SUMMER INTERNSHIP PROJECT REPORT

Report of work carried out during the

SUMMER INTERNSHIP

in

Department of Chemistry, IIT Indore

By

Ananthakrishna P
(Roll No.
IMS21227)
Indian Institute of Science Education and Research,
Thiruvananthapuram

Based on research carried out under the supervision of

Dr. Debayan Sarkar

Department of Chemistry
IIT Indore
 Indian Institute of Technology, Indore
July 2023

DECLARATION

I, Ananthakrishna P (Roll No: IMS21227), hereby declare that

this report of work carried out during the Summer Internship in
Department of Chemistry is an original work carried out by me
under the supervision of Dr. Debayan Sarkar and has not formed
the basis for the award of any degree or diploma, in this or any other
institution or university. I have sincerely tried to uphold academic
ethics and honesty. Wherever external information or statements, or
results have been used, they have been duly acknowledged.

Indore - 453552 Ananthakrishna P

July 2023

1
 CERTIFICATE

This is to certify that the work contained in this project report entitled
submitted to the Indian Institute of Technology, Indore, towards the
requirement of Summer Internship in the Department of
Chemistry has been carried out by him under my supervision and
that it has not been submitted elsewhere for the award of any degree.

Indore - 453552
Dr Debayan Sarkar
July 2023
Project Supervisor

2
 ACKNOWLEDGEMENT

At the outset, I wish to express my sincere gratitude to Dr. Debayan Sarkar

for kindly providing this opportunity to learn about organic synthesis and
experimental techniques by granting me an internship at the Organic Synthesis
and Molecular Engineering laboratory. His guidance and encouragement
throughout the project were indeed invaluable.

I would also like to express my heartfelt gratitude to my advisor and

supervisor, Mr Bhabani Sankar Lenka. His guidance, advice, encouragement
and patience greatly helped me in the course of my project.

I would like to take this opportunity to thank the Department of Chemistry,

IIT Indore for hosting me and providing logistical and infrastructural support.

I would be amiss if I failed to thank my colleagues and fellow interns Harshit

Chauhan and Priyangshu Garai at the Organic Synthesis and Molecular
Engineering laboratory, whose support, camaraderie and suggestions made my
internship a joyful and fruitful learning experience.

3
Contents

1 Synthesis of substituted naphthols 5

Introduction 5
1.1 Substrate 1: 7-Methoxy-naphthalen-2-ol 7
1.2 Substrate 2: 6-Hydroxy-2-naphthoic acid 11
1.3 Substrate 3: 7-Phenyl-naphthalen-2-ol 13
1.4 Substrate 4: 6-Methyl-naphthalen-2-ol 14
1.5 Substrate 5: 6-Bromo-naphthalen-2-ol 19
1.6 Substrate 6: 4-Chloro-naphthalen-1-ol 24
2 Conclusion and future directions 28
3 References 29

4
Synthesis of substituted naphthols

Introduction

This project aimed to explore the substrate scope and functional group tolerance of a
method of photocatalysed oxidative dearomatisation of 𝛽-naphthols. The main focus of the
project, therefore, was to synthesise or obtain diversely substituted 𝛽-naphthols as
substrates for processing and check which substituents were tolerated at every step. The
synthesis of substituted naphthols is a challenging task, owing to the aromaticity-driven
stability of the naphthalene ring system, the multistep reactions required for their synthesis,
and the requirement of harsh reaction conditions or otherwise extremely cost-inefficient
catalysts. Very few groups have reported the synthesis of 𝛽 naphthols that are substituted
on the 5, 6, 7 and 8 positions. The synthesis of functionalised naphthols is furthermore
highly interesting since they hold significant promise as substrates and synthetic
intermediates for pharmaceutical applications and natural product synthesis.

Dearomatisation reactions:

Dearomatisation reactions are a class of reactions in which the aromaticity of a system is

removed by adding functional groups to the aromatic ring. They are a very important
category of reactions for several reasons, the principal being the following-
1. Dearomatisation helps functionalise otherwise stable and unreactive aromatic systems,
thereby expanding the systems available for synthetic transformations.
2. Dearomatisation can generate complex non-planar structures from simple planar ones
and can even generate interesting and unique chiral centres. This is extremely useful
in designing and synthesising molecular scaffolds for synthetic and pharmaceutical
purposes.
3. Dearomatisation reactions can provide access to highly reactive intermediates, which
can provide facile access to a variety of bonds and reactions.

However, dearomatisation reactions are difficult to perform since they are energetically
unfavourable processes. The stability which aromaticity confers upon the system is
extremely difficult to surmount, and thus dearomatisation is intrinsically an endergonic

5
process. Thus, the designing of particular reagents and catalysts to effectively perform
dearomatisation is very much required. Hypervalent iodine and tribromide salt compounds,
amongst other reagents, have demonstrated significant promise in carrying out
dearomatisation reactions. Still, questions pertaining to efficient and sustainable paths to
access dearomatised products remain unanswered.

