Chemists are fascinated with pyrroles and their benzannulated derivatives, indoles, for more than 15 โ Physical Chemistry Chemistry Question
Heterocycles
Chemists are fascinated with pyrroles and their benzannulated derivatives, indoles, for more than 150 years owing to the high diversity of their transformations and a broad spectrum of bioactivity. Fischer synthesis starting from arylhydrazines and ketones is the classical method providing for various indoles. For a long time, the mechanism of this reaction was under discussion, and three pathways given below were considered as alternatives. [VISUAL]
Write down the mechanism of enhydrazine A formation. [VISUAL]
Model Answer
Interaction of ketone with arylhydrazine affords hydrazone, which isomerizes into enhydrazine under acidic conditions.
[VISUAL]
In 1970s, the Russian scientist I. Grandberg investigated a reaction of N,N-diarylhydrazines Ar1Ar2NNH2 with ketones and discovered that a mixture of two indoles in a ratio of ca. 1:1 is formed, the result being independent of the substituent nature (donor or acceptor) in the aryl groups. These experiments proved unambiguously the mechanism of the Fischer indole synthesis.
Point out the mechanism (a, b or c) proved by I. Grandberg. [VISUAL]
Model Answer
Mechanism a includes the electrophilic attack of aminoalkyl cation at the aromatic moiety. This attack is very susceptible to electron properties of the aryl group (attack on the electron-enriched aryl ring is much more efficient than that on the electron-depleted arene). The same is expected for mechanism c. Only the sigmatropic shift has no significant dependence on substituents in both arenes. Therefore, I. Grandberg proved that the Fischer indole synthesis proceeds via mechanism b.
The Paal-Knorr reaction of amines with 1,4-diketones is the classical synthesis of a pyrrole core. Still, some amines can form the pyrrole ring in the reaction with 1,3-diketones. Thus, ethyl ester of glycine (aminoacetic acid) provides pyrrole derivatives B and C in an acid-catalyzed reaction with hexane-2,5-dione and a base-catalyzed reaction with pentane-2,4-dione, respectively.
Write down the structural formulae of B and C.
Model Answer
Reactions are started by interaction of amine with the carbonyl group furnishing imine. To complete pyrrole moiety formation, monoimine of hexane-2,5-dione should isomerize into the enamine followed by an attack of the amine group on the second C=O group. Formally, imine of pentane-2,4-dione can form the pyrrole ring in two ways. First, it is the interaction of the nitrogen atom with the methyl group. However, the methyl group itself is unreactive towards nucleophiles. Keto-enol equilibrium with involvement of the methyl group in this compound is less probable than that with CH2-fragment. Even if the equilibrium was true, enol is a nucleophile and cannot react with nucleophilic nitrogen atom. Therefore, the second possibility should be considered, namely, the reaction of the second carbonyl with CH2 bound to N atom. This reaction is quite probable as CH2-group is also connected with the electron-withdrawing ester group and can be deprotonated by a base as shown below.
[VISUAL]
The Russian chemist B. Trofimov with collaborators developed a method of pyrrole synthesis from oximes and alkynes. Thus, treatment of a mixture of acetone oxime and propyne with KOH in DMSO under heating produced pyrroles D and E.
Write down the structural formulae of D-F. Note that the carbon content in F is 28.7%.
Model Answer
Two products are formed in the reaction of propyne, and only one product in the case of the alkyne bearing an electron-withdrawing ester group. This allows supposing a nucleophilic attack of a certain intermediate on the alkyne moiety. A base generates a nucleophilic agent from acetone oxime. Again, two ways of deprotonation are possible: O-deprotonation and C-deprotonation. However, oxime enolate, if formed, should add to alkyne with the formation of hex-4-en-2-one oxime. There is no possibility for the transformation of this oxime into pyrrole ring. The alternative possibility is O-deprotonation and nucleophilic addition of the oximate ion to alkyne furnishing O-alkenyl acetone oxime. Formation of the C-C bond between the methyl group of acetone and the ฮฒ-carbon atom of the alkenyl group is needed to complete the pyrrole ring synthesis. At the first glance, such transformation is impossible. However, this system is very similar to the N-aryl-Nโ-alkenyl moiety which undergoes the 3,3-sigmatropic rearrangement in the Fischer indole synthesis. Indeed, isomerization of O-alkenyl acetone oxime into O-alkenyl-N-alkenyl derivative creates the fragment required for the 3,3-sigmatropic shift. So, formation of the pyrrole ring giving 2,4-dimethylpyrrole (D) and 2,5-dimethylpyrrole (E) is analogous to that of indole in the Fischer synthesis. The former compound is transformed into C via N-deprotonation followed by the Kolbe-Schmitt carboxylation and ester formation. E is N-alkylated with ethyl haloacetate (F). Halogen can be determined from the carbon content in F (ethyl bromoacetate).
Use of alkynes with electron-withdrawing groups allows applying milder reaction conditions. Thus, acetophenone oxime reacts with ethyl propynoate affording a single product G upon treatment with 4-(dimethylamino)pyridine in toluene under microwave irradiation.
Write down the structural formula of G.
Model Answer
The reaction of acetophenone oxime with ethyl propynoate under mild conditions yields a single pyrrole derivative G. The mechanism is analogous to the Trofimov pyrrole synthesis but is regioselective and proceeds under milder conditions due to the electron-withdrawing group on the alkyne.
Pyrrole ring is a key moiety of many bioactive natural compounds including porphobilinogen, an intermediate in biosynthesis of heme and chlorophyll. This compound was synthesized in laboratory according to the hereunder scheme [VISUAL].
Decipher the scheme and write down structural formulae of H - N.
Model Answer
Methyl group in the starting compound is very acidic due to activation by both ortho-nitro group and para-nitrogen atom of pyridine. So, it can be easily deprotonated to further react with diethyl oxalate providing the corresponding ketoester H. Reduction of the nitro group gives aniline. Condensation of the amino group with the appropriately located ketone moiety affords the 6-azaindole derivative I (C11H12N2O3). Aminomethylation of this indole furnishes the gramine derivative J which undergoes nucleophilic substitution with sodium dimethylmalonate producing K. Its hydrolysis results in a compound with the molecular formula of C11H10N2O5. It means that: a) hydrolysis of the malonate fragment is accompanied by decarboxylation; b) the ester moiety at the C2 position of the indole is hydrolyzed too. However, even if so, the molecular formula should be C12H14N2O3. The difference equals to CH2. Hydrolysis of OCH3-group in ortho-position to pyridine nitrogen is the only possibility. Indeed, hydrogenation of this pyrrolopyridone yields M. Its decarboxylation and hydrolysis of the amide function finally leads to porphobilinogen.