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Efficient Melatonin Synthesis Methods

This document discusses recent advancements in the synthesis of melatonin, highlighting various methods developed by different research groups. Key strategies include the use of cyclic enamides, hydroformylation techniques, and novel synthetic pathways yielding varying percentages of melatonin. The document also summarizes the efficiency and novelty of these methods, providing insights into their potential for industrial application.

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14 views6 pages

Efficient Melatonin Synthesis Methods

This document discusses recent advancements in the synthesis of melatonin, highlighting various methods developed by different research groups. Key strategies include the use of cyclic enamides, hydroformylation techniques, and novel synthetic pathways yielding varying percentages of melatonin. The document also summarizes the efficiency and novelty of these methods, providing insights into their potential for industrial application.

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HETEROCYCLES, Vol. 60, No. 10, 2003, pp.

2349 - 2354,
Received, 29th May, 2003, Accepted, 22nd August, 2003, Published online, 25th August, 2003

SHORT SYNTHESES OF MELATONIN

Helmut M. Hügel*and Faizul Nurlawis

RMIT University, Department of Applied Chemistry, GPO Box 2476V


Melbourne 3001 Victoria Australia E-mail: [Link]@[Link]
Fax:+61396391321

Abstract - The chemistry concerning the most recent syntheses of melatonin (N-
acetyl-5-methoxytryptamine) is described.

INTRODUCTION
Biological time is measured in Circadian rhythms on a scale of 24 hours and these rhythms are generated
by molecular mechanisms that are present in many different tissues around the body. This concert of
rhythms is synchronized by the master clock found in the brain which controls time-dependent rhythms
according to light impacting from the environment. The production of melatonin is an expression of
Circadian rhythmic activity and may also reflect Circadian control by the master clock.

Melatonin Synthesis
For the laboratory synthesis of melatonin1 (N-acetyl-5-methoxytryptamine), the preparation of 5-
methoxytryptamine in a one pot reaction is desirable but this has been a low yielding reaction because of
the problems associated with making the required aminobutanal. Two research groups have developed
different strategies to improve this chemistry.

Marais and Holzapfel,2 by generating cyclic enamides and carbinolamines which act as surrogates for N-
acylbutanal and Sheldon and coworkers3 who used catalytic conditions to selectively hydroformylate N-
allylacetamide to furnish the elusive 4-acetamidobutanal, have completed short syntheses of melatonin.

The cyclic enamides as synthetic equivalents of amino aldehydes were prepared from pyrrolidine by
oxidation in aqueous alkaline peroxodisulfate and 0.5% silver nitrate to form the trimer which on heating
with an acyl chloride directly formed the enamides. This was followed by Fischer-indole synthesis with
p-methoxyphenylhydrazine hydrochloride in aqueous acetic acid-ethanol mixture under reflux for 20 min.
Melatonin (Scheme 1A) was isolated in overall 26% yield.

Scheme 1A NHCOR

Na2 S2 O8 MeO NHNH2 MeO


NaOH N N 800 C RCOCl

N 0.5% AgNO3 N N Base N H+ / H2 O / EtOH N


H ~ 60% H
COR
R = Me 58% R = Me 75%
R = Ph 67% R = Ph 85%

An efficient extension of this approach was achieved by starting with 2-pyrrolidone and pyroglutamic
acid (Scheme 1B) providing carbamate deriatives of 5-methoxytryptamine (80%) and l-tryptophan (87%).
Scheme 1B
NHCO 2CH 2Ph
R
NaH LiEt3 BH MeO NHNH2
CbzCl THF MeO

R N O R N O R N OH AcOH N
H CO 2CH 2Ph CO 2CH 2Ph H

R=H R=H R = H (2 steps) 84% R = H 95%


R = CO2 H R = CO2 Bu-t R = CO2 Bu-t (2steps) 91% R = CO2 Bu-t >95%

The critical step in the second approach to melatonin synthesis was the investigation of the
hydroformylation conditions required to selectively convert N-allylacetamide into N-acetylbutanal. Thus
in a one pot reaction sequence (Scheme 2), allylamine was acetylated, regioselectively hydroformylated
to provide N-acetylbutanal with the aid of Rh-Xantphos catalyst system in an inverted two phase
toluene/water solvent system. Subsequent hydrazone formation with 4-methoxyphenylhydrazine and
Fischer-indole synthesis yielded 44% melatonin when extracted from the aqueous phase. The
experimental details are available as electronic supplementary information from supplied website.

