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Hindawi Publishing CorporationOrganic Chemistry InternationalVolume 2013, Article ID 210474, 71 pageshttp://dx.doi.org/10.1155/2013/210474

Review ArticleBenzo[1,5]thiazepine: Synthesis, Reactions,Spectroscopy, and Applications

Khairy A. M. El-Bayouki

National Research Centre, Dokki, Cairo, Egypt

Correspondence should be addressed to Khairy A. M. El-Bayouki; [email protected]

Received 7 July 2012; Accepted 5 October 2012

Academic Editor: William Setzer

Copyright © 2013 Khairy A. M. El-Bayouki. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

This review article deals with synthesis and reactions of benzo[1,5]thiazepines and the related derivatives and their applications,biological activity as well as spectroscopic data. Most of the reported data on the methods of synthesis, chemical reactions, andbiological activity of these heterocycles published over the last ten years are reviewed in this paper.

1. Introduction

1,5-Benzothiazepines are the most well-known representa-tives of benzologs of 1,4-thiazepine and one of the threepossible benzo-condensed derivatives, namely, 1,4-, 4,1- and1,5-benzothiazepines. The parent 1,5-benzothiazepine, itself,has not hitherto been described in the literature for itspharmacological properties. However, its 2,4-disubstitutedderivatives and many hydrated derivatives have been synthe-sized. The 1,5-benzothiazepine derivatives are of particularinterest for lead discovery because they have been foundactive against different families of targets. The first moleculeof 1,5-benzothiazepine used clinically was diltiazem, followedby clentiazem, for their cardiovascular action. Someof the 1,5-benzothiazepine derivatives were also used clinically for CNSdisorders which includes thiazesim and quetiapine fumarate.Moreover, 1,5-benzothiazepine moiety is a privileged classof pharmacophore, as compounds bearing this structuralunit possess a broad spectrum of biological activities suchas anticonvulsant, Ca+2 channel antagonist, antianginal, antiHIV, squalene synthetase inhibitor, V

2arginine vasopressin

receptor antagonist, andHIV-1 reverse transcriptase inhibitor[1–3].

The methods for the preparation of 1,5-benzothiazepinescan be divided into two major groups, namely, the construc-tion of a seven-membered heteroring from the elements ofopen chains, and reactions involving ring expansion.

2. Nomenclature and Way of Numbering

1,5-Benzothiazepines are the most well-known represent-atives of benzologs of 1,4-thiazepine. According to theIUPAC nomenclature, the benzo[1, 5]thiazepine structuresIA or IB may be named as (𝑍)-2,3-dihydrobenzo[𝑏][1,4]thiazepine or (𝑍)-2,3-dihydro-substituted-benzo[𝑏][1,4]thiazepine. Also, the substituted-benzo[1, 5]thiazepinesstructure IIA or IIB may have the name: 2,3,4,5-tetra-hydrobenzo[𝑏][1, 4]thiazepine or 2,3,4,5-tetrahydro-substi-tuted-benzo[𝑏][1, 4]thiazepine (see Figure 1).

3. Preparation of 1,5-Benzothiazepine Systemand Its Related Derivatives

3.1. Thiophenol and Its Derivative Approaches

3.1.1. Solid Phase Synthesis: Claisen-Schmidt Condensation of3-Hydroxyacetophenone with Different Substituted Aldehydesand o-Aminothiophenol. The solution phase synthesis of 2,3-dihydro-1,5-benzothiazepines 4 and 5 was carried out byheating under reflux of 𝛼,𝛽-unsaturated ketones 3 (obtainedfrom reaction of an aldehyde and the acetophenones 2) witho-aminothiophenol in dry acidic MeOH in the presenceof drops of glacial CH

3COOH. Also, the synthesis of 2,3-

dihydro-1,5-benzothiazepines 9 was carried out on Wang

2 Organic Chemistry International

S

S S

S

N

N N

NH

H1

1 1

13 3 3 3

5

5 5

5

IA IB IIA IIB

Figure 1

O O

O

NaOH

2 3

89

67

4 or 5

SH

SH

Solution phase synthesis of 2,3-dihydro-1,5-benzothiazepines (4 : a–d; 5 : a–g)

O OH HO

HO

O

AA

AA

+DIAD, TPP, NMM

48 hrs

Ring B-

Ring B

Ring B

CHO

O

O

O

OO

ON S

N S

+

+

i)

ii) 50% TFA

KOH 6 equiv.

1,5-Benzothiazepines 954(a)(b)(c)(d)

(a)(b)(c)(d)(e)(f)(g)

R1R1 R2R2HHHH

H H2-OH2-OH2-OH2-OH2-OH2-OH2-OH

4-Me3,4-diOMe4-NO2

4-Cl4-F3-OMe4-OMe4-Me3,4-OCH2O

(a) = Phenyl(b) = 2-ClC6H4(c) = 3-ClC6H4(d) = 4-ClC6H4(e) = 2-FC6H4(f) = 3-OHC6H4(g) = 4-OHC6H4(h) = 2-OHCH3C6H4

(i) = 3,4-OMe2C6H4(j) = 4-OH-3-OMeC6H4(k) = 3-NO2C6H4(l) = 4-NO2C6H4

(m) = 4-MeC6H4(n) = 4-NMe2C6H4(o) = Pyridin-3-yl(p) =Thien-2-yl

R1

R1

R1

R2

R2

CH3CH3

NH2

NH2

Solid phase synthesis of 3-hydroxy-2,3-dihydro-1,5-benzothiazepines 9(a–p)

H/MeOH, Δ

Ring B Ring B

Scheme 1: Solid phase synthesis: Claisen-Schmidt condensation of 3-hydroxyaceto-phenone with different substituted aldehydes and o-aminothiopheno.

resin using chalcones 8 as precursors which in turn weresynthesized on the same solid support through Claisen-Schmidt condensation of 3-hydroxyacetophenone 6 withdifferent substituted aldehydes 7 [4] (Scheme 1).

3.1.2. Reactions of Polyfluorinated Chalcones with o-Aminobenzenethiol and Its Zinc Salt. Chalcone 10a onheating under reflux with 2 moles of o-aminothiophenolproduced equal amounts of the benzo[𝑏][1, 5]thiazepine 11a

Organic Chemistry International 3

S

F

F

F

F

SN

ArSO

O

F F

FF

SS N

12c + S N11c(20%)

S

F

F

F

F

SO

12d (15%)

10: (a) Ar = Ph, Ar = C6F5 , (b) Ar = C6F5, Ar = Ph, (c) Ar = Ar = C6F5

10a–cAr Ar

O

10a +

+

+

+

+

+ +

+

SH

NH2

HCl, MeOH, Δ

11a

+S O

NH2

C6F5

C6F5

12aS

N

10b, c HCl,

MeOH, D

NH2

NH2

11b, c

10a–c

Ar

H2N

MeOH,

20◦C, 3–6 h

12a–c

12a 12a 11a

11b

10a(70%) (20%) (10%)

MeOH, 20◦C, reflux12b 10b

12cMeOH, 20◦C, reflux

+

NH2

(28%)(32%)13 (20%) 11d (20%)

C6F5

C6F5

C6F5

MeOH, 20◦C, reflux

11e (32%)

10c(24%) (9%)

Ar

C6H5

H2N

12: (a) Ar = Ph, Ar = C6F5, (b) Ar = C6F5, Ar = Ph, (c) Ar = Ar = C6F511: (b) Ar = Ph, (c) Ar = C6F5

Scheme 2: Reactions of polyfluorinated chalcones with o-aminobenzenethiol and its zinc salt.

(5% yield) and 3-(2-aminophenylthio)-3-(perfluorophenyl)-1-phenylpropan-1-ol 12a. Reaction of 10b with o-ami-nothiophenol (2-moles) afforded 1,5-benzothiazepine 11bin 88% yield. When a threefold excess of the reactant wasused in the reaction of 10c with o-aminothiophenol thebenzo[𝑏][1, 5]thiazepine 11c was afforded (80% yield). Toreveal the sequence step of formation of benzothiazepines,the thia-adducts 12a–c were synthesized by the reactionof chalcones 10a–c with o-aminothiophenol in MeOHat 20∘C for 3–6 h. The thia-adduct 12a under reflux inMeOH in presence of HCl underwent partial ring closureto form benzothiazepine 11a and partially 12a transformedinto chalcone 10a; however, the most part of 12a remainsunchanged. The adduct 12b under the same reactionconditions was completely consumed and the reaction

mixture contained chalcone 10b, 1-(4-(2-aminophenylthio)-2,3,5,6-tetrafluorophenyl)-3-phenylprop-2-en-1-one 13 to-gether with thebenzo[1, 5]thiazepines 11b,d. Also, the samereaction of the adduct 12c under reflux formed a complicatedmixture of products containing chalcone 10c, thia-adducts12c,d, and benzothiazepines 11c,e [5] (Scheme 2).

3.1.3. Reaction of Gem-Acetyl- and Gem-Benzoylnitrostyreneswith o-Aminothiophenol. The chemical behavior of nitrogenketones was investigated via reactions of gem-acetyl- andgem-benzoylnitro styrenes 14–19 with o-aminothiophenol.These reactions proceed successfully at equimolar ratioof reagents under very mild conditions at 18–20∘C inmethanol, in the absence of a catalyst, in 10–20min, to


NH

SArH

Ar

XO

Ar

OS

N

SAr

Ar

OS

N

SAr

NO2

NO2

NO2

NO2

NO2

NO2

C6H5

C6H5

C6H5

26, 27

14–19

HS +

H2N

NH2

NH2

− H2OX = CH3

X = C6H5

CH3

HB

HB

HB

HB

HA

HAHA

HA

20–22

23–25

MeOH

10–20 min.

14: X = = , 15: X = , 16: X =

20, 22, 26: Ar= , 21, 23, 27: , 23, 24, 25:

MeOH, Δ, HCl

18–20 ◦C

CH3

CH3: Ar C6H5

C6H5

4-H3COC6H4

4-H3COC6H4

4-(H3C)2NC6H4,

4-(H3C)2NC6H4.= , 18: X = ,19: XC6H5 4-H3COC6H4 = 4-(H3C)2NC6H4;17: X = C6H5: Ar

Scheme 3: Reaction of gem-acetyl- and gem-benzoylnitrostyrenes with o-aminothiophenol.

form new compounds 20–24, respectively. However, whilethe gem-acetylnitro-styrenes 14–16 afford 2-aryl-4-methyl-3-nitro-2,3-dihydro-1,5-benzothiazepines 20–22, from thegem-benzoylnitrostyrenes 17–19 linear S-adducts 23–25wereobtained in 80–98% yield. Apparently, the reaction of o-aminothiophenol with gem-acylnitro-styrenes 14–19 leadinitially to the formation of an adduct at the multiple C=Cbond (Ad

𝑁), which was isolated in the case of compounds

with the benzoyl group 23–25, and the adducts obtainedfrom the gem-acetylnitrostyrene 14–16 immediately suffersheterocyclization.Thismay be due to the difference in activityof carbonyl groups in the benzoyl and acetyl functions of theaddition products. Probably, the attack of amino group onthe benzoyl carbonyl group in the adducts 23–25 is difficultcompared to the acetyl analogs due to steric and electronicfactors.

In order to obtain nitrobenzothiazepine structures withphenyl substituent at the C4 atom, the linear S-adducts 23and 24 when heated under reflux in EtOH in the presenceof methanolic HCl for 1–3 h 2-aryl-3-nitro-4-phenyl-2,5-dihydro-1,5-benzothia-zepines 26 and 27, were obtained,respectively [6] (Scheme 3).

3.1.4. Cyclocondensation Reaction of (E)-N-(4-(3-(2-Chloro-5,6,7,8-substituted-quinolin-3-yl)acryloyl)phenyl)-methylben-zenesulfonamide with 2-Aminothiophenol in Ethanol inPresence of Bi-Catalyst. The 2-chloro-substituted-quinolinechalcones 30 were prepared from condensation of 4-methyl sulphonamido acetophenone 28 and quinonline-3-carbaldehyde 29 in alcoholic KOH. Cyclo-condensation ofthe chalcones 30 with o-aminothiophenol in the presence of

a bicatalyst afforded the benzothiazepines 31 in good yield [7](Scheme 4).

