Synthesis of substituted naphthols

Summer Internship Work Presentation

Ananthakrishna P Dr. Debayan Sarkar

IISER Thiruvananthapuram Dept of Chemistry

IIT Indore

Presentation to YVR Lab group, 12th Aug 2023

 Contents
01 Introduction

02 Reaction mechanisms

03 Substrates chosen

04 Learning outcomes

05 References

12/8/2023 2
 Introduction The summer internship project
was aimed at exploring the
substrate scope of a
photocatalyzed dearomative
spiro-etherification protocol for
naphthols.

In particular, we attempted to
work with different kinds of
substituted naphthols.

12/8/2023 3
 Introduction
Why dearomatisation?
1. Dearomatisation helps functionalize 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
generate interesting and unique chiral centres.

3. Dearomatisation reactions can provide access to highly reactive intermediates, which can
provide facile access to a variety of bonds and reactions.

4. Dearomatisation is synthetically interesting and challenging, as it is an endergonic

process.

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 Introduction
Why substituted naphthols?
1. The project was aimed at studying the substrate scope of the developed method with respect to various
naphthol systems.

2. In all previous work on naphthols, very few groups have been successful in working with substituted
naphthols.

3. Particularly, very few groups have reported having explored substrate scopes with 𝛽 naphthol systems that
are substituted on the 5, 6, 7, and 8 positions.

4. The study of such substituted naphthols is furthermore highly interesting since they hold significant promise
as substrates and synthetic intermediates for pharmaceutical applications and natural product synthesis.

5. Synthesis of substituted naphthols is challenging, owing to the aromaticity-driven stability of the naphthalene
ring system, the multistep reactions required, and the requirement of harsh reaction conditions.

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 Introduction
General reaction scheme O O

O
OH OH
OH
Formylation Alkenylation
Reimer-Tiemann
Wittig
R R
R

Pd/C hydrogenation Alkene reduction

Wilkinson hydrogenation

O
OH
O

OH
OH
Ester reduction

NaBH4 reduction
R
R

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Reaction mechanisms
Reimer-Tiemann formylation
Cl Cl
H
-
OH
Cl Cl :
Cl Cl - Cl
Cl

-
O O -
O
Cl Cl Cl
Cl
: - Cl

Cl
H H

O
H -
O
Cl

O O
H Cl
OH
H

H
OH
-
-
OH

-
O
HO
H
H

O Acidic workup
O

12/8/2023 7
Reaction mechanisms
Wittig alkenylation
Ph Ph
Ph
Ph Ph P
+ Ph
O: P O

O
-
HC O
H
H
O
O
OH OH

OH
OEt
Ph
Ph Ph
P
+ O
O

12/8/2023 8
Reaction mechanisms
Pd/C Hydrogenation

OH OH
OEt OEt
OH
OEt
H2 (g)
H O
Pd/C O
O
H

12/8/2023 9
Reaction mechanisms
NaBH4 reduction
OH
OH OH H H
OEt OEt

O
O O-
H
H
H H
H H
B- -
Na+ B
Na+
H
H

OH H
OH H
H H

Acid
Workup O-
OH

12/8/2023 10
 Substrates chosen

1. 7-Methoxy naphthalen-2-ol

2. 6-Hydroxy-2-naphthoic acid

3. 7-Phenyl naphthalen-2-ol

4. 6-Methyl naphthalen-2-ol

5. 6-Bromo naphthalen-2-ol

6. 4-Chloro naphthalen-1-ol

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 7-Methoxy naphthalen-2-ol
1.1 Reimer-Tiemann reaction

O
O OH O OH
CHCl3, NaOH

EtOH, 80oC, 6 hr

Reactant/Product Equivalents mmol Amount

7-Methoxynaphthalen-2-ol 1 57 10 g
Chloroform 4.5 257 30 ml
Sodium hydroxide 7 399 10 g
7-Methoxy-2-hydroxy-1-naphthaldehyde 14.25 2.9 g
(25% recovered yield)
12/8/2023 12
 7-Methoxy naphthalen-2-ol
1.2 Wittig reaction
O O

