Phthalimide hydrazinolysis

Alkylation of phthalimide The Gabriel synthesis (Section 22 8) The potassium salt of phthalimide reacts with alkyl hal ides to give N alkylphthalimide deriva fives Hydrolysis or hydrazinolysis of this derivative yields a primary alkylamine... 

Pi peridinobenzimidazole also serves as starting material for the antipsychotic agent halopemide (69). In the absence of a specific reference, one may speculate that the first step involves alkylation with bromochloro-ethane to give halide The chlorine may then be converted to the primary amine by any of several methods such as reaction with phthalimide anion followed by hydrazinolysis. Acylation with j -fluorobenzoyl chloride then gives the desired product. 

Other classical synthetic approaches to 2-furanamine have failed, including the Curtius method and Beckmann rearrangement of 2-benzoylfuran oxime. However, hydrazinolysis of AT-(2-furyl)phthalimide, obtained from phthalimide and 2,5-dimethoxy-2,5-dihy-drofuran, gives 2-furanamine which was not isolated but detected by GLC-MS and H NMR spectroscopy. The latter reveals the absence of imino tautomers (75AP713). The chemistry of 2-dialkylamino-5-phenylfurans is typical of enamines protonation occurs on carbon to produce iminium salts. They are stable to base but afford 5-phenylfuran-2(3//)-one on hydrolysis with dilute acid. 2-Morpholino-5-phenylfuran couples with diazonium salts and affords Diels-Alder adducts with maleic anhydride and IV-phenylmaleimide (73JCS(P1)2523). 

Phthalimide protection is stable towards acids and bases, but can be cleaved with strong nucleophiles, such as hydrazines or sulfides, or by reduction with sodium boro-hydride [230]. More sensitive towards nucleophilic attack than unsubstituted phthalimide is tetrachlorophthalimide [33]. This group has been successfully used as N(a) protection of amino acids in the solid-phase synthesis of peptides (deprotection N2H4/DMF (15 85), 40 °C, 1 h coupling DIC/HOAt/amino acid (1 1 1), 3 equiv. of each, DMF, 25 °C, 4 h [294]). Typical conditions for the removal of phthaloyl protection on cross-linked polystyrene include treatment of the resin with hydrazine hydrate [295,296], with methyl hydrazine [297], or with primary aliphatic amines [298] in DMF, EtOH, or solvent mixtures for several hours at room temperature or above [296,299,300]. Illustrative examples are sketched in Figure 10.15. It has been claimed that the hydrazinolysis of polystyrene-bound phthalimides proceeds more readily in DCM or DCE than in DMF [301]. 

Bromination (Br2) of 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one affords either a 2-bromo or a 5-bromo derivative, depending on whether the reaction is carried out at 0° in ether,445,446 or at—5 to 0°in 50% aqueous acetic acid.354 The 5-bromo derivative condenses with morpholine or potassium phthalimide to give 140a or 140b, respectively.445, 446 Hydrazinolysis of 140b fails to give any of the 5-amino derivative.445,446 On nitration, the 2-bromo derivative affords the 3-nitro compound or 141 (R = N02), depending on the reaction conditions.354 With sodium azide in PPA the 2-bromo and 2-bromo-3-... 

Derivatives to Amines (Deprotection of SMA) a. Hydrazinolysis of SMA Phthalimides and Formamidines... 

A very interesting variant of the polymer-supported Mitsunobu reaction was recently disclosed by Gelb and Aronov (Scheme 14) [40]. Polymer-bound phthalimide 34 was designed which is able to trap alcohols such as nucleosides under Mitsunobu conditions. After purification by washing the loaded resin the corresponding amine was subsequently released into solution in high yield by hydrazinolysis. 

As a matter of course, polyvinyl-amine cannot be prepared from the corresponding monomer. Therefore, this polymer must be prepared from suitable polymeric precursors. The first way involves the hydrazinolysis of poly(N-vinyl-phthalimide)1. ... 

Cross-linked poly(vinyl-amine) was obtained by hydrazinolysis of a cross-linked poly(N-vinylphthalimide), in turn obtained by radical copolymerization of N-vinyl-phthalimide and divinylbenzene 6). 

Deprotection of phthalimidesJ Phthalimides arc useful for complete protection of primary amino groups, including amino acids, oven though hydrazinolysis is usually necessary for deprotection, A mild, two-step but one-flask cleavage involves reduction with NaBHi in aqueous 2-propanol followed by eyclization to a lactone with release of the amine (equation 1). Yields are generally 80-97%. Racemization docs not occur in deprotection of amino acids (four examples). 

