Convenient synthesis of 3-Hydroxyquinolines via dakin oxidation: A short synthesis of Jineol

Article abstract of DOI:10.1016/j.tetlet.2020.152294

A convenient synthesis of 3-hydroxyquinolines has been described via unprecedented Dakin oxidation of quinoline-3-carboxaldehydes. Subsequently, application of the methodology to a high yielding synthesis of quinoline alkaloid Jineol (1) is reported.

Full text of DOI:10.1016/j.tetlet.2020.152294

Journal Pre-proofs
Convenient synthesis of 3-Hydroxyquinolines via dakin oxidation: A short
synthesis of jineol
Sujit K. Ghorai, Mayukh Dasgupta, Piyali Dutta, Raphael Dumeunier, Sanjib
Mal, Rupesh Patre, Tapan Kumar Kuilya, Sitaram Pal, Bhanu N. Manjunath
PII:
S0040-4039(20)30761-9
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152294
TETL 152294
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 May 2020
18 July 2020
23 July 2020
Please cite this article as: Ghorai, S.K., Dasgupta, M., Dutta, P., Dumeunier, R., Mal, S., Patre, R., Kuilya, T.K.,
Pal, S., Manjunath, B.N., Convenient synthesis of 3-Hydroxyquinolines via dakin oxidation: A short synthesis of
jineol, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152294
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Convenient Synthesis of 3-Hydroxyquinolines via Dakin
Oxidation: A Short Synthesis of Jineol
Sujit K. Ghoraia*, Mayukh Dasguptaa, Piyali Duttaa, Raphael Dumeunierb,
Sanjib Mala, Rupesh Patrea, Tapan Kumar Kuilyaa, Sitaram Pala, Bhanu N.
Manjunatha*
-
2BF4
H2O2
Morpholine
HBr in AcOH
110 °C, 8 h
AcOH, 60 °C, 3 h
n-BuOH,
80 °C, 12 h
Jineol

Convenient Synthesis of 3-Hydroxyquinolines via Dakin
Oxidation: A Short Synthesis of Jineol
Sujit K. Ghoraia*, Mayukh Dasguptaa, Piyali Duttaa, Raphael Dumeunierb, Sanjib Mala,
Rupesh Patrea, Tapan Kumar Kuilyaa, Sitaram Pala, Bhanu N. Manjunatha*
aSyngenta Biosciences Pvt. Ltd., Santa Monica Works, Corlim, Ilhas, Goa, India-403110.
bSyngenta Crop Protection, Muenchwilen AG, Schaffhauestrasse, Stein, CH-4332.
Abstract: A convenient synthesis of 3-hydroxyquinolines has been described via unprecedented
Dakin oxidation of quinoline-3-carboxaldehydes. Subsequently, application of the
methodology to a high yielding synthesis of quinoline alkaloid Jineol (1) is reported.
Keywords: Quinoline, Quinoline-3-carboxaldehyde, 3-Hydroxyquinoline, Dakin Oxidation,
Jineol, Total synthesis
The quinoline core is a very common structural motif in both natural products and
synthetic organic molecules of biological interest.1 3-Hydroxyquinolines and their derivatives
possesses various pharmacological activities and also widely occur naturally.2 Jineol (1) is one
of such naturally occurring 3-hydroxyquinoline first isolated from the centipede Scolopendra
subspinipes in 1996 and reports to have antioxidant properties and shows cytotoxic activity in
vitro against the growth of various human tumor cell lines.3 Therefore, novel and innovative
synthetic methodologies for such 3-hydroxyquinolines are highly desirable. Most commonly
employed procedures for the synthesis of 3-hydroxyquinolines involve multi step synthesis
starting from suitably substituted aniline or indole via isatin.4 Direct transformation of 3-
functionalized quinolines such as 3-amino quinolines, 3-haloquinolines or quinoline-3-boronic
acids to the corresponding 3-hydroxyquinolines are also reported.5 All of these methodologies
either requires expensive metal catalysts or multistep synthesis of starting materials. Herein,
we report a simple and efficient methodology for the synthesis of 3-hydroxyquinolines from
quinoline-3-carboxaldehydes; which could be easily accessed in single step from aniline by the
reaction of vinamidinium salt.6 We have also shown that the methodology is applicable for the
shortest total synthesis of quinoline alkaloid Jineol (1).

