Reactivity and diverse synthetic applications of acyl

Review and Accounts

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Reactivity and diverse synthetic applications of acyl isothiocyanates Kibrom G. Bedane and Girija S. Singh* Chemistry Department, University of Botswana, Private Bag: UB00704, Gaborone, Botswana E-mail: [email protected] DOI: http://dx.doi.org/10.3998/ark.5550190.p009.052 Abstract Isothiocyanates constitute a group of heterocumulenes containing N=C=S functionality that is of immense importance in organic synthesis. The presence of carbonyl group in acyl isothiocyanates imparts unique reactivity to acyl isothiocyanates. The chemistry of acyl isothiocyanates, in particular, is very rich and diverse, and has been employed in synthesis of a number of biologically important heterocycles. This review article discusses the acyl isothiocyanate chemistry leading to the synthesis of biologically important heterocyclic skeletons. These include highly functionalized thiazoles, thiadiazoles, triazoles, benzimidazoles, dithiolane, spiro-fused oxazolines, triazines, and oxazines, etc. The role of acyl isothiocyanates as acylating agent and thiocyanate transfer reagent is also discussed. Keywords: Acyl isothiocyanates, thiocyanate-transfer reagent, acylating agent, heterocycles, thiazoles, imidazoles

Table of Contents 1. 2.

3. 4. 5.

Introduction Reactivity and Applications of Acyl Isothiocyanates 2.1. Cyclization reactions involving both electrophilic centers 2.1.1. Formation of five-membered heterocycles 2.1.2. Formation of six-membered heterocycles 2.2 Cyclization reactions involving the thiocarbonyl group 2.3 Cyclization reactions involving azomethine linkage 2.4 Acyl isothiocyanates as acylating agents 2.5 Acyl isothiocyanates as thiocyanate transfer reagents Multicomponent Reactions of Acyl Isothiocyanates Miscellaneous Reactions Concluding Remarks

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Acknowledgements References

1. Introduction Isothiocyanates (ITCs) constitute a group of heterocumulenes containing N=C=S functionality that is of immense importance in organic synthesis. Some of the edible plants such as Cruciferous vegetables (e.g. broccoli, kale, brussels sprouts, cabbage, mustard, garden cress, and cauliflower) are rich sources of benzyl-ITC (BITC), phenethyl-ITC (PEITC), allyl-ITC (AITC), and sulforaphane (SFN) (Figure 1).1 Recently, the isothiocyanate sesquiterpenes have been isolated from a sponge of the genus Axinyssa.2 The ITCs are of biological interest as well. They have been observed to exhibit anticancer activity in animals treated with chemical carcinogens due to their inhibition of carcinogen metabolic activation.3

Figure 1. Chemical structure of, benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), allyl-ITC (AITC) and sulforaphane (SFN). Isothiocyanates, well-known as a key reagent in the Edman peptide sequencing,4 are very useful synthons in organic chemistry, especially in the architecture of heterocycles such functionalized thiazoles, thiadiazoles, triazoles, benzimidazoles, dithiolane, spiro-fused oxazolines, triazines, and oxazines, etc.5-11 The methods of synthesis of isothiocyanates have drawn attention of chemists.12 Acyl isothiocyanates, in particular, are easily accessible by the reaction of acyl chlorides with thiocyanate salts such as lead thiocyanate, potassium thiocyanate and ammonium thiocyanate (Scheme 1). Recently, a simple, rapid and efficient method for the synthesis of benzoyl isothiocyanate under phase transfer catalysis using microwave irradiation under solvent-free conditions is reported (Scheme 2).13 O

O R

NH4SCN Cl

R

N C S

acyl isothiocyanates

Scheme 1

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O

O Cl

+

KSCN

PEG-400

N C S

MW solvent-free

Scheme 2 The chemistry of isothiocyanates is well documented. The presence of carbonyl group in acyl isothiocyanates imparts unique reactivity to acyl isothiocyanates. The chemistry of acyl isothiocyanates, in particular, is very rich and diverse, and has been employed in synthesis of a number of biologically important heterocycles. However, there is no review article in literature focusing on reactivity and application of acyl isothiocyanates in organic synthesis. This article, therefore, discusses acyl isothiocyanate chemistry leading to the synthesis of biologically important heterocyclic skeleton. The role of acyl isothiocyanates as acylating agent and thiocyanate transfer reagent is also discussed.

2. Reactivity and Applications of Acyl Isothiocyanates Acyl isothiocyanates are bifunctional compounds containing an acyl group and a thiocyanate group. They are more reactive than alkyl isothiocyanates obviously due to the presence of electron-withdrawing acyl group. There are evidences which suggest of a slight conjugative donation in the case of acyl isothiocyanates (Figure 2).14 The reactivity of acyl isothiocyanates are, thus, determined by three active centres - the nucleophilic nitrogen atom, and the electrophilic carbon atoms of the carbonyl and thiocarbonyl groups (Figure 3), which make them capable of participating in diverse type of addition and cyclization reactions. O R C N C S

O R C N C S

Figure 2. Resonance structures of acyl isothiocyanates.

Nu O R

N

Nu

C

S

E

E

Figure 3. Reactive sites of acyl isothiocyanates.

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A thermal 1,3-shift of substituent R in acyl isothiocyanates 1 is reported to proceed via the transition state TS (Figure 4).15,16 Goerdeler and coworkers have reported the isomerization of thioacyl isocyanates 1a to acyl isothiocyanates 1, in solution at temperatures around 100 C.17,18 Although the acyl isothiocyanates 1 are more stable an equilibrium between the two may be achieved from either side under favorable conditions. The migratory aptitude of the group R has been observed in the following order: (Alk)2N, Alk(Ar)N > ArS > AlkS > ArO > AlkO. If R was aryl, tert-butyl, or CCl3, no rearrangement occurred. 1,3-R N

N C S O

O R

O C N

S

S R 1a

R TS

1

Figure 4. 1,3-Rearrangement of acyl isothiocyanates. R2

N

R3

N H

SCN R1

R2OC N

Ph O

HN NH R

S

N

H N

R

S

2

COR

N

S NR1

NR1

NH O R2

N H N

N

O

R

R C N C S

HO

N

O

O

R O R HN R

S

O

S RO2C

N

N N

S

NH N

Ph

R O N N S

N

R

S N CO2R

N S

O

NCOR R

S

N

N R2

R3 R4

Figure 5. Selected heterocyclic compounds synthesized from acyl isothiocyanates.

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The strong electron-withdrawing nature of an adjacent acyl group enhances the reactivity of the isothiocyanate group and promotes nucleophilic addition at this site. The most common nucleophiles that have been investigated in reactions of acyl isothiocyanates are nitrogen nucleophiles such as amines, hydrazines, hydrazides, amidines, etc. Simultaneous or subsequent cyclization of the resulting adducts offer access to a variety of 5- or 6-membered heterocyclic molecules, including bicyclic condensed ring-systems. The use of reactants incorporating free amino group, such as benzoylhydrazine, thiosemicarbazide, phenylhydrazine, anthranilic acid, 2aminothiophenol, 2-aminophenol and o-phenylenediamine have provided access to diversely substituted 1,2,4-triazoline, thiadiazoline, benzoxazine, benzothiazole, benzoxazole, and benzimidazole derivatives (Figure 5) which will be discussed in the succeeding sections. 2.1. Cyclization reactions involving both electrophilic centers N C S

O R

Nu

R

N

C

S

Nu

The electrophilic sites in acyl isothiocyanates are located on the two carbon atoms. Due to the presence of these active sites, the reaction of acyl isothiocyanates may lead to the formation of different heterocyclic compounds depending on the starting isothiocyanate, the nature of the nucleophile, and the reaction conditions. Two- and three-component reactions of acyl isothiocyanates have been employed in the synthesis of functionalized thioureas and five- to sixmembered heterocycles with one or more heteroatoms.