O OH Ph3P=CHCOOEt O OH

DCM, 6 hr
Reactant/Product Equivalents mmol Amount
Set up with 1.2 g of substrate. 2.45 g of the1 product was recovered,
7-Methoxy-2-hydroxy-1-naphthaldehyde 6 with 1.2
a g
yield of 100%.
Wittig salt 1.2 8 3.31 g
Ethyl-3-(2-hydroxy-7-methoxynapthalen-1-yl) acrylate 6 2.45 g
(100% yield)

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 7-Methoxy naphthalen-2-ol
1.3 Pd/C catalytic hydrogenation

O O O O

H2 (g), Pd/C
O OH dry MeOH,10 hr O OH

Reactant/Product Equivalents mmol Amount

Ethyl-3-(2-hydroxy-7-methoxynapthalen-1-yl) acrylate 1 3.6 1g
Ethyl 3-(2-hydroxy-7-methoxynaphthalen-1-yl) propanoate 3.6 1.03 g
(100% yield)

12/8/2023 14
 7-Methoxy naphthalen-2-ol
1.4 NaBH4 reduction
O O OH

NaBH4, dry MeOH

O OH dry THF (3:1), 8 hr O OH

Reactant/Product Equivalents mmol Amount

Set up with 0.5 g of
Ethyl 3-(2-hydroxy-7-methoxynaphthalen-1-yl) substrate. 0.4 1g of the product
propanoate 1.8 0.5 g
was obtained, with a yield of 96%.
Sodium Borohydride 5 9 0.34 g
1-(3-hydroxypropyl)-7-methoxy-naphthalen-2-ol 6 0.4 g
(96% yield)

12/8/2023 15
 6-Hydroxy-2-naphthoic acid
2.1 Esterification (carboxylic acid protection)

O O
OH MeOH, H2SO4 O
HO 90oC, 24 hr
HO

Set up with 5 g (26.75 mmol) of substrate, 1 ml (20 N) conc. H2SO4.

5.37 g (26.48 mmol) of the product was obtained, with a yield of 99%.

Further step (formylation) unsuccessful.

12/8/2023 16
 7-Phenyl-naphthalen-2-ol
3.1 Suzuki coupling reaction

Br OH Ph-B(OH)2, Pd(OAc)2 OH

DMF:H2O (2:1), 12 hr

Reactant/Product Equivalents mmol Amount

7-Bromo-naphthalen-2-ol 1 2 0.5 g
Phenylboronic acid 1.2 2.4 0.33 g
Palladium acetate 5 mol%
7-Phenyl-naphthalen-2-ol 0.3 0.066 g
(15% recovered yield)

Further steps inviable as low yield.

12/8/2023 17
 6-Methyl-naphthalen-2-ol
4.1 Lithium halogen exchange reaction

OH OH
n-BuLi, MeI
THF, 6 hr, -78oC RT
Br

Reactant/Product Equivalents mmol Amount

Set up with 4.5 g of substrate. 4.5 g of the product
6-Bromo-naphthalen-2-ol 1 2.24 0.5 g
was obtained, with a yield of 90%.
n-Butyl lithium 2.3 5.15 0.68 g
Methyl Iodide 1 2.24 0.31 g
6-Methyl-naphthalen-2-ol 0.3 0.5 g
(90% yield)

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 6-Methyl-naphthalen-2-ol
4.2 Reimer-Tiemann reaction

O
OH
CHCl3, NaOH OH

EtOH, 80oC, 6 hr

Reactant/Product Equivalents mmol Amount

6-Methyl-naphthalen-2-ol 1 25 4g
Chloroform 5.12 128 15 ml
Sodium hydroxide 7 175 7g
6-Methyl-2-hydroxy-1- 2.1 g
naphthaldehyde (45% recovered yield)
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 6-Methyl-naphthalen-2-ol
4.3 Wittig reaction
O O