There are ample numbers of reports available for direct conversion of substituted
benzaldehyde to the corresponding phenol via Dakin oxidation. In general, Dakin oxidation is
limited to use for the oxidation of o- or p-hydroxylated benzaldehydes by alkaline H2O2.7 In
some cases H2O2 mediated acid catalysed conversion of suitably substituted benzaldehyde to
the phenol are also reported.8 Hydrogen peroxide mediated Dakin oxidation of 4-hydroxy
quinoline-3-carboxaldehydes and m-CPBA mediated Dakin oxidation of 4-amino quinoline-
3-carboxaldehyde have also been reported however, no substrates scope were explored.9 To the
best of our knowledge there is no report for Dakin oxidation of quinoline-3-carboxaldehydes
containing no hydroxy or amine substitution. Therefore, we decided to investigate further to
develop an efficient and general methodology for the direct oxidation of quinoline-3-
carboxaldehydes to 3-hydroxyquinolines.
H2O2
AcOH, 60oC, 1 h
(90%)
4a
5a
Scheme 1. Dakin oxidation of 8-methylquinoline-3-carboxaldehyde (4a)
We commenced the optimization work with 8-methylquinoline-3-carboxaldehyde (4a)
and treated with different oxidizing agents under different conditions (such as m-CPBA, H2O2,
t-BuOOH, urea hydrogen peroxide etc.) both in acidic and alkaline conditions in different
solvents.10 In most of the cases instead of desired hydroxy quinoline 5a, acid of 4a was obtained
as major by-product. However, treatment of 4a with H2O2 (3.0 equiv.) in acetic acid at 60 ℃
afforded the best result and 8-methylquinoline-3-ol (5a) was obtained as the major product with
an isolated yield of 90% (Scheme1).11 It seems peracetic acid, which is generated in-situ from
acetic acid and hydrogen peroxide play the key role for the desired oxidation. This was
confirmed by doing the reaction with peracetic acid (3.0 equiv.) in acetonitrile under same
reaction condition, which afforded comparable result as H2O2/AcOH condition (for details see
supporting information).10

H2O2, AcOH
60 oC, 1-3 h
4a-4j
5a-5j
5b; 84%
5e; 89%
5h; 55%
5a; 90%
5c; 75%
5f; 85%
5d; 58%
5i; 53%
5g; 43%
6k
5j; 40%
5k; 0%
Table 1. Scope of Dakin oxidation of quinoline-3-carboxaldehydes to 3-hydroxyquinolines.
To determine scope of the reaction, a brief array of quinoline-3-carboxyldehydes (Table
1, 4a-4j) was subjected under the optimized condition. Obtained results indicate that both the
steric bulk at 8-position of quinoline-3-carboxldehydes as well as electronic nature of the
substituents in quinoline ring play important role for the success of the desired Dakin reaction.
Quinoline-3-carboxaldehyde having methyl (4a) or methoxy (4c) at 8-position afforded higher
yield than quinoline-3-carboxaldehyde have ethyl (4b) or ethoxy (4d) at 8-position (Table 1,
5a-5d) could be due to higher steric bulk of methyl and methoxy. All the 8-substituted
quinoline-3-carboxaldehydes afforded desired hydroxyl product (Table 1, 5a-5i) in good to
excellent yield. On the other hand, under same reaction condition yield for non-substituted
quinoline-3-carbaxldehyde found to be low (Table 1, 5j) and major by-product obtained was
the quinoline-3-carbaxlic acid. This is probably due to less steric bulk of hydrogen at 8-position
compare to methyl or ethyl substitution. The analogy was further confirmed with the reaction
of pyridine-3-carboxldehydes. Unlike quinoline-3-carboxaldehyde, pyridine-3-carboxaldehyde
has no steric bulk near the nitrogen and under same condition it failed to give any desired
hydroxyl product (5k) instead it afforded pyridine-3-carboxylic acid (6k) as the sole product.
Presence of highly electron donating substituents (OMe or OEt) at 8-position afforded lower
yield (Table 1, 5c and 5d); which is contrary to the yield in Dakin reaction. Presence of electron
donating moiety is known to facilitate the formation of Dakin oxidation product in