Scheme 2
H2 / CO
Rh(acac)(CO)2 MeO NHNH2
Ac2 O Xantphos, 900 C
NH2 NHAc NHAc 44%
O melatonin
toluene:water
H

Xantphos = 4,5-is(diphenylphosphino)-9,9-dimethylxanthene

Furthermore, a method for regioselectively hydroformylating functionalized anilines has been developed
by Dong and Busacca4, leading to the syntheses of tryptamines and tryptophol. Employing the Heck
reaction conditions, meta- and para- fuctionalized 2-haloanilines and N-tosylallylamine or N,N-di-Boc-
allylamine with Pd(OAc)2 catalysis were converted into Heck adducts which underwent hydroformylation
in the presence of H2/CO (1:1) and HRh(CO)(PPh3)3 to yield tryptamines or tryptophol (10 examples,
yields 32-73%) (Scheme 3)
The application of this Heck and hydroformylation reaction sequence with 2-bromo-4-methoxyaniline
and N-allylacetamide would make melatonin.

Scheme 3
NR 1R2
N-tosylallylamine H O
5% Pd(OAc)2
(o-Tol)3 P, TEA,
X MeCN, reflux NR 1R2 NR 1R2
[Rh]
50-78% NH2 H2 / CO NH2 32-73% R N
R NH2 R R H

X = Br or I
R = variable
R1 R2 = (BOC)2

Somei and coworkers5 have developed their N-hydroxyindole chemistry to transform tryptamine in six
steps into melatonin with an overall 55% yield. In the key step, the introduction of the 5-methoxy group
was achieved by reacting the substrate, 1-hydroxy-N-acetyltryptamine with 20 % BF3-methanol solution
and refluxing the mixture for 30-40 min. (Scheme 4).
Scheme 4

NH2 NHR NHR NHR

Ac2 O or
ClCOOMe Et3 SiH Na2 WO4 20% [Link] 52%
melatonin
N N N 30% H2 O2 N R = Ac
H H H OH
R = Ac R = Ac, 99% R = Ac, 66%
R = COOMe R = COOMe, 97% R = COOMe, 65%

20% [Link]

94%

NH2 NHCOOMe

Ac2 O MeO H2 O-NaOH MeO


55%
melatonin
92% N 99% N
H H

Amat and coworkers6 recently described the preparation of 4-, 5-, and 6-methoxy substituted 3-lithio-1-
(trialkylsilyl) indoles and their reaction with electrophiles. When N-tosyl aziridine was the electrophile
(Scheme 5), their methodology produced melatonin in overall 11% yield.

Scheme 5
NHTs
1. t-BuLi / -780 C
Br
1. Base / ClSiR 3 MeO 2. BF3. OEt2
MeO N
2. NBS / THF MeO
Ts
N 78% (2steps) N
H SiR 3 50% N
SiR 3

Bu 4NF 89%

NH2 NHTs

11% Ac2 O MeO Na / NH3(l) MeO


melatonin
55% N 65% N
H H

Om Reddy and coworkers7 have revisited literature syntheses of melatonin with the objective of
developing a cost effective and industrial process that avoids the use of expensive chemicals, is a short
process, has no low yielding steps and requires limited purification of intermediates and products.
Scheme 6 O
Br Cl COOEt O

Phth-H Pht h Cl Pht h I Pht h


COOEt
acetone acetone
K2 CO 3 NaI 90% (3 combined steps)

N2 + X-
O
Japp
Klingemann
N = Phth Reactrion

O OMe

NH2 Phth

Hydrolysis
Deprotection
65% Ac2 O MeO Decarboxylation MeO
melatonin COOEt
96% N 65% N
H H
75% (2 steps)

Using the Japp Klingemann reaction to form the tryptamine ring system, the six step process (Scheme 6)
has been carefully optimized, yielded 65% melatonin in ~99.5% purity and has been performed on 5-10
kg scale.

