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Title: Mechanistic And Synthetic Investigations On Carboxylic Anhydrides And Their Analogs
Authors: Karri, Phaneendrasai
Advisors: Chandarasekhar, S
Srikrushna, A
Keywords: Amino Acid Synthesis
Carboxylic Anhydrides - Synthesis
Erlenmeyer Reaction
Perkin Reaction
Carboxylic Anhydrides
Erlenmeyer Azlactone Synthesis
Perkin Condensation
Dehydroamino Acids
Aliphatic Aldehydes
2,4,10-Trioxaadamantane
N-carboxyanhydrides (NCAs)
Oligopeptide Synthesis
Submitted Date: Mar-2008
Series/Report no.: G22332
Abstract: This thesis reports diverse synthetic and mechanistic studies in six chapters, as summarized below. Chapter 1. Revised mechanism and improved methodology for the perkin condensation.1 The generally accepted mechanism for the well-known Perkin condensation is unviable for at least two reasons: (1) the normally employed base, acetate ion, is too weak to deprotonate acetic anhydride (Ac2O, the substrate); and (2) even were Ac2O to be derprotonated , its anion would rapidly fragment to ketene and acetate ion at the high temperatures employed for the reaction. It has proved in this study that the Perkin condensation occurs most likely via the initial formation of a fem-diacetate (3, Scheme 1) from benzaldehyde (2) and acetic anhydride (1).1 The key nucleophile appears to be the enolate of 3 (and not of 1), which adds t the C=O group of the aldehyde 2 (present in equilibrium with 3). Thus cinnamic acid (4a) was formed in -75% yield with 3 as the substrate under the normal conditions of the Perkin reaction. The deprotonation of the diacetate appears to be electrophilically assisted by the neighbouring acetate group, the resulting enolate being also thermodynamically stabilized in form of an orthoester (I). The possibility that the diacetate 3 is the actual substrate in the Perkin reaction indicates that the reaction can be effected under far milder conditions, with a base much stronger than acetate ion. This was indeed realized with potassium t-butoxide in dioxane, which converted the gem-diacetates derived from a variety of aromatic aldehydes to the corresponding cinnamic acids (4), rapidly and in good yields at room temperature (Scheme 2). This represents a vast improvement in the synthetic protocol for the classical Perkin reaction, which remains an important carbon-carbon bond forming reaction to this day. Chapter 2. Aromaticity in azlactone anions and its sifnificance for the Erlenmeyer synthesis.2 The classical Erlenmeyer azlactone synthesis of amino acids occur via the formation of an intermediate azlactone, and its subsequent deprotonation by a relatively weak base(acetate ion),. The resulting azlactone anion (cf. II, Scheme 3) functions as a glycine enolate equilvalent, and is considered in situ with an aromatic aldehyde, subsequent dehydration leading to the 4-alkylidene oxazolone(analogously to the Perkin reaction). Interestingly, azlactone anions are possibly aromatic, as they possess 6π electrons in cyclic conjugation; this would explain their facile formation as also the overall success of the Erlenmeyer synthesis. The following studies evidence this possibility. The strategy involved studying the rates of base-catalyzed deprotonation in 2-phenyl-5(4H)-oxazolone (azlactone, 5) and its amide and ketone analogs, 3-methyl-2-phenyl-4(5H)-imidazolone (6), and 3,3-dimethyl-2-phenyl-493H)-pyrrolone (7) respectively.2 Two processes were studied, deuterium exchange and condensation with hexadeuteroacetone (Scheme3): both are presumably mediated by the anions II-IV, so their stabilities would govern the overall rates. These were followed by 1H NMR spectroscopy by monitoroing the disappearance of the resonance of the proton α to the carbonyl group. The order of deprotonation was found to be 6 > 5 > 7. However, the expected order based on pKa values would be ketone > ester > amide, i.e. 7 > 5 > 6. The inverted order observed strongly indicates the incursion of aromaticity, which would be enhanced by the electron-donor capabilities of the heteroatoms is 5 and 6. This is further substantiated by the greater reactivity in the case of the nitrogen analog 6 relative to the oxygen 5, which parallel the electronegativity order. (The aromaticity order would thus be: III > II > IV. The imidazole nucleus is indeed to be considerably more aromatic than the oxazole.) The synthesis of the analogs 6 and 7 was accomplished via an interesting intramolecular aza-Wittig reaction (Schemes 4 & 5) Chapter 3. Umpolung approach to the Erlenmeyer process in the