2.1.1. Formation of five-membered heterocycles. The reaction of acyl isothiocyanates with hydrazine, 1,2-diamines or 1,3-diamines is one of the earliest known heterocyclization reactions. Among five-membered heterocycles, the syntheses of triazolinethiones have been investigated due to their pharmacological properties. The reaction of acyl isothiocyanates 1 with 2hydrazinylethanol 2, afforded 1,2,4-triazole-3-thiones 3 in excellent yields (Scheme 3).19 Subsequent acylation of the hydroxyl group in products 3 led to the formation of corresponding O-acyl derivatives 4 which exhibited anti-inflammatory activity. In a similar fashion, the reaction of benzoyl isothiocyanate 1 with β-cyanoethylhydrazine 5 resulted in development of a new and efficient one-step synthesis of 5-thioxo-l,2,4-triazole derivative 6 (Scheme 4).20

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Scheme 3 O R C N C S

+

1

5

S

O Ph C NH C S (88%) Ph NH HN H2C CH2 CN

dioxane , 3 h

H2N NH CH2 CH2 CN

R = Ph

N NH N CH2CH2CN 6

Scheme 4 Several isatin derivatives have been reported in literature to have different types of biological activity.21-24According to a recent report, treatment  of N-acyl isothiocyanate substituted isatin 7 with hydrazine hydrate in boiling dry benzene afforded compound 8.25  The latter compound, on refluxing in freshly distilled acetic anhydride, yielded 1-[(5-thioxo-4,5-dihydro-1H-1,2,4-triazol3-yl) methyl]-1H-indole-2,3-dione 9 (Scheme 5). Some aroyl isothiocyantaes, however, react with hydrazine hydrate in ethanol at room temperature in just 5 min time to afford the 3-aryl-5mercapto-1,2,4-triazoles 11, in low yields, through the intermediate 4-acylthiosemicarbazide 10 which undergoes acid catalyzed cyclization (Scheme 6).26 O O N H2C

N C S

N2H4.H2O / PhH acetone, , 6 h

O N H2C

O

7

O

O

HN O

8

Ac2O

O

, 6 h

S N H

NH2

N H2C

(83%)

NH N

9

N H

S

Scheme 5 Page 211

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R O R C N C S + N2H4.H2O 1

S O R C NH C NH NH2

EtOH r.t., 5 min

N C HCl

HS C

N N H

10

11

11. R = Ph ( 23%), 4-MeOPh (37%), 4-ClPh (36%)

Scheme 6 Hemdan and co-workers have reported the synthesis of 1,2,4-triazoline-3-thione derivatives 13 and 14 via addition-cyclization sequence employing 2-phenylacetyl isothiocyanate.27 The reaction of 2-phenylacetylisothiocyanate 1 with benzoylhydrazine in acetonitrile furnished the corresponding thiosemicarbazide 12. The latter compound underwent a dehydrative cyclization in polyphosphoric acid to furnish the 1,2,4-triazoline-5-thione derivative 13 or 13’. Similarly, treatment of isothiocyanate 1 with phenylhydrazine in acetonitrile yielded the 1,2,4-triazoline derivative 14 (Scheme 7). This reaction was sensitive to solvent and substrate. The use of dry acetone instead of acetonitrile in the reaction of phenacyl isothiocyanate with phenylhydrazine afforded a thiadiazolidine derivative 15 in 37% yield together with 1,2,4-triazoline 14. Hydrazine hydrate failed to cyclize and afforded N,N’-di(phenylacetyl)hydrazine. There is scope for further structural elucidation of compound 13 in this report employing 2D NMR spectroscopy and single crystal X-ray. The formation of 15 was explained through the reaction of acetone with phenylhydrazine forming the corresponding hydrazone which underwent cyclocondensation with the isothiocyanate 1. PhCONHNH2 O R C N C S

MeCN, 

12



1 R = CH2Ph

O O S PhCH2CNHCNHNHCPh

PhNHNH2 MeCN,  (52%)

PPA 150 -180 °C 1h (71%)

H Ph N N

Ph

COCH2Ph N S or

N

S N

NH N

Ph

Ph O

Ph

13'

14 PhNHNH2 dry acetone, 

S

N NH 13

Me Me N NH Ph 15

PhH2COCN 14 +

S

Scheme 7 Benzoyl isothiocyanate 1 reacts with N-alkyl- and N-aryl-substituted hydrazines 16 to give the corresponding 1,2,4-triazoline-5-thiones 18, through the thiosemicarbazide 17 (Scheme 8).28

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O R C N C S +

R1NHNH2

PhH , 15 min

O S Ph C NH C

16

1 R = Ph

R1

R

17

HN N

NaOEt

N NH2

Ph C

1

N 18

C S

R1 = PhCH2CH2 (61%), Me (20%), PhMe (42%)

 

Scheme 8 Benzoyl isothiocyanate reacts with some N-alkyl hydrazones of acetone 19 readily to afford the 1,3,4,6-oxatriazepine-5(2H)-thiones 20 in 29-75% yields (Scheme 9).29 The oxatriazepinethiones 20 are highly sensitive to acids, and rapidly break down to yield the triazolinethiones 21 on acidic treatment with concomitant removal of acetone. The rate of acid hydrolysis was much faster than that expected for an acetone thiosemicarbazone derivative. It was, however, in accordance with the presence of the cyclic aminoacetal structure.

O R C N C S 1 R = Ph

Me + R1 NH N C

Me

PhH 15 min-3 h

Me 19 R1 = 2,6-Me2C6H3O(CH2)2, Me, Ph(CH2)2, PhCH2

Me HN

O

Ph N

N S R1 20 (29 - 75%)

H+ i-prOH

Ph

-Me2CO -H+

HN

N S N 1 R 21 (33 - 55%)

Scheme 9 The formation of oxatriazepinethiones 20 from the hydrazones 19 and benzoyl isothiocyanate 1 was envisaged as taking place by the nucleophilic reaction of hydrazone at thiocarbonyl carbon (Scheme 10). The nucleophilicity of the nitrogen carrying the proton in the hydrazones 19 must be of sufficient magnitude to make an attack at this centre, leading to the formation of product 22, the initial step in the reaction. The protonation of N-H in oxatriazepinethiones 20 followed by ring cleavage leads to the formation of intermediate 23. This intermediate affords the final products by nucleophilic attack of the amino group on azomethine carbon and subsequent removal of acetone and deprotonation (Scheme 10). The reaction of benzoyl isothiocyanate with ethoxycarbonyl hydrazine 24 yields 4-acyl-1ethoxycarbonyl-3-thiosemicarbazide 25, which is cyclized in alkaline medium, with loss of CO2 and ethanol, to triazoles 27 via triazolinethione 26 (Scheme11).30

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O Ph C N C S 1

CH3

R NH N C

O

H3C C H3C

CH3

N

19

H3C

Ph H+

+

(CH3)2CO

+

O

H3C

N HN

H3C H3C HN

H S

N R

21

O

Ph N

N R 20

S

H+ Ph H3C N

H2N

S

N R

N R 22

Ph

C N C

O

H3C H2N

S

Ph N

N R

S

23

Scheme 10

O R C N C S + NH2NHCO2Et 1 R = Ph

S O Ph C NH C NH NH CO2Et

DMF 100 °C, 1 h

25

24

NaOH N N HS

N H

CO2Et HN N

Ph

S C

90%

27

N

C Ph

26

Scheme 11 O R C N C S 1 R = Ph, 4-ClPh

+

NH NH2NH C NHR1

MeOH r.t., 1-2 h

O S NH R C NH C NH NH C NHR1

28 R1 = Ph

29 R = Ph, 4-ClPh R1 = Ph N N

alkaline 80-90%

O S NH R C NH C NH NH C NHR1 29

R = Ph, 4-ClPh R1 = Ph

acidic 35-45%

HS

R N H 30 N N

R CO N H

S

NHR1

31

Scheme 12

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An equimolar reaction of aroyl isothiocyanates 1 and aminoguanidine 28 affords amidinothiosemicarbazides 29 in excellent yields.31 The addition occurs at the more reactive hydrazino group. The adducts 29 are cyclized to 1,3,4-triazoles 30 in alkaline medium and to 1,3,4-thiadiazoles 31 in acidic medium (Scheme 12). 2.1.2. Formation of six-membered heterocycles. Amidines, isoureas, isothioureas and guanidines 32 have been added to aroyl isothiocyanates 1 to form the 1,3,5-triazinethione derivatives 33 (Scheme 13).32 Aroyl isothiocyanates 1 were reacted with urea in dry acetone to give the good yields of 1-aroyl-2-thiobiurets 34 (Scheme 14). The formation of 2-thiobiurets 34 was explained by exclusive attack of guanidines on the C=S function of the isothiocyanates. Treatment of an ethanolic solution of 2-thiobiurets 34 with aqueous NaOH afforded, after acidification, 6-aryl-4-thioxo-1,2,3,4(or 2,3,4,5)-tetrahydro-1,3,5-triazin-2-ones 35 in a good yields (Scheme 14). Similarly, 1-phenylsemicarbazide 36, a relatively weaker nucleophile, reacted with aroyl isothiocyanates 1 of varying electrophilicity to give 6-aryl/cinnamyl-2-(2phenylhydrazinyl)-2,3-dihydro-1,3,5-oxadiazine-4-thiones 37 in good yields (Scheme 15).33 O R C N C S 1

