Intermediates in the Ing-Manske reaction

Suggestions in the literature for the structures of the isolated intermediates formed in the Ing-Manske reaction under a variety of conditions are either confirmed or revised. The N-alkylphthalimide reacts with hydrazine at room temperature or under to afford the 2-( N-aminocarbamoyl)- N -alkylbenzamide. At higher temperatures, this cyclises to give the amine salt of phthalohydrazide. The amine can be isolated from either intermediate by acid, or from the salt with base.


Introduction
The Gabriel synthesis of primary amines 1 was greatly simplified when Ing and Manske 2 reported that a preparative method involving treatment of N-a1ky1phthalimides 1 with hydrazine followed by acid afforded the corresponding primary amine 2 as its salt 2.H + and phthalohydrazide (2,3-dihydro-1,4-phthalazinedione) 3. Radenhausen 3 was the first person to report (incidentally) the hydrazinolysis of an N-substituted phthalimide, though he did not identify all the products.Over the years, many experimental procedures have been recorded for different N-alkylphthalimide substrates, with variations in the molar proportions of hydrazine, solvent, reaction temperature and time, and conditions of acid/alkaline work-up.Workers frequently used the method without discussing the reaction details.Intermediates have been postulated, sometimes isolated, and had different structures assigned to them.We shall summarise the significant developments, and outline our own findings.

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The reaction pathway can be imagined as follows.Attack of hydrazine on the phthalimide would give the amidohydrazide 4 which could then ring close to give either phthalohydrazide 3 plus amine 2, N-aminophthalimide 5 plus amine 2, or the phthalazinone 6.This last compound, and also the amidohydrazide 4, could be envisaged as unstable in acid, breaking down to phthalohydrazide 3 plus the amine salt.Three further complications involve the attack of the liberated amine 2 on unreacted phthalimide 1 to afford the diamide 7, the attack of hydrazine on the N-aminophthalimide 5 to afford the dihydrazide 8, and thirdly the acidity of phthalohydrazide 3 so that relatively stable salts 9 are formed of it with the amine.In their original investigation in 1926, Ing and Manske 2 chose (without evidence) a phthalazinone 6 as the intermediate in the reaction, and stated that it was converted to the products, 2.H + and 3 on treatment with acid.Later (1959), Roth 4 in another system also adopted this type of structure, and produced analytical figures to support it, though his argument is weakened as calculations show that he had obtained greater than 100% yield.In 1993, the same type of intermediate was recorded uncritically by Toda et al. 5 They had overlooked the work of Flitsch and Peters 6 who already (1967) had synthesised compounds of the structure 6 by independent means, and shown that they were stable to acid under the conditions that converted the Ing-Manske intermediate to the amine salt.Some years before, both Mosher 7 and Barber and Wragg 8 (1946) as part of a considerable effort to develop new anti-malarials examined a phthalimidopropylaminoquinoline.Reacting it with hydrazine in refluxing ethanol, the latter postulated the intermediates as 4 and the amine salt 9 of phthalohydrazide 3 but did not isolate them.However they did isolate and characterise the corresponding salt derived from N-benzylphthalimide.This has a different molecular formula from an intermediate of type 6, and would show different analytical figures.The role of acid would merely release the phthalohydrazide from its salt.Both sets of authors realised the possibility of alkali workup.Barber and Wragg also found that when they used 0.5 mol of hydrazine to 1 mol of phthalimide, appreciable quantities of the diamide were formed.Even with a 1:1 molar ratio, some diamide was among the products.Gibson and Bradshaw 9 in 1968 in a review of the Gabriel synthesis favoured the amine salt of phthalohydrazide structure for the intermediate.
Petrow and Stephenson 10 earlier (1953) had used the hydrazinolysis reaction (boiling ethanol) to prepare a series of hydroxyamines, and preferred the ring-opened amidohydrazide 4 as the intermediate.They showed that their compound was converted to the primary amine salt and phthalohydrazide on treatment with acid.The same type of structure was favoured by Connors and Ross (1960)  11 (using ethanol as solvent at room temperature).4 and 9 have, of course, the same molecular formula and would provide the same analytical figures.Niyaz Khan 12 in a kinetic study implicates the existence of 4, 5, 8 and 3. Drew and Pearman 13 had found that ring opening and subsequent closure of 4-aminophthalimide 10 using one equivalent of hydrazine gave N,4-diaminophthalimide 11, while with two equivalents of hydrazine, it gave the six-membered aminophthalazinedione 12.Other substituted phthalimides gave the same result (4-chloro, 4,7-dichloro, 4,5,6,7-tetrachloro) while yet others (4-hydroxy, 5amino, and 5,6-dichloro) afforded only the phthalohydrazide under all conditions.It seemed worthwhile to sort out the conflicting results, and to determine the structures of the intermediates.

