Efficient synthesis of Nb-thioacyltryptamine derivatives by a three-component Willgerodt-Kindler reaction, and their transformation to 1-substituted-3,4-dihydro-β-carbolines

Article abstract of DOI:10.1016/j.tetlet.2015.09.007

A practical and efficient synthesis of N_b-thioacyltryptamines has been developed via the three-component reaction of tryptamine, various aldehydes and elemental sulfur. The products were obtained in moderate to excellent yields and proved to be

Full text of DOI:10.1016/j.tetlet.2015.09.007

Accepted Manuscript
Efficient synthesis of N b-thioacyltryptamine derivatives by a three-component
Willgerodt–Kindler reaction, and their transformation to 1-substituted-3,4-di-
hydro-β-carbolines
Mátyás Milen, Péter Slégel, Péter Keglevich, György Keglevich, Gyula Simig,
Balázs Volk
PII:
S0040-4039(15)30049-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.007
TETL 46679
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 March 2015
16 August 2015
2 September 2015
Please cite this article as: Milen, M., Slégel, P., Keglevich, P., Keglevich, G., Simig, G., Volk, B., Efficient synthesis
of N b-thioacyltryptamine derivatives by a three-component Willgerodt–Kindler reaction, and their transformation
to 1-substituted-3,4-dihydro-β-carbolines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.09.007
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GRAPHICAL ABSTRACT
Efficient synthesis of Nb-thioacyltryptamine derivatives by a three-
component Willgerodt–Kindler reaction, and their transformation to 1-
substituted-3,4-dihydro-β-carbolines
Mátyás Milena, Péter Slégela, Péter Keglevichb, György Keglevichb, Gyula Simiga, Balázs
Volka,*
a Egis Pharmaceuticals Plc., Directorate of Drug Substance Development, P.O. Box 100, H-
1475 Budapest, Hungary
b Budapest University of Technology and Economics, Department of Organic Chemistry and
Technology, P.O. Box 91, H-1521 Budapest, Hungary
* To whom correspondence should be addressed. Phone: +36 1 8035874, fax: +36 1 8035613,
e-mail: volk.balazs@egis.hu.
ABSTRACT
A practical and efficient synthesis of Nb-thioacyltryptamines has been developed via the
three-component reaction of tryptamine, various aldehydes and elemental sulfur. The products
were obtained in moderate to excellent yields and proved to be valuable intermediates for the
syntheses of 3,4-dihydro-β-carbolines, a compound family of biological significance.
KEYWORDS
Willgerodt–Kindler reaction; Three-component reaction; Tryptamine; Thioamides; β-
Carbolines

INTRODUCTION
Thioamides are an important functional group in organic and medicinal chemistry.1,2 In
particular, compounds bearing a thioamide moiety have been reported as useful intermediates
in the synthesis of natural products3 and other biologically active heterocycles.4‒7 Thioamides
are structural analogues of carboxamides, however, they possess different chemical
behaviour.2,8 Recently, the physical and biological properties of peptide derivatives containing
thioamide functional groups have been extensively studied.9‒12 Finally, thioamide containing
chiral compounds have been utilised as catalysts in asymmetric acylation.13,14 Due to the great
interest in thioamides, various methodologies for their preparation have been described in the
literature.15‒19
In continuation of our efforts to develop synthetic methods that can be applied to the field of
indole chemistry,20‒22 we herein describe a simple and efficient procedure for the preparation
of various N-[2-(1H-indol-3-yl)ethyl]carbothioamides (Nb-thioacyltryptamines, 1) via the one-
pot, three component reaction of tryptamine, an aldehyde and sulphur, as well as their
transformation into 1-substituted-3,4-dihydro-β-carboline derivatives (2, Scheme 1).
Scheme 1
β-Carbolines, incorporating a tricyclic pyrido[3,4-b]indole scaffold, form a prominent group
of alkaloids23‒25 which along with their reduced dihydro- and tetrahydro-β-carboline
analogues are found in various plants, mammals and marine invertebrates.26‒28 Both simple
and complex β-carboline derivatives possess a broad spectrum of biological and
pharmacological activities including antimicrobial,29 antimalarial,30 antithrombotic,31
parasiticidal,32 anti-HIV,33 anti-Alzheimer,34 and antifungal effects.35
While the widely used Bischler–Napieralski ring closure reaction of Nb-acyltryptamines
leading to 3,4-dihydro-β-carbolines (2) typically requires harsh conditions, the reaction
starting from the thio analogue 1 proceeds under mild, non-acidic conditions by heating in the
presence of an alkylating reagent (e.g. MeI, BnBr, allyl bromide).36‒38 This permits the
2

