Amides intramolecular cyclization, carbonyl

There are two important rhodium-catalyzed transformations that are broadly used in domino processes as the primary step. The first route is the formation of keto carbenoids by treatment of diazo keto compounds with Rh11 salts. This is then followed by the generation of a 1,3-dipole by an intramolecular cyclization of the keto carbenoid onto an oxygen atom of a neighboring keto group and an inter- or intramolecular 1,3-dipolar cycloaddition. A noteworthy point here is that the insertion can also take place onto carbonyl groups of aldehydes, esters, and amides. Moreover, cycloadditions of Rh-carbenes and ring chain isomerizations will also be discussed in this section. 

The proposed reaction pathway invokes initial formation of carbonyl ylide 100 by intramolecular cyclization of the intermediate keto carbenoid onto the oxygen atom of the amide. Subsequent isomerization to the azomethine ylide is followed by 1,3-dipolar cycloaddition to DMAD to furnish the intermediate cycloadduct 101, which undergoes in situ alkoxy 1,3-shift to the final drhydropyrrolizine 102 (Scheme 3.28). 

Oxazolidinones are the products of the acid-catalyzed condensation of a-hydroxyamides with aldehydes and ketones (equation 178). Tertiary amides derived from pyruvic acid undergo intramolecular cyclization when irradiated (equation 179) (78JOC419). Treatment of the a-bromo amide (308) with sodium hydride yields inter alia the dimeric oxazolidinone (309), presumably by way of an a-lactam, which adds to the carbonyl group of a second molecule of the amide (equation 180) (80JCS(P1)2249). 

The Rh(II)-catalyzed reaction of pyridone 96 with DMAD was also found to give cycloadducts derived from an intermediate azomethine ylide. The initial reaction involves generation of the expected carbonyl ylide by intramolecular cyclization of the keto carbenoid onto the oxygen atom of the amide group. A subsequent proton shift generates the thermodynamically more stable azomethine ylide, which is trapped by DMAD. This is an example of subsequent formation of ylides of two types, a phenomenon termed a dipole cascade (93JOC1144). 

Simple amides are satisfactory protecting groups only if the molecule as a whole can resist the vigorous acidic or alkaline conditions required for hydrolytic removal. Phthaloyl groups have been used to protect primary amine centers. The group can be removed hydrolytically or by treatment with hydrazine. The imide carbonyl groups are more reactive than simple amides and the deprotection is completed by an intramolecular cyclization. 

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)). 

While a carboxylate anion is a potent nucleophile in an intramolecular reaction it is not powerful enough to displace methoxide or an unprotonated amine, unless the nucleophile and the carbonyl group are held even more rigidly than in the phthalate system. Kirby and Lancaster (referred to by Kirby and Fersht, 1971) have found that such displacement can occur in disubstituted maleate monoesters and amides. The estimated rate constant for cyclization of N-methyl dime thy Imaleamic acid [equation (41)] is 16,000 times greater than that for the unsubstituted compound. Below pH 5-6 hydrolysis of the cyclic anhydride becomes rate-determining. 

Electrophilic additions to 7t-deficient heterocycles are less common than those to 7t-excessive heterocycles. However, intramolecular electrophilic cyclizations have been used to access the heterocycles of interest in this chapter <1996CHEC-II(7)49>. Recent examples include the preparation of a pyrrolo[2,3-f]pyrazole 165 by acid-catalyzed condensation of 163 and 164 (Equation 37) <1999SC311> and the reaction of 3-(4-pyrazolyl)acrylic acids 166 with excess thionyl chloride in the presence of benzyltriethylammonium chloride (BTEAC) to afford 4-chlorothieno[2,3-f]pyrazole-5-carbonyl chlorides 167 (Equation 38) <2003RJ0893, 2003ZOK942>. In the latter case, the reaction products were readily manipulated to prepare corresponding carboxylic acids, esters, and amides using standard procedures. 

Analogous intramolecular chelation-controlled ketone/olefin couplings with Sml2, in which Sm+3 was complexed in a cyclic manner to the ketyl anion and a /1-carbonyl of an ester or amide functionalilty, were reported as early as 1987 (Scheme 31)86. The cyclized samarium intermediate 49 could be further reacted with added electrophiles such... 

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