3-(Bromoacetyl)coumarins: unraveling their synthesis, chemistry, and applications.

This review emphasizes recent developments in synthetic routes of 3-(bromoacetyl)coumarin derivatives. Also, chemical reactions of 3-(bromoacetyl)coumarins as versatile building blocks in the preparation of critical polyfunctionalized heterocyclic systems and other industrially significant scaffolds are described. Recent advances of 3-(bromoacetyl)coumarins as attractive starting points towards a wide scale of five and six-membered heterocyclic systems such as thiophenes, imidazoles, pyrazoles, thiazoles, triazoles, pyrans, pyridines, thiadiazins as well as fused heterocyclic systems have been reported. Additionally, this review covers a wide range of analytical chemistry, fluorescent sensors, and biological applications of these moieties, covering the literature till May 2021. This journal is © The Royal Society of Chemistry.

Introduction

Coumarins are one of the most common host heterocyclic systems reported in the literature of organic chemistry.[1,2] Furthermore, coumarins and their derivatives are seen to be the pivotal components of a plethora of many natural products and pharmaceuticals[3] and synthetic dyes.[4-9] The pharmacological activities discovered amongst coumarin derivatives include the treatment categories of Alzheimer's[10] and haematopoietic necrosis (IHN);[11] they have shown potent anticoagulant, antibiotic, antiembolic, antioxidative, and anti-ischemic activities[12-16] (Fig. 1).

Fig. 1

Selected structures of coumarin derivatives in biological applications.

Among these compounds, 3-(bromoacetyl)coumarin 1 and its derivatives are a prominent structural class in the synthesis of various bioactive heterocyclic scaffolds,[17,18] they also are important components in drug discovery on account of their biological activities such as antiproliferative, antimicrobial activities,[19] and are promising inhibitors of type 2 diabetes mellitus.[20] In addition, numerous chemosensors are based on polyfunctional coumarin platforms used to detect multianalyte detection, such as different bioactive elements and various environmental pollutants.[21,22] There is no survey available on the biological and chemical applications achieved since the discovery of 3-(bromoacetyl)coumarins. The articles on this type of coumarin are scattered in scientific journals.

In continuation of our investigations on the chemistry of coumarins and their azo/thio isosteric analogs[23-28] and based on the above mentioned interesting biological and chemical aspects, this survey mainly highlights the advances in the synthesis of 3-(bromoacetyl)coumarin and its derivatives, besides, their transformations for the construction of different fused heterocyclic systems in detail. Additionally, a wide range of analytical chemistry, fluorescent sensors, and biological applications of these moieties are summarized.

Spectral data

Many papers have reported the spectroscopic measurements (IR, 1H NMR, 13C NMR, and Mass) of 3-(bromoacetyl)coumarin.[29,30] As IR spectrum of 3-(bromoacetyl)coumarin showed the characteristic ketonic group band at 1674, while C–H stretching vibrations at the aromatic region 3100–3000 cm−1 (ref. 29) and two carbonyl characteristic peaks at ν 1674 and 1729 cm−1 related to α,β-unsaturated ketonic and lactonic, respectively.[31]1H NMR spectrum of parent 3-(bromoacetyl)coumarin 1 shows singlet signal of H-4 at δ = 8.63 ppm, while the CH2 group appears as singlet signal at δ = 4.74 ppm. Also, 13C NMR spectrum of 3-(bromoacetyl)coumarin exhibits characteristic signals at δ = 188.9, 158.9, and 35.6 ppm corresponding to α,β-unsaturated ketonic, lactonic and methylene carbons, respectively.[30] In the same context, HRMS/MS is mentioned as characteristic spectrometric data for 3-(bromoacetyl)coumarin 1 shows that m/z 266.9665 (calcd. for C11H879BrO3 [M + H]+ 266.9657).[30]

In 1991, Vasudevan et al.[32] elucidated the structure 3-(bromoacetyl)coumarin 1 through its single-crystal X-ray, which showed that there are two conformers of the structure 1, S-cis (I) or S-trans (II) (Fig. 2).

Fig. 2

S-cis (I) or S-trans (II) conformers of 3-(bromoacetyl)coumarin 1.

Moreover, Sparkes and coworkers[33] reported a polymorph of 3-(bromoacetyl)coumarin (Fig. 3). Whereas, Chennuru et al.[34] reported a single-crystal X-ray of 6-chloro-3-(bromoacetyl)coumarin (Fig. 4).

Fig. 3

ORTEP diagram of 3-(bromoacetyl)coumarin 1 [reprinted from ref. 33].

Fig. 4

ORTEP diagram of 6-chloro-3-(bromoacetyl)coumarin [reprinted from ref. 34].

Synthesis

Using 3-acetylcoumarins

The reaction of 3-acetylcoumarins 2 with numerous reagents represents a general approach to preparing 3-bromoacetyl coumarin derivatives 1. Several brominating agents have been reported in the last two decades such as tetrabutylammonium tribromide (TBATB), bromine, phenyltrimethylammonium tribromide (PhTAPBr3), N-bromosuccinimide (NBS), and copper(ii) bromide (CuBr2) (Scheme 1).[35-47]

Scheme 1

Formation of 3-(bromoacetyl)coumarin derivatives 1.