benzaldehyde system. However, when the products in these reactions were analysed, it was
found that the starting aldehydes were fully consumed, and the major by-product formed is N-
oxide of the desired 3-hydroxy quinolines. This could be due to increase in electron density in
the N-containing ring of quinoline 3-carboxaldehyde, which is expected to increase the
reactivity towards formation of Dakin oxidation product as well as N-oxide product. The same
trend was observed in the reaction of 6, 8-dimethoxy 3-carboxaldehyde (4g), which is even
more electron rich than 8-mono alkoxide quinoline 3-carboxaldehydes and afforded lower yield
of hydroxyl product (5g) along with more of corresponding N-oxide product. These results
indicate that too much enrichment of the electron density in the ring is not suitable for the
reaction. However, both the di-methyl substituted quinoline 3-carboxaldehydes afforded
similar yield (Table 1, 5e, 5f) as mono methyl substituted quinoline 3-carboxaldehyde (5a).
Probably the mild electron donating property of one extra methyl in 4e or 4f is not enough to
increase electron density in N-containing ring to form considerable amount N-oxide by-product,
therefore, there is no significant impact on the yield of desired 5e or 5f. Presence of electron
withdrawing group at 8-position of quinoline-3-carboxaldehyde (Table 1, 5h, 5i) also
participated in desired Dakin oxidation though in low yields.
Having a general methodology for the synthesis of 3-hydroxy quinoline in hand, we
wanted to implement the same for the synthesis of 3-hydroxyquinoline alkaloid Jineol (1).
Previous Works:
5 steps13
(Overall yield: 14.4 %)
9 steps14
(Overall yield: 22.34 %)
1: Jineol
This Work:
3 steps
(Overall yield: 38.25 %)
Scheme 2. Synthesis of Jineol (1) from aniline derivatives in the context of present work.
So far, there are three reports known for the synthesis of Jineol (1). One of them are
direct hydroxylation of pre-functionalized quinoline moiety.12 Two other reports starts from
aniline derivatives, which involve multi-step sequences and poor overall yields (Scheme 2).13,

14
In our strategy, we proposed a short synthesis starting from 2-methoxy aniline (2) via
synthesis of quinoline carboxaldehyde 4c followed by Dakin oxidation and de-methylation.
2BF4-
3
n-BuOH, Morpholine,
80 oC, 12 h
2
4c
(85%)
H2O2, AcOH,
60 oC, 1 h
(75%)
33% HBr in AcOH
110 oC, 8 h
(60%)
5c
1: Jineol
Scheme 3. Synthesis of Jineol (1) via Dakin oxidation.
Our initial attempts for the synthesis of quinoline carboxaldehyde 4c from 2-methoxy
aniline (2) with the reaction of vinamidinium salt 3 in EtOH or AcOH6 found to be low yielding.
However, when the reaction was performed in n-BuOH in the presence of morpholine (3.0
o
equiv.) at 80 C, desired 8-methoxy quinoline-3-carboxaldehyde (4c) was obtained in 85%
yield (Scheme 3). To our gratification, 8-methoxyquinoline-3-carboxaldehyde was nicely
converted to the desired hydroxy intermediate 5c in 75% yield under previously optimized
condition. The de-methylation of 5c was found to be critical and low yielding. After careful
examination of the reagents (e.g. BBr3, TMSI, Py.HCl, HI, MgBr2 etc.) 33% HBr in acetic acid
found to be the best for de-methylation and afforded desired Jineol (1) in 60% yield. The
structure of synthesized Jineol (1) was confirmed by complete spectral (IR, 1H, 13C and HRMS)
analysis. The melting points and spectral data were in excellent agreement with the reported
values.13
In summary, we have introduced a convenient and simple methodology for the synthesis
of 3-hydroxy quinolines via unprecedented Dakin oxidation of quinoline-3-carboxaldehydes.
The methodology proved to be useful in achieving a short and high yielding total synthesis of
Jineol (1). Efforts are currently underway in our research group to apply this method to the
synthesis of natural products having 3-hydroxyquinoline moiety and other potentially valuable
organic molecules.

Acknowledgments
Authors would like to thank Syngenta Biosciences Pvt. Ltd., Goa, India management and
analytical department for their kind support and allowed to perform the experiments.
References and notes
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11. General procedure for the synthesis of 3-Hydroxyquinolines 5a-5j: To a stirred
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Highlights:
 Simple methodology for the synthesis of 3-hydroxy quinolines.
 Unprecedented Dakin oxidation of quinoline-3-carboxaldehydes.
 Substituted quinoline-3-carboxaldehydes are more suitable for Dakin oxidation.
 Efficient total synthesis of quinoline alkaloid Jineol via Dakin oxidation.