In recent work carried out by Nabakumar Bera, Dr. Debayan Sarkar and colleagues at the
Organic Synthesis and Molecular Engineering laboratory, an environmentally benign visible
light photocatalysed method to achieve the dearomatisation of phenols. In the protocol
developed, Riboflavin Tetraacetate was used as a photocatalyst, which in the presence of
blue light catalysed the oxidative dearomatisation of phenols. In the protocol developed,
under acidic conditions RFTA was capable of catalysing the spiro-esterification of phenols,
thereby dearomatising the ring. The advantages of this process were that all reagents used
were environmentally benign, and the final oxidant used was O 2 gas, which is readily
available.

In this project, we aspired to synthesise a variety of substituted naphthols, which would

be used as a library of substrates to explore the substrate scope of the developed spiro-
esterification procedure.

General scheme:

The general scheme of the process used for different substrates is explained herein. The
starting materials were different substituted 𝛽-naphthols. In the first step, the starting
material was formylated, which could be accomplished either by the Riemer-Tiemann
reaction, Duff reaction or Gattermann reaction. In this project, the Riemer-Tiemann
reaction was employed. This was then followed by the alkenylation of the carbonyl formed
via a Wittig reaction. Subsequently, the alkene formed was reduced to an alkane via
Palladium catalysed hydrogenation, followed by a reduction of the ester into an alcohol.
This scheme was designed to generate a diol system capable of cyclisation and oxidative
dearomatisation in the presence of the photocatalyst. Wherever suitable, schemes for
functionalising the substrates to generate diverse substitutions were designed. The substrates

6
were prepared according to literature, following previously optimised and reported protocols.

1.1 Substrate 1: 7-Methoxy-naphthalen-2-ol

Reaction 1: Reimer-Tiemann reaction

Procedure:

7-Methoxy-napthalen-2-ol (10 g, 57 mmol) was weighed and taken in a clean and dry two-
neck round-bottomed flask, fitted with a reflux condenser. The substrate was then dissolved
in a minimal amount of ethanol and kept for heating till the temperature reached 80 o C. An
aqueous solution of NaOH (3N, 150 ml) was prepared and added dropwise to the solution,
and the setup was allowed to heat with constant stirring for 30 minutes. To this, excess
CHCl3 (257 mmol, 30 ml) was added very slowly and dropwise. The reaction mixture was
left to stir for 6 hours, maintained at a constant temperature of 80 o C. The reaction mixture
was then quenched with dilute hydrochloric acid, the resultant 2-hydroxy-7-methoxy-1-
naphthaldehyde was extracted in DCM and purified by column chromatography.

Reaction:

7
Observations, results and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was
developed in a 20% EtOAc-PET solution and revealed significant by-products, as
well as some amount of the unreacted substrate. Upon performing column
chromatography, the product was eluted in a 15% EtOAc-Hexane solution. Upon
evaporating the solvent, 2.9 grams of the aldehyde was recovered, with a yield of
25%.

The low yield might be due to unquenched NaOH in the reaction mixture, which
might have led to the disproportionation of the aldehyde via the Cannizzaro
reaction. Another reason might be that the column chromatography purification
process was performed with a significant delay after the reaction was completed,
due to which the formed aldehyde degraded due to its high reactivity. Another reason for
the limited success of the reaction could have been experimental errors, such as the fast
injection of CHCl3 into the reaction mixture.

Reaction 2: Wittig reaction

Procedure:

2-Hydroxy-7-methoxy-1-naphthaldehyde (1.2 g, 6mmol) was treated with a Wittig salt

(Ph3P=CHCOOEt) (3.31 g, 8 mmol) in DCM at room temperature. Potassium tertiary butoxide (1.01
g, 9 mmol) was added, and the mixture was allowed to stir for 6 hours. The reaction was quenched with
water, and the organic layer was extracted with DCM. The organic layer was washed with brine
solution, dried over sodium sulphate, then concentrated by reduced pressure. The crude mixture was
subjected to column chromatography.

8
Reaction:

Observations, results and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was
developed in a 30% EtOAc-PET solution and revealed that the substrate was
almost entirely consumed, while some excess Wittig salt remained in the mixture.
There was a single spot which contained both the E and Z isomers of ethyl-3-(2-
hydroxy-7-methoxynapthalen-1-yl) acrylate, and it was estimated that the E
isomer would be the major product since the Wittig salt contains a stabilised
electron-withdrawing alkyl group. Since the next step in our scheme was to
hydrogenate the alkene here, it was decided not to separate the E and Z forms.

The obtained acrylate was purified by column chromatography, and was eluted in
a 20% EtOAc-Hexane solution. Upon evaporating the solvent, 2.45 g of the product was
recovered, with a yield of 100%.

