Table Of ContentToshiaki Murai Editor
Chemistry
of
Thioamides
Chemistry of Thioamides
Toshiaki Murai
Editor
Chemistry of Thioamides
123
Editor
ToshiakiMurai
GifuUniversity
Gifu, Japan
ISBN978-981-13-7827-0 ISBN978-981-13-7828-7 (eBook)
https://doi.org/10.1007/978-981-13-7828-7
©SpringerNatureSingaporePteLtd.2019
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart
of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission
orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar
methodologynowknownorhereafterdeveloped.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom
therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse.
The publisher, the authors and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authors or the editors give a warranty, expressed or implied, with respect to the material contained
hereinorforanyerrorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregard
tojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.
ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
Preface
I have been involved in the development of synthetic methods and new reactions
using thioamides for about 20 years. On the basis of the teaching that it is not
necessarytostayinabusyplacefromthebeginningwhenwestartnewresearchin
the fields of synthetic chemistry, at first I hesitated to start that chemistry. Until
then, I had studied compounds involving selenium and tellurium atoms, which are
heavier elements of the sulfur atom in the Periodic Table. A limited number of
researcherswereengagedinseleniumandtelluriumchemistry,andtherewasahigh
possibilitythattheoriginalityofourownresearchwasguaranteed.Inthosestudies,
one of graduate students in the laboratory discovered that new active chemical
species were generated from selenoamides, which was a selenium analogue of
amides, and the carbon–carbon bond-forming reaction using those was achieved.
Ithoughtwecouldprovidenewsyntheticchemistrywiththosereactions.However,
handling of organoselenium compounds are generally non-trivial. So I decided to
startresearchbasedonthioamides,whoserichchemistryhasalreadybeenreported
even at that time. Therefore, we had to be very careful to see if similar reactions
werealreadyreportedornot.Fortunately,eveninthosesituations,weencountered
several novel synthetic reactions.
Afewyearsago,SpringerJapaninvitedmetopublishbooksonchemistry.Asa
result ofsearchingliterature andon-linesearch, Inoticed that there wereno books
that overlook the chemistry of thioamides even if the abundant achievement with
thioamidesisknownoverhalfacentury.Fortunately,myproposalwiththechapters
shown in the table of Contents was approved.
I then asked an expert to write each chapter, and all the distinguished scientists
accepted my invitation. Since then, as I received the manuscript from them,
I strongly felt the responsibility to complete this book as soon as possible. At the
sametime,Iamfullofgratitudeforallthescientists,whowroteeachchapterusing
v
vi Preface
valuable time with expertise and enthusiasm. All the chapters provide abundant
informationandcoverbroadaspectsofthioamides.Alternatively,youmaybeable
to grasp the clues of new research by looking over a certain part.
Gifu, Japan Toshiaki Murai
March 2019
Contents
1 Thioamides: Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Toshiaki Murai
2 Theoretical Aspects of Thioamides . . . . . . . . . . . . . . . . . . . . . . . . . . 7
José V. Cuevas, José García-Calvo, Víctor García-Calvo,
Gabriel García-Herbosa and Tomás Torroba
3 Synthesis of Thioamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Toshiaki Murai
4 Reaction of Thioamides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Toshiaki Murai
5 Asymmetric Synthesis Using Thioamides . . . . . . . . . . . . . . . . . . . . . 103
Naoya Kumagai and Masakatsu Shibasaki
6 Synthesis of Heterocycles from Thioamides . . . . . . . . . . . . . . . . . . . 127
Hong Yan and Hai-Chao Xu
7 Thioamide-Based Transition Metal Complexes. . . . . . . . . . . . . . . . . 157
Ken Okamoto, Junpei Kuwabara and Takaki Kanbara
8 Thioamide-Containing Peptides and Proteins . . . . . . . . . . . . . . . . . . 193
Taylor M. Barrett, Kristen E. Fiore, Chunxiao Liu
and E. James Petersson
vii
Chapter 1
Thioamides: Overview
ToshiakiMurai
Abstract A range of sulfur isologues of carbonyl compounds are introduced.
Amongthem,focushasbeenlaidonthesulfurisologueofamides,i.e.,thioamides.
Researchfieldsonthioamideshavebeenspreadfromelucidationofthefundamental
propertiestobiologicalapplications.Historicalbackgroundofthioamidesisshortly
introduced.Recentresultsonthesestudiessuchasconformation,hydrogen-bonding
interaction,self-disproportionationofenantiomers,andbiologicalaspectsarethen
brieflyintroducedtoentereachchapterofthisbook,wherethedetailsareshown.
· · ·
Keywords Thioamides Conformation Hydrogen-bonding
· ·
Self-disproportionation Metalcomplexes Biologicalactivity
The replacement of the oxygen atom in amides with the sulfur atom gives rise to
the formation of thioamides. Amides have been recognized as the least reactive
carboxylic acid derivatives. In that sense, similar tendency may be seen when you
compare the reactivity of thioaldehydes 1 (thials), thioketones 2 (thiones) [1], and
thioicacidO-esters3(Fig.1.1).Theisolationofthioaldehydes1andthioketones2is
nontrivialunlessbulkysubstituentsareintroducedaroundthiocarbonylgroups[2].