N

R

X + HN C NH2

N

-H2O

32

S NH

X 33

X = alkyl or aryl, OR, SR, NR2

Scheme 13

O R C N C S

O + H2N C NH2

acetone , 2-3 h

O S O R C NH C NH C NH2 34

1

NaOH 35 R = Ph (80%), 4-MePh (85%), 4-MeOPh (78%), 4-BrPh (82%), 2-ClPh (75%)

H N

R N

S NH

O

N

R HN

S NH

O 35

Scheme 14

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O H2N C NH NHPh

acetone , 3 h

O S O R C NH C NH C NH NHPh

36

37. R = Ph (72%), PhCH = CH- (69%), R 4-ClPh (75%), 3,5-O2NPh (86%)

N O

S NH

NHNHPh

-H2O

R C N C S OH N HO C NHNHPh

37

Scheme 15 An excellent example of a solvent-free reaction of acyl isothiocyanates 1 with phenol, and 1and 2-naphthols 38 in the presence of N-methylimidazole (Scheme 16) leading to the formation of benz- and naphthoxazine-4-thiones 39 in very good yields has been reported by Khalilzadeh and coworkers.34 This procedure has the advantage that the reaction is performed under neutral conditions and the starting material can be used without any activation or modification. 4Chloro-substituted benzoyl isothiocyanate afforded the lowest yield. It was conceived that the protonation of 1:1 adduct 40 from isothiocyanate and N-methylbenzimidazole and the nucleophilic reaction of product naphtholate 42 with protonated intermediate 41 led to the formation of product 43 (Scheme 17). The cyclization of this product followed by elimination of water from the resulting fused heterocycle 44 led to the formation of final product. R

N O R C N C S +

N OH

O

Me

solvent -free, r.t. 1 38 56-95% R = Ph, 4-MePh, 4-O2NPh, 4-ClPh, 4BrPh 38. 1-naphthol, 2-naphthol

N S

39

Scheme 16 Benzoyl isothiocyanate 1 is reported to reacts with 6,7-dimethoxy-3,4-dihydroisoquinolin-1ylacetonitrile 45 in anhydrous acetonitrile leading to the formation of the 9,10-dimethoxy-2thioxo-4-phenyl-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile 46 in 85% yield (Scheme 18).35

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N

O R C N C S

OH O

N Me R

solvent -free, r.t.

1

N

R=Ph

O

S

O N

S +

R

NMe

N H

40

- N

NMe

42

41

R O O

N

NH

R

R

OH

O

NH

O

S

S

N

-H2O

S

H

N Me

43

39

44

Scheme 17

O R C N C S

MeO

MeO

MeCN

+

NH

MeO

1 R = Ph

Ph N

(85%)

NC

N

MeO

50 °C, 15 min

CN S

45

46

Scheme 18 Insuasty and coworkers have reported a simple synthesis of 4-aryl-2-ethylthio-7methylpyrazolo[1,5-a]-[1,3,5]-triazines 50 employing the chemistry of aroyl isothiocyanates 1.36 The latter compounds react with 5-amino-3-methyl-(1H)-pyrazole 47 in refluxing acetonitrile to give the corresponding thioureas 48 (Scheme 19). In next step, the thioureas 48 were treated with ethyl bromide in the presence of sodium hydride in DMF at room temperature to render the Salkylated product 49 which afforded the final product on refluxing. Me O R C N C S 1

HN N H2N Me 47 MeCN,  2h

N HN H N NH

R O

S

Me R

N HN NaH, EtBr DMF, r.t., 1h

R

N O

48

DMF,  0.5-1.5 h NH

N N

N

Me

N

EtS

SEt 49

50

50. R = Ph (90%), 4-MePh (74%), 4-ClPh (93%), 4-O2NPh (61%)

Scheme 19

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Benzoylisothiocyanate 1 reacts with enamine 1-(N-phenylamino)cyclohexene 51 at its C=C bond to afford an adduct 52. The adduct cyclizes in refluxing tetrahydrofuran to form the tetrahydroquinazoline-4(1H)-thione 53 (Scheme 20).37

O R C N C S +

Et2O NHPh

1

R = Ph

S O C NH C Ph



51

NHPh

S C

THF 

N H

52

N C

Ph

53

Scheme 20 2.2. Cyclization reactions involving the thiocarbonyl group O C R

S

O N C S R

C

C N

The thiazole scaffold is one of the privileged structures in medicinal chemistry. Various compounds featuring this particular scaffold have been prepared, many exhibiting remarkable biological activities such as anticonvulsant activity against administration of glutamic acid in rat and in the design of active H2 receptor histamine antagonists.38,39 A single-pot three-component condensation of aroylisothiocyanates, amines and -halocarbonyls constitutes an excellent example of synthesizing the 3-alkyl-3H-thiazoline ring system.40 Aroyl isothiocyanates 1 react smoothly with various amines in usual manner to afford acyl thioureas 54 (Scheme 21). The latter compounds have been condensed with -halocarbonyl derivatives to construct a 3-alkyl3H-thiazolines in a single-pot reaction. The configuration of the acylimino moiety was confirmed as syn. The syn selectivity in this reaction is explained on the basis of the steric hindrance of the acyl group and the R2 group in the isothiourea intermediates. Elimination of hydrogen halide from sulfonium intermediate 55 affords the final product through elimination of water from intermediate 56. An alternative route to thiazolines from sulfonium intermediates 55 via intermediate 58 to give anti-57 is avoided due to intermolecular steric hindrance. Diverse functionalities are accommodated at all four positions of the thiazoline skeleton to obtain -turn tripeptide mimics.

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X

R3

O

O R1 C N C S

1

R

2

R NH2

1

S

4

O R solvent,  X = Cl, Br

HN



NH R2

54

R3

O R

R4

N H

NHO

2 55 R

-HX

X-

56 R2 -H2O

R

1

N O

R

O

S

N

R

N

R4

R1

-H2O

2

4

R1

anti-57

S

R3

N

R4

N

NHO O

R4

N NHO

R3

R3

S

1

R

-HX S

R3

O

S

1

2

2

R

R

syn-57

58

(20 examples)

R1

57

R2

R3

R4

Yield (%) 77

a. 4-CNPh

isopropyl

CO2Et

Me

b. 4-CNPh

cyclopentyl CO2Et

Me

62

c. 4-O2NPh

isopropyl

CO2Et

Me

86

d. 4-MeOPh

isopropyl

CO2Et

Me

35

e. 4-O2NPh f. 4-O2NPh

isopentyl

H

Me

81

isopentyl

CO2Et

OH

36

Scheme 21 A solid-supported synthesis of 2-aminobenzothiazoles is reported by employing the resinbound acyl isothiocyanate 59 and a series of anilines (Scheme 22).41 The resin-bound isothiocyanate 59, prepared from the carboxy-polystyrene in two steps, got readily transformed to the corresponding thioureas 60 on treatment with anilines at room temperature. The cyclization of 60 to 2-acylaminobenzothiazole 61 was performed by treatment with six equivalents of bromine in acetic acid (Method A when X = H)). Alternatively, benzothiazoles were obtained by treatment of the corresponding N-acyl, N’-phenylthioureas (X = Cl, Br) with sodium hydride (Methods B) via an SNAri mechanism. Hydrazinolysis of solid-supported benzothiazoles afforded the 2-aminobenzothiazoles 62. O R