synthesis of β-carbolines with substituents that are sensitive to the reagents used in the
Bischler–Napieralski cyclisation. For example, Czarnocki and co-workers reported the
enantioselective synthesis of (1R)-1-(hydroxymethyl)-2-acetyl-1,2,3,4-tetrahydro-β-carboline
(6) in 98% ee utilising L-(+)-tartaric acid, as a cheap, natural source of chirality, for the
reduction of 3,4-dihydro-β-carboline derivative 5 (Scheme 2). Notably, attempted ring closure
of amide 3 to directly give compound 5 under typical Bischler–Napieralski conditions was
unsuccessful.39
Scheme 2
The key cyclisation intermediate, Nb-thioacyltryptamines (1) can be synthesised by two
methods. Yamada and co-workers prepared the required thioamides by the reaction of
tryptamine and the ethyl esters of dithiocarboxylic acids40 (Method A, Scheme 3). The
drawback of this method is the limited access and high price of dithioesters. The second
approach is a two-step process comprising of the acylation of tryptamine and subsequent
thionation using Lawesson’s reagent, a thionation agent of low atom efficiency36‒38 (Method
B, Scheme 3).
3

Scheme 3
We decided to apply the Willgerodt–Kindler reaction, which involves the reaction of an
amine, aldehyde and elemental sulfur, to give the corresponding Nb-thioacyltryptamines
(Method C, Scheme 3). Willgerodt described the synthesis of terminal amides or the
ammonium salt of the corresponding carboxylic acids from ketones and aqueous ammonium
polysulfide.41 Originally, the reaction was limited to alkyl aryl ketones, however, this was
later extended to aliphatic ketones, aldehydes and acetals.42 Kindler reported a modification of
the Willgerodt procedure using elemental sulfur and dry amines instead of aqueous
ammonium polysulfide.43 This preparation of thioamides is generally referred to as the
Willgerodt–Kindler reaction.19,44 Although, several accounts report the transformation of
related phenylethyl amines into the corresponding thioacylphenethylamines,45‒48 to the best of
our knowledge, the Willgerodt–Kindler reaction has not been applied to the preparation of
this family of compounds.
RESULTS AND DISCUSSION
Initially, a mixture of tryptamine (7), benzaldehyde (8a) and elemental sulfur were treated
under the standard conditions for the Willgerodt–Kindler reaction, using dimethylformamide
as the solvent at 110 °C (Scheme 4).49‒51
4

