Synthesis of indole MCQs With Answer

Mastering the Synthesis of Indole MCQs With Answer is essential for B. Pharm students focused on heterocyclic chemistry and drug discovery. This clear, exam-oriented introduction emphasizes major indole synthesis routes—Fischer indole synthesis, Bartoli, Leimgruber–Batcho, Hemetsberger and other modern methods—along with mechanisms, reagents, regioselectivity, and functional-group compatibility. Practical insights on catalysts, reaction conditions, protecting groups, and troubleshooting will help you predict products and design synthetic routes to pharmaceutically relevant indole derivatives. These Student-friendly, targeted MCQs reinforce understanding of named reactions, intermediates, and retrosynthetic strategies for better performance in exams and synthetic planning. Now let’s test your knowledge with 50 MCQs on this topic.

Q1. In the Fischer indole synthesis the initial condensation involves phenylhydrazine reacting primarily with which functional group?

• Carbonyl compound (aldehyde or ketone)
• Carboxylic acid
• Ether
• Nitrile

Correct Answer: Carbonyl compound (aldehyde or ketone)

Q2. The key rearrangement step in the Fischer indole synthesis is known as the:

• Beckmann rearrangement
• Fischer indole rearrangement
• Claisen rearrangement
• Fries rearrangement

Correct Answer: Fischer indole rearrangement

Q3. Which catalyst type is commonly used to promote the Fischer indole synthesis?

• Strong acid (e.g., HCl, H2SO4, PPA)
• Strong base (e.g., NaOH)
• Transition metal catalyst (e.g., Pd/C)
• Radical initiator (e.g., AIBN)

Correct Answer: Strong acid (e.g., HCl, H2SO4, PPA)

Q4. In indole electrophilic substitution, which ring position is generally the most nucleophilic and favored for substitution?

• C2 position
• C3 position
• N1 position
• C5 position

Correct Answer: C3 position

Q5. The Bartoli indole synthesis converts nitroarenes into indoles using which reagent class?

• Vinyl Grignard reagents
• Organolithium halides
• Hydrazine derivatives
• Diazonium salts

Correct Answer: Vinyl Grignard reagents

Q6. One advantage of the Bartoli reaction is:

• High tolerance for sensitive functional groups without optimization
• Direct construction of highly substituted indoles from nitroarenes
• No requirement for anhydrous conditions
• Works well at high temperatures only

Correct Answer: Direct construction of highly substituted indoles from nitroarenes

Q7. The Leimgruber–Batcho indole synthesis typically uses which o-substituted starting material?

• o-Aminophenol
• o-Nitrotoluene (o-nitroaryl methyl derivatives)
• o-Bromobenzaldehyde
• o-Formylbenzoic acid

Correct Answer: o-Nitrotoluene (o-nitroaryl methyl derivatives)

Q8. In Leimgruber–Batcho protocol, DMF-DMA (N,N-dimethylformamide dimethyl acetal) is often used to:

• Form an enamine intermediate from o-nitrotoluene
• Oxidize the aromatic ring
• Act as a radical initiator
• Protect the indole nitrogen as a carbamate

Correct Answer: Form an enamine intermediate from o-nitrotoluene

Q9. Hemetsberger–Knittel indole synthesis involves which key type of intermediate or process?

• Azido cinnamate thermolysis
• Fischer hydrazone rearrangement
• Organocuprate coupling
• Electrophilic nitration followed by reduction

Correct Answer: Azido cinnamate thermolysis

Q10. For regioselective C3 formylation of indole, which reagent set is commonly used (Vilsmeier–Haack)?

• DMF and POCl3
• KMnO4 and H2O
• BH3•THF
• NaBH4

Correct Answer: DMF and POCl3

Q11. Which protecting group is commonly used on the indole nitrogen to direct electrophilic substitution selectively on the ring?