N

NH2

+

C

O

DMF r.t., 16 h

N H

S

59

R = Cl, Br

R O

S N H

61

R

NH2NH2.H2O N

S

EtOH 150 °C, MW, 30 min

X

R

N H

X = H (method A) X = Cl, Br (method B)

60 Method A: Br2, AcOH, r.t., 16 h X = H, F, Br Method B: NaH, DMF, r.t., 100 °C, 16 h S NH2 N 62

R = Cl, Br

(57-74%)

Scheme 22

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Recent years have witnessed an extensive investigation on the formal [3+2]-cycloadditions to oxazoles 63 accompanied by opening of the oxazole ring and formation of another heterocyclic framework 64 (Scheme 23). A diverse type of systems with multiple bonds such as C=C, C=N, N=N, C=O, N=O, and C=S of thioaldehydes have been studied.42-47 Dudin et. al. for the first time reported the reaction of oxazoles with acyl isothiocyanate heterocumulenes.48 The reaction of acyl isothiocyanates 1 with 5-isopropoxy-4-methyloxazole 65 led to the synthesis of 5-Nacylimino-2-isopropoxy carbonyl-2-methyl-3-thiazolines 66. The transformation occurred via formal [3+2]-cycloaddition of the C=S bond of acyl isothiocyanate to the 2nd and 4th atoms of the oxazole ring. R2

R1 N

3

R

O

N

+

1

X

R

Y

X

63 O R C N C S

COR3

Y

64 Me + PriO

1

R2

3 51

N

O 65

PhMe

N

ROC N

, 7 h

S

Me CO2Pri

66

a. R = Ph (96%), b. R = Me (25%), c. R = 4-O2NPh (75%)

Scheme 23 Drach and coworkers have reported the reaction of hydrazino-1,3-oxazoles with acyl isothiocyanates to furnish 1,3,4-thiadiazole.49 The 2-methyl/phenyl-4-cyano-5-hydrazino-1,3oxazoles 67 add onto the acyl isothiocyanates 1 (Scheme 24). The reaction initially generated expected adducts 68 that were capable of prototropism. The prototropic tautomers 69 lacked the aromatic oxazole ring, and, therefore, could undergo recyclization under fairly mild conditions to form the new 1,3,4-thiadiazole derivatives 70. In a similar fashion, acyl isothiocyanates reacted with diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-yl-phosphonate 71 to give the phosphorylated derivatives of 1,3,4-thiadiazoles 72 (Scheme 25).50 In another approach to synthesize the 1,3,4-thiadiazole skeleton, the acyl thiosemicarbazides 74 from nicotinoyl/isonicotinoyl hydrazide 73 have been cyclized with phosgene in the presence of sodium acetate forming 1,3,4-thiadiazol-2(3H)-ones 75 in good to excellent yields (Scheme 26).51 Some of these compounds exhibited significant anti-inflammatory activity.

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O N R C N C S + R1 O

1

a. R1 = Me b. R1 = Ph

R1

min

NH NH2

a. R = Me b. R = Ph c. R = EtO

N

N dioxane

67

C N

C N

C N

R1

NH NH

O S HN

O S HN

R

R O

O

68 70 a. R = Me, R1 = Me, 66% b. R = EtO, R1 = Me, 71% c. R = Me, R1 = Ph, 90% d. R = Me, R1 = Ph, 82% e. R = EtO, R1 = Me, 70% f. R = Ph, R1 = Ph, 92%

N NH

69

N N

H N

R1

O N H

S

O

C

R

N

70

Scheme 24 (EtO)2(O)P

P(O)(OEt)2 N

O R C N C S +

PMP

1

71

O

O

MeCN 80 °C, 2 h

NH NH2

PMP

H N

S N H

N N

R

O

72

PMP = 4-MeOPh

a. R = Me (92%), b. R = Ph (99%), c. R = OEt (99%)

Scheme 25 O NH O R C N C S

1

NH2

73 THF r.t., 24 h

O

O

N N

N H

NH

NH C S

74

CO R

N

COCl2 AcONa r.t., 24 h

N

O

N

NH CO R

S

75

75 pyridin-3-yl: a. R = Ph (86%), b. 4-MePh (90%), c. 4-MeOPh (90%), d. 4-ClPh (84%), e. 2-furyl (65%) 75 pyridin-4-yl: a. R = Ph (90%), b. 4-MePh (90%), c. 4-MeOPh (55%), d. 4-ClPh (91%), e. 2-furyl (45%)

Scheme 26 Organic azides 76, bearing a nitrile function at the - or -position undergo tandem reaction with acyl isothiocyanates to give the fused dihydro-1,2,4-thiadiazolimines 79. The preparation of such heterocycles by tethering the nitrile group at the 4-position of the dihydrothiatriazole 77 was

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reported by L'abbe and coworkers.52 The dihydrothiatriazoles 77 were obtained by cycloaddition of azides across the C=S bond of the acyl isothiocyanates. The cycloaddition of azides across the C=S was not a new phenomenon. It was reported earlier.53 The heterocycles 77 are expected to be unstable since they would decompose by anchimeric assistance of the carbonyl group. The 1,2,4-oxathiazo1-3-imine 78 formed possess a reactive thioimidate structural unit and should be capable of undergoing intramolecular cycloaddition ring-opening reactions, leading to the fused thiadiazoles 79 (Scheme 27). Using this methodology, a series of azidonitriles have been reacted with benzoyl isothiocyanate, to get 1,2,4-thiadiazoles (Scheme 28). NC

N3

CN

O R C N C S

N N

76

N

N S

R

N

O

C

-N2

77

N

N

N

R

S O

NCOR

N S

79

78

Scheme 27 Ph Ph

N3 CN

Ph

CH2Cl2, , 22 h R = CCl3 (28%) N3

N N S

CN

NCOR

N

CH2Cl2, 40 °C, 30 h

N

a. R = CCl3 (37%) b. R = Ph (22%)

S

N3

O R C N C S

NCOR CN

1 a. R = CCl3 b. R = Ph

NCOR

Ph

N

CH2Cl2, , 16 h a. R = CCl3 (52%) b. R = Ph (83%)

S N

N3 CN CH2Cl2, r.t. 5 d a. R = CCl3 (46%) b. R = Ph (41%)

N

NCOR

N S

Scheme 28 Page 222

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The reaction of benzoyl isothiocyanate with diazomethane was reported in the mid 1960s by Martin and Mucke to furnish the 5-amino-1,2,3-thiadiazole.54 The diazo compounds with an  carbon incorporated into the heteroaromatic system are known to react as 1,7-dipoles with electron-rich olefins, acetylenes, and isocyanates leading to six-membered heterocyclic compounds.55-58 Recently, synthesis of new imidazo- and pyrazolo[5,1-d][1,2,3,5] thiatriazines based on the reaction of diazoazoles with acyl isothiocyanates controlled by S/O interaction has been reported.59 In principle, both the CN and CS bonds of isothiocyanates are capable of cycloaddition with diazoazoles to form either a 1,2,3,5-thiatriazine or a 1,2,3,5-tetrazine ring system or a mixture of both. Recently, the reactions of diazoazoles 80 with acyl isothiocyanates is reported to occur readily at C=S to give azolo[5,1-d] [1,2,3,5]thiatriazines 81 as the sole products (Scheme 29). It is noteworthy to mention that this reaction was unsuccessful with methyl-, phenyl- or benzenesulfonylisothiocyanate.60 The acyl substituent on the isothiocyanate probably led to a stabilization of the final product 81 due to an S/O interaction which could be the main reason of difference in the reactivity of acyl isothiocyanates with alkyl or aryl isothiocyanates in their reaction with diazoazoles. The Gibbs energies for two possible conformations of compound 81 were calculated which confirmed that conformer A with hypervalent thiadiazoles sulfur atom was more stable than the conformer B where non-bonded S/O through-space interactions were absent. 2

Y

R Y

O 1 R C N C S

+

X

N

1 a. R = OC2H5 b. R1 = Ph

a. b. c. d. e. e.