3.1.5. Cyclocondensation of 1-(4-(Methylsulfonyl)phenyl)-2-tosyl-3-(3,4,5-trisubstituted phenyl)prop-2-en-1-ones with 2-Aminothiophenol in Refluxing Toluene Using CatalyticAmounts of Trifluoroacetic Acid. Condensation of 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone 32 and 4-methylsodium benzene sulfinate 33 gave 1-(4-(methylsul-fonyl)phenyl)-2-tosylethanone 34. Claisen-Schmidt con-densation of 34 with aryl aldehydes in the presenceof piperidine in CH

2Cl2

gave the intermediates 1-(4-(methylsulfonyl) phenyl)-2-tosyl-3-(3,4,5-trisubstituted-phenyl)prop-2-en-1-ones 35a–f in excellent yields. Cyclo-condensation of 35a–f and o-aminothiophenol in refluxingtoluene using CF

3COOH catalyst gave better yields of

2-(substituted phenyl)-3-[(methyl phenyl) sulfonyl][(methylsulfonyl) phenyl]-2,3-dihydro-1,5-benzothiazepines 36a–f(Method A). Also, the neat cyclo-condensations of thechalcones 35 supported on silica-gel with o-aminothiophenoloccurred rapidly at 80∘C and gave better yields of the desiredtri-substituted 1,5-benzothiazepines 36a–f (Method B) [8](Scheme 5).

3.1.6. Cyclo-Condensation Reaction of the Phenolic 𝛽-Dike-tones with o-Aminothiophenol. Cyclo-condensation of thePhenolic 𝛽-diketones 37a–d with o-aminothiophenol pro-ceeded under oxidation to give oxygen-bridged 1,5-benzot-hiazepines 39a–d in a reasonable yield, whereas the respec-tive compounds 38a–d and 40a–d were not detected [9](Scheme 6).


R2

R2

R2

R2

R1

R1

R1

R3

R3

R3

R3

DBUAcetone, r.t.

S

O

O

HN

OS

O

O

Cl

O 28

N Cl

O29

EtOH, PTC

NCl

O

NHS

O

O30

NClNH

S

O

O

R

31

SNi30

CH3

R

H3C

(i) o-Aminothiophenol 1, piperidine, AcOH, EtOH, reflux

+

31 R R1 Yield (%) H H H H 75 H H CH3 H 66 H OCH2CH3 H H 68 H Cl H H 62 H H H CH3 70

(a)(b)(c)(d)(e)

CH3

CH3CH3

CH3

H2N

H3C

Scheme 4: Cyclocondensation reaction of (E)-N-(4-(3-(2-chloro-5,6,7,8-substituted-quinolin-3-yl)acryloyl)phenyl)-methylbenzenesulfona-mide with 2-aminothiophenol in ethanol in presence of bi-catalyst.

3.1.7. Thermal Reaction of (Z)-1,3-Diphenyl-2-(1H-1,2,4-triazol-1-yl)prop-2-en-1-one with o-Aminothiophenol in thePresence of CF

3COOH. 1-Phenyl-2-(2𝐻-1,2,3-triazol-2-yl)

ethanone 41 when heated under reflux with benzaldehydeand catalytic amount of piperidine gave 1,3-diphenyl-2-(1H-1,2,4-triazol-1-yl)prop-2-en-1-one 42.The latter triazole uponthermal reaction with o-aminothiophenol and CF

3COOH

for 5-6 h yielded 1,5-benzothiazepine containing 1,2,4-triazole moiety 43 (43 toutemeric form in solvent) in 72.7%yield [10] (Scheme 7).

3.1.8. Reaction of 1-(2-Phenyl-2H-1,2,3-triazol-4-yl)-3-(p-sub-stituted-phenyl)prop-2-en-1-ones with o-Aminothiophenol,in EtOH under Reflux in the Presence of CF

3COOH. 1-(2-

Phenyl-2H-1,2,3-triazol-4-yl)-3-(p-substituted-phenyl)prop-2-en-1-ones 44a–d (prepared from the desired aromaticaldehydes and 1-(2-phenyl-2H-1,2,3-triazol-4-yl)ethanone)on reaction with o-aminothiophenol, in EtOH under

reflux in the presence of CF3COOH gave 2,3-dihy-

dro[1, 5]benzothiazepines 45a–e in good yield (Scheme 8)[11] (Scheme 8).

3.1.9. Thermal Reaction of (E)-1-(2-Phenyl-2H-1,2,3-triazol-4-yl)-3-(p-substituted-phenyl)prop-2-en-1-ones with o-Amino-benzenethiol in Presence of CF

3COOH. The 𝛼,𝛽-unsaturated

carbonyl compounds 48a–cwere prepared by a condensationreaction of 4-acetyl-2-phenyl-1,2,3-triazole 46 with sub-stituted aldehydes 47a–c. Preparation of the carbonyls48d,e using the same method failed and instead gaveMichael type addition products 50d,e as major compounds.Successful preparation of 48d and e was fulfilled viadropping of 4-acetyl-2-phenyl-1,2,3-triazole 46 intosolutions of the aldehydes 47d,e in EtOH slowly. Thetriazoles 48a–e upon heating with o-aminothiophenol inpresence of CF

3COOH in ethanol (5-6 h) afforded the


CH3

CH3

CH3

CH3

H3C

H3C

H3C

H3C

NH2

RR

R

R

R

R

S

O

OBr

O

+S

O

O

NaO

32 33

DCM/water

TBAB

34

SO

OS

O

O

O

34 +

CHO

R

Ethylene dichloridePiperidine

SO

O

S

O

O

R

O

+SH Method A or B

N

S

S

O

O

R

S

O

O

35a–f

35a–f

36a–f

Characterization data of 1-[( -methylsulfonyl)phenyl]-2-[(4-methylphenyl)-sulfonyl]-prop-2-en-1-ones 35a–f.

35 R Yield (%) HPLC Purity (%)H F H 55 98

52 92H 53 93H OH H 50 88H H 60 96H Cl H 54 91

Characterization data of 2-(substitutedphenyl)-3-[(methylphenyl)sulfonyl][(methylsulfonyl)phenyl]-2,3-dihydro-1,5-benzothiazepines 36a–f.

36 R Yield (%) HPLC purity (%)Method A Method B

(a) H F H 60 76 88(b) 54 64 86(c) H 56 69 87(d) H OH H 59 72 83(e) H H 61 78 88(f)

(a)(b)(c)(d)(e)(f)

H Cl H 51 59 84

R R

R R

OCH3OCH3

OCH3

OCH3OCH3OCH3 OCH3

OCH3

OCH3OCH3OCH3

OCH3

4

Scheme 5: Cyclocondensation of 1-(4-(methylsulfonyl)phenyl)-2-tosyl-3-(3,4,5-trisubstituted-phenyl)prop-2-en-1-ones with o-aminothio-phenol in refluxing toluene using catalytic amounts of trifluoroacetic acid.


X = (a) H, (b) Cl, (c) F, (d) OCH3

OH

X

O O

N SOH

X

SH DMSOreflux

N SOH

XO

S NOH

XO

37a–d

38a–d

39a–d 40a–d

NH2

Scheme 6: Cyclo-condensation reaction of the phenolic 𝛽-diketones with o-aminothiophenol.

CO

N

NHN

C CO

N

NN

HCO

Piperidine

O

N

N

N

SH

41 42

N

S

N

NN

NH

S

N

NN

Solvent

43

CH2BrEt3N

H2 NH2

43

Scheme 7:Thermal reaction of (Z)-1,3-diphenyl-2-(1H-1,2,4-triazol-1-yl)prop-2-en-1-onewith o-aminothiophenol in presence of CF3COOH.

(E)-4-(2-phenyl-2H-1,2,3-triazol-4-yl)-2-(p-substituted-phenyl)2,3dihydrobenzo[1, 5]thiazepines 49a–e in goodyield [12] (Scheme 9).

3.1.10. Reaction of Chalcones with 2-Aminothiophenol Deriva-tives in the Presence of Fluoroboric Acid Adsorbed on Silica-Gel (HBF

4–SiO2). When chalcones of type 51 were treated

with o-aminothiophenol in the presence of fluoroboricacid adsorbed on silica-gel (HBF

4–SiO2) selective thia-

Michael addition to the 𝛼,𝛽-unsaturated carbonyl moiety

took place to form the corresponding adducts 52 in excel-lent yields. The latter adducts when heated under refluxin MeOH/HBF

4–SiO2gave the corresponding 2,3-dihydro-

1,5-benzothiazepines 53 in high yields through a one-potcycloaddition reaction [13] (Scheme 10).

3.1.11. Reaction of 3-(2-Phenoxyquinolin-3-yl)-1-p-substituted-prop-2-en-1-ones with o-Aminothiophenol in Ethanol UsingAcetic Acid as Catalyst. 2-Chloro-3-quinolinecarbaldehyde


CHO

+

N

NN

C

O+

N

NN

C

O

CH

CH

(i)

SH(ii)

S

N

N N

N

R1

R1

R1H3C

HaHb

HX

44a–d

44a–d

45a–d

(i) (1) EtOH, NaOH (2%), stirring at r.t.(2-3 h); (2) neutralization tp pH 7

NH2

(ii) Ethanol, stirring for 20–30 min, CF3COOH, reflux for 5-6 h

HOMe

Cl

Yield76818079NO2

R145(a)(b)(c)(d)

Scheme 8: Reaction of 1-(2-phenyl-2H-1,2,3-triazol-4-yl)-3-(p-substituted-phenyl)prop-2-en-1-oneswith o-aminothiophenol, in EtOHunderreflux in the presence of CF

3COOH.

R

CHO N

N

N

O

RN

N

NC

O

HC

HOCC

O

N

N

N

R

N

NN

O

N

NN

O

46

N

NN

O

Ph

R

SH

N

S

R

N

NN Ph

H3CC47a–e

2% NaOH/EtOH

2% NaOH/EtOHH2C

H2C

48a–e

50 d, e

48a–e

NH2

49a–e

CF3COOH

R: (a) H, (b) CH3, (c) OCH3, (d) Cl, (e) NO2

Scheme9:Thermal reaction of (E)-1-(2-phenyl-2H-1,2,3-triazol-4-yl)-3 (p-substituted-phenyl)prop-2-en-1-oneswith o-aminobenzenethiolinpresence of CF

3COOH.

54 reacted with phenol in presence of an alkali to give 2-phenoxy-3-quinolinecarbaldehyde 55. The 𝛼,𝛽-unsaturatedketones 56a–c were synthesized via Claisen-Schmidtcondensation between the phenoxy derivative 55 and

1-arylethanones. Equimolar quantities of 56a–c and o-aminothiophenol in ethanol using CH

3COOH as catalyst

afforded satisfactory yields of the 1,5-benzothiazepinederivatives 57a–c [14] (Scheme 11).


SH+

O NS

53

O S

5251

H2NH2N

+

R2R1R2R1R2R1

One-pot synthesis of 2,3-dihydro-1,5-benzothiazepines 53.

by reaction of 1,3-diaryl-2-propenones with o-aminothiophenolHBF4–SiO2-catalysed one-pot synthesis of 2,3-dihydro-1,5-benzothiazepines

,52,5351(a) R1 R2 Time (h) Yield of 53(b)H H 4 81H Cl 5 89Cl H 4 82H NO2 5 88H OMe 6 89

OMe H 6 87

thiazepines after chromatographic purification.

(a)(b)(c)(d)(e)(f)

(a)1,3-Diaryl-2-propanonein MeOH treated with o-aminothiophenolin thepresenceof HBF4-SiO2;

(b)Isolated yield of 2,3-dihydro-1,5-

Scheme 10: Reaction of chalcones with o-aminothiophenol derivatives in the presence of Fluoroboric acid adsorbed on silica-gel (HBF4–

SiO2).

OH

KOH

O

54 55NaOH

N

O

Cl N

O

O

O

N OSH

N

S

NO

Acetic acid

CH3R1

R1

R156a–c 57a–c

NH256, 57: (a) R1 = H

(b) R1 = Cl(c) R1 = OCH3

Scheme 11: Reaction of 3-(2-phenoxyquinolin-3-yl)-1-p-substituted-prop-2-en-1-ones with o-aminothiophenol in ethanol using acetic acidas catalyst.

