Cyclizations phthalimides

Condensation of o-aminoacetophenone with maleic, succinic or phthalic anhydrides gave 117 whose bromination with CuBr2 gave the bromides 118. Column chromatographic separation of the respective maleimide derivative on silica gel gave the bromoquinoline 119 whereas the phthalimide derivative was obtained from 118 by cyclization with EtsN (93MI11). On the... 

Chloroalkenes are used as 7i-nucleophiIes in the acid-catalyzcd reaction of phthalimide-derived hydroxylactams. These cyclizations lead to sole formation of the thermodynamically less stable e/ r/(t-l-acetylpyrrolo[2,1-(v isoindole derivatives92. 

Cyclization occurred at the N-3 atom when 4-(3-bromopropylaruino)-l, 6,7,1 1 b-tctrahydro-2//-pyrimido[6,l -zz -isoquinoline was treated with NaH to give a tetracyclic derivative <2003M1271>. 9,10-Dimethoxy-2-(arylimino)-2,3,6,7-tetrahydro-4//-pyrimido[6,l- ]isoquinolin-4-ones were N-3-alkylated with iV-(ra-bromoalkyl)phthalimides in the presence of K2C03 and a catalytic amount of I2 in boiling 2-butanone in 13-67% yields <2000W020/058308>. Treatment of the 2-[(4-methoxyphenyl)methyl] derivative of 2,3,6,7-tctrahydro-l //,5//-pyrido[3,2,l-/ylqninazolinc-... 

The mechanism presumably involves initial oxidative addition of the alkenyl halide to the Cu(I) species and ensuing cyclization analogy for this type of process is provided by the Cu(I)-mediated reaction of phthalimide anions with alkenyl and aryl halides.40 The -isomer of 15 reacts in a different fashion to give an isothiazolidinone derivative, albeit in low yield. 

In a more complex elaboration of the hydrogen atom abstraction/nucleo-philic cyclization route to tetrahydrofurans (Scheme 20), a carbohydrate-based N-alkoxy phthalimide was converted to a spirocyclic acetal in excellent yield and diastereoselectivity (Scheme 33) [136]. In this cyclization, nucleophilic attack takes place from the endo face of the trioxabicyclo [3.3.0] octane... 

These findings did encourage us to examine further the biological properties of the imidazoisoindoles, particularly since their physical properties were also quite different from their phthalimide precursors. The first requirement was an improved procedure for the synthesis of the imidazoisoindoles. A number of reagents, both acidic and basic, were found that would effect cyclization of these phthalimides. One o the most consistent methods utilized sodium hydride in hot toluene or xylene. Some large-scale preparations, e.g. of were successfully run using sodium hydroxide pels in xylene. 

It should be noted that when a substituted phthalimide is converted to the corresponding imidazoisoindole, a mixture results since cyclization can occur on both imide carbonyl groups. 

For the synthesis of isoindoles (benzo[c]pyrroles) by type la cyclization the required intermediate is an o -acylbenzylamine. The only viable route to these substances which has been developed starts with a -bromo-o -toluic acid which is converted first to a phthalimide and then to the acid chloride. The acid chloride is then elaborated to the requisite ketone by Friedel-Crafts acylation. Condensation to the isoindole occurs on liberation of the primary amino group using hydrazine (equation 18) (64JA4152). 

The versatile selenenylating agent N-(phenylseleno)phthalimide (NPSP) is an effective carbocyclization mediator, which is capable of effecting acid catalyzed cyclization reactions from open-chain olefins, including the formation of cyclopropanes1. This is demonstrated by the quantitative cyclization of 3-butenyltrimethyltin to (cyclopropyl-methylseleno)benzene upon treatment with 1.1 equivalents of NPSP in CH2C12 at 25 °C under acid (e.g. p-TsOH) catalysis (equation 47). 

Benzopyrrolizines were obtained from phthalimides by two different photochemical routes. A cyclization of jV-(2-alkenyl)phthalimides (47) with addition of the methanol solvent gave mixtures of benzopyrrolizines (48), whose configuration was carefully investigated. Treatment of 48 with hydrochloric acid in chloroform gave pyrrolizines (49).3 7... 

The formation of dibenzopyrrolizines (51) on irradiation of N-(2-alkylphenyl)phthalimides (50) with a high-pressure mercury lamp was reported. Phthalimides containing electron-donating groups resisted cyclization. Hydroxy compounds 51 were dehydrated to dibenzopyrrolizinones by treatment with acids.38... 

Photoinduced electron transfer from the carboxylate ion to the excited triplet phthalimide (fcT = 293-300 kj mol-1) appears to be followed by a rapid protonation of the radical anion and cyclization via a biradical recombination reaction (Scheme 9.1). Acetone (which also acts as photosensitizer) containing a small amount of water is the solvent of choice, whereas potassium carbonate is the ideal base to enhance cyclization versus simple decarboxylation and ring opening of the phthalimide [4]. 

N-substituted phthalimide functionality and containing a flexible N-terminal spacer or a flexible primary amino acid undergo efficient cyclization, as shown in Scheme 9.3 [5],... 

Moreover, clean and high-yielding photodecarboxylation reactions have also been performed in water. In this context, irradiation of a suspension of a carboxyalkyl-N-substituted phthalimide (50 mmol) in water (21) produces a suspension of the cyclization product which, after partial elimination of the solvent, precipitates and is isolated by filtration in 82% yield (Scheme 9.5) [7]. 

There were relatively few examples reported, in which the chromo-phoric group was an aryl ketone (Ilia) whereas much more PET induced cyclizations with phthalimides (Illb) are known, sometimes other imides, such as succinimides and maleimides were also used. Phthalimides differ from aryl ketones in some respects despite their apparently similar photophysical properties. On one hand, their reduction potential is remarkably lower in comparison with aryl ketones [13]. On the other hand, the radical anion derived from phthalimides is clearly more stable than the corresponding species from aryl ketones [15]. Both facts increase the thermodynamic driving force of a PET and facilitates applications that are unknown from aryl ketones. In this context, one of the most successful approaches is a PET-induced decarboxylation-cyclization route, developed by Griesbeck [13]. The details of this interesting method will be discussed in Sec. 3.4.6. 

As mentioned in Sec. 3.3.1.2.2 PET-promoted cyclization reactions are above all a domain of phthalimides in contrast to aromatic ketones. It is well-known that the PET process of phthalimides occurs via the Si (71,71 ) [28] excited state which has an excitation energy of about 335kJ/mol [29] and, therefore, is unsignificantly higher than the triplet energy of aromatic ketones (e.g., valerophenone = 300-311 kJ/mol, depending on the solvent used)... 

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