x

y

CH CH CH CH N N

N N N N CH CH

R1

CO2Et CO2Et CONHMe CONHMe CO2Et CO2Et

S

N

O 81

79 88 69 76 72 84

X N N

N N

% Yield

R2 N

S

N

R2

OEt Ph OEt Ph OEt Ph

Y

R1

N

r.t., 3-20 h

80 R1 a. R2 = CO2Et X = CH, N b. R2 = CONHMe Y = CH, N

1

81

X

anhydrous EtOAc

N2

R2

R1 O

R2

Y X N N

S

N N

O

Conformation A

Conformation B

Scheme 29

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2.3. Cyclization reactions involving azomethine linkage of isothiocyanates O C R

S

O N C S

C

R

C N

Tolpygin and co-workers, in order to develop cation and anion sensors,61 have carried out the reactions of 4-arylalkyl- and 4-arylthiosemicarbazides 82 with benzoyl isothiocyanates 1 to get substituted 1,2-bis(thiocarbamoyl)hydrazines 83.62 These compounds readily cyclized to 1,2,4triazole-5-thiones 84 containing N-arylamino group at C-5 (Scheme 30). An alternative cyclization to 1,2,4-triazole-5-thiones 85 containing N-acylamino group on C-5 was ruled out by spectroscopic studies of the product but no explanation has been advanced for this selectivity. route B S

O R1 C N C S + H2N 1

N H

N H

R2

MeCN,  1h

O R1

S N H

N

H N

H N S

H

S 2 route B R

HN

82

84 a. R1 = 4-ClPh, R2 = 9-anthrylmethyl (67%) b. R1 = 4-FPh, R2 = CH2Ph (79%) c. R1 = 3-FPh, R2 = CH2CH2Ph (76%) d. R1 = 4-MePh, R2 = 2-OMePh (72%) e. R1 = 4-MePh, R2 = CH2Ph (67%) f. R1 = 2-MePh, R2 = thien-2-yl (78%) g. R1 =4-ClPh, R2 = CH2Ph (81%) h. R1 = 4-ClPh, R2 = CH2CH2Ph (76%)

R1

NH N

COR1

route A 83 , 1-BuOH -H2S 4-6 h O

N

R2

85

S N

HN R2

NH N 84

Scheme 30 Saeed and Batool have reported the synthesis of 1-(isomeric methyl) benzoyl-3-aryl-4methylimidazole-2-thiones by base-catalyzed condensation of acetone with thioureas obtained from benzoyl iosothiocyanates.63 Various derivatives of imidazole-2-thione have attracted widespread attention owing to their diverse pharmacological properties and bioactivities. Isothiocyanates 86 reacted with anilines 87 providing 1-isomeric methylbenzoyl thioureas 88. The base-catalyzed condensation of 88 was achieved in the presence of bromine to get the 1tolyl-3-aryl-4-methylimidazole-2-thiones 89-91 in reasonable yields (Scheme 31).

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O

Me

R N C S

O

NH2

+

86

S

R

Me

acetone 1-2 h, 

N H

N H

87

88 Et3N, Br2/acetone/N2

86: 2-Me, 3-Me, 4-Me 87: R = H, 2-Cl, 3-Cl, 4-Cl, 4-Br, 2-Me, 3-Me, 2-OMe, 3-OMe O

Me

S N

89: 2-Me (50-64%) 90: 3-Me (50-66%) 91: 4-Me (57-79%)

R

N Me

89-91

Scheme 31 NH2 CO2H

O

O Ac2O , 2 h (77%)

O , 6 h

N H2C

NHCS

O

NH

Ac2O

O N H2C

S

, 2 h

NH C

O HO2C

O

(87%) N COPh

NCS O

92

acetone, , 6 h

O S N H2C NH NH O Ph NH

Ac2O , 2 h (69%)

O

O N H2C O

S

N

O

N

COPh

O

Ac2O H S , 2 h NC N COPh (82%)

HO2C

O N H 2C

S

N NH N O Ph 96

O

O PhCONH-CH2CO2H PhCHO acetone, , 6 h

O N H2C

O

O PhCONH-NH2

NH

95

O N H2C

N

94 O

O PhCONHCH2CO2H acetone, , 6 h

S

OO

HO2C

93

O

N H2C

CHPh

O N H2C

N

O

O 97

S N

COPh

CHPh

Scheme 32

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Since the isatin ring is present in the structures of many biologically active compounds, methods for synthesis of its derivatives still hold the interest of chemists.64 In a recent report, 2(2,3-dioxoindolin-1-yl)acetyl isothiocyanate 92 was used as a substrate to synthesize some new heterocyclic compounds containing isatin ring (Scheme 32).25 The thiourea derivative 93, obtained from treatment of the acyl isothiocyanate 92 with anthranilic acid, was cyclized in acetic anhydride to afford the isatin-thioxoquinazolinone derivative 94. Similar reactions of acyl isothiocyanate 92 with N-benzoyl glycine, bezoyl hydrazine, and N-benzoyl glycine in the presence of benzaldehyde forming adducts, and their cyclization to heterocycles 95-97 are also described by the authors. El-Sharkawi and coworkers have recently reported the reaction of benzoylisothiocyanate with 2-aminotetrahydrobenzothiophenes in the synthesis of annulated thiophenes containing tetrahydropyrimidine ring of pharmaceutical interest.65 The reaction of benzoylisothiocyanate 1 with 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene derivatives 98 in 1,4-dioxane at room temperature gave the N-benzoylthiourea derivatives 99 (Scheme 33). Thioureass 99 underwent cyclization on heating in under basic conditions to give the tetrahydrobezo[b]thieno[2,3d]pyrimidine derivatives 100. X O R C N C S

+

NH2 S

1 R = Ph

Y

X

98 a. X = CN b. X = COOEt

COPh N S

NaOEt

1, 4-dioxane r. t., 12 h

S

NHCNHCOPh S

99 a. X = CN (70%) b. X = COOEt (60%)

EtOH 100 °C 6h

NH S 100 a. Y = NH (70%) b. Y = O (88%)

Scheme 33 2.4. Acyl isothiocyanates as acylating agents There are several reports in the literature on chemoselective acylation of amines using diverse reagents under different conditions. A few examples include the chemoselective acylation and benzoylation of the amino group in preference to the hydroxyl group by carboxylic anhydrides in the presence of sodium dodecyl sulfate as a catalyst,66 and by carboxylic acids using carbonyldiimidazole.67 Chemoselective N-acylation has also been achieved using amine hydrochlorides and anhydrides in the presence of sodium bicarbonate.68 Nair and Joshua have reported mixed benzoic dithiocarbamic anhydrides as benzoylating reagents.69 Katritzky and coworkers have suggested N-acyl-benzotriazoles as useful acylating reagents for amines.70 Acyl isothiocyanates are also used as acylating agents in different reactions. Recently our group has reported a chemoselective N-benzoylation of aminophenols using benzoyl isothiocyanates as acylating agents.71 An equimolar reaction of benzoyl isothiocyanates 1 with aminophenol 101 in refluxing pyridine afforded the corresponding N-(hydroxyl-phenyl)benzamides 102 in good yields (Scheme 34). The formation of product has been explained through formation of the

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corresponding thioureas followed by elimination of HSCN as shown in Scheme 34. When the reactions of benzoyl isothiocyanates with salicylamide were carried out O-benzoyl derivatives 103 were obtained (Scheme 35) by similar method.72 The use of a base, pyridine in this case, was a necessity for the reaction of isothiocyanates with a phenolic hydroxyl group.73 HO

O

NH2

R C N C S + 101

S

N H

a. b. c. d. e.

OH R

R OH Ph 2-OH 2-MePh 2-OH 3-MePh 2-OH 4-MePh 2-OH 4-MeOPh 2-OH

102 -HS C N

SH O

N H f. g. h. i. j.