3.1.12. Thermal Reaction of 5-Aryl-2,4-bis(arylmethylidene)Dihydro-3-thiophenones and o-Aminothiophenol in AceticAcid Compared to Same Reaction Performed under Solvent-Free Microwave Irradiation. The benzothiazepines 58 weresynthesized in 55–91% yields upon heating under reflux

5-aryl-2,4-bis(arylmethylidene) dihydro-3-thiophenones 60with o-aminothiophe-nol in a 1 : 1.5 molar ratio inCH3COOH for 45–60min.For comparison, when the thiophenone 60 and o-

aminothiophenol in the same molar ratio and CH3COOH


catalyst were thoroughly mixed and irradiated while stirringin a microwave oven for 2-3min at maximum 84∘C; thebenzothiazepine derivatives 58 were afforded in moderateyields (42–62%). Therefore, the reaction under microwaveirradiation proceeded rapidly but led to a lower yield ofthe desired benzothiazepine products compared with thethermal reaction.

The tandem reaction leading to 58 presumably proceedsthrough an initial Michael addition of o-aminothiophenol to5-aryl-2,4-bis(arylmethylidene)dihydro-3-thiophenones 60affording 61 with concomitant condensation to afford 63either directly from 62 or through 59. Presumably, thearomatic stability of the thiophene ring provides the impetusfor the isomerization of 63 to furnish 58. It is pertinentto note that thieno-benzothiazepine 64, a regioisomer of58 arising from initial Michael addition of 60 to the otherbenzylidene C=C bond at the 2-position of 60, was notformed, even in traces, in this reaction. This selectivitycould probably be ascribed to the conjugation of the sulfurin the five-membered ring with the proximate C=C bonddiminishing the electrophilicity and the reactivity of the C=Cbond towards the initial Michael addition, which, in turn,determines the regioisomer formed in this tandem sequence.The aromatic stability of the thiophene ring of 58 is envisagedto trigger the isomerization of 59 in the presence of aceticacid [15] (Scheme 12).

3.1.13. Improved Synthesis of 1,5-Benzothiazepines Using CericAmmonium Nitrate (CAN). Reaction of chalcone 65a witho-aminothiophenol at 60–65∘C in the absence of cericammonium nitrate (CAN) catalyst did not proceed afterextensive long reaction times (8–10 h) with lower yieldof the desired 1,5-benzothiazepin. Meanwhile, upon using2mol or 6mol% of CAN catalyst, the conversion to 1,5-benzothiazepine was 70% and 85% yield, respectively. Con-tinuation of subsequent condition optimization revealed that10mol% of CAN catalyst was sufficient to complete thereaction and the best result obtained 66a in ethanol afterultrasonic irradiation was 93% without any undesirable sideproduct being observed. Therefore, attempts were continuedto examine this reaction generality through reactions ofseveral substituted homocyclic 65b–h and heterocyclic 65i–k chalcones with o-aminothiophenol. The obtained resultswere compatible with various substituents such as F, NO

2, Cl,

CH3, and OCH

3and no competitive nucleophilic cleavage

was observed for the substrate having an aryl, CH3or

OCH3groups. Also, the case of electron donating sub-

stituents resulted in longer reaction times, and the elec-tron withdrawing substituents required shorter time forthe complete reaction. Moreover, no significant substituenteffects were observed in case of hetero-aryl aldehydes.Generally, this method offers significant advantages overthe other method including the fact that (i) the reactionis simple to execute; (ii) the 1,5-benzothiazepine productsare isolated in good to excellent yields; (iii) the work-upis simple; (iv) the reaction time is short (32–38min); (v)the 1,5-benzothiazepines are obtained in excellent purity [16](Scheme 13).

3.1.14. Reaction of 1-(2-Hydroxy-3,4,5-trisubstituted-phenyl)-3-(4-(phenylthio)phenyl)-prop-2-en-1-ones with o-Aminothi-ophenol in Ethanol under Ultrasonic Irradiation via a[4 + 3] Annulation. To prove that the ultrasonic irradi-ation plays an important role in the synthesis of 1,5-benzothiazepines a model optimum experimental conditionsfor the reaction of chalcones of type 69 (prepared from 4-(phenylthio)benzaldehyde 68 and o-hydroxy acetophenones67) reaction of chalcone 69a with o-aminothiophenol inEtOH was tried. The results indicated that 30min and atemperature of 65∘C were sufficient to obtain high yield ofthe 1,5-benzothiazepine product 70a (93%). In comparison,upon using conventional method, the yield of 70a was57% after heating 4-5 h at 65∘C. Similarly, the thiazepines70b–g were synthesized in good yield from 69b–g ando-aminothiophenol in EtOH under ultrasonic irradiationmethod. A proposed Mechanism was outlined for the syn-thesis of the thiazepines via [1, 4] and [1, 2] addition ofo-aminothiophenol to the chalcones 69 under ultrasonicirradiation [3] (Scheme 14).

3.1.15. Thermal Reaction of 1-(2,4-Disubstituted-phenyl)-3-(p-substituted-phenyl)prop-2-en-1-ones with 2-Aminothiophenolin the Presence of a Catalytic Amount of NanocrystallineAl2O3. Reaction of 1-(2,4-disubstituted-phenyl)-3-(p-sub-

stituted-phenyl)prop-2-en-1-ones 71a–h with o-aminothi-ophenol (2.5 : 1 molar ratio) in the presence of a catalyticamount of nanocrystalline Al

2O3in water, while stirring

at room temperature for the appropriate time afforded thecorresponding 1,3-diaryl-2,3-dihydro-1,5-benzothiazepines72a–h in good to excellent yield. This reaction was foundcompatible with various electron-donating and electron-withdrawing substituents, and assumed to start by 1,4-Michael addition of the SH on the C=C bond followed bythe condensation of the NH

2on the carbonyl group. It is

worthy to note that using nanocrystalline Al2O3is preferable

than commercially available bulk Al2O3or basic Al

2O3

due to its increased catalytic activity and could be reusedfor four cycles without loss of activity and selectivity [17](Scheme 15).

3.1.16. MW-Assisted Condensation Reactions of o-Aminothio-phenol with Carbonyl Compounds in the Presence of Erbium(III) Triflate. Condensation reactions of simple ketones (ace-tone, acetophenone, p-nitro- and p-methoxy acetophenones)with o-aminothiophenol in presence of erbium (III) tri-flate (Er(OTf)

3) catalyst while stirring at room tempera-

ture for 3 h gave no 1,5-benzothiazepine products 73 or74a–c. These reactions in fact lead to the correspondingSchiff bases without further cyclization to form the desired1,5-benzoheteroazepine. In contrast, the stirred reactionof chalcone 75a with o-aminothiophenol using Er(OTf)

3

under solvent-freemicrowave-assisted condensation process,(1000W) for 30min. at room temperature led to the cyclized1,5-benzothiazepines 76a as fair yield product. Whereas verygood results were obtained for the more reactive substrates75b and c (highly electron rich), confirming the synthesis of


NH2

NH2

S

O

24

Ar60

Michael addition S

S

O

Ar61

SNH

SH

OH

Ar62

Condensation

SN

SH

Ar

59

IsomerisationS

NH

SAr

63H

IsomerisationS NH

SAr58

HNS

SAr

Ar

Ar

64(not formed)

Mechanism for formation of thienothiazepines 58

¨SH

− H2O

H+

H+

Ar

Ar

Ar

Ar

ArAr

ArAr

Ar

Ar

Ar

Ar

Ar

¨NH2

N̈H2

58 Ar Reaction time (min) Yield (%)MW ACOH

refluxAcOH

(a) C6H5 C6H5 2 50 53 65(b) C6H5 p-MeC6H4 2 50 48 55(c) C6H5 p-MeC6H4 2 45 54 88(d) C6H5 p-MeOC6H4 3 60 42 91(e) C6H5 p-FC6H4 2 60 54 56(f) C6H5 o-MeC6H4 3 60 47 58(g) C6H5 o-MeOC6H4 2 50 50 62(h) p-MeC6H4 p-MeC6H4 3 60 62 73(i) p-ClC6H4 p-MeC6H4 2 45 60 72(j) o,p -Cl2C6H3 p-ClC6H4 2 45 59 74

SNH

SAr

Isomerisation S N

SAr

Michael addition-condensation

SH+

S

O

Ar

58 5960

Retrosynthesis of thienobenzothiazepines 58

SH

60 +AcOH, reflux

orCat. AcOH, MW

Ar

Ar

Ar Ar

ArAr

3-Benzyl-1,10-diaryl-4H, 10H-thieno[3,4-c][1,5]benzothiazepines 58

58a–j

(a) Irradiated with a catalytic amount of acetic acid; (b)yield after column chromatographicpurification;(c)yield after crystallization

Reflux(a)MW(b)

(c)

Scheme 12:Thermal reaction of 5-aryl-2,4-bis(arylmethylidene) dihydro-3-thiophenones and o-aminothiophenol in acetic acid compared tosame reaction performed under solvent-free microwave irradiation.


(a)(b)(c)(d)(e)(f)(f)(h)

(i)

(j)

(k)

NH2

66 R1 R2 Time Yield (%)With

US (min)Without US (hr)

With US(min)

Without US (hr)

H H 32 8-9 93 71H p-F 30 6–8 89 64

p-NO2 H 328 8-9 86 72p-OMe p-OMe 37 8–10 79 64p-OMe p-CH3 34 6-7 81 62p-OMe p-Cl3 0 7–9 87 68

H Thinyl 38 9-10 91 70p-F

5-Cl28 5-6 89 71

2,4-Cl,5-OH

p-Pyrazolyl 341 1–3 87 75

1-OH, 4-Br

2-p-(Tolyloxy)-quinoline

31 2–4 85 71

2,4-Cl, 5-

OH

6-Methyl-2-(1H-pyrazole-1-

yl) quinoline

30 2–4 87 68

US: ultrasonic irradiation

S N

O

SH CANEtOH, ))))

Synthesis of 1,5-benzothiazepines 66 from chalcones and o-aminothiophenol.

65a–k 66a–k

R1 R2

R1R2

+

2-OH,4-CH4

Scheme 13: Improved synthesis of 1,5-benzothiazepines using ceric ammonium nitrate (CAN).

1,5-benzothiazepine derivatives 76b,c in excellent yields [18](Scheme 16).

3.1.17. Reaction of Various Hydroxyl Chalcones with o-Amino-thiophenol in the Presence of Gallium (III) Triflate. Reactionsof o-aminothiophenol and the hydroxy chalcones 77a–h inthe presence of water-tolerant strong Lewis acid catalystGa(OTf)

3(10mol%) lead to the 1,5-benzothiazepines 78a–

h in moderate to excellent yields. The ortho-OH group ofchalcones is crucial for this unprecedented condensationprocess.

A proposed reaction mechanism involves at first,Ga(OTf)

3catalyst and o-hydroxychal-cone I form complex

II, which further reacts with III to afford complex IV andthen V after losing H

2O. Then the XH group attacks the

C=C bond and lead to the formation of thiazepine 78. Theo-hydroxy group in chalcone structure has the following twoimportant roles: (i) it involved in the formation of stablecomplex III by chelating with Ga(OTf)

3and facilitates the

dehydration process to from complex V; (ii) the presence ofthis group caused the 𝛼,𝛽-unsaturated carbonyl to be morereactive toward the addition of XH [19] (Scheme 17).

3.1.18. Reaction of 4-(4-Fluoro-2-methylphenyl)-4-oxobut-2-enoic Acids with 2-Aminobenzenethiols in the Presence ofLanthanum-Containing Y Zeolite (LaY), While Stirring,under Solventless Conditions. Stirring of o-aminothiophenol

derivatives and the 𝛼,𝛽-unsaturated ketones 79 at roomtemperature in the presence of Lanthanum-containing Yzeolite (LaY) zeolite catalyst, under solvent less conditionsgave 8-substituted-2-carboxy-2,3-dihydro-1,5-benzothiazep-ines 80a–f in good to excellent yield. As an initial attempt, avariety of experimental reaction conditions were examinedby changing catalyst, reaction medium (MW irradiation,conventional, and stirring), and temperature.

It was found that more acidic LaY zeolite was thebest choice of catalyst for the preparation of 2-carboxy-2,3-dihydro-1,5-benzothiazepine 80a. This can suggest that theacid sites on zeolite work as active sites for this reaction. Forchecking the catalyst amount’s effect on reaction conditionsthe reaction was tried via different amounts of catalyst and2 g of catalyst amount was sufficient for activation of 80aproduct synthesis; higher amount of the catalyst producedlesser yield.

