Synthesis of phthalimides

The first example of Rh(III)-catalyzed oxidative carbonylation of aromatic amides by C-H/N-H activation to synthesize phthalimides, such as 42, was reported by Rovis in 2011 [26a]. The presence of KH2PO is crucial to obtain the products in high yields (Eq. (5.41)). This reaction tolerates a variety of functional groups under standard conditions to afford phthalimides in excellent yields. Similarly, a Rh(III)-catalyzed direct C-H amidation of benzoic acids with isocyanates and subsequent intramolecular cyclization to give Af-substituted phthalimides, such as 43, is also known. This cascade cyclization reaction provided various phthalimides in 26-91% yield [26b]. In this case, NaOAc plays a vital role for the annulation and stimulation of the ortho-C-H bond activation of the benzoic acids (Eq. (5.42)). 

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In a joint paper, Loupy and Gedye [45] reported an investigation of the influence of MW activation on the synthesis of phthalimides by the reaction of phthalic anhydride with several amino compounds (Scheme 4.20) both in the absence of solvent and in the presence of a nonpolar solvent. 

This study was prompted by a report that phthalimidoacetic acid (R = CH2C02H, see also Scheme 4.11, vide supra) could be synthesized by the reaction of phthalic anhydride with glycine in the absence of solvent, which involves the reaction between two solids [56], However, in this study [45], it was established that the synthesis of phthalimides under solvent-free reactions requires at least one liquid reactant in order to occur. This was possible when reacting a liquid amine (e.g. R = CH2Ph) or a solid with a sufficiently low melting point to melt rapidly under MW (e.g. R = (CH2)6OH, m.p. 56-58). In these cases, the reaction temperature was typically over 135 °C after 2 or 3 min of MW heating resulting in dissolution of phthalic anhydride in the molten... 

Where R = PhCH2, -(CH2)6OH, -(CH2)7CH3, -CH2COOH Scheme 9 Synthesis of phthalimides under microwave irradiation [56]... 

Vidal T, Petit A, Loupy A et al (2000) Re-examination of microwave-induced synthesis of phthalimides. Tetrahedron 56 5473-5478... 

The synthesis of phthalimides has also been achieved using the Rh(III)-catalyzed oxidative addition of aromatic amides via C-H/N-H activation. The reaction was carried out using RhCp (MeCN)3(C104)2, KH2PO4 as an additive under 1 atmosphere of carbon monoxide in the presence of an oxidizing agent. Various phthalimides were obtained in up to 94% yield. 

A synthesis of phthalimides via double carbonylative coupling of ortho-diiodo arenes with anilines has also been reported [98]. The conversion of 149 to 150 proceeded in good yield using a Pd/PPh3-based catalyst system (Eq. (1.59)). 

In 2011, Bhanage and co-workers reported a carbon monoxide-free one-step synthesis of phthalimides by using formamides as an amine and CO source. With POCI3 as the activator, various phthalimides were produced in moderate to excellent yields (Scheme 2.2). In addition to 1,2-dihalobenzenes, 2-iodobenzoic acid and methyl 2-iodobenzoate can be applied as substrates for phthalimide preparation with formamides as an amine and CO source as well. This methodology was extended and applied in the synthesis of isobenzofuran-l(3/f)-one (70% yield) by using o-iodoben l alcohol as the substrate. 

At the end of 2013, our group described a palladium-catalyzed carbonylative synthesis of phthalimides from 1,2-dibromoarenes. Molybdenum hexacarbonyl was applied as a CO source here. In this easy and convenient way, various N-substituted phthalimides were produced in a one-pot manner. A wide range of different primary amines as well as a variety of miscellaneous 1,2-dibromobenzenes can be applied as substrates, and the corresponding phthalimides were obtained in moderate to excellent yields (Scheme 2.4). 

Loupy A, Petit A, Hamelin J, Texier-Boullet F, Jacquault P, Math e D (1998) New solvent-free organie synthesis using foeused mierowaves. Synthesis 1213-1234 Loupy A (1999) Solvent-free reaetions. Top Curr Chem 206 153-208 Vidal T, Petit A, Loupy A, Gedye RN (2000) Re-examination of microwave-induced synthesis of phthalimides. Tetrahedron 56 5473-5478... 