• Tosyl (Ts)
• Methyl (Me)
• Benzyl (Bn)
• Nitro (NO2)

Correct Answer: Tosyl (Ts)

Q12. The indole nitrogen lone pair participates in aromaticity, making the nitrogen:

• Highly basic and nucleophilic
• Less basic and not strongly nucleophilic at N
• Capable of forming stable ammonium salts under mild conditions
• Unreactive in all electrophilic processes

Correct Answer: Less basic and not strongly nucleophilic at N

Q13. In retrosynthetic planning, a common disconnection to access indole C3 substituents is to consider:

• Cleavage of the N–C2 bond only
• Disconnection at the C3–C substituent via electrophile introduction
• Removal of the whole benzene ring
• Formation of an N-oxide intermediate

Correct Answer: Disconnection at the C3–C substituent via electrophile introduction

Q14. Which reagent is typically used for N-protection as a Boc group on indole nitrogen?

• Boc2O (di-tert-butyl dicarbonate) with base
• Tosyl chloride with pyridine
• MeI with NaH
• HBr in acetic acid

Correct Answer: Boc2O (di-tert-butyl dicarbonate) with base

Q15. The indole skeleton is present in which essential amino acid and many natural products?

• Tyrosine
• Tryptophan
• Phenylalanine
• Histidine

Correct Answer: Tryptophan

Q16. Which method is well-suited to synthesize 2-substituted indoles via metal-catalyzed annulation of ortho-alkynylanilines?

• Palladium-catalyzed Larock indole synthesis
• Fischer indole synthesis
• Bartoli reaction
• Grignard addition to nitrobenzene

Correct Answer: Palladium-catalyzed Larock indole synthesis

Q17. The Larock indole synthesis typically requires which of the following components?

• o-Alkynylaniline and Pd(0) catalyst
• o-Nitrotoluene and vinyl magnesium bromide
• Phenylhydrazine and ketone under acid
• Azido alkene thermolysis

Correct Answer: o-Alkynylaniline and Pd(0) catalyst

Q18. Which statement about the Fischer indole synthesis scope is true?

• It cannot produce substituted indoles at C2 or C3
• It tolerates a variety of ketones and gives access to 2,3-disubstituted indoles
• It only works with formaldehyde
• It always requires transition metal catalysts

Correct Answer: It tolerates a variety of ketones and gives access to 2,3-disubstituted indoles

Q19. Which reagent is commonly used to oxidize indoline to indole (aromatization)?

• DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone)
• NaBH4
• LiAlH4
• SOCl2

Correct Answer: DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone)

Q20. In drug synthesis, indole derivatives are prized for which property?

• High lipophilicity only
• Versatile binding interactions with biological targets and aromatic heterocycle properties
• Inertness to metabolic enzymes
• Absolute water solubility

Correct Answer: Versatile binding interactions with biological targets and aromatic heterocycle properties

Q21. The Nenitzescu indole synthesis involves reaction between which two types of partners?

• 1,4-Benzoquinone and enamines (or activated alkenes)
• Nitroarenes and vinyl lithium
• Phenylhydrazine and carboxylic acids
• Azides and alkynes

Correct Answer: 1,4-Benzoquinone and enamines (or activated alkenes)

Q22. In practice, to brominate indole selectively at C3 you should:

• Use N-bromosuccinimide (NBS) on unprotected indole at low temperature
• Brominate without any control; bromine will give a single product
• Protect C3 first then add bromine
• Use HBr alone

Correct Answer: Use N-bromosuccinimide (NBS) on unprotected indole at low temperature

Q23. Which catalyst is commonly used for C–H functionalization of indoles in modern methods?

• Pd, Rh, or Ru transition metal catalysts
• Strong mineral acids only
• Photoinitiators only
• No catalysts are ever used

Correct Answer: Pd, Rh, or Ru transition metal catalysts

Q24. The Bartoli reaction is most effective when the nitroarene bears which substituent pattern?

• Ortho-substitution that can direct addition of vinyl Grignard
• Only para-substituents are tolerated
• No substituents at all on the aromatic ring
• Only strongly electron-withdrawing groups at meta position

Correct Answer: Ortho-substitution that can direct addition of vinyl Grignard

Q25. Which step is often required after a Fischer synthesis to obtain free indole if nitrogen was temporarily protected?