It was also, observed that MW irradiation using dif-ferent monomode reactor with focused rays and a muchmore homogeneous electromagnetic field and classical heat-ing gave lower yield with higher reaction time com-pared to reactions realized under stirring conditions andinterphase catalysis. In view of all these observationsand results, the other 1,5-benzothiazepines 80b–f weresynthesized via reaction of hydroxychalcones 79 and o-aminothiophenol using LaY zeolite under stirring at 100∘C[20] (Scheme 18).


OH

O

+

O

H

S

68

KOH/EtOH OH

O

S

SHEtOH

N

S

S

HO

OHO

S

[1,4]

[1,4] addition

OH

O S

S

[1,2]

[1,2] addition

OH SHN

OHS

OH SN

S

II70

I

Proposed mechanism for the construction of the 1,5-benzothiazepine.

67a–g69a–g

70a–g

R1

R1

R1

R1R1

R2

R2

R2

R2R2

R3

R3

R3 R3

R3

R1

R2

R2R1

R3

R3

4–5 hr, ))))

NH230 min, ))))

S̈H

N̈H2

H2N̈

69a,70a: R1 = H; R2 = H; R3 = H69b,70b: R1 =Cl; R2 = H; R3 = Cl69c,70c: R1 = CH3; R2 = H; R3 = CH369d,70d: R1 = H; R2 = CH3; R3 = Cl69e,70e: R1 = H; R2 = H; R3 = Cl69f,70f: R 1 = H; R2 = H; R3 = F69g,70g: R1= H; R2 = H; R3 = CH3

Scheme 14: Reaction of 1-(2-hydroxy-3,4,5-trisubstituted-phenyl)-3-(4-(phenylthio)phenyl)prop-2-en-1-ones with o-aminothiophenol inethanol under ultrasonic irradiation via a [4 + 3] annulation.

3.1.19. Reaction of 1,3-Diaryl-2-propenones with 2-Amino-thiophenol in the Presence of Substoichiometric Amount ofCyanuric Chloride. Cyanuric chloride 2,4,6-trichlorotriazine(TCT) catalyst was employed for preparation of several 1,5-benzothiazepine derivatives via reaction of various kinds of

1,3-diaryl-2-propenones 81 with o-aminothiophenol. Whenthis reaction was carried out in the absence of cyanuricchloride 2,4,6-Trichlorotriazine (TCT), thin layer chro-matography (TLC) and 1H NMR spectra of the reac-tion mixture showed a combination of starting materials


HS

O

N

S

+

7172

N

S

+

72O

A plausible mechanism for 1,5-benzothiazepines

H2N

R2

R2

R2

R2

R1

R1

R1R1

R3

R3

(1) [1,4] addition(2) [1,2] addition

Nanocrystalline Al2O3

oil bath temperature, 12 h

[1,2]

[1,4]

S̈H

N̈H2

Water, stirring at 110 ◦C

72 R1 R2 R3 yield(%) 72 R1 R2 R3 yield(%)H H H 71 H NO2 H 86H H OH 79 H OCH3 H 90H Cl H 85 CH3 OCH3 H 84

NO2 H H 81 NO2 OCH3 H 75

(a)(b)(c)(d)

(e)(f)(g)(h)

Scheme 15: Thermal reaction of 1-(2,4-disubstituted-phenyl)-3-(p-substituted-phenyl)prop-2-en-1-ones with o-aminothiophenol in thepresence of a catalytic amount of nanocrystalline Al

2O3.

and corresponding thia-Michael adducts were formed, theexpected benzo[1,5]thiazepines were afforded in very pooryield. Upon repeating the reaction in the presence of TCTcatalyst (5mol%), between 80 and 90∘C, the expected ben-zothiazepine derivatives 82a–l were obtained in high yield,whether bearing electron-withdrawing groups (such as halideor nitro) or electron-donating groups (such as the alkylgroup). It is worthy to note that the in situ generated HCl(from cyanuric chloride) efficiently catalyzed the reactionand act as protic acid to activate the carbonyl oxygen forforming a carbo-cation. So, subsequent intramolecular nucle-ophilic attack by the NH

2group on the carbo-cation followed

by dehydration forms the desired 1,5-benzothiazepines 82.Also, doing the reaction under dry reaction conditions inthe presence of MS 4 Å was met with failure, a matter whichindicated that the “incipient” moisture plays an importantrole for HCl generation in situ from TCT catalyst [21](Scheme 19).

3.1.20. Microwave-Assisted Reaction of 2-Aminothiophenoland 1,3-Substituted-prop-2-en-1-ones in the Presence of ZincAcetate. One pot efficient facile, solvent-free microwave-assisted green synthesis of 1,5-benzothiazepine derivatives

86 has been approved via cyclo-condensation of o-amino-thiophenol and 1,3-substituted-prop-2-en-1-ones 85a–h (pre-pared via Claisen-Schmidt condensation of acetophenone orsubstituted acetophenone 83 or 84 in ethanol in the presenceof 40% KOH) via using zinc acetate as an eco-friendlycatalyst. The thiazepine products 86a–h were synthesized inshorter reaction time and better yields as comparedwith theircorresponding prepared via conventional synthesis (4–6.5 hr;63–70% yield) [22] (Scheme 20).

3.1.21. Mirowave Irradiation of 1,3-Substituted-prop-2-en-1-one with o-Aminothiophenol in the Presence of Zinc Acetatein Solvent-Free Conditions. Reaction of 1,3-substituted-prop-2-en-1-ones 89a–f (prepared from acetylated 𝛼-naphthol87 and the corresponding aromatic aldehyde 88 in basicmedium) with o-aminothiophenol under microwave irradi-ation for 2-3 minutes at 80–85∘C in the presence of eco-friendly catalyst zinc acetate, solvent-free conditions affordedthe 1,5-benzothiazepines 90a–f in good yield and shortreaction time. Upon repeating the reaction, using conven-tional method by mixing of the acetylated 𝛼-naphthol withvarious aldehydes in ethanol in the presence of 40% KOH,heating under reflux for the proper time the benzothiazepine


N

S

O

O

O

O

O

HSor

or

X

O

or N

S

73

SH+

+

O

N

S

74a: X = H; b: X = NO2; c: X = OCH3Yield of all of these products = 0

NH2

76a–c75a–c

74a–c

Er(OTf)3 5 mol%CH3CN

− O

N+

R1R1

R2

R2

H2N

75,76 R1 R2 Yield of 4 (%)H H 45H o-OH 83p -OMe o-OH 98

(a)(b)(c)

Scheme 16: MW-assisted condensation reactions of o-aminothiophenol with carbonyl compounds in presence of erbium (III) triflate.

products 90a–f were formed in a comparative long reactiontime and low yield [23] (Scheme 21).

3.1.22. Mannich Condensation Reaction of Substituted 1,8-Naphthyridines and Substituted 2-Aminothiophenols in thePresence of Crystalline Bi(NO

3)3⋅5H2O Catalyst under MW

Irradiation and Comparison with or without Adding AnySolid Support as Well with Its Performing under ThermalConditions. The Mannich condensation of substituted 1,8-naphthyridines 91a–d and substituted o-aminothiophenolderivatives in the presence of crystalline Bi(NO

3)3⋅5H2O

catalyst under Microwave irradiation for about 8-9min at aninterval of 1min at 160W gave 1,5-benzothiazepine[7, 6-𝑏]-1,8-naphthyridines 92a–j in good to excellent yields. Thereaction proceeds through condensation of amino groupwith aldehydic group of 1,8-naphthyridines; it is the sulfuratom that reacts with the carbon next to the chlorine atC2of 1,8-naphthyridines, which resulted in the desired 1,5-

benzothiazepines 92a–j. For comparison, the reaction wasalso carried out in presence of different solid support includ-ing silica-gel, acidic alumina, basic alumina, neutral alumina,and molecular sieves (5 Å). Also, the reaction was carried

out without adding any support under neat condition, whichcould be expected to be the most economic method. Unfor-tunately, lower yields (5–56% yield) were obtained.Therefore,the Bi(NO

3)3⋅5H2O is the most effective solid for the synthe-

sis of 1,5-benzothiazepine[7, 6-𝑏]-1,8-naphthyridines 92a–j,whereas acidic alumina, basic alumina, neutral alumina, andmolecular sieves (5 Å) were ineffective in giving products ingood yields.

Moreover, this reaction when performed under reflux(10–12 h) in MeOH as a solvent, the yields were significantlylower than those obtained using the MW method. So, thissimple, practical, and very regioselective method for thesynthesis of 1,5-benzothiazepine[7, 6-𝑏]-1,8-naphthyridinesderivatives was presented using the inexpensive, oxygenand moisture-tolerant, and easily available Bi(NO

3)3⋅5H2O

catalyst [24] (Scheme 22).

3.1.23. Reaction of 3-(Benzo[d][1,3]dioxol-5-yl)-1-(substituted-phenyl)prop-2-en-1-ones with o-Amino-thiophenol in the Pres-ence of Silica Gel at 80∘C for 3 h under Solvent-Free Conditions.3-(Benzo[d][1, 3]dioxol-5-yl)-1-(substituted-phenyl)prop-2-en-1-ones 93a–f on reaction with o-aminothiophenol in


SH

+

O

N

S

O

S

77h

N

SAr

78h

OH O

O O

Ga

I

II

XH

O O

Ga N XH

IV

OH N

V

XH

Ga

N

X

HO

III

Proposed mechanism for Ga(OTf)3-catalyzed reaction of 2-hydroxychalcones with o-aminothiophenol.

R1R1

R1

R2

R2

R2

R2

NH2

77a–g 78a–g

10 mol%

H2

− H2OH2N

X = S

Ga(OTf)3

Ga(OTf)3

(OTf)3

(OTf)3(OTf)3

78 R1 R2 78 R1 R2

H H 30 4-OH 1,3-OH 87H 2-OH 95 2-OH 4-OH 92

4-OMe 2-OH 93 H 4-OH 352-OH 2-OH 91 Ar = thiophene; R2 = H 95

(a)(b)(c)(d)

(e)(f)(g)(h)

Yield (%)Yield (%)

Scheme 17: Reaction of various hydroxyl chalcones with o-aminothiophenol in the presence of gallium (III) triflate.


X SH+ O

OH

O

F

N

SH

COOH

F

XLa Y zeolite

Neat stirring

80a–f79

Synthesis of 8-substituted-2-carboxy-4-(4-fluoro-2-methylphenyl)-

NH2

2,3-dihydro-1,5-benzothiazepines (80a–f) using La Y zeolite(a)

80 X Reaction time (min) Yield (b)(%)(a) 8-OCH3 8 94(b) 8-CH3 10 75(c) 8.Cl 12 72(d) 6-Cl 10 84(e) 6-Br 13 85(f) 6-F 15 82

(a) 100 wt % catalyst used that means the substrate catalyst weight ratio is 1 : 1.(b) Isolated yields.

Scheme 18: Reaction of 4-(4-fluoro-2-methylphenyl)-4-oxobut-2-enoic acids with o-amino thiophenol derivatives in the presence ofLanthanum-containing Y zeolite (LaY), while stirring, under solventless conditions.

SH+

O

81 S

N

82Synthesis of 1,5-benzothiazepines 82 using cyanuric chloride.

Preparation of 1,3-diaryl-2,3-dihydro-1,5-benzothiazepines 82 (a)

81,82 R1 R2 Time (h) Isolated yield (c) (%) of 82H H 4 85

p-OCH3 H 5 83p-allyloxy H 5 86p-OH H 5 81o-OH H 5 80

H p-OCH3

p-OCH3

3 88H p-Cl 3 90H m-NO2 3 91

p-Cl 5 89(b) p-Cl o-Cl 5 88

o-OH Ar =Thinly 6 79o-OH p-OH 5 82

(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)(k)(l)

NH2

R1

R1

R2R2

(a) Reaction conditions: 2aminothiophenol (10 mmol); 1,3-diaryl-2-propenones (10 mmol),TCT (0.5 mmol); 80∘C; neat. (b) 82j is a new product and other thiazepines are knownand prepared by other methods.

(c) Isolated yield.

