Malonic ester amides

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh2(OAe)4-catalyzed reaction with dimethyl diazomalonate 146 but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. 2S4)). From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly 254). Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated earbenoid reactions. Formation of a diazo-malonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to take place instead. 

The substrate scope was extended to A, A -disubstituted 2-diazo-acetoacetamides and malonic ester amides. Here, the chosen acetoacetamides contain a second-... 

N-Phenyl-N-(2-emino5malonic acid ethyl ester amide... 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

The title compounds, which are of pharmaceutical interest, are easily obtained in a one-pot procedure as a result of the formal amidation of malonic ester derivatives with an aniline followed by the cydization of the intermediate malondianilides [102] (Scheme 8.73). 

Substituted malonates and (5-keto-esters have also been successfully used as pronucleophiles (Scheme 9.11) [25a, 36]. From P-ketoesters, approximately 1 1 mixtures of epimers are generally formed. Products derived from 2-alkenylmalo-nates have been subjected to Ru-catalyzed ring-closing metathesis to give cyclo-pentene derivatives in good yield [25a, 36]. With the ester-amide displayed in Scheme 9.11 as pronucleophile, 1 1 mixtures of epimers were also formed [44]. 

With malonic esters and amides substituted at the central carbon, triazole formation is accompanied by decarboxylation and 4-alkyl-or 4-aryl-5-hydroxytriazoles are isolated. ... 

If a C—H bond is acidic enough, it couples with diazonium salts in the presence of a base, most often aqueous sodium acetate.153 The reaction is commonly carried out on compounds of the form Z—CH2—Z, where Z and Z are as defined on p. 464, e.g., P-keto esters, p-keto amides, malonic ester. 

Most C,H-acidic compounds can be condensed with aldehydes or ketones to yield alkenes. Some of these reactions have also been realized on insoluble supports, with either the C,H-acidic (nucleophilic) reactant or the electrophilic reactant linked to the support. Some illustrative examples are listed in Table 5.6. Polystyrene-bound malonic esters or amides, cyanoacetamides, nitroacetic ester [95], and 3-oxo esters undergo Knoevenagel condensation with aromatic or aliphatic aldehydes. Catalytic amounts of piperidine and heating are generally required, although reactive substrates can react at room temperature. 

Esters, amides, and primary alcohols are obtained from benzo[6]-thiophene carboxylic acids by standard procedures.337 481,585 692 093,695 Acid chlorides undergo the Arndt-Eistert reaction,337,568,689 react with diethyl ethoxymagnesium malonate to give the corresponding methyl ketone,144 557 and are reduced to the aldehyde with 1 ithium tri-ferf-butoxy aluminohydride.33 7... 

The tetracyclines (Table 3.3) are a group of broad spectrum, orally active antibiotics produced by species of Streptomyces, and several natural and semi-synthetic members are used clinically. They contain a linear tetracyclic skeleton of polyketide origin in which the starter group is malonamyl-CoA (Figure 3.54), i.e. the coenzyme A ester of malonate semi-amide. Thus, in contrast to most acetate-derived compounds, malonate supplies all carbon atoms of the tetracycline skeleton, the starter group as well as the chain extenders. The main features of the pathway (Figure 3.54) were deduced from extensive studies of mutant strains of Streptomyces aureofaciens with genetic blocks... 

Cyclizations that form a single carbon-carbon bond can be accomplished by oxidative cydization of unsaturated /3-diketones, /3-keto esters, or /3-keto amides 11 that lead to cycloalkanones, unsaturated /3-diketones, /3-keto esters, or malonate esters 12 that lead to cycloalkanes, and unsaturated esters, or amides 13 that lead to lactams or lactones (Scheme 3) [5, 6]. 

Although Newkome et al. reported 127 a series of two-directional arborols, this original process was a 1 — 3 C-branching scheme under more drastic amidation conditions, the triester, especially the methyl ester, readily decomposed to the 1 — 2 C-branched products - the same as those derived from the monoalkylation of malonates. Subsequent treatment of the malonate esters with tris gave rise to the [6]-(X) -[6] arborol series (e.g., 114). 

Malonic ester syntheses are the classical analog of acetoacetic ester syntheses of methyl ketones. Neither case requires the use of an amide base for the enolate formation, and in both cases alkoxides suffice to deprotonate the substrate completely. Malonic esters are active-methylene compounds just like acetoacetic ester and its derivatives. 

A third amino acid synthesis begins with diethyl a-bromomalonate. First the Br is replaced by a protected amino group using the Gabriel synthesis (see Section 10.6). Then the side chain of the amino acid is added by an alkylation reaction that resembles the malonic ester synthesis (see Section 20.4). Hydrolysis of the ester and amide bonds followed by decarboxylation of the diacid produces the amino acid. An example that shows the use of this method to prepare aspartic acid is shown in the following sequence ... 

First all three ester bonds and both amide bonds are hydrolyzed to carboxylic acid groups by the aqueous acid. The mechanisms for these reactions are discussed in Section 19.5. The ester hydrolyses follow the exact reverse of the Fischer esterification mechanism shown in Figure 19.3, and the amide hydrolysis occurs by a very similar mechanism. The product of these hydrolysis steps has three carboxylic acid groups and one amino group. Two of these acid groups are attached to the same carbon so that one can be eliminated as carbon dioxide by the cyclic mechanism described in Section 20.4 for the malonic ester synthesis ... 

To adapt this synthesis to making amino acids, we begin with a malonic ester that contains an a-amino group. The amino group is protected as a non-nucleophilic amide to prevent it from attacking the alkylating agent (RX). 

The Gabriel-malonic ester synthesis begins with (V-phthalimidomalonic ester. Think of (V-phthalimidomalonic ester as a molecule of glycine (aminoacetic acid) with the amino group protected as an amide (a phthalimide in this case) to keep it from acting as a nucleophile. The acid is protected as an ethyl ester, and the a position is further activated by the additional (temporary) ester group of diethyl malonate. 

The 1,3-dicarbonyl compound is a combination of an aldehyde and an amide but is very similar to a malonic ester so we might think of making this compound by alkylation of that stable enolate (Chapter 26) with the convenient benzylic bromide. 

The direct fluorination with elemental fluorine at — 78 "C of trimethylsilyl enol ethers derived from diketones results in the formation of the corresponding monofluoro diketones 11 in moderate yield. The trimethylsilyl ethers from cyclic diketones undergo smooth fluorination to give the enol forms, c.g. 12, and not the keto forms.Higher yields are generally observed for the analogous reactions of silyl derivatives of esters, carboxylic acids, malonates, dimethyl amides and lactones (Table 4). ... 

The conversion of esters to the corresponding amides is usually carried out by shaking with concentrated ammonium hydroxide, as in the preparations of chloroacetamide (67%), ° cyanoacetamide (88%), and nicotinamide (78%). The reaction is catalyzed by water and other hydroxylated solvents. Malonic ester gives a practically quantitative... 

With malonic esters and amides substituted at the central carbon atom, triazole formation is accompanied by decarboxylation and 4-alkyl- or 4-aryl-5-hydroxytriazoles are isolated (69ACS(B)i09i). The 4-methoxybenzyl group has recently been found to be a versatile W-protecting group for the synthesis of AT-substituted 1,2,3-triazoles (82jcs(pi)627). 

---