Reaction 3: Pd/C catalytic hydrogenation

Procedure:

9
Ethyl-3-(2-hydroxy-7-methoxynapthalen-1-yl) acrylate (1 g, 3.6 mmol) was added to a dry
two-necked round-bottomed flask. To this, a catalytic amount of Pd/C was added, and the
setup was sealed with two septa. Through the side, dry methanol (30 ml) as a solvent was added
slowly. H2 gas was taken in a balloon attached to a syringe. The syringe was then inserted into the flask,
thus maintaining a pressurised hydrogen atmosphere for the reaction. The reaction was left to stir at
room temperature for 10 hours. The reaction mixture was then taken out, and the solvent was
evaporated. The crude mixture was subjected to column chromatography.

Reaction:

Observations, results and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate
was developed in a 30% EtOAc-PET solution and revealed that the substrate
was entirely consumed. There was a single spot which contained ethyl 3-(2-
hydroxy-7-methoxynaphthalen-1-yl) propanoate.

The obtained product was purified by column chromatography and was

eluted in 20% EtOAC-Hexane solution. Upon evaporating the solvent, 1.03 g
of the product was recovered, with a yield of 100%.

Ideally, the reaction must, however, be carried out in an autoclave with controlled
temperature and pressure. Under appropriate conditions, the reaction time can be
reduced.

10
Reaction 4: Sodium borohydride reduction

Procedure:

Ethyl 3-(2-hydroxy-7-methoxynaphthalen-1-yl) propanoate (0.5 g, 1.8 mmol) was added to a

dry two-necked round-bottomed flask. To this, an excess of NaBH4 (0.34 g, 9 mmol) was
added, and the setup was sealed with two septa. Through the side, a solution of dry THF and dry
Methanol (3:1, THF is added first and Methanol later) as a solvent was added slowly. The setup was left
at RT with constant stirring for 8 hours. The reaction mixture was then taken out, and the solvent was
evaporated. The crude mixture was subjected to an EtOAc-H 2O workup, in which the product was
isolated in the organic layer. The organic layer was separated, concentrated and then purified by column
chromatography.

Reaction:

8 hr

Observations, results and inferences:

The reaction was monitored using thin-layer chromatography. The TLC was
developed in a 30% EtOAc-PET solution and revealed that the substrate was
entirely consumed. There was a single spot of the product 1-(3-hydroxypropyl)-
7-methoxynaphthalen-2-ol, and the substrate was entirely consumed.

The product was eluted in a 20% EtOAc-hexane solution, and upon

evaporating the solvent, 0.4 g of the product was obtained. This was stored for
future processing.

11
1.2 Substrate 2: 6-Hydroxy-2-naphthoic acid

Reaction 1: Esterification (for protection)

Procedure:

6-Hydroxy-2-naphthoic acid (1 g, 5.35 mmol) was weighed and taken in a clean and dry
two-neck round-bottomed flask, fitted with a reflux condenser. The substrate was then
dissolved in 20 ml of methanol. Concentrated H2SO4 (0.5 g, 5.1 mmol, 0.25 ml) was added
dropwise to the solution, and the setup was allowed to reflux with constant stirring at 90 oC
for 24 hours. The reaction mixture was then subjected to a neutral workup, and the
resultant methyl 6-hydroxy-2 naphthoate was extracted in Ethyl Acetate and purified by
column chromatography.

Reaction scheme:

Observations, results and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed

12
in a 10% EtOAc-PET solution and revealed that the substrate was entirely consumed. The
obtained product was purified by column chromatography and was eluted in 20% EtOAC-
Hexane solution. Upon evaporating the solvent, 1.07 g of the product was recovered, with a
yield of 100%. Since the reaction yield was excellent, the reaction was repeated in a bulk
scale with 5 g (26.75 mmol) of the substrate. 5.37 g of the ester was obtained and stored for
further processing. The characterisation of the compound was done using NMR.

Reaction 2: Reimer-Tiemann formylation

Procedure:

Methyl 6-hydroxy-2 naphthoate (5 g, 24 mmol) was weighed and taken in a clean and dry
two-neck round-bottomed flask, fitted with a reflux condenser. The substrate was then
dissolved in a minimal amount of ethanol and kept for heating till the temperature reached
80o C. An aqueous solution of NaOH (12N, 100 ml) was prepared and added dropwise to the
solution, and the setup was allowed to heat with constant stirring for 30 minutes. To this,
excess CHCl3 (107.8 mmol, 12 ml) was added very slowly and dropwise. The reaction
mixture was left to stir for 6 hours, maintained at a constant temperature of 80 o C. The
reaction mixture was then quenched with dilute hydrochloric acid, the resultant 2-hydroxy-
7-methoxy-1-naphthaldehyde was extracted in DCM and purified by column

13
chromatography.

Observations, result and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 20% EtOAc-PET solution and revealed that the substrate was hydrolysed to recover
the acid. This was despite having added Sodium Hydroxide in great excess. The same result
was achieved upon performing the formylation reaction directly on the acid, without ester
protection, and formylation did not occur. It is hypothesised that the strongly deactivating
nature of the carboxy group is the reason behind the failure of the reaction.

