ETHYL ISOTHIOCYANATOACETATE 1

Ethyl Isothiocyanatoacetate

O

OSCN

[24066-82-8] C5H7NO2S (MW 145.18)InChI = 1/C5H7NO2S/c1-2-8-5(7)3-6-4-9/h2-3H2,1H3InChIKey = IYPSSPPKMLXXRN-UHFFFAOYAL

(reagent used as polyfunctional compound, having electrophilicand nucleophilic reactive sites. Usually more than one reactionsite of the reagent participates in reaction with various substrates)

Physical Data: bp 104–106 ◦C at 7 mm Hg; d 1.171 g cm−3.Solubility: alcohols, tetrahydrofuran, pyridine, toluene.Form Supplied in: colorless to yellow liquid, widely available.Handling, Storage, and Precautions: tightly closed container

should be stored in a cool and dry place; avoid breathing, dust,mist, and vapor, and avoid contact with skin and eyes. Stableunder normal temperatures and pressures; upon decompositioncarbon monoxide, nitrogen oxides, sulfur oxides, and carbondioxide are released. Incompatible with strong oxidizing agentsand strong bases.

Preparation. One of the first methods of preparation is basedon the reaction of glycine ethyl ester with thiophosgene (eq 1).1

ClCl

S

OHCl · H2N

O

3 HCl

O

OSCN

+

+ (1)

toluene

reflux

Avoiding toxicity of thiophosgene, other methods of prepa-ration were introduced. When using carbon disulfide and ethylglycinate, dithiocarbamino intermediates are formed. Treatmentwith HgII or AgI salts gives ethyl isothiocyanatoacetate withrelease of H2S (eq 2).2,3

CS2O

H2N

O O

OEt

HN

S

HS

HgCl2

O

OEtSCN + H2S (2)

base+

H2O

Reagent Reactive Sites. Ethyl isothiocyanatoacetate is ahighly functionalized reagent, bearing several reactive sites.Polyreactivity is often observed, meaning that after initial reactionsubsequent transformations are possible, resulting in a wide arrayof products.

O

ON

CS

Nu

54

3

21

E

(3)

E—electrophile, Nu—nucleophile

Reactions with Nucleophiles on C === S Carbon Atom. Mostreactions on ethyl isothiocyanatoacetate start with nucleophilicattack on the thiocarbonyl group on position 4. Hydrazines,4,5

hydrazones,6 hydrazides,7 and pyrazoles8 react to give the corres-ponding thiosemicarbazides (eq 4).

N NHNH2

OEtSCN

O

NHNHNNHCH2COOEt

S

(4)

+0 °C

EtOH

With N-protected α-amino acids, formation of a peptide bond ispossible through Goldschmidt peptide synthesis.2,9,10 The initialtransformation is frequently followed by cyclization. Dependingon the nature of the substrate, nucleophilic attacks of the reagentposition 3 nitrogen are possible. Reactions with β-amino acidesters or aromatic o-amino esters lead to the formation of various2-thioxopyrimidin-4-ones11 and their fused analogs.12–15 Reac-tions with aromatic o-amino ketones give 2-thioxopyrimidines(eq 5).16

N ArMeOOC

SHN

COOEtN

N

S

O

COOEt

Ar

(5)80 °C

R

R

Et3N

The corresponding thiohydantoins are formed when α-aminoacid esters are used.17–19 Changing α-amino acid esters withα-mercapto acetic acid esters gives rhodanine.20 With aromatico-amino nitriles, fused pyrimidines are obtained through the con-secutive attack of the newly formed imino group at position 1 ofthe ester group of isothiocyanatoacetate (eq 6).13,21,22

S S

CN

NH2

O

OEtSCN

O

S SNH

NN

S

+pyridine

(6)

reflux

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2 ETHYL ISOTHIOCYANATOACETATE

o-Phenylenediamine reacts with isothiocyanatoacetate, form-ing a stable thiourea intermediate, which is then converted toNα-substituted aminobenzimidazoles using a desulfurizing agent(eq 7).23