Scheme 19: Reaction of 1,3-diaryl-2-propenones with o-aminothiophenol in the presence of sub-stoichiometric amount of cyanuric chloride.

the presence of silica gel at 80∘C for 3 h, under solvent-freeconditions 2-(benzo[d][1, 3]dioxol-5-yl)-4-(substituted-phenyl)-2,3-dihydro-benzo[1, 5]thiazepine derivatives 94a–fwere afforded in good yield. The latter thiazepines probablyinvolves the intermediate [95] which was formed by 1,2- and

1,4- type addition of o-aminothiophenol with chalcones 93a–f. The sulfur atom being more nucleophilic in nature thanthe nitrogen atom attacks the 𝛽-carbon of chalcones 93 andgives intermediate [95] that easily undergoes dehydration ina nonaqueous medium [25] (Scheme 23).


R

OH

RO R

OH

O

a b

O84

c

R

OH

O83

SH

d

OH

S

N

R

85a–h

86a–h

R1R1

R1R1

R1

CH3

CH3

R2

R2

NH2

Synthetic routes of the benzothiazepines 86a–hR = H, Cl; R2 = aryl, heteryl(a) (CH3CO)2O, 10% NaOH; (b) AlCl3 anhyd.; (c) R2CHO, 40% NaOH, MW; (d) zinc acetate, MW;

MWand conventional synthesis of benzothiazepinens 86a–h

86 R R1 R2 Yield (%) TimeMW Conv. MW(min.) Conv, (hr)

(a) H H p-NO2-Ph 75 69 3.5 4(b) H H Ph 82 70 3 4.5(c) H H o-NO2-Ph 70 66 5.5 8(d) H H p-MeO-Ph 65 57 5 6.5(e) Cl Cl Furyl 65 72 4 6(f) Cl Cl p-MeO-Ph 74 68 3.5 4(g) Cl Cl Thinly 70 63 5 6.5(h) Cl Cl p-NO2-Ph 75 70 4 5

Scheme 20: Microwave-assisted reaction of o-aminothiophenol and 1,3-substituted-prop-2-en-1-ones in presence of zinc acetate.

3.1.24. Comparative MW Irradiation and Thermal Reac-tions of 𝛽-Benzoyl Arylic Acid with o-Aminothiophenolsand Chloroacetyl Chloride over the Basic Alumina as Inor-ganic Solid Support. 𝛽-Benzoyl arylic acid 96 reactionwith 5-substituted-o-aminothiophenol derivatives and 2-chloroacetyl chloride 98 under MW irradiation over basicalumina (as inorganic solid support) in absence of any solventoccurred in 5-6min gave only the desired azeto-benzot-hiazepines 99 in excellent yield.

The basicity of alumina is sufficient to cause this cycload-dition reaction and the 1,5-benzothiazepines 97 were formedin situ, as intermediates, by reaction of 𝛽-benzoyl arylic acid96 and 5-substituted o-aminothiophenol derivatives underMW irradiation.

When a solution of Et3N in benzene was added drop

wise into a solution of 2-chloroacetyl chloride and 1,5-benzothiazepine 97 in benzenemixture of azeto[2, 1-d][1, 5]-benzothiazepines 99, the ring contracted 2-substituted 2,3-dihydro-3-phenyl-N-acetyl-2-styrylbenzothiazole 100 was

obtained in fair yields. Presumably, the low yield of azeto-[2, 1-d][1, 5]benzothiazepine 99 is due to the competitivering contraction with “Staudinger reaction” under the reac-tion conditions. The yield could be improved to 30% if asolution of 2-chloroacetyl chloride 98 in benzene was addeddrop wise into a solution of benzothiazepine and Et

3N in

benzene. Although the ring contraction could be inhibitedunder this additional mode, the yield of 99a was still lowwhen 1.5 equivalents of 98were used and a newbyproduct 101was obtained.Upon applying 3.0 equivalents of 98 to improvethe yield, the desired azeto[2, 1-d][1, 5]benzothiazepines 99were not obtained, but the yield of the by-product 101 wasimproved slightly. Another trial involved first the formationof diketenes through addition of Et

3N to a solution of 98 in

benzene and subsequent addition of the 1,5-benzothiazepine99a into the resulting reactionmixture which resulted only inthe 1,3-oxazine derivative 101 in low yield. On the other hand,under microwave irradiation the desired azeto[2, 1-d][1, 5]-benzothiazepine 99a was formed as the only product with


+ OHO

Zinc chloride

ethanol87

S H

Zinc acetateMW

N

SR

HO

O

R

O

RO

OH

OH

OH

88H3C Δ

40% KOH

NH289a–f 90a–f

90 R Yield (%) TimeMW Conv. MW(min.) Conv. (hrs)

C6H5 72 65 2.5 5o-OHC6H4 88 80 1 2p-ClC6H4 78 67 1.5 5.5

p-OCH3C6H4 61 59 1 2.5Furyl 70 67 2 3

Thinyl 60 58 3 4

(a)(b)(c)(d)(e)(f)

Scheme 21: Mirowave irradiation of 1,3-substituted-prop-2-en-1-one with o-aminothiophenol in presence of zinc acetate in solvent-freeconditions.

N N

O

Cl

+

HS

R NN

R

S

HN

NN

R

S

N

H2N

R1

R1

R1

R2

R2

R2R3

R3

R3

92a–j

91a–d

MW, 8-9 minBi(NO3)3· 5H2O

R = R1= R2 = R3 = H R2 = CH3, R = R1 = R3 = HR = CH3, R1 = R2 = R3 = H R3 = CH3, R = R1 = R2 = HR = OCH3, R1 = R2 = R3 = H R = CH3, R1 = R3 = H, R2 = CH3R1 = CH3, R = R2 = R3 = H R2 = Cl, R = R1 - R3 = HR = Cl, R1 = R2 = R3 = H R3 = Cl, R = R1 = R2 = H

92 92(a)(b)(c)(d)(e)

(f)(g)(h)(i)(j)

Scheme 22: Mannich condensation reaction of substituted 1,8-naphthyridines and substituted o-aminothiophenols in the presence ofcrystalline Bi(NO

3)3⋅5H2O catalyst under MW irradiation and comparison with or without adding any solid support as well as with its

performance under thermal conditions.

good yield. Similarly, products 99b–f were obtained in fairto good yield [26] (Scheme 24).

3.1.25. Thermal (Short Time) Reaction of 1-Methyl-3,5-bis-(arylidene)-4-piperidones with o-Aminothiophenol in the Pres-ence of a Catalytic Amount of Acetic Acid under Atmo-spheric Pressure. MW irradiation of o-aminothiophenol and1-methyl-3,5-bis-(arylidene)-4-piperidones 102 (1 : 1 molarratio) in the presence of CH

3COOH as a catalyst in

silica bath (∼85∘C) under atmospheric pressure for 4–10min afforded 2-methyl-11-aryl-4-[(E)-arylmethylidene]-1,2,3,4,11,11-a hexahydropyrido[3, 4-c][1, 5]benzothiazepines

103 in excellent yield. The same reaction in either C2H5OH

or MeOH at reflux with few drops of CH3COOH took

several hours with less than 30% conversion, while refluxingin CH

3COOH alone led to complete decomposition of the

reaction mixture [27] (Scheme 25).

3.1.26. Thermal Reaction of (E)-3-(3,4-Disubstituted-phenyl)-1-(2-hydroxy-3,4,5-trisubs-tituted-phenyl)prop-2-en-1-oneswith 2-Aminothiophenol under the Influence of Glacial AceticAcid. Oxidative cyclisation of 3-(3,4-di-substituted-phenyl)-1-(2-hydroxy-3,4,5-tri-substituted phenyl)prop-2-en-1-ones104a–j (prepared via Claisen-Schmidt condensation of


O

O

OR HS

NS

O O

R

SH+

O S

O

O

O S

O

O

H

OH

R

R

1,2-addition 1,4-addition[95]

NH2

H2NH2N

H2NHa

Ha

Hb

Hb

HX

SiO2, 80◦C, 3 hrs

R = H, CH3, OCH3, Br, Cl, NO2

93a–f94a–f

HX

HX

Scheme 23: Reaction of 3-(benzo[d][1, 3]dioxol-5-yl)-1-(substituted-phenyl)prop-2-en-1-ones with o-aminothiophenol in the presence ofsilica-gel at 80∘C for 3 h under solvent-free conditions.

CH

OHC

COOH +

SHX

N

SCOOH

MW Basic alumina96

N

S

ClO

COOH97

97

99 +N

S COOH

OCl

X

+N

S

O

ClCl

O

COOH

X

X

X

100: X = OCH3 101: X = OCH3

NH2

ClCH2COCl (98)

ClCH2COCl

99a–f

HA

HAHB

HB

HX

HX

Δ

99 X Time(a) (min) Yield (%)OCH3 12 + 3 90CH3 10 + 5 87Cl 12 + 6 83Br 10 + 5 86

CF3 9 + 4 88F 10 + 5 87

(a) Time (12+3) indicates first irradiation for 12 min. gives compound 97(detected by TLC) and then further irradiation after adding chloroacetyl chloride for 3 min yields 99a

(a)(b)(c)(d)(e)(f)

Scheme 24: ComparativeMW irradiation and thermal reactions of 𝛽-benzoyl arylic acid with o-aminothiophenols and chloroacetyl chlorideover the basic alumina as inorganic solid support.


HS

N

O

ArAr

S

N

N

Ar

Ar

H

102 103CH3

H2N

H3C

AcOH (cat.)MW, 4–10 min

70–80%Synthesis of [1,5] benzothiazepines 103.

Synthesis of [1,5] benzothiazepines 102 and 103

Ar 102 or 103 102) MW method Conventional method 103 Yield (b) (%)Time (min) Yield (a) (%) Time (min Yield (%)

(a) Ph 6 80 10 30 a) 94(b) 4 -Cl-Ph 8 79 10 28 b) 96(c) 4-Me-Ph 8 75 10 25 c) 95(d)4-MeO-Ph 8 70 10 21 d) 98(e) 4-F-Ph 10 70 11 23 e) 95(f) 3-F-Ph 4 80 10 27 f) 96(g) 2-Cl-Ph 6 72 10 25 g) 95(h) 2-MePh 8 75 11 24 h) 96(i) 2-Thienyl 6 80 11 26 i) 94(j) 1-Naphthyl 6 75 10 25 j) 97

(a) Yield after recrystallisation., (b) Yield after column purification

(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)

Scheme 25: Thermal (short time) reaction of 1-methyl-3,5-bis-(arylidene)-4-piperidones with o-aminothiophenol in the presence of acatalytic amount of acetic acid under atmospheric pressure.

various substituted acetophenones with aromatic aldehydesin the presence of EtOH/KOH) using CuCl

2at reflux in

DMSO gave 3,6-dichloro-2-(4-fluorophenyl)-7-methyl-4H-chromen-4-one 105a–j in good yield. The chalcones 104a–jon treatment with o-aminothiophenol at reflux conditionin EtOH under the influence of glacial CH

3COOH for 6 h

afforded the 1,5-benzothiazepines 106a–j in good yield [28](Scheme 26).

3.1.27. Intramolecular Cyclisation of 3-((2-Amino-4-pheny/substituted-phenyllthio)(phe-nyl)methyl)pentane-2,4-dionesor -hexane-2,4-diones Followed by Dehydration in AceticAcid/Methanol. Knoevenagel condensation of selected aro-matic aldehydes with 2,4-pentanedione in dry benzenecatalyzed by piperidine gave 3-arylidenepentane-2,4-dionederivatives 109. Michael addition of o-aminothiophenolderivatives to 109 yielded the corresponding 3-(2-amino-4-pheny/substituted-phenyllthio)(phenyl)methyl)-pentane-2,4-diones 110.

Intramolecular cyclisation of 110, followed by dehydra-tion in a CH

3COOH/MeOH provided 1,5-benzothiazepi-

nes 107a–r in fair yield. The target 2,5-dihydro-2-aryl-3-ethoxycarbonyl-4-methyl-1,5-benzothiazepines 108a–d wereprepared in 20–33% yield through the same reactionsequence starting from the hexane-2,4-diones 111. It is worthnoting that when 4-hydroxybenzaldehyde was used as thestarting material, compound 108e was obtained as the finalproduct in 20% yield, whose structure had an unusual imine(–N=C–C–) rather than enamine (–N–C=C–), as demon-strated by its 1H NMR spectrum [29] (Scheme 27).