Scheme 4
Table 1. The synthesis of Nb-thioacyltryptamine derivatives (1a–r)
Entry
1
R
Product Yield (%)
C6H5
94
60
67
90
73
79
87
90
73
66
57
83
93
95
59a
82
83
35
1a
1b
1c
1d
1e
1f
2
4-BrC6H4
3
4-O2NC6H4
4-F3CC6H4
4-[(HO)2B]C6H4
4-PhOC6H4
3-FC6H4
4
5
6
7
1g
1h
1i
8
3-PhOC6H4
3-NCC6H4
3,5-(MeO)2C6H3
i-Bu
9
10
11
12
13
14
15
1j
1k
1l
furan-2-yl
thiophen-2-yl
pyridin-3-yl
indol-3-yl
1m
1n
1o
1p
1q
1r
16 5-Cl-benzothiophen-2-yl
17
18
naphthalen-2-yl
9H-fluoren-2-yl
a Reaction time was 4 h.
The reaction proceeded smoothly and resulted in the formation of the desired product 1a
within 1 h in 94% yield (Table 1, entry 1). Next, we turned our attention to the investigation
of the scope and limitations of this reaction using a series of aldehydes (Table 1). Thioamides
1b–j starting from meta- or para-, mono- or disubstituted benzaldehydes 8b–j were obtained
in variable yields (60–90%, entries 2–10). Various functional groups on the aromatic ring
were well tolerated under the examined reaction conditions. The reaction was also
investigated using an aliphatic aldehyde, isovaleraldehyde (8k), giving the corresponding
thioamide (1k) in 57% yield (entry 11). Various heterocyclic carbaldehydes (8l–p) were
applied to the synthesis of thioacyltryptamines and the reaction proceeded efficiently with
5

furfural (8l), thiophene-2-carbaldehyde (8m), nicotinaldehyde (8n), and 5-chloro-1-
benzothiophene-2-carbaldehyde (8p) (entries 12–14 and 16). However, the reaction of indole-
3-carbaldehyde (8o) took four times longer and the yield of the product (8o) was only 59%
(entry 15). Finally, the Willgerodt–Kindler reaction was investigated with naphthalene-2-
carbaldehyde (8q) and 9H-fluorene-2-carbaldehyde (8r) giving the corresponding products
(1q and 1r) in 83% and 35% yields, respectively (entries 17, 18). The low yield and by-
products observed in the latter reaction might be explained by the steric hindrance of the
bulky aldehyde 8r and the facile formation of fluorene-type radical species resulting from
radical side reactions.
After the successful preparation of thioamides 1, the ring closure reaction of representative
thioamides (1b–d,f,h,i,m,p,q) was studied (Scheme 5). The corresponding 1-substituted-3,4-
dihydro-β-carboline derivatives (2a–i) were synthesized in reasonable to good yields (61–
90%) according to literature procedure36,39 using 5 equiv. of CH3I in boiling acetone (Table
2).
Scheme 5
Table 2. The synthesis of 1-substituted-3,4-dihydro-β-carboline derivatives (2a–i)
Entry
R
Starting Product
material
Yield
(%)
1
2
3
4
5
6
7
8
9
4-BrC6H4
4-O2NC6H4
75
89
78
72
68
70
90
61
67
1b
1c
2a
2b
2c
2d
2e
2f
4-F3CC6H4
1d
1f
4-PhOC6H4
3-PhOC6H4
1h
1i
3-NCC6H4
thiophen-2-yl
5-Cl-benzothiophen-2-yl
naphthalen-2-yl
1m
1p
1q
2g
2h
2i
6

All Nb-thioacyltryptamine derivatives (1a–r) and 1-substituted-3,4-dihydro-β-carbolines (2a–
1
i) were characterized by IR, H NMR and 13C NMR spectroscopy, and HRMS. Products 1a40
and 2a52 have previously been described and fully characterized, compounds 2b,53 2c,54 and
2i55 are known but poorly characterized, while compounds 1b–r, 2d–h are novel.
In summary, we have described a simple and efficient method for the preparation of Nb-
thioacyltryptamine derivatives using a three-component reaction of the corresponding
aldehyde, tryptamine and elemental sulfur. The advantages of this procedure are the one-step
approach, short reaction times, good yields, inexpensive starting materials and the wide
variety of aldehydes that can be used. In addition, a representative set of Nb-
thioacyltryptamines were transformed to the appropriate 1-substituted-3,4-dihydro-β-
carboline derivatives.
Supporting information
Preparation and characterization of the title compounds. This material is available free of
charge via the internet.
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