Hydrazine, reaction with phthalimides

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) ... 

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. 

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. 

We have already seen various syntheses of SMA phthalimides, either through nucleophilic animation of a-chlorosilanes (see Sections III.A.l and III.A.2), hydro-silylation of A-vinyl phthalimide (see Section III.B.5.f) or by reaction of SMA with phthalic anhydride (see Section IV.A.2.h). The deprotection and recovery of free SMA has been conducted in the usual way by reaction with hydrazine.81,88,211... 

Phenylethylamine has been made by a number of reactions, many of which are unsuitable for preparative purposes. Only the most important methods, from a preparative point of view, are given here. The present method is adapted from that of Adkins,1 which in turn was based upon those of Mignonac,2 von Braun and coworkers,3 and Mailhe.4 Benzyl cyanide has been converted to the amine by catalytic reduction with palladium on charcoal,5 with palladium on barium sulfate,6 and with Adams catalyst 7 by chemical reduction with sodium and alcohol,8 and with zinc dust and mineral acids.9 Hydrocinnamic acid has been converted to the azide and thence by the Curtius rearrangement to /3-phenyl-ethylamine 10 also the Hofmann degradation of hydrocinnamide has been used successfully.11 /3-Nitrostyrene,12 phenylthioaceta-mide,13 and the benzoyl derivative of mandelonitrile 14 all yield /3-phenylethylamine upon reduction. The amine has also been prepared by cleavage of N- (/3-phenylethyl) -phthalimide 15 with hydrazine by the Delepine synthesis from /3-phenylethyl iodide and hexamethylenetetramine 16 by the hydrolysis of the corre-... 

Alkynyl ketones can be formed from addition of alkynyllithium or Grignard reagents to phthalimides and then the products converted into pyrazoles by reaction with hydrazines. For example, A -alkyl-substituted phthalimides 633 were easily transformed to mono-, di-, or trisubstituted pyrazoles 634 via a one-pot addition/decyclization/cyclocon-densation process (Equation 131) <2002J(P1)207>. A -Alkyl-substituted phthalimides 635 were easily converted into di-, tri-, and tetrasubstituted pyrazoles 636 via a one-pot addition-decyclization-cyclocondensation process (Equation 132) <2003H(60)2499>. 

Amino-V-methylphthalimide was treated with sodium hydride and then reacted with penta(ethylene glycol) ditosylate to afford a crowned phthalimide 3. In this reaction, an a,(0-bichromophoric podand 4 was also obtained. Subsequent reaction of the phthalimide 3 with hydrazine provided the desired crowned isoluminol 1,... 

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). ... 

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... 

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 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. 

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. 

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 ... 

It was reported in 1993 that reaction of Ar-(2-bromoethyl)phthalimide with the dianion of isobutyric acid gave the aroylaziridine 1, and that treatment of 1 with hydrazine in ethanol at 60°C gave the phthalazin-1 (2//)-one 2. Tentative mechanisms were suggested for the formation of 1 and 2. It was subsequently rapidly established, however, that while the condensation of the phthalimide with the dianion was fully reproducible (almost quantitative crude yield), the structure of the product was not 1 as claimed. It was shown that the correct structure for the... 

Potassium phthalimide is a "NH2-synthon which allows the preparation of primary amines by reaction with alkyl halides. After alkylation, the phthalimid is not nucleophile and does not react anymore. Product is cleaved by reaction with base or hydrazine, which leads to a stable cyclic product. 

The enantioselective complexation technique can also be applied as one step in the reaction sequence, providing chiral substrates for the next step. We will now discuss the example of Gabriel synthesis between potassium phthalimide 41 and alkyl bromide 42, which leads to optically active amines (Scheme 1) [51], Instead of the complicated preparation of chiral alkyl bromides (halides), imides (43), which are reaction intermediates, have been resolved. Upon treatment with hydrazine and KOH, these gave optically active amines. The chiral host (S,S)-(-)-6 or the chiral biaryl host (,S>(-j-40 was used for the effective resolution of the intermediates 43. Racemic mixtures 43a-d were resolved by complex formation with the host (S,S)-(-)-6 in a mixture of diethyl ether and light petroleum. 

For example (+)-43a was obtained after two purifications at 55 % ee and 10 % yield. Treatment of (+)-43a with hydrazine and KOH gave (+)-45a at 55 % ee and 40 % yield. The chiral host (S)-(—)-40 has been found to be extremely effective as a chiral selector towards comparatively bulky molecules of the phthalimide formed from of l- < r -butyl-3-chloro-azetidin-2-one, 47. A crystalline inclusion complex of 1 1 stoichiometry was formed between one mole of (S)-(—)-40 and two moles of rac-47 dissolved in benzene/hexane 1 1 solution. After one recrystallization, the complex was chromatographed on silica gel, and the crystalline product was treated with hydrazine. Optically pure (—)-3-amino-l-ieri-butyl-azetidin-2-one (—)-47, was obtained at 100% ee and 44% yield [51]. Primary diamines, like 1,3-dibromobutane (49), can undergo a similar reaction with potassium phthalimide, yielding diphthalimide, 50. The complexation process between rac-diphthalimide 50 and host (S,S)-(—)-6 gave a 1 1 complex containing (—)-50... 

The Gabriel synthesis is a classical but useful preparative method for primary amines. Reaction of an alkyl bromide (24) with potassium phthalimide (25) gives the corresponding A -alkylphthalinude (26), which upon treatment with hydrazine followed by KOH affords the primary amine (27). When a chiral alkyl halide is used in the Gabriel synthesis, a chiral primary amine is obtained. However, preparation of optically active alkyl halides is not easy. If optical resolution of 26 which has a chiral alkyl group can be done, a new preparative method for optically active amines can be established by a combination of the resolution with the Gabriel synthetic method. Some examples of the combination method are described. 

Reaction of rac-1 -tert-buty l-3-chloroazetidin-2-one (28) with 25 gave the rac-phthalimide derivative (29). Optical resolution of rac-29 was accomplished efficiently by complexation with 15. When a solution of 15b and two molar equivalents of rac-29 in benzene-hexane (1 1) was kept at room temperature for 12 h, a crystalline 1 1 inclusion complex of 15b and (-)-29 was obtained. After one recrystallization from benzene-hexane, the crystals were chromatographed on silica gel to give pure complex consisting of (-)-29 of 100% ee in 63% yield. Decomposition of the complex with hydrazine gave optically pine (-)-3-amino- l-/m-butylazetidin-2-onc (30) in 44% yield.15 Mechanism of the precise chiral recognition between 15b and (-)-29 in their 1 1 complex was clarified by X-ray crystal structural analysis.15... 

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