R 4-ClPh 4-O2NPh Ph 3-MePh 4-MeOPh

R O

(70-80%)

O N H

H N

, 4-5 h

1

OH

HO

pyridine

N

R

OH 2-OH 2-OH 4-OH 4-OH 4-OH

Scheme 34

O R C N C S

+

O

O

O NH2 OH

NH2

NH2

xylene-pyridine (5:1) O

, 1 h S

N H

O

-HSCN

O

O

R

R

103 103. R = Ph (86%), 2-MePh (74%), 3-MePh (79%), 4-MePh (83%), 4-MeOPh (80%), 4-Cl(Ph 75%), 4-O2NPh (73%)

Scheme 35 A 2:1 molar reaction of benzoyl isothiocyanates 1 with 1,2-phenylenediamines 104 in benzene afforded the corresponding N,N’-bis(benzoylthiocarbamoyl)-1,2-phenylene diamines 105.74 The products 105, were cyclized in pyridine to afford 2-aryl benzimidazoles 106. The formation of products 105 has been explained by usual nucleophilic attack of amines 104 on carbon atom of the isothiocyanate linkage in substrates 1 (Scheme 36). On refluxing in pyridine, the removal of one aroyl isothiocyanate moiety may lead to the formation of N(benzoylthiocarbamoyl)-1,2-phenylenediamines 107. The formation of 107 from the reaction of amines 104 with isothiocyanates 1 has been reported previously by refluxing in acetonitrile.75 The intermediate product 107 leads to the formation of 2-arylbenzimidazoles 106 by Page 227

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dethiocyanation to intermediate product 108 and concomitant cyclodehydration.75 Nucleophilic addition reactions of α,β-unsaturated acyl isothiocyanates with aromatic and heteroaromatic amines such as 3-amino-1,2,4-triazole and 2-aminothiazole were also reported earlier to yield the acyl amino derivatives through elimination of HSCN.76

2

O 1 R C N C S

R +

NH2

2

R

PhH, r.t.

NH2

e. f. g. h.

S

NH

NHCOR1

R1OCHN S 105

R2

N

120 °C, 8 h R2

N H

pyridine

R1

106

2

R % H 75% Ph 4-MeOPh H 88% 4-ClPh H 68% 3-MePh H 82% Me 85% Ph 3-MePh Me 94% 4-MeOPh Me 79% Me 87% 4-ClPh R

106 a. b. c. d.

1

2

R

104

1

H N

R2

-1

-H2O

R2

NH2

R2

NH

R1OCHN

NH2

R2

-HSCN

O

2

R

N H

S

107

R1

108

Scheme 36 The reactivity of β-cyanoethylhydrazine 109 with aroyl isothiocyanates has been investigated Elmoghayar and coworkers.20 This work has resulted in development of new efficient one-step synthesis of 5-thioxo-l,2,4-triazole derivatives. The reaction of benzoyl isothiocyanate 1 with βcyanoethyl hydrazine 109 in dioxane at room temperature yielded the 5-thioxo-l,2,4-triazole 110. Treatment of compound 110 with benzoyl isothiocyanate resulted in the formation of imidazole3-thione derivative 111 via loss of HSCN (Scheme 37). O R C N C S + H2NHNCH2CH2CN 1 R = Ph

dioxane , 3 h

109

O Ph C NH C S HN NH

S N Ph

N

NH

CH2CH2CN

CH2CH2CN

110 PhCONCS S

S

N Ph

N

N COPh CH2CH2CN

-HSCN (65%)

Ph

S N C NH COPh CH2CH2CN

111

Scheme 37

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The reaction of acyl isothiocyanates with β-dicarbony compounds proceeds as Cthiocarbamoylation of the dicarbonyl component. For example, the formation of Cthiocarbamoylated derivatives of 1,3-cyclohexanedione77 or dimedone78,79 in good yields are reported. However, in the reaction of the benzoyl isothiocyanate 1 with cyclic diketone 112 in the presence of an equimolar amount of KOH at room temperature, the former reacted as an acylating agent to furnish O-acylation products 113 (Scheme 38).80 O O

1

R C N C S

+

R

O 1

R

KOH, EtOH

R1

R1

-KSCN

O O C R 113

O 112

1 1

R = Ph, R = H (76%); R = 4-ClPh, R1 = H (61%); R = Ph, R1 = Me (72%); R = 4-ClPh, R1 = Me (63%); R = 4-BrPh, R1 = Me (60%); R = 4-MeOPh, R1 = Me (65%)

Scheme 38 2.5. Acyl isothiocyanates as thiocyanate transfer reagents An unprecedented transfer of a thiocyanate (SCN) group from aroyl/acyl isothiocyanate to alkyl or benzylic bromide in the presence of a tertiary amine has been reported by Patel and coworkers.81 Treatment of benzoyl isothiocyanate 1 with -bromoacetophenones 114 in the presence of N-methylimidazole in acetonitrile afforded the acyl thiocyanates 115 (Scheme 39). Since no reaction was observed in the absence of N-methylimidazole, it was definitely involved in the reaction process. The reaction has been further extended to benzyl bromide and pnitrobenzyl bromide. The methodology is also compatible in the presence of amide and ester functionalities.

O R1 C N C S

+ R2

O C

Br H H

1

N N Me (1 equiv.) MeCN r.t., 2 h

114

R2

O C

S C N H H

115

R1 = Ph R2 = Ph (64%), 4-MeOPh (81%), 4-BrPh (77%)

Scheme 39 The authors have proposed two possible mechanisms– (i) through an attack of imidazole nitrogen on carbonyl carbon (path A) and (ii) through an attack of imidazole carbon on

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cumulenic carbon of benzoyl isothiocyanate (Scheme 40). In path A, the resulting activated intermediate 116 transfers the NCS group to the -bromoketone. In path B, the resulting activated thiourea species 117 may react with haloketone giving the S-alkylated product 118, which may undergo nucleophilic attack (N-methylimidazole or water from MeCN) giving rise to a tetrahedral intermediate 119. The collapse of the latter intermediate with concomitant departure of N-methylimidazole may give the final product. path A Ph

O C

N Me

N N C S path B

path A

Ph

O

O

N C S Br

N

O

R2

1 path B

S

R2

N Me 116

C N

115

O O Ph

R2

S N H

N

Ph Nu

N Me

S

O

Br

R2

N

117

O

O N

Nu

Me

N

N

O N

N Me

118

N -H + Br

R2

Ph S

N Me

119

Ph

O C

O + Nu

S N

R2

115

Scheme 40 The reaction of benzoylisothiocyanate with 2-bromoethylacetoacetate 120 under the identical reaction conditions, however, yielded the 1,3-oxathiol-2-ylidine 122 as a major product and thiocyanate transfer product 123 only in 10% yield (Scheme 41).81 The formation of the 1,3oxathiol-2-ylidine 122 has been explained by the S-alkylation of zwitterionic intermediate 117 with 2-bromoethylacetoacetate 117 followed by an intramolecular enol attack on the imine carbon in intermediate 124 displacing the 2-methylimidazole. The product 123 is obtained by a thiocyanate transfer process from the isomerized 2-bromoethylacetoacetate 120 to 4bromoethylacetoacetate 121.

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O O

O

Me

Ph OEt

Br

S Ph

r.t., 2 h

O OEt

N O

N Me

120

O

N

O

O

N C S 1

+

OEt SCN 123

Me

122

O

(55%)

(10%)

O

Br

O

OEt 121 O Ph

O

S N

O Br 117

N

N

117

H

O O

S

O Ph

N

O N

N

124

Scheme 41

3. Multicomponent Reactions of Acyl Isothiocyanates In recent years, multicomponent reactions have acquired conspicuous popularity in design and synthesis of complex organic molecules.82-84 Acyl isothiocyanates have also been employed in multicomponent reactions to synthesize functionalized thiourea and heterocyles. A multicomponent reaction of benzoyl isothiocyanates 125, alkyl propiolates 126, secondary amines 127, and Ph3P leading to an efficient synthesis of functionalized thioureas has been reported.85 Addition of Ph3P to various activated alkynes like dibenzoylacetylene, dicyanoacetylene, or dimethylacetylenedicarboxylate (DMAD) generating zwitterionic intermediate was reported as early as 1961 by Tebby and coworkers.86 Initially a 1,3-dipolar intermediate 130 was formed from Ph3P and the acetylenic ester, which was subsequently protonated by the benzoyl thiourea 129, formed from addition of amine 127 to aroyl isothiocyanates 125. A nucleophilic attack of the nitrogen atom of the conjugate base 132 to the vinylphosphonium cation 131 leads to the formation of an ylide 133, which is converted to products 128 by elimination of Ph3P (Scheme 42).