In a new approach to the synthesis of melatonin and related compounds, Pfau and coworkers8 found that
the Michael addition of the N-cyclohexylimine of commercial1,4-cyclohexanedione mono- ethylene ketal
with maleic anhydride as shown in Scheme 7 provides the indole-3-acetic acid skeleton. This was
followed by the reaction sequence: esterification, transacetalization and aromatization which produced the
key compound methyl 1-benzyl-5-methoxy-1 H-indole-3-acetate in 74% yield from the starting material
without purification of the intermediates. Side chain transformations and indole-N-deprotection gave
melatonin in around 20% overall yield.
Scheme 7
O
O
O COOH
O H O O
O O
O O
O O O O
O
N N
N NHBn Bn
Bu Bn

COOMe COOH
Esterification O
MeO
Transacetalization
O O O
N 91% (4 steps) N
Bn Bn
Scheme 7 continued

POCl3
82%
Aromatisation
NHAc
1. NH3
COOMe 2. LiAlH4
MeO 3. Na / NH3 MeO
4. Ac2 O
N N
27.5% (4 steps)
Bn Bn
21%

Sortais and coworkers9 have applied their free radical reaction methodology to a route to indolines which
was elaborated to give in seven steps a 32% overall yield of melatonin as illusrated in Scheme 8. The first
step involved an intermolecular catalytic radical addition of a xanthate to a protected N-allylaniline which
was followed by stoichiometric radical formation and indoline ring closure. The three carbon ester side
chain was hydrolysed and the acid underwent a Curtius rearrangement using diphenylphosphoryl azide, in
situ acetylation followed by simultaneous N-mesyl group deprotection / aromatization using 95%
concentrated sulfuric acid. Alternatively, when the indoline ring was aromatized prior to the side chain
refunctionalisation, the six step sequence gave slightly lower yields of melatonin.

OEt
Scheme 8
O

OEt 0.2 eq. Lauroyl peroxide MeO


MeO
SCSOEt
+ O
1,2-dichloroethane, reflux N
N SCSOEt
79% SO 2Me
SO 2Me
1.2 eq. Lauroyl peroxide
73%
1,2-dichloroethane, reflux

HO EtO
O 95% H2 SO4 O
MeO MeO
O0C, 30 min
N N
H 81%
SO 2Me

1. [PhO]2P(O)N3, 1. conc. HCl, rt


Et3N, THF, rt 2. [PhO]2P(O)N3,
2. Ac2O / AcOH 5/95 69% Et3N, THF, rt 32%
reflux 3. Ac2O / AcOH 5/95
3. K2CO3 , MeOH, rt reflux
4. K2CO3 , MeOH, rt

AcHN AcHN
95% H2 SO4 MeO
MeO
O0C, 30 min N
N
H 72% SO 2Me
overall 32%

In the last five years, there have been new approaches and improvements to existing methods of
tryptamine synthesis. This has translated into shorter routes and more efficient methods of melatonin
synthesis as summarized in the Table.
Table

Novelty of Method Synthetic Steps % Melatonin Researchers

Use of N-acetylbutanal 3 26 Marais and


surrogate Holzapfel
Generation of N- 3 steps, one pot 44 Sheldon and
acetylbutanal coworkers
Hydroformylation of 3 32-73 [tryptamines] Dong and
anilines Busacca
5-Methoxy group 6 55 Somei and
introduction coworkers
Ethanamide side chain 7 11 Amat and
introduction coworkers
Large scale synthesis 6 65 Om Reddy et al.

Michael addition, 9 21 Pfau et al.


indole ring formation
Free radical synthesis 7 32 Sortais and
of indolines coworkers

REFERENCES

1. H.M.Hügel and D.J. Kennaway, Org. Prep. Proc. Int., 1995, 27, 1.

2. W. Marais and C.W. Holzapfel, Synth. Commun., 1998, 28, 3681.

3. G. Verspui, G. Elbertse, F.A. Sheldon, M.A.P.J. Hacking and R.A. Sheldon, Chem. Commun., 2000,
1363.

4. Y. Dong and C.A. Busacca, J. Org. Chem., 1997, 62, 6464.

5. [Link], Y. Fukui, M. Hasegawa, N. Oshikiri and T. Hayashi, Heterocycles, 2000, 53, 1725.

