Three-component reaction between alkynes, elemental sulfur, and aliphatic amines: A general, straightforward, and atom economical approach to thioamides

Article abstract of DOI:10.1021/ol403345e

A general, straightforward, and atom-economical three-component synthesis of thioamides from alkynes, elemental sulfur, and aliphatic amines has been developed.

Full text of DOI:10.1021/ol403345e

Letter
pubs.acs.org/OrgLett
Three-Component Reaction between Alkynes, Elemental Sulfur, and
Aliphatic Amines: A General, Straightforward, and Atom Economical
Approach to Thioamides
Thanh Binh Nguyen,* Minh Quan Tran, Ludmila Ermolenko, and Ali Al-Mourabit
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
S
* Supporting Information
ABSTRACT: A general, straightforward, and atom-economical
three-component synthesis of thioamides from alkynes, elemental
sulfur, and aliphatic amines has been developed.
hioamide moieties1 are among the most widely used
Table 1. Survey of Reaction between Phenylacetylene,
Elemental Sulfur, and 2-Phenethylamine
a
Tfunctional groups in the synthesis of sulfur-containing
molecules,2 and other compounds3 including heterocycles4 and
natural products.5 Moreover, the thioamide group, an isosteric
replacement of the amide group,6 is present in a variety of
bioactive molecules although the presence of a thioamide group
c
is very rare in natural products.7 Replacement of the oxygen
atom by a sulfur one in the carboxamide moieties in peptides
and other amide compounds has been used to modify the
stability,8 biological,9 physical,10 and catalytic11 activities of the
target molecules or to act as an efficient tool for monitoring
structural changes in proteins.12
entry
catalyst
V pyridine (mL)
temp (°C)
conversion (%)
1
−
−
−
−
0
100
80
60
50
60
60
60
60
60
60
50
>95
>95
>95
85
2
0
3
0
4
0
5
−
0.5
0.5
0.5
0.5
0.5
0.5
0.5
>95
93
6
CuCl
NiCl2
CoCl2
MnCl2
Although a wide range of preparative methods of thioamides
have been developed, there is an ongoing search for new
methods which should (1) be operationally simple, (2) be
based on an atom-, step-, and redox-economical trans-
formations, (3) use readily available and inexpensive starting
materials, and (4) tolerate a wide range of functional groups
that are generally incompatible with Lawesson’s reagent and
other known reaction conditions. As a consequence of our
recent efforts on the development of new reactions taking
advantage of the unique and interesting physicochemical
properties of elemental sulfur,13 we were eager to search for
a general three-component approach to thioamides starting
from amines, elemental sulfur, and alkynes (Scheme 1). Indeed,
such an approach has been described at 145 °C and higher
temperatures by simple heating14 or under microwave
irradiation15 for phenylacetylene and stable secondary amines
(morpholine,14a dimethylamine16) or ammonia14a,b and for
unsubstituted acetylene and unfunctionalized simple amines to
provide thioacetamides or dithiooxalodiamides17 under un-
7
90
8
72
9
81
b
10
11
Ag2O
>95
85
b
Ag2O
a
Reaction conditions: 2-phenethylamine (5 mmol), sulfur (10 mmol,
320 mg), phenylacetylene (7.5 mmol), catalyst (5 mol % unless
b
c
otherwise noted). 2.5 mol %. Determined by 1H NMR spectroscopy
based on 2a; >95% means no trace of 2a was observed.
catalyzed conditions. On the other hand, lithium alkynides
(generated in situ from the parent alkynes and n-BuLi) are
reported to react with sulfur in refluxed diethylamine to provide
the corresponding N,N-diethyl thioamides.18 Such experimental
procedures are obviously of limited scope.
At the beginning of our study, we examined the reaction
between phenylacetylene, 2-phenethylamine, and elemental
sulfur (Table 1).19 To our surprise, we found, however, that
this reaction always works to more or less the same extent even
at temperatures as low as 60 °C in high conversion (entries 1,2
vs entry 3). The presence of pyridine even in a small quantity
(0.1 mL for 1 mmol amine) results in a more homogeneous
reaction mixture and cleaner conversion. The addition of
simple metallic salts (CuCl, NiCl2, CoCl2, MnCl2, Ag2O) which
Scheme 1. Atom-, Step-, and Redox-Economical Approach to
Thioamide
Received: November 19, 2013