1.3 Substrate 3: 7-Phenyl-napththalen-2-ol

Reaction 1: Synthesis of 7-Phenyl-2-naphthol

Following the procedure set by Zhang and co-workers, we tried to synthesise 7-Phenyl -2-
naphthol from 7-bromo-2-naphthol via Suzuki coupling. Zhang and coworkers used [1,1′-
Bis(diphenylphosphino)ferrocene]dichloropalladium as a catalyst, but we used palladium(II)
acetate instead.

Procedure:

7-Bromo-2-naphthol (0.5 g, 2 mmol) was weighed and taken in a clean and dry two-neck
round-bottomed flask. To this, phenylboronic acid (0.33 g, 2.4 mmol) and Na 2CO3 (0.21 g, 2
mmol). A mixture of DMF and H2O was added (3 ml, 2:1) as a solvent. The system was
then purged and placed in an inert atmosphere. After 5 minutes, a catalytic amount of
Pd(OAc)2 was added. The system was left to stir at room temperature for 12 hours.

Reaction:

14
Observations, results and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 20% EtOAc-PET solution and revealed that a significant amount of the substrate
remained unconsumed. The reaction yield was 15%, which was insufficient to proceed
further.

1.4 Substrate 4: 6-Methyl-naphthalen-2-ol

Reaction 1: Synthesis of 6-Methyl-naphthalen-2-ol

Procedure:

6-Bromo-napthalen-2-ol (0.5 g, 2.24 mmol) was weighed and taken in a clean and dry two-
neck round-bottomed flask and was then fully sealed. The substrate was then dissolved in a
minimal amount of THF and kept for cooling till the temperature reached -78 o C. To this, a
solution of n-butyl lithium in hexane (0.68 g, 2.5M, 5.15 mmol) and the setup was allowed
to stir at -78o C for 60 minutes. To this, methyl iodide (0.31 g, 2.24 mmol) was added slowly
and dropwise. The cooling was then ceased, and the reaction mixture was left to stir and
reach room temperature. The reaction mixture was then quenched with saturated
ammonium chloride solution, and the resultant 6-methyl-naphthalen-2-ol was extracted in
EtOAc and purified by column chromatography.

Reaction:

15
Observations, inferences and conclusions:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 10% EtOAc-PET solution. The TLC revealed that the substrate was fully consumed
but had formed significant by-products. The product was eluted in a 30% EtOAc-Hexane
solution. Upon evaporating the solvent, 0.5 g of the product was recovered, with a yield of
90%.

The n-butyl lithium must be added dropwise to ensure that the reaction progresses without
decomposition. Since the reagent contains a metal, ammonium chloride solution is used to
quench the reaction. Due to the high reactivity of n-butyl lithium, using pure substrates and
ensuring completely inert conditions is of paramount importance.

Since the reaction had a good yield, the procedure was repeated with 4 g of 6-bromo-
napthalene-2-ol. In total, 4.5 g of 6-methyl-naphthalen-2-ol was recovered and stored for
further processing.

Reaction 2: Reimer-Tiemann reaction

Procedure:

6-Methyl-napthalene-2-ol (4 g, 25 mmol) was weighed and taken in a clean and dry two-neck
round-bottomed flask, fitted with a reflux condenser. The substrate was then dissolved in a
minimal amount of ethanol and kept for heating till the temperature reached 80o C. An
aqueous solution of NaOH (3N, 150 ml) was prepared and added dropwise to the solution,
and the setup was allowed to heat with constant stirring for 30 minutes. To this, excess
CHCl3 (128 mmol, 15 ml) was added very slowly and dropwise. The reaction mixture was

16
left to stir for 6 hours, maintained at a constant temperature of 80 o C. The reaction mixture
was then quenched with dilute hydrochloric acid, the resultant 2-hydroxy-6-methyl-1-
naphthaldehyde was extracted in DCM and purified by column chromatography.

Reaction:

Observations, conclusions and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 20% EtOAc-PET solution and revealed significant by-products, as well as some amount
of the unreacted substrate. Upon performing column chromatography, the product was
eluted in a 15% EtOAc-Hexane solution. Upon evaporating the solvent, 2.1 grams of the
aldehyde was recovered, with a yield of 45%.

The low yield might be due to unquenched NaOH in the reaction mixture, which might have
led to the disproportionation of the aldehyde via the Cannizzaro reaction. Another reason
might be that the column chromatography purification process was performed with a
significant delay after the reaction was completed, due to which the formed aldehyde
degraded due to its high reactivity.

Reaction 3: Wittig reaction

Procedure:

17
2-Hydroxy-6-methyl-1-naphthaldehyde (1.2 g, 6 mmol) was treated with a Wittig salt
(Ph3P=CHCOOEt) (3.31 g, 8 mmol) in DCM at room temperature. Potassium tertiary butoxide (1.01
g, 9 mmol) was added, and the mixture was allowed to stir for 6 hours. The reaction was quenched with
water, and the organic layer was extracted with DCM. The organic layer was washed with brine
solution, dried over sodium sulphate, then concentrated by reduced pressure. The crude mixture was
subjected to column chromatography.