6. M. Amat, F. Seffar, N. Llor and J. Bosch, Synthesis, 2001, 267.

7. C. Prabhakar, N.V. Kumar, M.R. Reddy, M.R. Sarma and G. Om Reddy, Organic Process Research
& Development, 1999, 3, 155.

8. G. Revial, I. Jabin, S. Lim and M. Pfau, J. Org. Chem., 2002, 67, 2252.

9. B. Quiclet-Sire, B. Sortais and S.Z. Zard, Chem. Commun., 2002, 1692.

Common questions

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Reddy's team optimized a six-step process using the Japp Klingemann reaction for large-scale melatonin synthesis, achieving yields of 65% with 99.5% purity on a multi-kilogram scale . This process was designed to be cost-effective by avoiding expensive chemicals and minimizing purification steps, supporting scalability and industrial application .

Fischer-indole synthesis is critical in multiple strategies for synthesizing melatonin. It serves as the key step for forming the indole ring system after major intermediate compounds are achieved. For instance, Sheldon and coworkers utilized this method following the hydrazone formation to obtain melatonin . Marais and Holzapfel used the Fischer-indole synthesis with cyclic enamides as surrogates for N-acylbutanal .

Key strategies for improving melatonin synthesis include the use of synthetic equivalents for key intermediates, such as cyclic enamides used as N-acylbutanal surrogates by Marais and Holzapfel , and the hydroformylation of N-allylacetamide to N-acetylbutanal using a Rh-Xantphos catalyst by Sheldon and coworkers . Additionally, Pfau and coworkers used Michael addition to generate the indole skeleton via subsequent esterification, transacetalization, and aromatization .

Pfau et al.'s method differs by utilizing Michael addition to construct the indole-3-acetic acid skeleton followed by esterification, transacetalization, and aromatization, a sequence allowing the direct formation of a key indole derivative. Side chain transformations after this setup produced melatonin in around 20% yield, highlighting a novel pathway that differs from traditional approaches relying on stepwise indole synthesis or condensation reactions .

Sortais and coworkers applied free radical methodologies by employing intermolecular catalytic radical addition of a xanthate to N-allylaniline, followed by a series of stoichiometric radical formations and cyclization steps. These lead to the indoline system, which is further elaborated to give melatonin in a seven-step process with a 32% overall yield .

Somei and coworkers introduced the 5-methoxy group by reacting 1-hydroxy-N-acetyltryptamine with a 20% boron trifluoride methanol solution under reflux conditions for 30-40 minutes, leading to a melatonin yield of 55% .

Dong and Busacca developed conditions for regioselectively hydroformylating functionalized anilines through a sequence involving Heck reactions and hydroformylation, facilitating improved synthesis of tryptamines with yields of 32-73%. This method was pivotal for refining tryptamine production, necessary for melatonin synthesis .

Challenges include achieving high yields with high purity while minimizing costs related to complex catalysts or reagents, as exemplified by the Reddy approach which achieved high purity and yield but required innovative process optimization. Additionally, scalability often requires balancing reaction conditions, purification steps, and material costs, which remain significant barriers .

The Rh-Xantphos catalyst system allows for regioselective hydroformylation of N-allylacetamide to form N-acetylbutanal, a crucial intermediate, in a one-pot reaction. This results in enhanced efficiency and a fairly high yield (44%) for the melatonin synthesis . However, such catalytic systems may require special handling and conditions, potentially increasing complexity and cost .

Scheme 1A represents a strategic approach in the laboratory synthesis of melatonin where cyclic enamides act as surrogates for N-acylbutanal, demonstrating an efficient pathway to circumvent low-yielding traditional methods. The process involves oxidation of pyrrolidine and subsequent Fischer-indole synthesis, resulting in a 26% yield of melatonin .

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