synthesis of dehydro amino acids. These studies are based on the general observation that most of the strategies for the synthesis of α-amino acids introduce the side chain (or part was inverted in an umpolung sense. The key reaction studied was that of 2-phenyl-4-ethoxymethylne-5(4H)-oxazolone (11) with Grignard reagents: this resulted in the opening to yield a protected dehydro amino acid (12), in good to excellent yields (65-87%)(Scheme ^). As the azlactone reactant 11 is the ekectrophilic partner, this may be viewed as a partial umpolung version of the classical Erlenmeyer process. The readily available reactants, simple procedure and mild reaction conditions make this a very attractive method for the synthesis of a variety of α-dehydro amino acids. Chapter 4. The Erlenmeyer azlactone synthesis with aliphatic aldehydes under solvent-free microwave conditions. 3 A serious limitation to the classical Erlenmeyer reaction is that it generally fails in the case of aliphatic aldehydes. This chapter describes a convenient approach to this problem that extends the scope of the Erlenmeyer synthesis, via a novel microwave-induced, solvent-free process. This, it was observed that azlactones (5) react with aliphatic aldehydes (13) upon adsorption on neutral alumina and irradiation with microwaves (< 2 min), forming the corresponding Erlenmeyer products (14) in good yields (62-78%, Scheme 7). (The possible mechanistic basis of the procedure, which is presumably mediated by V , is discussed).3 Chapter 5. 2,4, 10-Trioxaadamantane as a carboxyl protecting group: application to the asymmetric synthesis of α-amino acids (umpolung approach).It is known that the 2,4,10-trioxaadamantane moiety is not only remarkably stable to nucleophilic attack, but can also be easily hydrolyzed to the corresponding carboxylic acid.4 It was of interest to apply this carboxyl protection strategy for designing a synthesis of α-amino acids, essentially by starting with a protected glyoxylic acid. The corresponding aldimine was expected to (nucleophilically) add organometallic reagents at the C=N moiety (cf. Shceme 8), the side chain of the amino acid being thus introduced in umpolung fashion. Also, a chiral aldimine would define an asymmetric synthesis of amino acids. Indeed, the chiral aldimine 17, derived from 2,4,10-troxaadamantane-3-carbaldehyde 15 and [(S)-(-)-1-phenylethylamine] 16, reacted with a variety of Grignard reagents to furnish the corresponding protected α-amino acids (18) in good yields, with moderate diastereometric excess (Scheme 8). Better yields and ‘de’ values were obtained with organolithium reagents. Chapter 6: possible one-pot oligopeptide synthesis with azlactones or amino acid N-carboxyanhydrides (NCAs). This chapter describes a novel approach to oligopeptide synthesis employing azlactones or NCA’s as amino acid equivalents which are simultaneously protected and activated (Scheme 9). Thus, the addition of the 4-substituted 2-benzyloxyazlactone (19) to an N-protected amino acid under basic conditions, was initially explored. The reaction was expected to yield a dipeptide (21) via the rearrangement of the mixed anhydride intermediate (VI) (Scheme 9). The subsequent addition of a different azlactone to the dipeptide (21) would analogously lead to the formation of a tripeptide (22). This may be performed repetitively to define a strategy for C-terminal extension of an oligopeptide chain, noting that no intervening deprotecting and activating steps are necessary. (In toto deprotection may be effected finally via the hydrogenolyis of the bvenzyloxy groups, to obtain 23.) A closely analogous strategy may also be envisaged by employing N.carboxyanhydrides (NCA’S, 24) instead of azlactones, as shown in Scheme 10 (forming dipeptide 26 and tripeptide 27). The main difference n this case is that the carbamic acid moiety of the intermediate mixed anhydride (VII) is expected to undergo decarboxylation to VIII (thus obviating the need for a deprotection step). However, this putative advantage is offset by the instability of NCA’s and their tendency toward polymerization. However, only partial success could be achieved in these attempts, although a variety of conditions were explored. The strategy and the experimental results have been analyzed in detail, as this interesting approach appears to be promising, and worth further study. (For structural formula pl refer the pdf file)
URI: http://hdl.handle.net/2005/1058
Appears in Collections:Organic Chemistry (orgchem)

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