Reaction:

Observations, results and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 30% EtOAc-PET solution and revealed that the substrate was almost entirely
consumed, while some excess Wittig salt remained in the mixture. There was a single spot
which contained both the E and Z isomers of ethyl-3-(2-hydroxy-6-methyl-napthalen-1-yl)
acrylate, and it was estimated that the E isomer would be the major product since the
Wittig salt contains a stabilised electron-withdrawing alkyl group. Since the next step in our
scheme was to hydrogenate the alkene here, it was decided not to separate the E and Z
forms.

The obtained acrylate was purified by column chromatography, and was eluted in a 20%
EtOAc-Hexane solution. Upon evaporating the solvent, 2.45 g of the product was recovered,
with a yield of 100%.

18
Reaction 4: Pd/C catalytic hydrogenation

Procedure:

Ethyl-3-(2-hydroxy-6-methyl-napthalen-1-yl) acrylate (1 g, 3.6 mmol) was added to a dry

two-necked round-bottomed flask. To this, a catalytic amount of Pd/C was added, and the
setup was sealed with two septa. Through the side, dry methanol (30 ml) as a solvent was added
slowly. H2 gas was taken in a balloon attached to a syringe. The syringe was then inserted into the flask,
thus maintaining a pressurised hydrogen atmosphere for the reaction. The reaction was left to stir at
room temperature for 10 hours. The reaction mixture was then taken out, and the solvent was
evaporated. The crude mixture was subjected to column chromatography.

Reaction:

Observations, conclusions and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 30% EtOAc-PET solution and revealed that the substrate was entirely consumed.
There was a single spot which contained ethyl 3-(2-hydroxy-6-methylnaphthalen-1-yl)
propanoate.

The obtained product was purified by column chromatography and was eluted in 20%
EtOAC-Hexane solution. Upon evaporating the solvent, 1.02 g of the product was recovered,
with a yield of 100%.

Ideally, the reaction must, however, be carried out in an autoclave with controlled temperature
and pressure. Under appropriate conditions, the reaction time can be reduced.

19
Reaction 5: Sodium borohydride reduction

Procedure:

Ethyl 3-(2-hydroxy-6-methyl-naphthalen-1-yl) propanoate (0.5 g, 1.8 mmol) was added to a

dry two-necked round-bottomed flask. To this, an excess of NaBH4 (0.34 g, 9 mmol) was
added, and the setup was sealed with two septa. Through the side, a solution of dry THF and dry
Methanol (3:1, THF is added first and Methanol later) as a solvent was added slowly. The setup was left
at RT with constant stirring for 6 hours. The reaction mixture was then taken out, and the solvent was
evaporated. The crude mixture was subjected to an EtOAc-H 2O workup, in which the product was
isolated in the organic layer. The organic layer was separated, concentrated and then purified by column
chromatography.

Reaction:

Observations, results and inferences:

The reaction was monitored using thin-layer chromatography. The TLC was developed in a
30% EtOAc-PET solution and revealed that the substrate was entirely consumed. There was
a single spot of the product 1-(3-hydroxypropyl)-6-methylnaphthalen-2-ol, and the substrate
was entirely consumed.

The product was eluted in a 20% EtOAc-hexane solution, and upon evaporating the solvent,

20
0.3 g of the product was obtained. This was stored for future processing.

1.5 Substrate 5: 6-Bromo-napththalen-2-ol

Reaction 1: Reimer-Tiemann reaction

Procedure:

6-Bromo-napthalen-2-ol (15 g, 67 mmol) was weighed and taken in a clean and dry two-neck
round-bottomed flask, fitted with a reflux condenser. The substrate was then dissolved in a
minimal amount of ethanol and kept for heating till the temperature reached 80o C. An
aqueous solution of NaOH (4N, 200 ml) was prepared and added dropwise to the solution,
and the setup was allowed to heat with constant stirring for 30 minutes. To this, excess
CHCl3 (257 mmol, 30 ml) was added very slowly and dropwise. The reaction mixture was
left to stir for 6 hours, maintained at a constant temperature of 80 o C. The reaction mixture
was then quenched with dilute hydrochloric acid, the resultant 2-hydroxy-6-bromo-1-
naphthaldehyde was extracted in DCM and purified by column chromatography.

Reaction:

Observations, conclusions and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 20% EtOAc-PET solution and revealed significant by-products, as well as some amount
of the unreacted substrate. Upon performing column chromatography, the product was

21
eluted in a 15% EtOAc-Hexane solution. Upon evaporating the solvent, 8 grams of the
aldehyde was recovered, with a yield of 46%.