Haloalkyl-l-silacycloalkanes were also used in the synthesis of fungicidal triazolopyrimidines (06WOP2006066873). Thus, 113 on treatment with potassium phthalimide in DMF, followed by hydrazinolysis afforded amines 114. Their reaction with 7-halotriazolo[l,5-fl]pyrimidines gave 115 (Scheme 22). 

For the replacement of boron by an amino groiqi in aryl-, styryl- and ferrocenyl-dihydroxyboranes, the reaction of copper(II) phthalimide followed by hydrazinolysis or hydrolysis, has been used (equation 64). - ... 

Although alkylation of phthalimide can now be performed under mild conditions as described in the preceding section, the final deprotection step still requires somewhat drastic conditions, e.g. the use of strong acid or base, or, alternatively, hydrazinolysis, at elevated temperature, due to the inherent stability of the phthaloyl group. This has prompted investigation of a number of alternatives to phthalimide which afford iV-alkyl derivatives amenable to milder deprotection. 

The first step of the Gabriel synthesis, the alkylation of potassium phthalimide with alkyl halides, proceeds via an Sn2 reaction. The second step, the hydrazinolysis of the A/-alkylphthalimide, proceeds by a nucleophilic addition of hydrazine across one of the carbonyl groups of the phthalimide. Subsequently, the following steps occur ringopening then proton-transfer followed by an intramolecular SnAc reaction, another proton-transfer and finally, the breakdown of the tetrahedral intermediate to give the desired primary amine and the side product phthalyl hydrazide. 

Aminoethyl ether groups were obtained by using azide as a nucleophile and subsequent reduction. Longer aminoalkyl ethers were prepared by O-alkylation with )-bromonitriles or A-((w-bromoalkyl)phthalimides followed by reduction or hydrazinolysis, respectively. 

Copper-mediated coupling reactions of / -iodocalixarenes with phthalimide followed by hydrazinolysis should be mentioned as an alternative and independent strategy to obtain p-aminocalixarenes . The carbazole-substituted derivatives 50 (Figure 8) were obtained similarly by Ulhnan coupling . CMPO derivatives (51c), urea compounds (51b), available also via the isocyanates (51a), may be mentioned additionally. Mono- (52) and diimides with acidic functions pointing towards the cavity, and the calix[6]arene-based acetylcholine esterase mimic (53) are more sophisticated examples. 

Scheme 12.8 Synthesis of ferrocene amino acid according to Heinze (i) f-BuLi, -70°C (ii) quenching with iodine (iii) reaction in pyridine with phthalimide and Cu20 as catalyst (iv) hydrazinolysis in ethanol (v) A-acetylation with Ac20 (vi) selective Friedel-Crafts acylation with 2,6-dichlorobenzoyl chloride at the unsubstituted Cp ring (vii) base hydrolysis (viii) removal of the acetyl protection group with hydrochloric acid.

The preparation of a phthalimide-containing resin to be used under Mitsunobu conditions means that primary amines can be generated cleanly after cleavage by hydrazinolysis.30 With this goal in mind, the resin linker 57 was obtained in > 90% yield via the synthesis outlined below. An example of the resin in use is shown with M-benzyladenosine 58, where the less hindered hydroxyl group was successfully converted to the amine 59 in 85%. 

Arguably one of the most valuable exploitations of an amination reaction is in the formation of amino acids. Wu and Zhang have employed chiral reverse micelles as asymmetric microenvironments for enantioselective synthesis of 2-phthalimides-esters 72.33 Hydrazinolysis and hydrolysis of the esters then lead to a-amino acids. It was found that asymmetric induction varied according to the reaction temperature, the alkyl chain of the surfactants, and the structure of the surfactants. 

HMR-3647 (telithromycin TLM) (91i), one of the 11,12-cyclic carbamate ketolides bearing various heterocyclic butyl substituents at 11-Ai of carbamate (91), was synthesized from 10,ll-anhydro-12-O-imidazolyl carbonyl ketolide (90) by the reaction with the corresponding amine (Scheme 8) [125]. The synthesis of the heterocyclicbutylamines (Scheme 8, a-i) was achieved by alkylation of the respective heterocyclic amine with 4-bromobutylphthalimide in the presence of NaH or K2CO3 in DMF, followed by hydrazinolysis of phthalimide intermediates. The overall yields of these steps were 24-64%. 

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