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R O S N C +

R

CO2R1 +

R2

N H

R2

126

R2

N

S N R2

N H

127 R

O CO2R1

R2

+

R2

129

R1 Et Me

128 R a H b H c H d H e Br H f g H

Et Me Et Et Me

N R

N

R2 C2H5

Yield % Z/E 85 3 C2H5 80 2 (CH2)5 90 3.8 (CH2)5 87 5.8 (CH2)5 75 2 80 (CH2)4 4 (CH2)2O(CH2)2 90 3 O

CO2R1 Ph3P

CO2R

+

1

1

CO2R

126

Ph3P

S N

R

R2

132 O

-Ph3P

N R2

R

131

(Z)-128 + (E)-128

S N

+

Ph3P 130

126

O

2

1 (E)-128 CO2R

(Z)-128

O +

N

2

127

125. R = H, Br 126. R1 = Me, Et 127. R2 = Et, (CH2)5, (CH2)4, (CH2)2O(CH2)2

125

S

S

PPh3 CH2Cl2

R 125

R

Ph3P

R2 N R2

CO2R1

133

Scheme 42 Yavari and coworkers have described an equimolar reaction of benzoyl isothiocyanate 1, dialkyl acetylenedicarboxylates 134 and Ph3P to afford the dialkyl 2-(benzoylimino)-5-phenyl4H-[1,3]dithiolo[4,5-b]pyrrole-4,6-dicarboxylates 135, with double insertion of the isothiocyanate, and dialkyl 2-phenyl-4-thioxo-4H-1,3-oxazine-5,6-dicarboxylates 136 in a 3:1 ratio (Scheme 43).87 O R C N C S + 1 R = Ph

O

CO2R1 +

PPh3

CH2Cl2 r.t., 24 h

CO2R1 134 134. R1 = Me, Et, tBu

R1O2C Ph

S

N

S N CO2R1 135 R1 a Me b Et c tBu

S

Ph

CO2R1

N

+

O

Ph

CO2R1

136

Yield (%) of 135 Yield (%) of 136 38 40 35

10 8 10

Scheme 43

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The plausible mechanistic rationalization suggests that the zwitterionic intermediate 137, formed from Ph3P and dialkylacetylenedicarboxylates, adds onto the benzoyl isothiocyanate to furnish an intermediate 138, which then adds onto another molecule of benzoyl isothiocyanate to form another intermediate 139 (Scheme 44). This intermediate undergoes cyclization to furnish the fused structure 140 by the elimination of triphenylphosphine oxide. The pyrrole derivative 140 rearranges to the final product 135 by a carbon to nitrogen carboxyl transfer via the tricyclic intermediate 141. Formation of oxazinethiones 136 involves addition of the zwitterionic intermediate 137 to benzoyl isothiocyanate. The cyclization of intermediate 142 and subsequent elimination of Ph3P leads to the formation of oxazines 143. S N Ph O

S

CO2R

C

N

CO2R Ph

Ph3P

S CO2R

O

CO2R

+

PPh3

Ph3P

O

O Ph C N C S

CO2R CO2R

CO2R

O N C S

Ph

O CO2R Ph C N C S

Ph3P CO2R

CO2R

134

137

138

Ph Ph

Ph

136

O Ph C N C S

CO2R

-Ph3P

PPh3

143

142

CO2R

N

N C O Ph3P

S C

N

S CO2R

O

N Ph N O

S

Ph3P RO2C O

S OR

S

Ph N

Ph

N S

-Ph3=O

RO2C O

O

CO2R

Ph O

OR

140

139

[1,3]CO2R shift O RO2C Ph

S

O

Ph N

S

N CO2R

135

N Ph

OR S N S

Ph

RO2C

O

141

Scheme 44 Several methods for the synthesis of thiazole derivatives have been developed employing acyl isothiocyanates, the most widely used method being the Hantzsch’s synthesis.88 A threecomponent reaction of acyl isothiocyanates 1, ethyl bromopyruvate 144 and secondary amines

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145 in acetone at room temperature affords ethyl 2-(4-aryl-2-dialkylamino-1,3-thiazole-5-yl)-2oxoacetates 146 (Scheme 45). This procedure modified the Hantzsch method for thiazole synthesis via the reaction of thioureas with α-halocarbonyl compounds.89 In this method, thiourea derivatives are formed in situ from acyl isothiocyanates 1 and amines 145 which react with bromopyruvate 144 to afford highly functionalized thiazoles 146. O

CO2Et

Br

R1 C N C S +

R2

+

1. R1= Ph, 4-MePh, 4-BrPh, 4-O2NPh, tBu, Et

Acetone r.t., 1-3 h

N H 145

O 144

1

R1

R2

N

EtO2C

2 N R R

S O 146

145. R2 = Me, (CH2)4, (CH2)5 (CH2)2O(CH2)2

(16 examples) Yield: 76-88%

Scheme 45 The formation of thiazoles 146 from in situ generated thioureas 147 has been explained by nucleophilic alkylation of the thioureas with ethyl bromopyruvate forming intermediate 148, which undergoes HBr elimination and subsequent enolization to generate another intermediate 149. This intermediate undergoes intramolecular cyclization to form the heterocyclic intermediate 150 which loses water to afford thiazoles 146 (Scheme 46). R2

N H 145

O R C N C S 1

O

R2 R

O R

H

R1

O 144

N N C S H 147

R1

1

EtO2C 148

N S

HO

N

R1

R2

N

S Br

R2

O -HBr

O R2

N N

S

R2

R2

EtO2C OH

150

R2

N

O

R1 O EtO2C

Br

2

2

CO2Et

Enolization

R1 EtO2C

S O

149

N N R2

R2

H+ transfer

EtO2C

R1

R1 OH N 2

S O

N R R2

-H2O

N

EtO2C

S O

2 N R

R2 146

Scheme 46

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Recently, the formation of thiazol-2(3H)-imines in a three-component reaction of -amino acids 151, aroylisothiocyanates 1 and -bromoketones 152 in an ionic liquid 1-butyl-3methylimidazolium bromide [bmim]Br as a solvent has been reported (Scheme 47).90 Functionalized thiazol-2(3H)-imines 153 are obtained in excellent yields. The method is also advantageous because the ionic liquid can be recycled by extraction from the aqueous base. Also, the configuration of the amino acid component remained unchanged after the reaction. The reaction presumably starts with the formation of thiourea derivative 154, followed by its alkylation by 152 to generate intermediate 155 (Scheme 48). This intermediate underwent a cyclization reaction to afford 156, which is converted to product 153 by elimination of H2O.

R2

NH2

R1 Ph Ph Ph Ph Ph Ph

R2 H H H Me Me Me

[bmim]Br

R3

N

OH N

S

a. R3 = CO2Et b. R3 = 4-MeOPh c. R3 = 4-BrPh

Yiled (%) R3 CO2Et 76 4-MeOPh 79 4-BrPh 86 CO2Et 96 4-MeOPh 94 4-BrPh 97

O

R2

50 °C

152

a. R2 = H b. R2 = Me c. R2 = i -Pr

a. R = Ph b. R = p-Tolyl

Br

R3

+

151

1

153 a. b. c. d. e. f.

O

CO2H

O 1 R C N C S +

153 g. h. i. j. k. l.

R1 Ph Ph Ph p-Tolyl p-Tolyl p-Tolyl

R1

O 153

R2 Yiled (%) R3 i-Pr CO2Et 92 i-Pr 4-MeOPh 89 i-Pr 4-BrPh 96 Me CO2Et 80 Me 4-MeOPh 85 Me 4-BrPh 83

Scheme 47 O O R C N C S 1

CO2H +

R2

1

O

NH2

R1

N H

R2

O

N

R

151 O

R2

3

O R3

S

HO N

S O 155

R1

R

R3

N

S O 156

R1

Br 152

CO2H

R2

O

N

OH

3

R

R

OH

HN

N H 154

2

-H2O

N

S O 153

R1

Scheme 48

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Yavari and Djahaniani have reported a three-component reaction in which two moles of alkyl(aryl) isocyanides 157 react with one mole each of the benzoyl isothiocyanate 1 and dialkylacetylenedicarboxylates or dibenzoylacetylene 158 to afford the spiro-fused heterocyclic compounds dialkyl 4,7-bis[alkyl(aryl)imino]-2-phenyl-3-oxa-6-thia-1-azaspiro[4.4]nona-1,8diene-8,9-dicarboxy-lates 159a-e or [8-benzyoyl-4,7-bis[(tert-butyl imino)-2-phenyl-3-oxa-6thia-1-aza-spiro[4.4]nona-1,8-dien-9-yl](phenyl)methanone 159f, with double insertion of the isocyanide, in reasonable yields (Scheme 49).91

R

COR2

O C

1

2 R N C S +

1

N

C

Ph CH2Cl2 r.t., 24 h

+ COR2 158

157

R = Ph R1 = tBu,1,1,3,3-tetramethylbutyl, 2,6-dimethylphenyl

a. b. c. d. e. f.