The low yield might be due to unquenched NaOH in the reaction mixture, which might have
led to the disproportionation of the aldehyde via the Cannizzaro reaction. Another reason
might be that the column chromatography purification process was performed with a
significant delay after the reaction was completed, due to which the formed aldehyde
degraded due to its high reactivity. Another reason for the limited success of the reaction
could have been experimental errors, such as the fast injection of CHCl3 into the reaction
mixture.

Reaction 2: Wittig reaction

Procedure:

2-Hydroxy-6-bromo-1-naphthaldehyde (1.2 g, 6 mmol) was treated with a Wittig salt

(Ph3P=CHCOOEt) (3.31 g, 8 mmol) in DCM at room temperature. Potassium tertiary butoxide (1.01
g, 9 mmol) was added, and the mixture was allowed to stir for 6 hours. The reaction was quenched with
water, and the organic layer was extracted with DCM. The organic layer was washed with brine
solution, dried over sodium sulphate, then concentrated by reduced pressure. The crude mixture was
subjected to column chromatography.

Reaction:

Observations, conclusions and inferences:

22
The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 30% EtOAc-PET solution and revealed that the substrate was almost entirely
consumed, while some excess Wittig salt remained in the mixture. There was a single spot
which contained both the E and Z isomers of ethyl-3-(2-hydroxy-6-bromo-napthalen-1-yl)
acrylate, and it was estimated that the E isomer would be the major product since the
Wittig salt contains a stabilised electron-withdrawing alkyl group. Since the next step in our
scheme was to hydrogenate the alkene here, it was decided not to separate the E and Z
forms.

The obtained acrylate was purified by column chromatography, and was eluted in a 20%
EtOAc-Hexane solution. Upon evaporating the solvent, 1.5 g of the product was recovered,
with a yield of 80%.

Reaction 3: Pd/C catalytic hydrogenation

Procedure:

Ethyl-3-(2-hydroxy-6-bromo-napthalen-1-yl) acrylate (1 g, 3.6 mmol) was added to a dry

two-necked round-bottomed flask. To this, a catalytic amount of Pd/C was added, and the
setup was sealed with two septa. Through the side, dry methanol (30 ml) as a solvent was added
slowly. H2 gas was taken in a balloon attached to a syringe. The syringe was then inserted into the flask,
thus maintaining a pressurised hydrogen atmosphere for the reaction. The reaction was left to stir at
room temperature for 10 hours. The reaction mixture was routinely monitored using thin-layer
chromatography. The reaction mixture was taken out, and the solvent was evaporated. The crude
mixture was subjected to column chromatography.

Reactions:

23
Observations, conclusions and inference:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 30% EtOAc-PET solution. Interestingly, after 10 hours, the aromatic benzene ring was
reduced, and the bromine group was removed. After 4 hours, the bromine group was
removed while aromaticity in the benzene ring was retained. It was observed that within
two hours, the alkene of interest is reduced without affecting the rest of the molecule, and
prolonged exposure to H2 gas beyond that time would result in the formation of these side
products.
Due to the multiple side reactions observed during this reaction, it was decided to carry out
the alkene reduction via Wilkinson’s hydrogenation.

24
Reaction 4: Wilkinson hydrogenation

Procedure:

Ethyl-3-(2-hydroxy-6-bromo-napthalen-1-yl) acrylate (1 g, 3.6 mmol) was added to a dry

two-necked round-bottomed flask. The flask was equipped with a reflux condenser. The
acrylate was dissolved in Benzene and placed in a hydrogen environment. To this, a
catalytic amount of Wilkinson’s catalyst ([RhCl(PPh₃)₃]) was added. The system was
allowed to stir for 3 hours. The reaction mixture was taken out, and the solvent was evaporated. The
crude mixture was subjected to column chromatography.

Reaction:

Observations, conclusions and inferences:

The reaction was monitored using thin-layer chromatography. TLC plates were developed in
a 20% EtOAc-PET solution and revealed that the substrate was partially consumed. There
was a significant spot above that of the substrate, which corresponded to the product. The
formed alkane was extracted using column chromatography and stored for further
processing. Upon evaporating the solvent, 0.9 g of ethyl-3-(6-bromo-2-hydroxy-naphthalen-1-
yl) propanoate was recovered, with a yield of 90%.

Reaction 5: Sodium borohydride reduction

Procedure:

Ethyl 3-(2-hydroxy-6-bromo-naphthalen-1-yl) propanoate (0.5 g, 1.8 mmol) was added to a

dry two-necked round-bottomed flask. To this, an excess of NaBH4 (0.34 g, 9 mmol) was

25
added, and the setup was sealed with two septa. Through the side, a solution of dry THF and dry
Methanol (3:1, THF is added first and Methanol later) as a solvent was added slowly. The setup was left
at RT with constant stirring for 6 hours. The reaction mixture was then taken out, and the solvent was
evaporated. The crude mixture was subjected to an EtOAc-H 2O workup, in which the product was
isolated in the organic layer. The organic layer was separated, concentrated and then purified by column
chromatography.

