Synthesis of Substituted Thioamides from gem-Dibromoalkenes and Sodiumsulfide

Article abstract of DOI:10.1002/ejoc.201901411

A three-component reaction of 1,1-dibromoalkenes, sodium sulfide, and N-substituted formamide for the synthesis of disubstituted thioamides has been developed. Various dibromoalkenes were found to be compatible under these conditions and gave corresponding thioamides in good to excellent yields.

Full text of DOI:10.1002/ejoc.201901411

A Journal of
Accepted Article
Title: Catalyst/Additive-free Synthesis of Substituted Thioamides from
gem-Dibromoalkenes and Sodiumsulfide
Authors: Ashok Morri, Yadagiri Thummala, Ramesh Adepu,
Gangavaram V. M. Sharma, Shubash Ghosh, and Venkata
Ramana Doddi
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10.1002/ejoc.201901411
European Journal of Organic Chemistry
COMMUNICATION
Catalyst/Additive-free Synthesis of Substituted Thioamides from
gem-Dibromoalkenes and Sodiumsulfide
Ashok K. Morri, [a] Yadagiri Thummala,[a] Ramesh Adepu,[a] Gangavaram V. M. Sharma,[a] Subhash
Ghosh,[a] Venkata Ramana Doddi*[b]
Dedicated Prof. H. Ila on her 74th birthday
Abstract: The three component reaction of 1,1-dibromoalkene,
sodiumsulfide and N-substituted formamide for the synthesis of
disubstituted thioamides has been developed. Various dibromoalkene
derivatives were found to be compatible under these conditions and
gave corresponding thioamides in good to excellent yields.
Thioamides are an important class of functional groups used in
the synthesis of several sulfur containing heterocyclic compounds
and polypeptides.8 Thioamide functionality containing several
compounds are having significant medicinal properties includes
immunosuppressive activity,9 opioid activity10 and antituberculotic
activity.11 Thioamide group was used instead of amide group in
peptides and other compounds to monitor the biological,12
physical,13 stability,14 catalytic15 functions of target molecules or
structural changes in proteins.16 Owing to their synthetic and
biological importance, the motivation exists for discovering new
and efficient strategies for the synthesis of thioamides.
We have been working on the substrates 1,1-dibromoalkenes,
since we first reported their use in the synthesis of terminal
acetylenes.17 Terminal acetylenes in the presence of pyridine are
best used for the synthesis of thioamides (Scheme 1b), and since,
acetylenes are to be synthesized from 1,1-dibromoalkenes,17
therefore, our attention turned to work on the synthesis of
thioamides starting directly from 1,1-dibromoalkenes (Scheme
1a). We have chosen formamide DMF as solvent for this reaction
as it is well evident from the previous reports that DMF can also
act as dimethylamine source.7
Understanding a reaction’ pathway/mechanism often leads to
correlations between systems not otherwise obviously related.
Synthesis of thioamides from alkynes or its derivatives is one of
the interesting transformation with different possible pathways
(Scheme 1).1,2 Some interesting methods have been reported for
the synthesis of thioamides from different starting materials like
amides,3a-e amines,3f-h carboxylic acids,4 aldehydes,5 ketones,6
and nitriles.7 Out of which, synthesis of thioamides starting from
acetylenes, sulfur and amines in the presence of pyridine is one
of the most efficient and atom economical method (Scheme 1b).2
The catalyst or additive is usually employed in the aforesaid
synthetic methods for the synthesis of thioamides starting from
various starting materials.
S.
Na2S
·
9H2O DMF
Temp Time Yieldb
No. (equiv)
(mL)
°C
(h)
%
2a 3a
1
2
3
4
5
1
1
1
1
1
2
RT
60
24
8
-
23
28
-
2
-
Scheme 1. Our method of Synthesis of N,N-dimethylethanethioamides
comparison with the recent literature.
1.5
2.5
2.5
120
120
120
16
1
25
91
85
-
1
-
a Reaction conditions: 1a (0.5 mmol), Sodium sulfide (Na2S·9H2O, 2.5 equiv),
DMF (1 mL) at 120 °C. b Isolated yields.
[a]
[b]
Ashok K. Morri, Yadagiri Thummala, Ramesh Adepu, Dr.
Gangavaram V. M. Sharma, Dr. Subhash Ghosh
OBC Division
Academy of Scientific and Innovative Research, and CSIR-Indian
Institute of Chemical Technology, Hyderabad, 500007, India
Table 1 Optimization studya
To examine the substrate scope of this reaction, wide range of
1,1-dibromoalkenes 1a-z are subjected to the optimized reaction
conditions (entry 4, Table 1) to give the corresponding N,N-
Dr. Venkata Ramana Doddi*
Department of Chemistry and Chemical Sciences
Central University of Jammu
dimethylethanethioamides
substrates containing electron donating groups were converted to
2a-z.
The
1,1-dibromoalkene
Jammu and Kashmir, India-181143
Email: doddi@cujammu.ac.in
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201901411
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the external supply of amines diethylamine, benzylamine,
octylamine and tbutylamine instead of in situ formation of
dimethylamine from
the
solvent
DMF.
Interestingly,
corresponding N,N-diethylthioamide 2la (Scheme 2), N-
benzylthioamide 2lb, N-octylthioamide 2lc and N-tbutylthioamide
2ld, (Scheme 2) formed in good yields. These experiments
clearly shows that presence of external amines in the reaction
leads to formation of corresponding N,N-disubstituted thioamides
2la-ld instead of N,N-dimethylthioamide 2l. The ability to
synthesize N-substitutted thioamide 2le by using N-
phenylformamide (PhNHCHO) as an amine precursor
demonstrates another niche for this protocol (Scheme 2), which
clearly shows the compatibility of alkyl and aryl formamides in this
transformation.
Scheme 3 Preliminary thoughts on reaction mechanism with thioacyl bromide
as an intermediate
Initially, we thought, synthesis of thioamides 2 from 1,1-