R2 = OMe, OEt, OiPr, Ph

R2OC N

R2 OMe OEt OiPr OMe OMe Ph

O

COR2

S NR1 1 NR 159

R1

Yield %

t

Bu Bu t Bu 1,1,3,3-tetramethylbutyl 2,6-dimethylphenyl t Bu

48 48 40 44 40 38

t

Scheme 49 The reaction may involve the initial formation of a 1:1 zwitterionic intermediate 160 between the isocyanide and the acetylenic compound, which can undergo further reaction with 1 to produce 161. Cyclization of intermediate 161 leads to the formation of 162, which undergoes [4+1]-cycloaddition with isocyanides 157 to form the final products 159 (Scheme 50). COR2

R OC

R1 N C + 157

2

COR2

160

158 R2OC COR2

1

COR2

R1 N C

R2OC

COR2

R1 N C [4+1]-cycloaddn.

R N C S 161

R1 N

N O

O C Ph N C S 1

Ph

S

N

Ph

COR2 N

2

R OC

S R1N

R1N

Ph

O

O 162

159

Scheme 50

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4. Miscellaneous Reactions The reaction of isothiocyanate 1 with thiosemicarbazide 163 yielded the 1,2,4-triazoline derivative 166 (Scheme 51).27 The formation of product 166 was explained through cyclization of the nucleophilic addition product 164 forming the heterocycle 165. The elimination of H2S from this heterocycle afforded the final product. The release of H2S gas during the reaction progress was detected by turning a paper wet with lead acetate solution into black. O

S R C N C S + NH2CNHNH2

1 R = CH2Ph

MeCN , 3 h

O

H R C N

S

H2N N H 164

163

O

NH

HS H N

R C N H

S

NH

HN

S

165 -H2S

HN

H N

S

N

or

H N NH

N PhH2COCHN

PhH2COCHN

S

166'

166

(81%)

Scheme 51

O O RNH2 PhH

S NHCNHR

167

NH S S 170 Yield (%)

NHR

R = Ph (57%), 4-MePh (62%), 4-MeOPh (68%), 4-ClPh (55%), 4-MeOCMePh (54%), CH2Ph (66%) O

O 1. NaOH, H2S MeOH 2. Acetone

S 169

168

O NCS

N

BF3.Et2O,CHCl3

+

OH 171

Scheme 52 α,β-Unsaturated acyl isothioucyanates react with primary and secondary amines in usual manner forming stable thioureas, which are synthons for the synthesis of diverse types of thiaand thiaza-heterocycles such as 1,3-thiazines, thiouracils, thiazolines, and benzothiazoles.92-94 Treatment of isothiocyanate 167 with amines in benzene or acetone afforded the corresponding N-substituted N’-(hexa-2,4-dienoyl)thioureas 168 in 79-92 % yields (Scheme 52).95 Boron

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trifluoride-catalyzed cyclization of thioureas 168 in chloroform resulted into the formation of the 2-substituted 6-(propen-l-yl)-5,6- dihydro-4H-l,3-thiazin-4-ones 169. A nucleophilic addition of sodium hydrogen sulfide to isothiocyanate 167 affords two products, 6-(propen-l-yl)-2thioxotetrahydro-4H-l,3-thiazin-4-one 170 and hexa-2,4-dienoic acid 171 in 37% and 31% yields, respectively. The formation of carboxylic acid 171 could be explained by partial hydrolysis of transiently formed sodium N-(hexa-2,4-dienoyl)dithiocarbamate.

5. Concluding Remarks Acyl isothiocyanates are bifunctional reagents capable of participating in a wide range of additions and cyclizations. The reactivity of acyl isothiocyanates is determined by the three active centers. One of them is associated with the nitrogen atom with the unshared pair of electrons, and the others are on the thiocarbonyl and carbonyl groups. The strong electronwithdrawing potential of the acyl group enhances the reactivity of the adjacent isothiocyanate functionality and promotes the nucleophilic addition at this center. Acyl isothiocyanates are reported to undergo cyclization involving thiocarbonyl and carbonyl carbon with nitrogen nucleophiles forming triazolinethiones, l,2,4-triazoles, 1,2,4-triazoline-5thiones, 1,3,5-triazinethiones, and oxadiazines. Cyclization through thiocarbonyl group results into the formation of different thiazoline skeletons and thiadiazoles. Organic azides, bearing a nitrile function at the - or -position, react with acyl isothiocyanates to furnish the fused dihydro-1,2,4-thiadiazolimines. In the reaction of diazo compounds with acyl isothiocyanates, thiadiazole derivatives are formed, apparently by a 1,3-cycloaddition across the C=S bond. The [3+2]-cycloaddition of oxazoles to the C=S group of acyl isothiocyanates have been employed in the synthesis of thiazolines. Another commonly investigated reaction of acyl isothiocyanates is as an acylation reagent in different reactions through an elimination of thiocyanic acid from the reaction intermediate products. The reaction of acyl isothiocyanates with β-dicarbonyl compounds furnished Oacylation products. A novel transfer of a thiocyanate (SCN) group from acyl isothiocyanate to alkyl or benzylic bromide in the presence of an N-methylimidazole is reported recently. The ability of acyl isothiocyanates to form a variety of nitrogen- and sulphur-containing heterocyclic compounds makes it an important building block in organic synthesis. Use of acyl isothiocyanates as acylating agents and thiocyanate-transfer reagent has further diversified its chemistry. We anticipate a lot more interesting chemistry of acyl isothiocyanates to appear in coming days.

6. Acknowledgements The authors are grateful to the Chemistry Department, University of Botswana, Gaborone, Botswana, for providing the necessary facilities. KGB is thankful to the DAAD scholarship through NAPRECA.

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Authors’ Biographies

Girija S. Singh was born in Sasaram (Bihar), India. He received his B. Sc. and M. Sc. degrees from the U. P. College (then Gorakhpur University), Varanasi, India, in 1977 and 1979, respectively. He received his Ph. D. degree from the Banaras Hindu University (BHU), India, completing his doctoral thesis on the reactions of diazoalkanes and diazoketones with imines, amines and hydrazones in October, 1984. Since then he has occupied teaching and research positions in various universities such as Banaras Hindu University, India (JRF, SRF, PDF, Research Associate, Pool-Officer, Reader), Osaka University, Japan (PDF), University of Zambia (Lecturer), and University of Botswana (Lecturer, Senior Lecturer, Associate Professor). He is currently working as Professor of Chemistry at the University of Botswana. He has authored over ninety publications in books and in peer-reviewed journals. He is member of the American Chemical Society, Chemical Research Society of India, and Indian Chemical Society. He is on the editorial board of over half a dozen chemistry journals. His research interests include the study of synthesis and reactivity of biologically important heterocycles, reactions of carbenoids, metal-catalyzed oxidations and organic chemistry education.

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Kibrom G. Bedane was born in Addis Ababa, Ethiopia. He received his B.Sc. in 2000 from Bahir Dar University, Ethiopia and M.Sc. in Organic Chemistry from Addis Ababa University, Ethiopia in 2006. From 2002 to 2008 he was working as a Lecturer at the Department of Chemistry, Abiyi Addi College of Teacher Education, Ethiopia. Since 2009 he has been lecturing organic chemistry at the Department of Chemistry, Addis Ababa University. In 2011, he stayed for three months at Spiez Laboratory, Switzerland, with OPCW internship program: Internship for organic chemistry skills development. The internship was on synthesis of compounds related to precursors, degradation products and by-products of chemical weapon agents. Currently, he is a Ph.D. student at the Chemistry Department of the University of Botswana with DAAD (the German Academic Exchange Service) scholarship through the Natural Products Research Network for Eastern and Central Africa (NAPRECA). His current research work involves phytochemical investigations of medicinal plants and organic synthesis.

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