• Deprotection under acidic or reductive conditions (depending on protecting group)
• Methylation with methyl iodide
• Oxidation with permanganate
• Direct distillation without workup

Correct Answer: Deprotection under acidic or reductive conditions (depending on protecting group)

Q26. A common laboratory method to prepare 3-arylindoles is via:

• Palladium-catalyzed cross-coupling at C3 after halogenation
• Direct nitration at C3
• Oxidation of anilines with KMnO4
• Hydrogenation of nitrobenzene

Correct Answer: Palladium-catalyzed cross-coupling at C3 after halogenation

Q27. Which of the following is a limitation of the Fisher indole synthesis?

• Inability to form indoles with substitution at both C2 and C3
• Sometimes harsh acidic conditions limit functional-group compatibility
• Requires transition metals
• Cannot form indoles larger than 5-membered rings

Correct Answer: Sometimes harsh acidic conditions limit functional-group compatibility

Q28. In many syntheses, N-tosyl indoles are used because the tosyl group:

• Increases nitrogen basicity
• Protects the nitrogen and directs regioselectivity while being removable
• Is inert and impossible to remove
• Converts indoles into pyrroles

Correct Answer: Protects the nitrogen and directs regioselectivity while being removable

Q29. For oxidative C2–C3 bond formation to create fused indole systems, a commonly used oxidant is:

• MnO2
• DDQ or hypervalent iodine reagents
• NaBH4
• Triethylamine

Correct Answer: DDQ or hypervalent iodine reagents

Q30. Which statement accurately describes the aromaticity of indole?

• Only the benzene ring is aromatic; the pyrrole part is not
• The whole bicyclic system shares a conjugated sextet; indole is aromatic
• Indole is antiaromatic
• Indole is non-aromatic due to nitrogen lone pair localization

Correct Answer: The whole bicyclic system shares a conjugated sextet; indole is aromatic

Q31. In synthetic planning, converting a 2,3-dihydroindole (indoline) to indole typically requires:

• Reduction
• Aromatization/oxidation
• Nitration
• Hydrolysis

Correct Answer: Aromatization/oxidation

Q32. The Pictet–Spengler reaction is often used to form which type of indole-derived framework?

• Isoquinoline derivatives only
• Tryptamine-derived tetrahydro-β-carbolines (fused indole frameworks)
• Simple unfunctionalized indoles only
• Saturated cyclohexanes

Correct Answer: Tryptamine-derived tetrahydro-β-carbolines (fused indole frameworks)

Q33. Which solvent is commonly avoided in Grignard-based Bartoli reactions because it reacts with Grignard reagents?

• Ether (THF)
• Water or alcohols
• Hexane
• Toluene

Correct Answer: Water or alcohols

Q34. A common laboratory method to introduce a nitro group onto an aniline derivative (precursor for indole syntheses) is:

• Nitration using HNO3/H2SO4 under controlled conditions
• Fischer indole synthesis
• Hydrogenation with Pd/C
• Grignard reaction

Correct Answer: Nitration using HNO3/H2SO4 under controlled conditions

Q35. In electrophilic bromination of indole, protecting the N–H often:

• Decreases reactivity at C3
• Prevents N-bromination and increases ring-selectivity
• Makes the molecule inert
• Leads to oxidation of the benzene ring

Correct Answer: Prevents N-bromination and increases ring-selectivity

Q36. The Gassman indole synthesis typically involves:

• Cyclization of o-alkynyl anilines via sulfur transfer
• Condensation of phenylhydrazine with ketones
• Thermal decomposition of azido esters
• Electrochemical oxidation of anilines

Correct Answer: Cyclization of o-alkynyl anilines via sulfur transfer

Q37. For large-scale pharmaceutical synthesis, which factors are critical when choosing an indole synthetic route?

• Yield, scalability, reagent cost, safety, and functional-group tolerance
• Only the aesthetic appeal of the route
• Color of intermediates
• Ability to avoid purification steps entirely

Correct Answer: Yield, scalability, reagent cost, safety, and functional-group tolerance

Q38. Which transformation converts indoles into indole N-oxides useful for further functionalization?