OH Ph3P=CHCOOEt OH

DCM, 6 hr
Reactant/Product Equivalents mmol Amount
Set up with 1.2 g of substrate. 2.45 g of the product
6-Methyl-2-hydroxy-1-naphthaldehyde
was obtained, with a yield 1of 100%. 6 1.2 g
Wittig salt 1.2 8 3.31 g
Ethyl-3-(2-hydroxy-6-methyl-napthalen-1-yl) 6 2.45 g
acrylate (100% yield)

12/8/2023 20
 6-Methyl-naphthalen-2-ol
4.4 Pd/C catalytic hydrogenation

O O O O

H2 (g), Pd/C
OH dry MeOH,10 hr OH

Reactant/Product Equivalents mmol Amount

Set up with 1 g acrylate
Ethyl-3-(2-hydroxy-6-methyl-napthalen-1-yl) of substrate. 1.021 g of the product3.6 1g
was obtained, with a yield of 100%.
Ethyl 3-(2-hydroxy-6-methyl-naphthalen-1-yl) propanoate 3.6 1.02 g
(100% yield)

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 6-Methyl-naphthalen-2-ol
4.5 NaBH4 reduction

O O OH

NaBH4, dry MeOH

OH dry THF (3:1), 8 hr OH

Reactant/Product Equivalents mmol Amount

Set up with 0.5 g propanoate
Ethyl 3-(2-hydroxy-6-methyl-naphthalen-1-yl) of substrate. 10.3 g of the product
1.8 0.5 g
Sodium Borohydride was obtained, with a yield of 77%.5 9 0.34 g
1-(3-hydroxypropyl)-6-methyl-naphthalen-2-ol 6 0.3 g
(77% yield)

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 6-Bromo-naphthalen-2-ol
5.1 Reimer-Tiemann reaction

O
OH
CHCl3, NaOH OH

Br EtOH, 80oC, 6 hr
Br
Reactant/Product Equivalents mmol Amount
6-Bromo-naphthalen-2-ol 1 67 15 g
Chloroform 3.8 257 30 ml
Sodium hydroxide 6 402 16.08 g
6-Bromo-2-hydroxy-1-naphthaldehyde 30.82 8g
(46% recovered yield)

12/8/2023 23
 6-Bromo-naphthalen-2-ol
5.2 Wittig reaction

O O

OH Ph3P=CHCOOEt OH

DCM, 6 hr
Br Br
Reactant/Product Equivalents mmol Amount
Set up with 1.2 g of substrate. 1.5 g of the product
6-Bromo-2-hydroxy-1-naphthaldehyde 1 5 1.2 g
was obtained, with a yield of 80%.
Wittig salt 1.6 8 3.31 g
Ethyl-3-(2-hydroxy-6-bromo-napthalen-1-yl) acrylate 1.5 g
(80% yield)

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 6-Bromo-naphthalen-2-ol
5.3 Pd/C catalytic hydrogenation
O O O O

H2 (g), Pd/C
OH dry MeOH, 2 hr OH

Br Br
O O O O

H2 (g), Pd/C
OH dry MeOH, 4 hr OH

Br

O O O O

OH H2 (g), Pd/C OH
dry MeOH, 10 hr
12/8/2023 Br 25
 6-Bromo-naphthalen-2-ol
5.4 Wilkinson hydrogenation

O O
O O

H2 (g), [RhCl(PPh₃)₃]
OH
OH Benzene, 3 hr
Br
Br
Reactant/Product Equivalents mmol Amount
Set up with 1 g of substrate. 0.9 g of the product was
Ethyl-3-(2-hydroxy-7-methoxynapthalen-1-yl) acrylate
obtained, with a yield of 90%. 1 3.1 1g
Ethyl 3-(2-hydroxy-6-bromo-naphthalen-1-yl) propanoate 0.9 g
(90% yield)

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 6-Bromo-naphthalen-2-ol
5.5 NaBH4 reduction