Reaction:

Observations, conclusions and inferences:

The reaction was monitored using thin-layer chromatography. The TLC was developed in a
30% EtOAc-PET solution and revealed that the substrate was entirely consumed. There was
a single spot of the product 1-(3-hydroxypropyl)-6-bromo-naphthalen-2-ol, and the substrate
was entirely consumed.

The product was eluted in a 20% EtOAc-hexane solution, and upon evaporating the solvent,
0.3 g of the product was obtained. This was stored for future processing.

1.6 Substrate 6: 4-Chloro-napththalen-1-ol

Reaction 1: Reimer-Tiemann reaction

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Procedure:

4-Chloro-napthalen-1-ol (5 g, 27 mmol) was weighed and taken in a clean and dry two-neck
round-bottomed flask, fitted with a reflux condenser. The substrate was then dissolved in a
minimal amount of ethanol and kept for heating till the temperature reached 80o C. An
aqueous solution of NaOH (4N, 100 ml) was prepared and added dropwise to the solution,
and the setup was allowed to heat with constant stirring for 30 minutes. To this, excess
CHCl3 (129 mmol, 15 ml) was added very slowly and dropwise. The reaction mixture was
left to stir for 6 hours, maintained at a constant temperature of 80 o C. The reaction mixture
was then quenched with dilute hydrochloric acid, the resultant 1-hydroxy-4-chloro-2-
naphthaldehyde was extracted in DCM and purified by column chromatography.

Reaction:

Observations, conclusions and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 20% EtOAc-PET solution and revealed significant by-products, as well as some amount
of the unreacted substrate. Upon performing column chromatography, the product was
eluted in a 15% EtOAc-Hexane solution. Upon evaporating the solvent, 2.5 grams of the
aldehyde was recovered, with a yield of 44%.

The low yield might be due to unquenched NaOH in the reaction mixture, which might have
led to the disproportionation of the aldehyde via the Cannizzaro reaction. Another reason
might be that the column chromatography purification process was performed with a
significant delay after the reaction was completed, due to which the formed aldehyde
degraded due to its high reactivity. Another reason for the limited success of the reaction

27
could have been experimental errors, such as the fast injection of CHCl3 into the reaction
mixture.

Reaction 2: Wittig reaction

Procedure:

1-Hydroxy-4-chloro-2-naphthaldehyde (0.5 g, 2.4 mmol) was treated with a Wittig salt

(Ph3P=CHCOOEt) (3.31 g, 0.008 mmol) in DCM at room temperature. Potassium tertiary butoxide
(1.0o g, 2.88 mmol) was added, and the mixture was allowed to stir for 6 hours. The reaction was
quenched with water, and the organic layer was extracted with DCM. The organic layer was washed
with brine solution, dried over sodium sulphate, then concentrated by reduced pressure. The crude
mixture was subjected to column chromatography.

Reaction:

Observations, conclusions and inferences:

The reaction was monitored using thin-layer chromatography. The TLC plate was developed
in a 30% EtOAc-PET solution and revealed that the substrate was almost entirely
consumed, while some excess Wittig salt remained in the mixture. There was a single spot
which contained both the E and Z isomers of ethyl-3-(1-hydroxy-4-chloro-napthalen-2-yl)
acrylate, and it was estimated that the E isomer would be the major product since the
Wittig salt contains a stabilised electron-withdrawing alkyl group. Since the next step in our
scheme was to hydrogenate the alkene here, it was decided not to separate the E and Z
forms.

The obtained acrylate was purified by column chromatography, and was eluted in a 20%

28
EtOAc-Hexane solution. Upon evaporating the solvent, 0.6 g of the product was recovered,
with a yield of 89%.

Reaction 3: Pd/C catalytic hydrogenation

Procedure:

Ethyl-3-(1-hydroxy-4-chloro-napthalen-2-yl) acrylate (0.6 g, 2.1 mmol) was added to a dry

two-necked round-bottomed flask. To this, a catalytic amount of Pd/C was added, and the
setup was sealed with two septa. Through the side, dry methanol (30 ml) as a solvent was added
slowly. H2 gas was taken in a balloon attached to a syringe. The syringe was then inserted into the flask,
thus maintaining a pressurised hydrogen atmosphere for the reaction. The reaction was left to stir at
room temperature for 10 hours. The reaction mixture was routinely monitored using thin-layer
chromatography. The reaction mixture was taken out, and the solvent was evaporated. The crude
mixture was subjected to column chromatography.

Reaction:

Observations, conclusions and inferences:

The reaction was monitored using thin-layer chromatography. TLC plates were developed in
a 20% EtOAc-PET solution and revealed that the substrate was partially consumed. There
was a significant spot above that of the substrate, which corresponded to the product. The

29
formed alkane was extracted using column chromatography and stored for further
processing. Upon evaporating the solvent, 0.6 g of ethyl-3-(4-chloro-1-hydroxy-naphthalen-2-
yl) propanoate was recovered, with a yield of 100%.

