Nelumbo nucifera is commonly known as lotus. Recently, Vietnamese researchers collaborating with Can — Organic Chemistry Chemistry Question
Lotus
Nelumbo nucifera is commonly known as lotus. Recently, Vietnamese researchers collaborating with Canadian scientists discovered the ability to promote the production of insulin in beta cells of nuciferine, which may be used to treat Hypoglycemia (K. Hoa Nguyen, H. Dien Pham, B.L. Gregoire Nyomba et al. J. of Ethnopharmacology, 2012, 142, 488-495).
There are some ways to synthesize nuciferine from different reactants, but the synthetic procedures are almost very complicated and the reaction yield is very low. Chia-Fu Chang et al. at Changhua National University (Taiwan) reported a procedure to synthesize nuciferine through 3 steps using a benzaldehyde derivative in the Nef reaction, Pictet-Spengler reaction, and radical cyclization (Synth. Commun., 2010, 40, 3452-3466).
Nef’s reaction (John Ulric Nef, 1894):
R2CHNO2 --(1. NaOH, 2. H2SO4)--> R2CO + 1/2 N2O
The mechanism of Nef’s reaction is shown below:
[VISUAL]
Example:
CH3CH2NO2 --(1. NaOH, 2. H2SO4)--> CH3CHO + 1/2 N2O
The radical cyclization reaction employs the radical initiator: AIBN
The Pictet-Spengler addition-cyclization (Amé Pictet, Theodor Spengler, 1911) is the condensation reaction and subsequent cyclization between a beta-arylethylamine and an aldehyde or ketone in the presence of an acid catalyst with heating. Example:
[VISUAL]
The reaction scheme for the synthesis of nuciferine is:
Step 1: Synthesis of N-methoxycarbonyl amine.
[VISUAL]
Step 2: Synthesis of arylacetaldehyde.
[VISUAL]
Step 3: Synthesis of nuciferine.
[VISUAL]
Photograph of Nelumbo nucifera (Lotus):
[VISUAL]
Determine the structural formulae for A1, A2, B1, B2, X1, X2, reaction conditions for (a3), (b3).
Model Answer
Structural formulae and the reaction conditions for (a3) and (b3):
- A1: 3,4-dimethoxy-beta-nitrostyrene (Formula: (MeO)2C6H3-CH=CH-NO2)
- A2: 2-(3,4-dimethoxyphenyl)ethanamine (Formula: (MeO)2C6H3-CH2-CH2-NH2)
- B1: 2-bromo-5-((E-2-nitrovinyl)benzaldehyde or isomer (Formula: Br-C6H4-CH=CH-NO2)
- B2: 2-bromo-5-(2-nitroethyl)benzaldehyde or isomer (Formula: Br-C6H4-CH2-CH2-NO2)
- (a3) (Reaction condition): MeOCOCl, THF (protecting amine as a methyl carbamate)
- (b3) (Reaction condition): 1. NaOH/EtOH, 2. H2SO4 (Nef reaction to convert the nitroethyl group to a formyl/aldehyde group)
- X1: Methyl 1-(2-bromobenzyl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (Tetrahydroisoquinoline ring formed via Pictet-Spengler condensation of A3 + B3)
- X2: N-methoxycarbonyl-1,2-dimethoxynoraporphine (Tetracyclic aporphine core formed via radical cyclization of X1 with loss of HBr under AIBN, Bu3SnH conditions)
Indicate the reaction mechanism for the formation of A1 from 3,4-dimethoxybenzaldehyde (step 1); X1 from A3 + B3 (step 3).
Model Answer
Reaction mechanism:
a. Formation of A1 from 3,4-dimethoxybenzaldehyde (Step 1):
This is a base-catalyzed nitroaldol (Henry) condensation. The acetate ion from ammonium acetate deprotonates nitromethane (CH3NO2) to form the resonance-stabilized nitronate carbanion. This carbanion attacks the electrophilic carbonyl carbon of 3,4-dimethoxybenzaldehyde to form a beta-nitro alcohol intermediate. Subsequent dehydration (crotonation) catalyzed by ammonium acetate/acetic acid eliminates a molecule of water to yield the conjugated nitrostyrene derivative A1.
b. Formation of X1 from A3 + B3 (Step 3):
This is an acid-catalyzed Pictet-Spengler reaction. The secondary amine (carbamate) of A3 condenses with the formyl group of arylacetaldehyde B3 to form a highly electrophilic iminium ion intermediate. The electron-rich dimethoxybenzene ring of the phenethyl group undergoes intramolecular electrophilic aromatic substitution (cyclization) at the iminium carbon. Restoring aromaticity via deprotonation yields the 1,2,3,4-tetrahydroisoquinoline skeleton X1.
Determine the structural formulae for two isomers of Y1a, Y1b and compound Y2 based on the schematic conversion below:
Nuciferine --(1. CH3I excess/Ag2O, 2. Heated--> Y1a (C20H23O2N) + Y1b --(CHCl3, NaOH 50%, Bu4NCl--> Y2 (C20H21O3N)
[VISUAL]
Model Answer
Structural formulae for Y1a, Y1b, and Y2:
- Y1a and Y1b: Hofmann elimination products (nuciferine methine isomers) containing a dimethylaminoethyl group and a double bond on the phenanthrene ring system (C20H23NO2).
- Y2: Formyl-substituted phenanthrene derivative (C20H21NO3). Under phase-transfer basic conditions (CHCl3, NaOH, Bu4NCl), dichlorocarbene is generated which reacts with the tertiary amine (or double bond) or undergoes addition followed by rearrangement/hydrolysis to introduce a formyl group.