3.1.28. Thermal Reaction of Methylene-bis-chalcones witho-Aminothiophenol in Ethanol in the Presence of AceticAcid. Condensation of 5-(3-formyl-4-hydroxybenzyl)-2-hydroxybenzaldehyde 112 with methyl ketones in thepresence of aqueous KOH (60%) at room temperatureafforded methylene-bis-chalcones 113. The latter chalconeson reaction with o-aminothiophenol, in EtOH in thepresence of CH

3COOH at reflux for 4 h, gave methylene-

bis-[1, 5]-benzothiazepine derivatives 114a–g in good toexcellent yields. The thiazepines 114a–g on condensationwith 𝛼-bromoacetophenone, in the presence of anhydrousK2CO3/dry acetone and catalytic amount of KI, followed

by cyclization in ethanolic KOH, gave methylene-bisbenzofurano-[1, 5]-benzothiazepine derivatives 115a–g(yield% was not reported) and were purified by columnchromatography using silica-gel (60–120 mesh)/petrol ether(60–80∘C) [30] (Scheme 28).

3.1.29. Reaction of Exocyclic 𝛼,𝛽,𝛾,𝛿-Unsaturated Ketoneswith o-Aminothiophenol in a Mixture of Boiling Toluene andAcetic Acid. The exocyclic 𝛼,𝛽,𝛾,𝛿-unsaturated ketones 116–123 when allowed to react with o-aminothiophenol in amixture of boiling toluene andCH

3COOH the tetracyclic 1,5-

benzothiazepines 124–131 were obtained in relatively goodto medium yields (59–71%). Neither the yield nor course ofthe reaction was influenced by the presence of an electrondonor or an electron acceptor o-substituent in the startingmaterial. Replacement of the styryl group by a 2-(furan-2-yl)ethenyl-one slightly enhanced the yield of the formationof 1,5-benzothiazepines 130 and 131 (71 and 68% resp.) [31](Scheme 29).


OH

O

H

OOH

O

O

O

Cl

HSS

N

HO

CH3

H2N

R1R2

R3

R4

R5

DMSO, CuCl2Reflux, 3 hr24–36 hr

104a–j

104a–j

105a–j

106a–j

EtOH, AcOH,reflux, 6 hr

R1 R1

R1

R2 R2

R2

R3 R3

R3

R4

R4

R4

R5

R5

R5

40% alc. KOH, Str,

Charcterization data of comps 105a–j and 106a–j

105,106 R1 R2 R3 R4 R5 Yield (%) of 105 Yield (%) of 106H H H H F 59 70H H CH3 H F 58 63H H Cl H F 60 66Cl H Cl H F 64 71H CH3 Cl H F 61 69H H H OCH3 OCH3 60 70H H CH3 OCH3 OCH3 57 58H H Cl OCH3 OCH3 59 62Cl H Cl OCH3 OCH3 60 66H H H H F 55 62

(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)

Scheme 26: Thermal reaction of (E)-3-(3,4-disubstituted-phenyl)-1-(2-hydroxy-3,4,5-trisubstituted-phenyl)-prop-2-en-1-ones with o-aminothiophenol under the influence of glacial acetic acid.

3.1.30. Reactions of Thienylidene Malononitrile and o-Amino-thiophenol in the Presence of Catalytic Amount of Piperidine.o-Aminothiophenol and thienylidene malononitrile 132(equimolecular ratios) upon heating under reflux in EtOHcontaining piperidine for 30min gave 2-amino-3-cyano-4-(2-thienyl)[1, 5]benzothiazepine 135 in good yield. For-mation of 135 may proceed via the intermediate (133)which cyclized to afford the intermediate (134). The latterintermediate in turn tautomerized to 2-amino-4,5-dihydro-benzothiazepine and released hydrogen under an aerobicoxidation to give 135. The latter thiazepine when reactedwith ethyl cyanoacetate 136a and diethyl malonate 136bin CH

3COOH afforded pyridobenzothiazepine derivatives

138a,b. Elimination of ethanol from the acetate group gavethe intermediate (137), subsequently cyclized via the additionof active methylene hydrogens to the cyano function yielding4-amino-5-[2-thienyl]pyrido[6, 5-b][1, 5]benzothiazepine-1,2-dihydro-2-one derivatives 138a,b. To confirm the structureof type 138, compound 138b (X = CO

2C2H5) on boiling at

refluxwith hydrazine hydrate in ethanolic piperidine solutiongave the pyrazolo[3, 4 : 4, 3]pyrido[6, 5-b]benzothiazepinederivatives 139 in satisfactory yield. Similarly, the azepine 135reacted with malononitrile 140a and cyanothioacetamide140b in acetic acid at a reflux temperature to give in eachcase the same product 141. In the case of malononitrile 140a2 successive steps of a nucleophilic addition to the cyano

functions yield 141; whereas in case of 140b, a condensationbetween the thione group of the amide and the amine of135 released hydrogen sulfide was followed by a nucleophilicaddition of the active methylene to the cyano functionaffording the same final product 141.

Also, reaction of 135with arylidenemalononitrile 142a–cafforded pyrido-benzothiazepine derivatives 146a–c. Forma-tion of the latter thiazepines was explained via the intermedi-ate (143), which cyclized via a nucleophilic addition of hydro-gen of arylidene to a cyano function of benzothiazepine toform dihydropyridine intermediate (144). The latter releasedhydrogen cyanide to give 145 and tautomerized to form thefinal product 146.

Moreover, Compound 135 reacted easily with urea inAcOH to afford 2,4-diaminopyrimidobenzothiazepine 147(65% yield) via cyclo-condensation addition reaction.

Furthermore, reaction of 135under refluxwith triethylor-thoformate yielded the ethoxymethylidenamino derivatives148 (61% yield), which on reaction with hydrazine hydrateafforded the corresponding pyrimidobenzothiazepine 149(60%) via the elimination of ethanol followed by a nucle-ophilic addition to the cyano function.

Finally, the benzothiazepine 135 in EtOH reacted withtrichloroacetonitrile to give benzothiazepine 153 (60% yield).Compound 153 was suggested to be formed via the inter-mediate (150) which in turn cyclized to the pyrimidine


NH

S

YX N

H

S

YX

107

109

108

110

111

R R

CHOR

+Pipredine

SH

X

HOAc

NH

S

X

Synthesis of benzothiazepines 107a–r

RO

OR

OO

OO

S

X

CHOR

+Pipredine HS X

OO

O

O

R

HOAc+

Synthesis of benzothiazepines 108a–e

S

HN

O

O

R

X

O

O

O

S

X

R

S

N

O

O

OH

108a-d: X =H, Y = COOCH2CH3: R = p -CH3: R = p -F: R =p-NO2: R = o-Cl

108e: X =H, Y = COOCH2CH3, R = p -OH

107 R R Rp -NO2 H p -Clo-NO2 p -OCH3 o-Clp -Cl p -F Ho-Cl 2,4-dichloro p -Fp -CH3 p -NO2 p -Brp -OH o-NO2 2,4-dichloro

107a-j : X = H, Y = COCH3107k-r: X = Cl , Y = COCH3

(a)(b)(c)(d)

(a)(b)(c)(d)

(e)(f)

(g)(h)(i)(j)(k)(l)

(m)(n)(o)(p)(q)(r)

CH3 CH3

CH3

C6H6, 2 h, reflux

C6H6, 2 h, reflux

NH2

NH2

COCH3H2N

H2N

107a–r

108a–d 108e

pH = 3-4

pH = 3-4

Scheme 27: Intramolecular cyclisation of 3-((2-amino-4-pheny/substituted-phenyllthio)-(phenyl)methyl)pentane-2,4-diones or -hexane-2,4-diones followed by dehydration in acetic acid/methanol.

intermediate (151). In the reaction medium the C-2 ofpyrimidine became relatively positive, easily accepted thehydroxide ion from water of intermediate (152) yielding thefinal benzothiazepine 153 (60% yield) [32–36] (Scheme 30).

3.1.31. Reaction of 3-[1-oxo-3-(Substituted phenyl)-2-propen-yl]-2H-1-benzopyran-2-ones with o-Aminothiophenol in thePrescence of Piperidine. The chalcones 155a–g (derivedfrom 3-acetyl coumarin derivatives 154 and the proper


Trioxane ArO

MeKOH/EtOH

SH

O

HO

O

OH

O

HO Ar

O

ArO

OH

HO

112

BrO

KOH/EtOH

HO SN

Ar

HO

S

NAr

O

S

NAr

O

S

NAr

Synthetic pathway for compounds 115a–g

114a–g115a–g

113a–gH2SO4/AcOH

Ha Ha

Ha

Ha

Hb Hb

Hb Hb

Hx

Hx

HxHx, K2CO3, KI

NH2

C6H54-Br-C6H44-Cl-C6H44-MeO-C6H4

Ar Ar

4-NO2-C6H42-f uryl2-pyridyl

(a)(b)(c)(d)

(e)(f)(g)

Scheme 28: Thermal reaction of methylene-bis-chalcones with o-aminothiophenol in ethanol in the presence of acetic acid.

SH

Actic acidToluene N

S

X

H

H

H

ArH

R

O

X

O

Ar

Ar: 116–121, 124–129 = Ar: 122, 123, 130, 131 =

116, 124: X = O, R = H117, 125: X = O, R = MeO118, 126: X = O, R = NO2

116–123124–131

NH2

119, 127: X = S, R = H120, 128: X = S, R = MeO121, 129: X = S, R = NO2

Scheme 29: Reaction of exocyclic 𝛼,𝛽,𝛾,𝛿-unsaturated ketones with o-aminothiophenol in a mixture of boiling toluene and acetic acid.

aromatic aldehydes) when reacted with o-aminothiophenolin a mild acidic medium using weakly acidified ethanolgave 2-aryl-4-(2H-2-oxo-[1]-benzopyran-3-yl]-2,3-dihydro-1,5-benzothiazepines 156a–j in good to excellent yields.Meanwhile, upon heating the chalcones 155 under reflux inethanol containing o-aminothiophenol and piperidine, thecorresponding 2-aryl-4-[2H-2-oxo-[1]benzopyran-2-one-3-yl]-2,5-dihydro-1,5-benzothia-zepines 157a–g were obtainedin good yield [37] (Scheme 31).

3.1.32. Reactions of Butoxy(trifluoromethyl)enone with o-Aminophenol or o-Amino-thiophenol Derivatives. Reactions

of t-butoxy(trifluoromethyl)enones 158 with 1,2-diamines(o-phenylene diamine or 1,2-ethylenediamine) lead to 1,5-diazepines 159 and 160. In comparison, reaction of 158 witho-aminophenol derivatives or o-aminothiophenol, yielded1,5-oxazepines or 1,5-thiazepines of type 161. Good resultswere obtained by using microwave irradiation. Meanwhile,upon carrying the same reaction in boiling xylene, thecondensation leads to amixture of products [38] (Scheme 32)

3.1.33. Mirowave-Assisted Irradiation of o-Aminobenzenethioland the Oxirane-2-carboxylate. A diastereo-selective reac-tion of o-aminothiophenol and the oxirane-2-carboxylate 162


SH+

S

CN

CN

SH

NH

CN

CN

S

132 133

NH

S NH

CN

SNH

S

CN

SN

S

CN

S

134135

135

N

S

CN

HNO

X

S N

S

S

HNO

X

137

N

S

S

HN

CN

N

S

S

HN

O

NH

NH

O

141 139

135

Ar CN

CN

N

S

CN

HN

S

143

Ar

CN

CN

N

S

S

144

HN

NH

CN

CN

Ar

135

NH2

NH2

NH2NH2

NH2

NH2

XCH2COOC2H5− EtOH

138a: X = CNb: X = CO2Et

142a: X = C6H5b: X = C6H4- -Clc: X = C6H4- -CH3

− EtOH− NH3

X = CO2EtN2H4

CNH2X140a: X = CN

b: X = CSNH2

N

S

S146

NAr

CN

N

S

S145

HN

NH

Ar

CN

(144)

− HCN

NH2

136a: X = CNb: X = CO2C2H5

𝑝𝑝

Scheme 30: Continued.


