, filtered, and washed with boiling water. The combined filtrate and washings was concentrated, made alkaline, extracted with benzene, and distilled in vacuo to give 20.5 g primaquine 6, which was treated with 19 mL 85% phosphoric acid in absolute ethanol, formed 42.5% primaquine diphosphate. 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an 8, 2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

Simple amides are satisfactory protective groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

Alternatively, lactone 20 could be converted to bromide 23 in the presence of hydro-bromic acid (Scheme 14.4). Subsequent treatment with thionyl chloride generated the doubly functionalized intermediate 24, which was subsequently treated with diethylamine to install the required amide functionality. Nucleophilic attack with potassium phthalimide on the bromide moiety resulted in the generation of intermediate amide 22, at which point this route intersected that already described in Scheme 14.3. Treatment with hydrazine provided milnacipran (2) in 37% overall yield. 

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