Ring Closure Reactions Kedhkar et al. studied the synthesis of phthalimides 41 by double carbonyl-ation of o-dihaloarenes, o-halobenzoates, and o-iodobenzoic acid with CO and amines catalyzed by palladium on carbon (Pd/C) in the presence of DABCO (1,4-diazabicyclo (2.2.2) octane) as base additive (Scheme 27) [116]. The... 

An interesting approach to the synthesis of phthalimides has been reported that starts from aminoquinoline benzamides (Scheme 3.85) [89]. The reaction entailed the carbonylation of the substrate using a cobalt(II) acetylacetonate as the catalyst. The reaction conditions were remarkably mild and could be carried out without exclusion of air. Indeed, air was critical to the success of the reaction, and the oxygen in air was proposed to act as a terminal oxidant for the process. 

In 2014, a cobalt-catalyzed carbonyiative synthesis of phthalimide motifs from benzamides was demonstrated by Daugulis and coworker [8]. Here it uses the 8-aminoquinoline as the Ar,AT-bidentate directing system. Reactions... 

Santos et al. (2006) reported an alternative method for the synthesis of phthalimide derivatives by exploiting the condensation of phthalic anhydride with amino groups under microwave radiation. The results showed that phthalimide derivatives were obtained in shorter reaction times (5-10 min) and higher yields (60-89%) than with conventional heating. 

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... 

Gabriel synthesis (Section 22 8) Method for the synthesis of primary alkylamines in which a key step is the formation of a carbon-nitrogen bond by alkylation of the potassium salt of phthalimide... 

Phthalocyanines. Phthalocyanine is the only novel chromogen of commercial importance discovered siace the nineteenth century. It was discovered accidendy ia 1928, when duriag the routine manufacture of phthalimide from phthaUc anhydride and ammonia it was found that the product contained a blue contaminant. Chemists of Scottish Dyes Ltd, now part of Zeneca, carried out an iadependent synthesis of the blue material by passiag ammonia gas iato molten phthaUc anhydride containing iron filings. The importance of the colorant was realized (it was iatensely colored and very stable), and a patent appHcation was filed ia the same year. 

However, not all nucleophiles show the same bias as shown in Scheme 4 5 on addidon to the nirroalkene The product of the addidon of potassium phthalimide has 5(R) stereochemistry fEq 4 38 This stereoselecdve addidon is applied for the synthesis of other related andbiodcs, such as nikkomycine B ... 

The Gabriel synthesis represents another indirect but highly valuable approach to amines. Trost has demonstrated a method for the asymmetric ring-opening of butadiene monoepoxide by use of one equivalent of phthalimide, 7t-allylpalladium chloride dimer, and the chiral bisphosphine 22 (Scheme 7.37). The dynamic kinetic asymmetric transformation proceeded through a putative achiral intermedi-... 

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. 

Amides are weakly nucleophilic and react only slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.58... 

The most successful approach to producing an aminomethyl derivative was the Gabriel synthesis. A phthalimide substituent can be introduced by Sn2 displacement of the chloride on 17 with potassium phthalimide under homogeneous conditions in DMF. The reaction is quantitative in all D.F. ranges and the phthalimldo-methyl intermediates, 18, are quite soluble in organic solvents. 

Sulfur dichloride is difficult to handle it disproportionates readily, has an unpleasant odor, and tends to introduce extra, unwanted chlorine atoms. Several reagents have been developed, especially by Harpp and co-workers, in which these undesirable features have been modified or eliminated. Succinimide-N-sulfenyl chloride (28) and phthalimide-N-sulfenyl chloride (29) are both stable crystalline compounds which undergo many of the reactions of the sulfur dichloride itself. They can, for example, be used in a facile, high yield synthesis of thiiranes from alkenes.33... 

Phenothiazines are well-known as intermediates for pharmaceuticals, and are also active as insecticides and antioxidants. These compounds are usually prepared by the thiation of diphenylamines with elemental sulfur. In this context, the group of Toma has elaborated a synthesis of 3-phthalimidophenothiazine, as shown in Scheme 6.265 [455]. Using a variety of high-boiling solvents under conventional thermal reflux conditions, low isolated yields of the desired product were obtained. The highest conversion and isolated product yield (55%) was achieved by microwave irradiation of a mixture of the starting N-(4-phenylaminophenyl)phthalimide with... 

Phthalimides undergo a variety of photochemical reactions416). The sequence of a Norrish type II reaction has been utilized in the synthesis of medium ring thiacyclols (4.15)417). 

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