Results and Discussion
We decided to repeat experiments using the substituted phthalimide 1a reported by Roth, 4 which was very close in structure to those synthesised by Petrow and Stephenson 10 -these carried pchloro-and p-nitro-substituents on the phenyl ring.Using the conditions described by Roth (7.5 equivalents of hydrazine in MeOH, reflux for 40 min) and also those of Petrow and Stephenson (1 equivalent of hydrazine added to refluxing ethanol, followed by cooling), we obtained the same product.This proved to be the amine salt of phthalohydrazide 9a.
In the interests of simplifying the NMR spectra, any further experiments were carried out on N-benzylphthalimide 1b.Again under the conditions specified by Roth 4 and also those described by Petrow and Stephenson 10 , the product was the amine salt 9b.This compound also could be prepared by adding 1 equivalent of benzylamine to phthalohydrazide 3. It is clear that both sets of workers obtained the amine salts 9 as intermediates in their systems, and were incorrect in their assignment of structure to their intermediates.
We also investigated the hydrazinolysis reaction at various temperatures, requiring the use of DMF as solvent.If the reaction is carried out under much milder conditions at -15 o C (1.1 equivalents hydrazine, 14 h), then another type of product was obtained in 76% yield.This proved to be the amidohydrazide 4b, which was characterised by spectral analysis (see below).We also were able to react it with benzaldehyde to afford the corresponding hydrazone 13.
At 20 o C (1.1 eq.hydrazine in DMF for 5 h), the amidohydrazide 4b was the main product, but with 20% starting material.The reaction may not have gone to completion.At 50 o C (same conditions, 5 h), the recovered mixture (80%) was the phthalohydrazide salt 9b, 65%) with some amidohydrazide (30%).While Petrow and Stephenson 10 were evidently wrong, Connors and Ross 11 were almost certainly correct in their assignment of the amidohydrazide structure to their intermediate, and this type of structure can be given confidently to any intermediate isolated in a room temperature experiment.We also confirmed Barber and Wragg's observation that excess hydrazine hydrate was required in order to get a clean reaction and good yields of the amine salt 9b.The use of a 1:1 molar ratio of hydrazine and phthalimide gave rise to mixtures which were difficult to purify.
Treatment of either the amidohydrazide 4b or amine salt 9b with acid gave phthalohydrazide 3 and the amine as its salt 2.H + .In order to confirm that compounds of type 6 were not intermediates, we synthesised 6b using a method employed by Flitsch and Peters. 6Reaction of 2-cyanobenzamide 14 with sodium hydroxide solution for a short period afforded the monoimino analogue 14 of phthalimide, 14 which in turn reacted with benzylamine hydrochloride 6 to give 3-benzyliminoisoindolin-1-one 15.This with hydrazine afforded 6b and 4-aminophthalazin-1-one 6c. 6In another attempt to synthesise 6b from 3, we reacted the latter with phosphorus pentachloride, which gave a mixture of 1,4-dichlorophthalazine 16 and 4-chlorophthalazin-l-one 17. 15 The former compound reacted with benzylamine to afford l-benzylamino-4-chlorophthalazine 18, 6 but we were unable to convert this into 6b.Flitsch and Peters 6 had been successful in a number of related reactions to make compounds of the general formula 6, but did not investigate the benzyl derivative.The monochloro compound 16 failed to react with benzylamine.We also made 4-methoxyphthalazin-1-one 19, 16 in the hope that we could replace the methoxy-group using benzylamine.We were unsuccessful.These results clarify which compounds earlier workers had isolated as intermediates during the hydrazinolysis reaction; this proceeds from 1 to give the amidohydrazide 4 that then cyclises to afford the amine salt 9.It is clear that the phthalazinone 6 is not an intermediate.Furthermore, no N-aminophthalimide 5 was detected, even in the crude reaction mixtures as determined by NMR, though the kinetic scheme 12 implies that it might not be found.Substituted analogues of this compound are implicated in the reactions of the corresponding phthalimides. 13
The principal features of the 1 H-NMR spectra that enable us to distinguish the various compounds are the methylene protons and the aromatic, excluding the phenyl protons.Where there is symmetry, the aromatic protons appear as an AA'BB' signal, and where there is not, as a more complex pattern.In the former category are N-benzylphthalimide 1b and the amine salt 9b, and in the latter, 5b, 15 and 4b.The amine salt 9b is in the former category because of rapid proton exchange between the two hydrogens on the nitrogens (cf.9 and 9').All the methylene signals are singlets but at distinctive positions.Exceptionally that of 4b is a doublet as it couples to the neighbouring NH.The NH signals themselves are also distinctive for the individual compounds.
Similar symmetry considerations also apply to the 13 NMR spectra and provide means of distinguishing between the different classes of compounds.The CO peak of the salt 9b occurs downfield (δ C 155.2) of those of the other compounds as expected from the deshielding effects of the anion.

Experimental Section
General Procedures.Melting points are uncorrected.The hydrazine hydrate solution used in some experiments refers to a 5M solution of 98% hydrazine hydrate in DMF.The 1 H-and 13 C-NMR spectra were measured on a Bruker MSL 300 spectrometer at 300 and 75 MHz respectively.d 6 -DMSO was used as solvent and as internal standard.Chemical shifts are measured in ppm from TMS and coupling constants in Hertz.IR spectra were measured in cm -1 using a Perkin Elmer 883 IR or a Paragon 1000 FT-IR instrument in Nujol mulls.