dibromoalkenes 1 proceeds through the reaction of in situ fomed
thioacyl bromide with amine derived from formamide (Scheme 3).
But, we have isolated an intermediate terminal alkyne 3 in this
reaction (Table 1, entry 1). Therefore, it is concluded that reaction
is proceeds through the formation of terminal alkyne 3 but not
through the formation of thioacyl bromide as proposed in scheme
3.
a
b
c
d
e
Diethylamine,
Benzylamine,
Octylamine,
tButylamine,
N-
phenylformamide (PhNHCHO) are used as external amines in DMF.
Scheme 2. Substrate scope of 1,1-dibromoalkenes for the synthesis of
thioamides.
give the desired thioamides in 65–91% yields (2a–i; Scheme 2).
It is worth noting that the phenol group sustained well under this
conditions to give corresponding thioamide 2j in 65 % yield. A
number of halogenated substrates 1k-q also reacted with sodium
sulfide to give the expected products 2k-q in very good yields.
The bromo and chloro substituents are useful handles for further
synthetic elaboration. Dibromoalkenes containing electron-
withdrawing groups including fluoro 2p-q, nitro 2r, and cyano 2s
groups are also compatible with this protocol to give
corresponding desired thioamides 2p-s. The thioamidation of
dibromoalkene containing heterocyclic substituents proceeded
smoothly to give the desired products 2t-v in very good yields,
suggesting heterocyclic substrates other than simple aromatic
substrates is also reactive. Moreover, by using polyaromatic
substrates, this protocol could furnish thioamides 2w-y in very
good yields. Furthermore, aliphatic substrate citronellal derived
1,1-dibromoalkene also could give corresponding thioamide 2z,
albeit in low yield 54 %. Finally, we have performed reactions by
Scheme 4 Proposed mechanism for the synthesis of N,N-disubstituted
thioamides from 1,1-dibromo alkenes and formamide
A new plausible mechanism is suggested sulfidesulfurin Scheme
4. The reaction starts with a sodium sulfide mediated formation of
terminal alkynes 3 from 1,1-dibromoalkenes 1. Herein, we
propose the nucleophilic attack of sulfide (1 mol) on the bromine
atom to give carbene along with another intermediate sodium
hypobromothioite NaSBr (Scheme 4). Carbene undergoes 1,2-H
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10.1002/ejoc.201901411
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COMMUNICATION
shift to give the terminal alkyne intermediate and simultaneously
another intermediate sodium hypobromothioite NaSBr undergo
elimination of sodium bromide NaBr to give elemental sulfur (Sn).
On the other hand, hydrated sodium sulfide is also basic in nature
and it’s another molar equivalent induces the cleavage of dialkyl
formamides to give amine RR’NH2.19 Hence, this reaction needs
minimum two equivalents of sodium sulfide to complete the
reaction (2.5 equiv, entry 4, Table 1). The subsequent step
involves the three component reaction of in situ formed three
intermediates elemental sulfur Sn, amine RR’NH2 and terminal
alkyne 3 to give corresponding thioamide 2 as proposed by
Nguyen et al1 (Scheme 4).
in situ formation of three starting materials reported in Nguyen’s
method (Scheme 5).
Conclusions
In summary, an efficient synthetic procedure for generating N,N-
disubstituted thioamides by the reaction of 1,1-dibromoalkene,
Na2S·9H2O and formamide R2NCHO. The wide substrate scope
of the reactants allowed synthesis of corresponding thioamides in
good to excellent yields. No additive or catalyst used in this
reaction unlike previously reported methods employed. Control
experiments and optimization studies supported our newly
proposed mechanism and confirmed the reaction proceeds
through the formation of terminal alkyne intermediate not thioacyl
bromide. This developed method could be a better alternative to
the methods starting from acetylenes or their derivatives for the
synthesis of thioamides.
Acknowledgements
Scheme 5 Our method in comparison with previous method.
V.R.D. is grateful to DST-India for the financial support
ECR/2017/000419 & IFA-12-CH-36. We are thankful to Srivari
Chandra Sekhar, Director, IICT for the congenial atmosphere and
continuous support. CSIR-IICT manuscript communication no.
IICT/Pubs./2018/118
We can visualize the present developed method as as a triple
telescopic reaction to the method developed by Nguyen et al
(Scheme 5). Three starting materials used in Nguyen’s method
can be obtained from their precursors used in this present method
(Scheme 5). Two starting materials terminal alkyne 3 and sulfur
S8 can be obtained from the reaction of their two precursors 1,1-
dibromoalkene and sodiumsulfide. Another starting material
amine HNR2 can be obtained from base induced cleavage of
precursor formamide R2NCHO (Scheme 5). Further, our results
are in full accordance with the results obtained by Nguyen et al.1
Keywords: Dibromoalkene • Sulfide • Elemental sulfur •
Thioamide • Formamide
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Scheme 6 Control experimentssulfide
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Entry for the Table of Contents
COMMUNICATION
Ashok K. Morri, Yadagiri Thummala,
Ramesh Adepu, Gangavaram V. M.
Sharma, Subhash Ghosh, Venkata
Ramana Doddi*
Page No. – Page No.
Catalyst/Additive-free Synthesis of
Substituted Thioamides from gem-
Dibromoalkenes and Sodiumsulfide
Synthesis of thioamides from geminal dibromoalkenes, sodium sulfide and
formamide have been reported under catalyst or additive free conditions . Control
experiment and mechanistic studies revealed that necessary role of sodium sulfide
in this overall transformation.
Key topic: Thioamides
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