• Oxidation with peracids (e.g., mCPBA) to give N-oxide
• Hydrogenation with H2/Pd
• Reduction with LiAlH4
• Methylation with MeI

Correct Answer: Oxidation with peracids (e.g., mCPBA) to give N-oxide

Q39. Which named indole synthesis is notable for proceeding under relatively mild, neutral conditions and is useful for sensitive substituents?

• Bartoli reaction
• Larock Pd-catalyzed synthesis
• Fischer indole synthesis
• Leimgruber–Batcho synthesis (mild sequence for many substrates)

Correct Answer: Leimgruber–Batcho synthesis (mild sequence for many substrates)

Q40. Indole C2 lithiation often uses which base for directed metalation?

• n-Butyllithium with a directing group or TMEDA
• Sodium carbonate
• Pyridine only
• Sodium borohydride

Correct Answer: n-Butyllithium with a directing group or TMEDA

Q41. The presence of electron-withdrawing groups on the benzene portion of indole tends to:

• Increase reactivity at C3
• Decrease overall electron density and reduce electrophilic substitution rates
• Make the nitrogen more basic
• Convert indole into pyrrole

Correct Answer: Decrease overall electron density and reduce electrophilic substitution rates

Q42. Which common laboratory technique is essential for removing moisture before carrying out Grignard-based indole syntheses?

• Drying solvents using molecular sieves or distillation over sodium/benzophenone
• Adding water to the reaction
• Running the reaction open to air
• Using aqueous buffers

Correct Answer: Drying solvents using molecular sieves or distillation over sodium/benzophenone

Q43. In medicinal chemistry, indole derivatives often mimic which endogenous scaffold?

• Adenine
• Tryptamine/serotonin-like frameworks
• Fatty acids
• Carbohydrates

Correct Answer: Tryptamine/serotonin-like frameworks

Q44. Which reagent combination is typically used to convert an indole to a 3-acylindole via Friedel–Crafts acylation at C3?

• Acyl chloride with AlCl3
• H2O2 only
• Sodium hydroxide with ethanol
• LiAlH4

Correct Answer: Acyl chloride with AlCl3

Q45. Which of the following named reactions specifically forms indoles by intramolecular cyclization of o-alkynyl anilines under Pd catalysis?

• Bartoli reaction
• Larock indole synthesis
• Fischer indole synthesis
• Nenitzescu synthesis

Correct Answer: Larock indole synthesis

Q46. The stability of substituted indoles toward oxidation depends largely on:

• Substituents and their electronic effects (electron-rich indoles oxidize more easily)
• Only the solvent used
• The presence of traces of salt
• The phase of the moon

Correct Answer: Substituents and their electronic effects (electron-rich indoles oxidize more easily)

Q47. Which method can convert anilines to indoles via diazotization followed by intramolecular cyclization under appropriate conditions?

• Fischer indole synthesis
• Cadogan cyclization of o-nitrostyrenes (or related pathways involving nitro → amine reduction and cyclization)
• Bartoli reaction
• Grignard addition to carbonyls

Correct Answer: Cadogan cyclization of o-nitrostyrenes (or related pathways involving nitro → amine reduction and cyclization)

Q48. When performing indole syntheses, purification challenges commonly arise from:

• Similar polarity of starting materials, intermediates and indole products requiring careful chromatography
• Indoles are always gaseous
• No need for purification ever
• Indoles always crystallize as pure solids

Correct Answer: Similar polarity of starting materials, intermediates and indole products requiring careful chromatography

Q49. Which safety consideration is particularly important in Bartoli and Grignard-based indole syntheses?

• Handling air-sensitive and moisture-sensitive reagents under inert atmosphere
• Ensuring excess water is present to quench the Grignard reagent
• Using open flames near ether solvents without concern
• Never using protective equipment

Correct Answer: Handling air-sensitive and moisture-sensitive reagents under inert atmosphere

Q50. For academic exams, the best strategy to answer MCQs on indole synthesis is to:

• Memorize only reaction names without mechanisms
• Understand mechanisms, reagents, regioselectivity and practical limitations to rationalize answers
• Only memorize product structures for a few examples
• Ignore reagent conditions

Correct Answer: Understand mechanisms, reagents, regioselectivity and practical limitations to rationalize answers

Download