Incontrast,sulfurisologuesofamidessuchasthioformamide4(methanethioamide),
thioacetamide5(ethanethioamide),andbenzothioamide6(benzenecarbothioamide)
haveappearedintheliteratureinthelatenineteenthcenturies[3–6],andtheirsynthe-
sisandpropertieshavebeencontinuouslystudied,althoughtheseprimarythioamides
can decompose via the elimination of hydrogen sulfide to give mixtures including
nitriles.
Studiesintheearlytwentiethcenturymayhavelaidonaviewpointofhowthe
propertiesofthecompoundschangewhenoneoftheelementsinmoleculesbelong-
ingtothesecondrowoftheperiodictableisreplacedbytheelementinthethirdand
subsequent periods. Hereafter, the thioamide moiety (C=S–N) was found to show
unique properties, and compounds having this unit were found in nature, so that
B
T.Murai( )
DepartmentofChemistryandBiomolecularScience,FacultyofEngineering,GifuUniversity,
Yanagido,Gifu501-1193,Japan
e-mail:[email protected]
©SpringerNatureSingaporePteLtd.2019 1
T.Murai(ed.),ChemistryofThioamides,
https://doi.org/10.1007/978-981-13-7828-7_1
2 T.Murai
Fig.1.1 Someof S S S
thiocarbonylcompounds
R H R1 R2 R1 OR2
1 2 3
thioaldehydes thioketones thioic acid
O-esters
S S S
H 4 NH2 H3C 5 NH2 Ph 6 NH2
thioformamides thioacetamides benzothioamide
Fig.1.2 Resonance S S S
structuresofthioamides H + H + H
R N R N R N
8 9 10
H H H
researchfieldshaveextensivelyexpandedfromfundamentalchemistrytobiochem-
istryandmaterialchemistry.
Similarly to amides, resonance structures of thioamides 8 can be depicted as 9
and10(Fig.1.2).However,thecontributionoftheresonancestructure9ismarkedly
smallerthanthatinthecorrespondingamidesmainlybecauseofthesimilarityofthe
electronegativityofcarbonandsulfuratoms[7].Asaresult,thioamidesarelesspolar
thanthecorrespondingamides,andthepurificationofthioamidesiseasierthanthe
amideshavingidenticalcarbonskeletons.Incontrasttoamides,thechargetransfer
fromthenitrogenatomtotheC=Sbondsisgreater,andtherotationalbarrierofC=N
bondislarger[8].
Hydrogen-bonding including S–H bonds and conformations around C=S–NH
bondsareofinterestinthefieldsofpurechemistryaswellasthiopeptidechemistry.
Generally, the C=S–NH bonds are weaker acceptor of the hydrogen bonds, and
the NH proton is more acidic and can work as a hydrogen bond donor [9, 10].
To gain insights of the hydrogen-bonded systems, thioamides such as 11 and 12
(Fig.1.3)areprepared,andtheirstructuresandhydrogen-bondinginteraction,and
π-π stacking are elucidated. The relationship of the substituents on the aromatic
rings and conformation around C=S–NH bonds is extensively studied with N-aryl
arylthioamides 13 (Fig. 1.4) [11]. Z-Conformation is usually preferable, and the
detail of the isomerization is revealed by variable-temperature NMR and NOESY
experimentsandDFTcalculations.
Self-disproportionationofenantiomers(SDE)isobservedduringthepurification
of the optically active compounds with some enantiomeric excess (ee) [12]. The
ee of the purified products is not identical in some fractions collected during the
achiralchromatographicseparation.Thephenomenaarerelatedtothestrengthofthe
hydrogen-bondinginteractions.Toshowthisphenomenonofthioamides,optically
active thioamide 14 is prepared (Fig. 1.5). Its SDE is observed, although SDE is
substantiallylowerthanthatofthecorrespondingamide.Thesoftnessofthesulfur
atomenablesthioamidestobehaveasligandsmainlytosoftmetals.
1 Thioamides:Overview 3
Fig.1.3 benzene-1,3,5- R
tricarbothioamides R S HN
S HN
R
R N S
N S H
H
S NH
S NH
R
R 12
11
R =
R =
Fig.1.4 N-Aryl R3
arylthioamides R1 S
N R4
H
13
R2
Fig.1.5 ChiralN-1- S Me
phenylethyl
thioacetamide N *
H
14
* chiral center
E
S S
Br N NH 1156 EE == OS Et NH2 n-Pr NH2
N 17 N 18
Br
OH
O
S S S S S S
N N N N N N
H H H H H H
HO 19 OH
Fig.1.6 Someofbiologicallyrelevantthioamides
Thereplacementoftheoxygenatomtothesulfuratomalsoaffectsthephysio-
logicalactivityofthemolecules.Insomecases,theactivitymaydecrease,butsome
oftheresultshaveshownthatthereplacementenhancedtheactivity[13].Forexam-
ple, the oxygen atom of longamide B (15) is replaced with a sulfur atom to form
thioamide16(Fig.1.6)[14].Thecompound16showshigherinhibitoryactivitythan
15asanindoleamine2,3-dioxygenase1inhibitor.