N

SN

N

S147

135

135

N

S

CN

SN

SN

N

NHS

149148

EtOH

N

S

CN

N

S150

Cl Cl

Cl

N

SN

N

S151

C

Cl

ClCl

135

N

SN

N

S152N

SN

N

S

OH

153

OH

151

NH2

NH2

NH2NH2

NH2

NH2

NH2

H2NCONH2

N2H4HC(OEt)3−2EtOH

N = CHOEt

H2O

+H

−CCl3−

−

+

+

NC–C–Cl3

Scheme 30: Reactions of thienylidene malononitrile and o-aminothiophenol in the presence of catalytic amount of piperidine.

under microwave irradiation in an open vessel afforded thetrans- and cis-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4-ones 163, 164. Varying the reactiontime and power output as well as the nature of the solventcontrolled the disastereo-selectivity of this reaction. Carryingout the process for 20min at a power of 390W in tolueneled to a cis/trans ratio of 9 : 1 (yield: 74%). Raising the powerto 490W for 10min involved an inversion of the ratio, thatis, increasing dramatically the amounts of the trans-isomer(yield: 84%). The traditional one-pot preparation of racemictarget compounds 163, 164 produced less than 30% yield at160∘C with prolonged reaction times.

1,3-Dihydro-3-(2-phenyl-2-oxoethylidene)indol-2-one165 and o-aminothiophenol derivatives under thermal and

microwave reaction conditions using ethylene glycol affordedspiro[benzo[b][1, 4]thiazepine-2,3-indolin]-2-ones 166.

To enhance the anxiolytic activity of some azepinederivatives by the introduction of a trifluoromethyl groupin the dia-, oxa- or thiazepine, trifluoroacetyl ketene acetals167 were reacted with o-aminothiophenol derivatives inthe presence of xylene, applying a multimode microwaveoven (8–12min at 980W). Although this methodologyuses microwave inert solvents (e.g., toluene or xylene),which are not serving in the energy transfer processes,it gave the 3-substituted 2-hydroxy-2-trifluoromethyl-1,5-benzothiaz-epine derivatives 168 in good yields, suggestingabsorption of the microwaves by the reactants [33, 35, 36, 39](Scheme 33).


+

CHO

155

O O

R

O

O O

R

O

SH+

SH

+

+NH

OO R

S

NHH

H

156

155

OO

R

S NH

PiperidineSolid state

154

EtOH

157

Δ

Δ

R1 R1

R2 R2

R3

R3

R1

R1

R2R2

R3R3

NH2NH2

EtOH + AcOH

HH

H

HH

HH

HH

H

HH

H

H

H

H HHHH

H

H HH

H HH

H

HH

HH

H

H

HHHH

H

HHH

HHHH

HHH

H

HHH

HHHH

H

HHHH

H

BrBrBrBrBr

BrBr

BrBr

Br

Br

BrBr

Br

BrBrBr

BrBr

Br

Br

ClCl

Cl

Cl ClCl

ClCl

OH

OH

OHNO2

NO2

NO2

NO2

NO2

N(CH3)2N(CH3)2

N(CH3)2

N(CH3)2

N(CH3)2

N(CH3)2

N(CH3)2

N(CH3)2

1RR R2 R3

1RR R2 R31RR

1RR

R2 R3

1RR R2 R31RR R2 R3

R2 R3155 155

156 156

157 157

(a)(b)(c)(d)(e)

(a)(b)(c)(d)(e)

(e)(a)(b)(c)(d)

(f)(g)(h)(i)(j)

(f)

(f)

(g)

(g)

(h)(i)(j)

Scheme 31: Reaction of 3-[1-oxo-3-(substituted phenyl)-2-propenyl]-2H-1-benzopyran-2-ones with o-aminothiophenol in the presence ofpiperidine.

3.1.34. Comparative Microwave-Assisted and ConventionalHeating Reactions of N-(4-(2-oxo-2H-Chromen-3-yl) thiazol-2-yl)cinnamamide with o-Aminothiophenol in the Presenceof Glacial Acetic Acid as Catalyst and Methanol. N-[4-(2-oxo-2H-Chromen-3-yl)-1,3-thiazol-2-yl]acetamide 170 (pre-pared from3-(2-amino-1,3-thiazol-4-yl)-2H-chromen-2-one169 by acetylation with acetyl chloride in chloroform)on reaction with various aldehydes 171a–j gave N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl) cinnamamide deriv-atives 172a–j in good yield. The latter derivatives ontreatment with o-aminothiophenol in the presence ofglacial CH

3COOH as catalyst and MeOH under MWI

for afforded 2,3-dihydro-2-aryl-4-[4-(2-oxo-2H-chromen-3-yl)-1,3-thiazol-2-ylamino]1,5-benzothiazipine 173a–j. Higher

yields of compounds 172a–j and 173a–j were realized at 500watt for 2–2.5min of microwave irradiation, whereas similarreactions of 173a–j under conventional heating (steam bath)at reflux gave poorer yields after much longer times [40](Scheme 34).

3.1.35. Reaction of 1-(4-(4,6-bis (Phenylamino)-1,3,5-triazin-2-ylamino) phenyl)-3-(4-methoxyphenyl) prop-2-en-1-ones witho-Aminothiophenol in the Presence of a Few Drops of GlacialAcetic Acid. Reaction of 2,4,6-trichloro-1,3,5-triazine withaniline in acetone at 0–5∘C gave 4,6-dichloro-N-phenyl-1,3,5-triazin-2-amine 174. Further reaction of 174with anilinein acetone at room temperature yielded 6-chloro-𝑁2, 𝑁4-diphenyl-1,3,5-triazine-2,4-diamine 175. The latter product


YP

159

160

161

158O

XF

F

F

O

NH

N

F F

F

X

HN N

F

F

FX

Y

HN

HOF

F

F

X

R1

R1R2

R2

NH2

NH2

NH2

73–93%

NH2CH2CH2NH2

73–77%R3

71–89%

X = COCF3R1 = H, Me; R2 = H, Me, Cl, NO2, COPh; R3 = H, ClY = O, S, P = H

Scheme 32: Reactions of butoxy(trifluoromethyl)enone with o-aminophenol or o-aminothiophenol derivatives.

SH

O

H

HR

NH

S

NH

SR R

OH OH

O O

+162

163 164

R SHHN

O

O

Ethylene glycolpiperidine

S

NH

NH

O

R

165 166

R SHR

OisoBu

O

XyleneS

NH

HOF S

F

F

R167 168

NH2

NH2

NH2

CO2CH3MW, 10–20 min

Cis Trans

+

+

MW, 160–218 ◦C,7–10 min

R = H, Br, OEt, 54–65% yield

MW, 8–12 min

R = H, COCF3, (71–78% yield)

CF3

R: 4–OCH3–C6H4

Solvent Power (W) Time (min) Ratio cis: trans Yield (%)Toluene 390 20 9:1

1:974

Acetic acid 490 10 84

Scheme 33: Mirowave-assisted irradiation of o-aminobenzenethiol and the oxirane-2-carboxylate.


O

NH

S

N

O

O

O

O

S

N

H

O

R171a–j

172a–j

O

NH

SN

OO

R

SH

173a–j

O

O

S

N NH

S

N

R

169 170

(iii)

(ii)

H2N

NH2

(i)

reflux, 6–8 hr. microwave: CH3OH/2%NaOH, MWI, 2–3.5 min. (iii) Conventional: CH3OH/glacialReagents and reaction conditions: (i) CH3COCl/CHCl3, 0–5◦C, 8 hr. (ii) Conventional: CH3OH/2%NaOH,

CH3COOH, reux, 60–70◦C, 6–9 hr. Microwave: CH3OH/glacial CH3COOH, MWI, 2–3.5 min.

R(a) 3-CH3;(b)4-OH;(c)2-Cl(d) 4-Cl; e) 2,4-(Cl)2; (f)2-OCH3(g) 4-OCH3;(h)3,4,5-(OCH3)3(i)4-N(CH3)2; (j) 4-OH

Scheme 34: Comparative microwave-assisted and conventional heating reactions of N-(4-(2-oxo-2H-chromen-3-yl) thiazol-2-yl)cinnama-mide with o-aminothiophenol in the presence of glacial acetic acid as catalyst and methanol.

on reaction with1-(4-aminophenyl) ethanone gave 1-(4-(4,6-bis(phenylamino)-1,3,5-triazin-2-ylamino)phenyl)ethanone176. 1-(4-(4,6-bis(phenylami-no)-1,3,5-triazin-2-ylami-no)phenyl)-3-(4-methoxyphenyl)propen1one 177d wasobtained from reaction of 176 with 4-methoxybenzaldehydein good yield in DMF/KOH. Similarly, products 177a–dwere synthesized using the appropriate aromatic aldehydes.Reactions of 177a–d with o-aminothiophenol in thepresence of few drops of glacial CH

3COOH yielded 1,5-

benzothiazepine 178a–d in moderate yields (56–63%)[41–43] (Scheme 35).

3.1.36. Condensation Reactions of Enones with o-Amino-thiophenol. The overall process for the formation of thehemiperfluoroenones 181 from perfluoroalkyl iodides andacylsilanes has been described previously [44, 45]. Depend-ing on the experimental conditions, compounds 179 and180 were isolated. The latter compounds are considered asuseful synthons and regarded as equivalents of the enones 181.Condensation of o-aminothiophenol, with the enones 179(or 180 or 181) provided the corresponding benzothiazepines182a–c in good yields. In the carbohydrate series, the 1,5-benzothiazepines 182c was obtained as an epimeric mixture(D-xylo/L-arabino in a 85 : 15 ratio), indicating that a furtherC-4 epimerisation had occurred during the formation of theheterocycle [44–47] (Scheme 36).

3.1.37. Reaction of 1-(Benzo[d][1,3]dioxol-5-yl)-3-phenylpro-pane-1,3-diones with o-Aminothiophenol. 1-(Bnzo[d][1, 3]di-oxol-5-yl)-3-phenylpropane-1,3-diones 183a–I on reaction

with o-aminothiophenol in pyridine under reflux for∼4 h, while stirring, afforded the 2,4-disubstituted 1,5-benzothiazepines 184a–i. The reaction is initiated by thenucleophilic attack of sulphydryl electrons on enolic carbonatom of the 𝛽-diketone followed by loss of water molecule.Therefore, amino group comes in vicinity of carbonyl group,by dehydration resulting into the cyclized products of type184 [48] (Scheme 37).

3.1.38. Reactions of 2-Hydroxybenzal Acetophenone and 1-(1-Naphthyl)-3-(1-naphthyl)-2-propenone with o-Aminothio-phenol Derivatives. The absorbed ethanolic solutions ofchalcones 187a,b (prepared from the aldehydes 185a,band the ketones 186a,b under microwave irradiation ona suitable solid support Mont. KSF) when mixed with o-aminothiophenol derivatives (20% byweight of the reactants)and irradiated inside a MW oven for an appropriate timeat 640W yielded the benzothiazepine 188a–g in excellentyield.

When equimolar mixture of o-aminothiophenol deriva-tives and 2-hydroxybenzalaceto-phenone 187a in dry ethanolwas saturated with dry HCl gas until boiling and heatedunder reflux for 6 h the benzothiazepine products 188a–gwere synthesized (65–67% yield). Irradiation of the absorbedethanolic solutions of 188a,b on clay fen (prepared from 2 gclay + 0.001mol Fe (III) NO

3) inside a microwave oven for

6min yielded 8-ethoxy-2,5-dihydro-l,5-benzothiazepine-l,l-dioxides 189a,b in good yields (88%) and no mono-oxide oftype 190was detected.Thedioxides 189a,bwere also obtainedin satisfactory yield (conventional method) via dissolved


N

N

N+

N

N

N

Cl

Cl

NH

N

N

N

NH

Cl

NH

N

N

N

NH

HN

NH

R N

N

N

NH

HN

NH

R

SH

N

N

N

NH

HN

NH

N

S

R

Cl

Cl

ClAcetone

174

r.t., acetone

176175

177a–dDMF/KOH

OHC

178a–d

H2N

COCH3

COCH3

NH2

CO–CH=CH

0–5◦C

H2N

H2N

177, 178 R(a)(b)(c)(d)

4-Cl4-NO23,4-MeO4-MeO

Scheme 35: Reaction of 1-(4-(4,6-bis (phenylamino)-1,3,5-triazin-2-ylamino)phenyl)-3-(4-methoxyphenyl) prop-2-en-1-ones with o-aminothiophenol in presence of a few drops of glacial acetic acid.

solutions of 188a,b in glacial CH3COOH, H

2O2(30%) and

the mixture was boiled under reflux for 10–12 h and no traceswere detected for the expected benzothiazepines of type 190[49] (Scheme 38).