Reaction 4: Sodium borohydride reduction

Procedure:

Ethyl 3-(1-hydroxy-4-chloro-naphthalen-2-yl) propanoate (0.650 g, 2.74 mmol) was added to

a dry two-necked round-bottomed flask. To this, an excess of NaBH4 (0.45 g, 14 mmol) was
added, and the setup was sealed with two septa. Through the side, a solution of dry THF and dry
Methanol (3:1, THF is added first and Methanol later) as a solvent was added slowly. The setup was left
at RT with constant stirring for 6 hours. The reaction mixture was then taken out, and the solvent was
evaporated. The crude mixture was subjected to an EtOAc-H 2O workup, in which the product was
isolated in the organic layer. The organic layer was separated, concentrated and then purified by column
chromatography.

Reaction:

Observations, conclusions and inferences:

The reaction was monitored using thin-layer chromatography. The TLC was developed in a

30
30% EtOAc-PET solution and revealed that the substrate was entirely consumed. There was
a single spot of the product 1-(3-hydroxypropyl)-6-bromo-naphthalen-2-ol, and the substrate
was entirely consumed.

The product was eluted in a 20% EtOAc-hexane solution, and upon evaporating the solvent,
0.5 g of the product was obtained. This was stored for future processing.

Conclusion and future directions

Four substrates with different substituents on the naphthalene system were thus synthesised
and prepared for the oxidative dearomatisation procedure. However, the protocol did not
work with 6-hydroxy-2-naphthoic acid and 7-phenyl-naphthalen-2-ol. The possible future
work on these substrates is discussed below. The substrates were precursors to their
respective substituted spiro-dearomatised naphthols.

In the case of 6-hydroxy-2-naphthoic acid, this was perhaps due to the highly deactivating
nature of the carboxy moiety, which prevented the electrophile carbene generated from
attacking the substrate. This can be circumvented by using formylation reactions which
involve stronger nucleophiles, such as the Gattermann reaction (Cl(H)C=N(H)AlCl3) or the
Hoesch reaction (R-C(+)=NHCl(-)). Such approaches, performed in the acidic medium,
might also help avoid side reactions such as the Cannizzaro reaction.

In the case of 7-phenyl-naphthalen-2-ol, since the yield of the coupling reaction was low at
room temperature, the question of whether yields can be improved if the reaction setup is
refluxed and heated can be explored.

Additionally, further substrates can also be thought of. Esterifying 6-hydroxy-naphthalen-2-

31
ol and then performing a Fries rearrangement on the phenolic ester could lead to several
kinds of substituted naphthols.

Future directions concerning this project involve understanding the naphthalene system
better such that a larger and more diverse library of substituted naphthols can be prepared.
Developing such protocols will be extremely important to synthetic chemists who wish to
explore the substrate scope of any transformations discovered that pertain to naphthalene-
like systems. These can also be parts of procedures to access pharmaceutically and
synthetically important scaffolds.

Learning outcomes from this internship:

Through this internship, I have learnt about organic synthesis and how one may design
multistep reaction protocols. I have also equipped myself with knowledge of laboratory
techniques. This internship and the understanding it has given me with regard to reaction
planning, research methodology and organic chemistry will I believe hold me in good stead
as I attempt to explore the field of organic synthesis and catalysis further.

References
1. Roche, Stéphane P., and John A. Porco. “Dearomatization Strategies in the Synthesis of
Complex Natural Products.” Angewandte Chemie International Edition, vol. 50, no. 18,
Wiley, Apr. 2011, pp. 4068–93. Crossref, https://doi.org/10.1002/anie.201006017.
2. Sarkar, Debayan. “Dearomatization- an Unsolved Riddle.” NIT Rourkela Institutional
Repository, NIT Rourkela, 18 Dec. 2021, dspace.nitrkl.ac.in/dspace/handle/2080/3636.
3. Dohi, Toshifumi, et al. “First Hypervalent Iodine(III)-Catalyzed C—N Bond Forming
Reaction: Catalytic Spirocyclization of Amides to N-Fused Spirolactams.” ChemInform, vol.
38, no. 30, Wiley, July 2007. Crossref, https://doi.org/10.1002/chin.200730036.
4. Sarkar, Debayan, et al. “Phenyl Trimethyl Ammonium Tribromide Mediated Robust One-pot
Synthesis of Spiro-oxacycles – an Economic Route – Stereoselective Synthesis of
Oxaspirohexacyclodieneones.” Organic & Biomolecular Chemistry, vol. 14, no. 33, Royal
Society of Chemistry (RSC), 2016, pp. 7883–98. Crossref,

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 https://doi.org/10.1039/c6ob01116k.
5. Bera, Nabakumar, et al. “Riboflavin Photocatalyzed Dearomative Spiro-Etherification of
Naphthols.” The Journal of Organic Chemistry, vol. 88, no. 13, American Chemical Society
(ACS), June 2023, pp. 7977–87. Crossref, https://doi.org/10.1021/acs.joc.2c03037.

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