© XXXX American Chemical Society
A
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Letter
a
Table 2. Reaction of Phenylacetylene with Sulfur and
Amines
Table 3. Reaction of Alkynes with Sulfur and Amines
a
a
Reaction conditions: amine (5 mmol), sulfur (10 mmol, 320 mg),
alkyne (7.5 mmol).
Scheme 2. Investigation of the Reaction Pathway
a
Reaction conditions: amine (5 mmol), sulfur (10 mmol, 320 mg),
phenylacetylene (7.5 mmol).
The optimized reaction conditions (Table 1, entry 5) were
next applied to a wide range of amines (Table 2).
were known to be catalytically active in other reactions
involving alkynes were shown to be detrimental (entries 6−
9) or ineffective (entry 10 vs 5, entry 11 vs 4) in accelerating
this transformation.
Different primary (entries 1−15) and secondary (entries 16−
18) aliphatic amines were proven to be competent substrates
and provided the corresponding thioamides in moderate to
high yields. Functional groups such as aromatic halogens
B
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Letter
criteria provides a straightforward and uncatalyzed access to a
wide range of thioamides. Further study and extension of the
present result are underway in our laboratory.
Scheme 3. Proposed Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization, and copies
1
of the H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(entries 4−5), methoxy (6−7), hydroxy (entries 12−13),
tertiary amine (entry 14), and aniline (entries 8 and 15) were
shown to be highly compatible with the present reaction
conditions. Due to the lower reaction temperature of the
present conditions compared to that of our previous work (60
°C vs 110 °C),13a the reaction of benzylamines 2g,h with
phenylacetylene 1a afforded the desired N-benzyl thiobenza-
mides 3af, 3ag in high yields. Finally, an aliphatic alcohol such
as n-butanol (entry 19) and aniline (entry 20) were totally
inactive under these conditions.
The scope of alkyne was shown in Table 3. While
phenylacetylene derivatives (entries 1−3) displayed a com-
parably high reactivity, reactions with aliphatic alkynes (entries
4−9) required higher temperatures (80−100 °C) than with
phenylacetylene. Finally, the reactions with 3-phenylpropyne
(entry 9) and 1-phenylpropyne (entry 10) provided the same
terminal thioamide 3gb as a result of the migration of the triple
bond in 1g′. This observation revealed that the reaction shared
some characters with the Willgerodt rearrangement.20 Finally,
by using silylated acetylene 1h instead of gaseous acetylene, this
protocol could furnish thioacetamide 3hc′ as a result of a
desilylative hydrolysis of the corresponding silylated thioamide
3hc initially obtained during column chromatography purifica-
tion on silica gel.
We next explored the reaction mechanism of the formation
of thioamide 3aa from 1a, 2a, and elemental S. To this end, the
starting materials were heated at 60 °C for 24 h in pyridine
(Scheme 2, eqs 1−3). In all cases, all starting materials were
recovered unchanged. No trace of products issued from
hydroamination21 (eq 1) or thiolation22 (eq 2) was observed.
It should be noted that when 2-phenethylamine 2a and sulfur
were mixed together in pyridine (eq 3), an intensely brown
solution was yielded but sulfur was crystallized out when the
solution was diluted with chloroform. This intense coloration
has been attributed to polysulfides resulted from the scission of
S−S bonds by stepwise nucleophilic attack on S8 rings by the
aliphatic amines.23
Based on these elements, we tentatively proposed a
mechanism which probably begins with the nucleophilic attack
of amine 2 on S8 to generate polysulfide A (Scheme 3). Highly
nucleophilic due to the α effect of the polysulfur chain, A
subsequently adds to the triple bond of alkyne 1a to yield vinyl
polysulfide B. Polarized by the presence of a sulfur substituent,
the double bond of B is further attacked by amine 2 to provide
thioaminal C. Finally, elimination of polysulfide A′ from C
leads to thioamide 3.
*E-mail: nguyen@icsn.cnrs-gif.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from CNRS and ICSN is gratefully
acknowledged.
■
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