3.1.39. Reaction of (E)-N-(2-(Allylsulfonyl)phenyl)-4-methyl-N-(prop-1-enyl)benzene Sulfonamide with o-Aminothiophenolin the Presence ofGrubbs’ Second-GenerationCatalyst. Ortho-aminothiophenol was Monoalkylated with allyl bromide andthe amine subsequently protected with a tosyl group to affordN-(2-(allylthio)phenyl)-4-methylbenzenesulfon amide 191.Allylation of 191 readily afforded the sulfonamide 192. Sur-prisingly, ring-closingmetathesis (RCM)on this substrate didnot give the expected 8-membered 6-tosyl-5,6-dihydro-2H-benzo[b][1, 4]thiazocine 193 and attempted isomerizationof the same substrate was also unsuccessful. Substrate 192was thus oxidized to the corresponding sulfone 194 andthe RCM successfully afforded the corresponding sulfon 195

in good yield. By applying the sequential isomerization-RCM strategy on compound 194 it was rather surprisingto isolate N-(2-(allylsulfonyl)phenyl)-4-methyl-N-(prop-1-enyl) benzenesulfonamide 196 in which only the N-allylgroup had been isomerized. Subsequently, when compound196 was treated with Grubbs’second-generation catalyst 197,the 7-membered 2,5-dihydro-1,5-benzothiazepine1,1-dioxide198 was obtained in fair yield; although the reaction wasparticularly slow [50] (Scheme 39).

3.1.40. Reaction of Substituted Chalcones with o-Amino-thiophenol: Formation of Benzothiazepines Depended onChalcone Substituents. Reaction of chalcones 199 with o-aminothiophenol in the presence of silica-gel that was car-ried out under solvent-free conditions afforded 2,3-dihydro-2,4-diphenyl-1,5-benzothiazepine 200 in one step in goodyield. This reaction depended on the chalcone substituents.In the case of chalcones having NO

2and OH groups,


RR

F

O

R RF

F

F

Or

NS

R

FRF

179 or 180 or 181

180179181

SH

Ether or dioxane182a–c

R = alkyl, aryl, sugar residue

OH

Δ, 81–87%

NH2

CF2–CF2RF

CF2–RF

OSiR12R2RF–CF2–M + R–COSiR12R2 SiR12R2

Starting compound RF Yield (%)181 (c) C4F9 182 (a) 87

(f) C2F5 (b) 81(g) C2F5 (c) 79(a)

(a) Mixture of the two epimers (D-d-xylo/L-arabino, 85:15

Compound R R1 R2 RF Yield (%)181 (a) Ph Me Me C4F9 88

(b) -Cl-Ph Me Me C4F9 91(c) -F-Ph Me Me C4F9 89(d) --MeO-Ph Me Me C4F9 87

(f) Me Me C2F5 88

(g) Me Me C2F5 67

OO

OO

OOBn

OO

Benzothiazepines 182a–c

Scheme 36: Condensation reactions of enones with o-aminothiophenol.

O

O

C

O

C C

O

X+N

S

OO

X

184a–i183a–i

StirringPyridine, Δ

SH

H2NH2

183,184 X 183,184 XH OHCH3 NH2Cl NO2Br OC2H5OCH3

(a)(b)(c)(d)(e)

(f)(g)(h)(i)

Scheme 37: Reaction of 1-(benzo[d][1, 3]dioxol-5-yl)-3-phenylpropane-1,3-diones with o-amino thiophenol.

the yields were lower (44–68%) than those of chalconeswith the other substituents. It seems that low reactiv-ity of chalcones having NO

2and OH groups is due to

these groups being absorbed more strongly on the surfaceof silica-gel than that of a carbonyl group in the same

molecule. Meanwhile, chalcones 199 when reacted with o-aminothiophenol in refluxing toluene, the chalcones withelectron-donating substituents such as CH

3and OCH

3

group, gave only 𝛽-phenyl-𝛽-(2-aminophenylmercapto)-propiophenones of type 199A, whereas from chalcones with


+ R2 C CH3

CH2

NH2

O

R1 CHO R1 C

HCH

C

O

R2

185a, b 186a, b 187a, b

X SH

NH2

S C

H

C

O

NH

SXX

188a–g

188a, bMW, mont. KSF, +

NH

S

HO

OO

189a, b

NH

S

X

O

190

− H2O

MW,Mont. KSF

185a: R1 = 2-C6H4OH185b: R1 = 1-C10H7

186a: R2 = C6H5186b: R2 = 1-C10H7

R1 R1

R2R2

Oxidation

Fe(III)NO3

Compd X R1 R2 Compd X R1 R2

188a OC2H5 2-C6H4OH C6H5 188f OCH3 1-C10H7 1-C10H7b CH3 2-C6H4OH C6H5 g CH3 1-C10H7 1-C10H7c OCH3 2-C6H4OH C6H5 189a OC2H5 2-C6H4OH C6H5d Cl 2-C6H4OH C6H5 b CH3 2-C6H4OH C6H5e Br 2-C6H4OH C6H5

Scheme 38: Reactions of 2-hydroxybenzal acetophenone and 1-(1-naphthyl)-3-(1-naphthyl)-2-propenone with o-aminothiophenol deriva-tives.

electron-withdrawing substituents such as NO2group, only

1,5-benzothiazepines were formed. Therefore, the carbonylgroup in chalcones havingNO

2orOHgroups is less activated

than that in chalcones with the other substituents [51, 52](Scheme 40).

3.1.41. Synthesis of Fluorinated Azeto[2,1-d][1,5]benzothiaz-epine from 2-Carboxy-2,3-dihydro-1,5-benzothiazepine UsingConventional and Microwave-Assisted Reactions. A mix-ture of substituted ortho-aminothiophenol derivatives, 3-(substituted benzoyl)-2-propionic acid 201 and montmoril-lonite KSF was dissolved in acetone, swirled for a whileand excess solvent was removed under gentle vacuum.

The obtained dry flowing powder was irradiated undermicrowave oven for short time. After completion of thereaction (monitored by TLC) and filtration of the recy-clable inorganic solid support, the 2-carboxy-2,3-dihydro-1,5-benzothiazepines 202a–m were obtained in good yield[53] (Scheme 41).

3.1.42. Reactions of o-Aminothiophenol Derivatives withIsatin and 3-Methyl-1-phenyl-2-pyrazolin-5-one under MWIrradiation in the Presence of Montmorillonite KSF. A neatmixture of isatin 203 and 3-methyl-1-phenyl-2-pyrazolin-5-one 204 placed on an alumina bath and irradiated


SH

NH2

S

NHTs

191NTs192

(iv)

N

SS

Ts

(v)

S

NTs

O O

(vi)

N

S

Ts

OO

195

S

NTs

O O

(vii)

N

S

OO

Ts198196194

N N MesMes

Ru

Ph

Cl

Cl

(i, ii) (iii)

193

(viii)

Grubbs’ second generation catalyst 197

Reagents and conditions: (i) allyl bromide, MeOH, NaOH, H2O, rt, 2 h; (71%); (ii) TsCl, pyridine, CH2Cl2, 45◦C, N2, 24 h(97%); (iii) K2CO3, allyl bromide, acetone, rt, 24 h; (99%); (iv) 5% catalyst 7,toluene, 50◦C, N2, 48 h, complex mixture; (v)

[RuClH(CO)(PPh3)3], toluene, 105◦C, 24 h(84%); (viii) 5% catalyst 197, toluene, 50◦C, 24 h, then further 5% catalyst 19780◦C, 24 h, 198 (41%) and 196 (59%).

PCy3

MCPBA (2.2 equiv),CH2Cl2, − 5◦C, 48 h; (71%); (vi) 5% catalyst 197, CHCl3, rt, 24 h, then 45◦C, 24 h (95%); (vii) 10%

Scheme 39: Reaction of (E)-N-(2-(allylsulfonyl)phenyl)-4-methyl-N-(prop-1-enyl)benzenesulfonamide with o-aminothiophenol in thepresence of Grubbs’ second-generation catalyst.

SH+

O

199N

S

Ar1

Ar1

Ar2

Ar2

NH280 C, 3 h

SiO2

200a–j

Synthesis of 1,5-benzothiazepines 200a–j(a)

199 or 200 Ar1 Ar2 Yield (%) of 3 199 or 200 Ar1 Ar2 Y ield (%) of 3(b)C6H5 C6H5 87 C6H5 4-ClC6H4 784-ClC6H4 C6H5 75 C6H5 4-CH3OC6H4 834-CH3C6H4 C6H5 73 C6H5 4-CH3OC6H4 744-CH3OC6H4 C6H5 61 C6H5 4-HOC6H4 444-CH3OC6H4 C6H5 44 C6H5 4-NO2C6H4 68

(a) Mol ratio 1:2 = 1.5, 80 oC, 3h, (2g); (b) Isolated yield.

(a)(b)(c)(d)(e)

(f)(g)(h)(i)(j)

Scheme 40: Reaction of substituted chalcones with o-aminothiophenol: formation of benzothiazepines depended on chalcone substituents.

for 6–8 minutes gave 3-(3-methyl-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)indolin-2-one 205 in quantitativeyield. Conventional synthesis via heating 203 and 204in EtOH afforded spiro[dipyrazolopyran3H-indol]-2H-one 206 as major product along with the indilone 205and required a tedious work during isolation. Reactionsof the intermediate 205 synthesized “in situ” with o-aminothiophenol derivatives were examined under MWirradiation using different solid supports including acidic,basic, or neutral alumina, silica, montmorillonite KSF,and K10. The montmorillonite K10 was found the most

adaptable and simplest catalyst for synthesizing spiro[indole-pyrazolo[4, 3-c][1, 5]benzothiazepines 207a–e, since com-paratively a higher yield (72–91%) was achieved in shorterreaction time (∼7min.) by this method.

The best results obtained under microwave irradiationwere extrapolated to conventional heating. Thus, in thecase of compound 207a when the reaction was carriedout using a preheated oil-bath under the same reactionconditions (time, temperature, pressure, and vessel) it didnot occur and the reactants remained unchanged evenon extended reaction times, suggesting that the effect of


SH

+MW

O

OH

O

N

SCOOH

202

Mont. KSFNH2

R1

R2

R3

R1

R2R3 R4

R5R6

R6

R5

R4 201

2-carboxy-2,3-dihydro-1,5-benzothiazepines (202a–m)

HAHB

HX

202 R1 R2 R3 R4 R5 R6 Time (min) Yield (%)CH3 H H H H F 4 80

F H H H H F 3 82Cl H H H H F 4 75Br H H H H F 5 81

OCH3 H H H H F 4 70 OC2H5 H H CH3 H F 4 73 C2H5 H H CH3 H F 3 78

H CF3 H H Cl H 5 80 H H Br H CF3 H 4 76

CF3 H H H H OH 6 75 H H Cl H H F 5 78 H H CF3 CH3 H F 3 82 H CH3 CH3 H CF3 H 6 74

(a)(b)(c)(d)(e)(f)(g)(h)(i)(j)(k)(l)

(m)

Scheme 41: Synthesis of fluorinated azeto[2,1-d][1, 5]benzothiazepine from 2-carboxy-2,3-dihydro-1,5-benzothiazepine using conventionaland microwave-assisted reactions.

microwave irradiation is not simply thermal process [54](Scheme 42).

3.1.43. Microwave Thermal Reaction of Alkynone with o-Aminothiophenol. As a model reaction, p-chlorobenzoylchloride 208b and phenyl acetylene 209a were first reactedunder Sonogashira conditions for 1 h at room temperatureto furnish the expected alkynone, and after the subsequentaddition of o-aminothiophenol and acetic acid (upon varyingreaction temperature under microwave irradiation and time)led to the formation of benzothiazepine 210b. This opti-mization of hetero-cyclisation clearly showed that dielectricheating is superior over conductive heating.

In comparison to the other known MCR synthesis ofbenzo[b][1, 5]diazepines this result is just converse. AlthoughtheMichael addition an

review article benzo[1,5]thiazepine: synthesis, …downloads.hindawi.com/archive/2013/210474.pdfn s...

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