O O OH

NaBH4, dry MeOH

OH dry THF (3:1), 8 hr OH

Br Br
Reactant/Product Equivalents mmol Amount
Set up with 0.5 gpropanoate
Ethyl 3-(2-hydroxy-6-bromo-naphthalen-1-yl) of substrate. 0.3 1g of the product
1.5 0.5 g
was obtained, with a yield of 77%.
Sodium Borohydride 5 7.5 0.26 g
1-(3-hydroxypropyl)-6-bromo-naphthalen-2-ol 6 0.3 g
(77% yield)

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 4-Chloro-naphthalen-1-ol
6.1 Reimer-Tiemann reaction
OH OH O
CHCl3, NaOH

EtOH, 80oC, 6 hr
Cl Cl
Reactant/Product Equivalents mmol Amount
4-Chloro-naphthalen-1-ol 1 27 5g
Chloroform 4.8 129 15 ml
Sodium hydroxide 7 189 7.56 g
4-Chloro-1-hydroxy-2-naphthaldehyde 11.88 2.5 g
(44% recovered yield)

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 4-Chloro-naphthalen-1-ol
6.2 Wittig reaction
O
OH O
OH O
Ph3P=CHCOOEt
dry DCM, 8 hr

Cl
Cl
Reactant/Product Equivalents mmol Amount
Set up with 0.5 g of substrate.
4-Chloro-1-hydroxy-2-naphthaldehyde 1 0.6 g of the product
2.4 0.5 g
was obtained, with a yield of 89%.
Wittig salt 2.9 6.91 2.86 g
Ethyl-3-(1-hydroxy-4-chloro-napthalen-2-yl) acrylate 2.14 0.6 g
(89% yield)

12/8/2023 29
 4-Chloro-naphthalen-1-ol
6.3 Pd/C catalytic hydrogenation

OH O

OH O H2 (g), Pd/C
O
dry MeOH, 2 hr
O
Cl

Cl

OH O
H2 (g), Pd/C
OH O
O
dry MeOH, 4 hr
O

Cl

OH O OH O
H2 (g), Pd/C O
O
dry MeOH, 10 hr

Cl

12/8/2023 30
 4-Chloro-naphthalen-1-ol
6.4 Wilkinson hydrogenation

H2 (g), [RhCl(PPh₃)₃] OH O
OH O
Benzene, 3 hr O
O

Cl
Cl
Reactant/Product Equivalents mmol Amount
Set up with 1 g ofacrylate
Ethyl-3-(1-hydroxy-4-chloro-napthalen-2-yl) substrate. 0.9 g of
1 the product was3.6 1g
obtained, with a yield of 90%.
Ethyl 3-(1-hydroxy-4-chloro-naphthalen-2-yl) propanoate 3.24 0.9 g
(90% yield)

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 4-Chloro-naphthalen-1-ol
6.5 NaBH4 reduction

OH
OH O NaBH4, dry MeOH
OH
O dry MeOH (3:1), 8 hr

Cl
Cl
Reactant/Product Equivalents mmol Amount
Set up with 0.65 g of substrate. 0.5 g of the product
was obtained, with
Ethyl 3-(1-hydroxy-4-chloro-naphthalen-2-yl) a yield of 77%.
propanoate 1 2.74 0.65 g
Sodium Borohydride 5 13.7 0.44 g
2-(3-hydroxypropyl)-4-chloro-naphthalen-1-ol 0.5 g
(77% yield)

12/8/2023 32
 Learning outcomes
• 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.

• Through this internship, I have learned 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.

12/8/2023 37
 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.

2. Sarkar, Debayan. “Dearomatization- an Unsolved Riddle.” NIT Rourkela Institutional Repository, NIT Rourkela, 18
Dec. 2021.

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.

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.

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.

6. Tanaka, Nao, and Toyonobu Usuki. “Can Heteroarenes/Arenes Be Hydrogenated over Catalytic Pd/C under Ambient
Conditions?” European Journal of Organic Chemistry, vol. 2020, no. 34, 18 June 2020, pp. 5514–5522.

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