NH

NH2

S NH

COOEt

NH

NNH

COOEt

polymer supportedcarbodiimide

(7)THF, 70 °C

In some cases, it is also possible that sulfur at position 5 of theisothiocyanatoacetate acts as a nucleophile. In this manner, 1,3,4-thiadiazines24 and diaminobenzobisthiazoles25 can be prepared.When using 3-hydrazinopyridine, thiosemicarbazide is formedthat can be transformed under acidic conditions into the corres-ponding 5-hydrazino-substituted thiazolone by sulfur attack onthe ester group at position 1 (eq 8).26

N

NH

HN

S

HN COOEt

Cl HClN

NH

HN

S

HN

Cl

O

(8)reflux

Ethyl β-amino crotonate reacts with isothiocyanatoacetateforming isothiazoles. The first step is the α-C nucleophilic at-tack of amino crotonate instead of its poorly nucleophilic aminogroup. The formed intermediate is then oxidatively cyclized withbromine to give the isothiazole derivative.27

Reactions of Methylene Group with Electrophiles. Themethylene group in isothiocyanatoacetate is usually used toprepare enolates, which react in aldol-type reactions formingthe aldol-like intermediates, which are afterward cyclized intovarious heterocyclic systems such as oxazolidine-,28,29

thiazolidine-,30,31 and imidazolidine-2-thiones.32 In this manner,reaction with N-protected-6-indolylisopropyl ketone was carriedout, giving diastereomeric oxazolidine-2-thiones.28

N

BocOONa

OEtSCN

N

BocO

HN

EtOOC

S

THF+

(9)

When carbon disulfide reacts with the above mentionedenolate, 4,5-disubstituted thiazolidine-2-thione is formed. Thisproduct spontaneously dimerizes into its -S-S-disulfide dimer.30

With hexaphenylcarbodiphosphorans, intermolecular cyclizationof isothiocyanatoacetate is possible, yielding mercaptothiazoles(eq 10).31

OK

SCNOEt

CS2

S

HN S

HS

EtOOC

S NH

S COOEt

S

S

HN

S

COOEtS

[O]

(10)

THFinert atm

For the purpose of D-biotin synthesis, stereocontrolled addi-tion of isothiocyanatoacetate enolate to boron trifluoride activatedchiral 3-thiazoline is used, giving a fused imidazoline-2-thioneintermediate (eq 11).32

N

N

F

H

OB

S

CS

OR

NS

H

NHH

EtOOC

S

THF

NS

H

NHH

EtOOC

S

+ (11)

–78 °CF

In the aldol-type reaction of isothiocyanatoacetate with methylarylcarbodithioate, in the presence of sodium hydride, an unsta-ble condensation intermediate is formed, which is cyclized intosodium ethyl 5-aryl-2-mercapto-1,3-thiazole-4-carboxylate. Fur-ther S-methylation affords the 2-methylthio derivative.33

Isothiocyanatoacetate and Rearrangement Reactions. Twotypes of rearrangement reactions involving ethyl isothiocyana-toacetate are described in the literature. In the first case whenusing oxalamidines, imidazolidine derivatives are formed. Thefinal product is formed directly or through the Dimroth typerearrangement (eq 12).34

N NR1 R1

R1

N

SN

COOEt

NN

N NR1 R1

R1

S

COOEt (12)

In the second case, rearrangement is carried out onD-glucosamine. A thiourea derivative is formed initially,and then transformed directly into the final product, which is anacyclic sugar substituted imidazole derivative. However, in somecases, octahydropyrano [2,3-d] imidazoles are formed first andthen converted through the Amadori rearrangement into the finalproduct (eq 13).35

A list of General Abbreviations appears on the front Endpapers

ETHYL ISOTHIOCYANATOACETATE 3

O

HN

OH

S

HN

EtOOC

HOHO

OH

O

OH

HNN

S

COOEt

HOHO

NH

HO

OH

OH

CH2OH

NS

COOEt

acid

acidac

id

(13)

Related Reagents. Methyl Isothiocyanatoacetate; Ethyl Isoth-iocyanatoformate; Ethyl Isocyanatoacetate.

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Jernej Wagger, David Kralj, Jurij Svete & Branko StanovnikUniversity of Ljubljana, Ljubljana, Slovenia

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