Reactivity

On the treatment of 3-(bromoacetyl)coumarin 1 with various nucleophiles, four possible electrophilic positions are susceptible to attack: the exo-carbonyl group (position 1), bromomethanide group (CH2Br) (position 2), lactonic carbonyl group (position 3) and the bromo atom (position 4) susceptible to attack (Fig. 5). Besides, the typically nucleophilic position for attacking is carbon 4. The reactivity of α-bromoacetylcoumarin towards oxygen, nitrogen, and sulphur nucleophiles is discussed in this review.

Fig. 5

Reactive sites in 3-(bromoacetyl)coumarin.

Reactions

Amination

Sinnur et al.[48] reported a short and efficient synthesis for aminomethyl-3-coumarinyl ketone hydrochloride 4via refluxing 3-(bromoacetyl)coumarin 1 with hexamethylenetetramine 3 in drops of concentrated hydrochloric acid (Scheme 2).

Scheme 2

Synthesis of aminomethyl-3-coumarinyl ketone hydrochloride 4.

Moreover, 3-(bromoacetyl)coumarin 1 was condensed with an amino group of various heterocyclic derivatives 5 such as 2-aminothiazole, 2-aminobenzothiazole, 2-amino-1,3,4-oxadiazole, 2-amino-1,3,4-thiadiazole, and 3-amino-4H-1,2,4-triazole derivatives in DMF to give the corresponding 2H-chromen-2-ones 6 (Scheme 3).[49]

Scheme 3

Condensation of 3-(bromoacetyl)coumarin 1 with various heterocyclic amino groups.

Treatment of 3-(bromoacetyl)coumarin 1 with di(2-picolyl)amine 7 in chloroform under basic condition at room temperature afforded the corresponding 3-(bis(pyridin-2-ylmethyl)glycyl)-2H-chromen-2-one 8 (Scheme 4).[50,51]

Scheme 4

Reaction of 3-(bromoacetyl)coumarin 1 and di(2-picolyl)amine 7.

Selective nucleophilic substitution of 3-(bromoacetyl)coumarin 1 was accomplished through stirring with benzimidazole 9 in acetonitrile at ambient temperature afforded corresponding imidazole-1-carbonyl-chromenone 10 (Scheme 5).[52]

Scheme 5

Treatment of 3-(bromoacetyl)coumarin 1 with benzimidazole 9.

Valadbeigi et al.[53] reported the synthesis of thiazolidinedione derivatives 12 through heating of 3-(bromoacetyl)coumarin 1 with thiazolidine-2,4-dione 11 in alcoholic potassium hydroxide (Scheme 6).

Scheme 6

Transformation of 3-(bromoacetyl)coumarin 1 to thiazolidine-2,4-dione 11.

The reaction of the 3-(bromoacetyl)coumarin derivatives 1 with substituted arylamine 13 in ethanol in the absence[54] or the presence of sodium bicarbonate[41,55,56] or under solvent-free condition using K2CO3 (ref. 57) yielded the corresponding 3-(2-(phenylanliino)acetyl)-2H-chromen-2-ones 14 (Scheme 7).

Scheme 7

Transformation of 3-(bromoacetyl)coumarins 1 to chromenones 14.

Whereas, refluxing of 3-(bromoacetyl)coumarin derivatives 1 with arylamines 13 in a mixture of ethanol and chloroform afforded the corresponding imino derivatives 15a-f (Scheme 8).[54]

Scheme 8

Synthesis of imino derivatives 15.

Coupling of 3-(bromoacetyl)coumarin derivatives 1 with amine hydrochlorides 16 such as hydroxylamine hydrochloride, methoxyamine hydrochloride, o-benzylhydroxylamine hydrochloride, and ethoxyamine hydrochloride in methyl alcohol to afford 3-(bromoacetyl) coumarin oximes 17 (Scheme 9).[53,58-62]

Scheme 9

Synthesis of bromoacetylcoumarin oximes 17.

Azidation

Evans and coworkers[58] reported the synthesis of coumarin fluorophore bearing an azidoacyl group 19via the treatment of 3-(bromoacetyl)coumarin 1 with sodium azide (NaN3) 18 at tetrahydrofuran (Scheme 10).

Scheme 10

Synthesis of 3-azidoacyl coumarins 19.

Thiocyanation reaction

Ramanna et al.[63] reported the treatment of 3-(bromoacetyl)coumarin derivatives 1 with potassium thiocyanate (KSCN) 20 in ethanol furnished 3-thiocyanatoacetyl coumarin derivatives 21 in good yields (Scheme 11).

Scheme 11

Treatment of 3-(bromoacetyl)coumarins 1a-f with potassium thiocyanate 20.

Sulfonation reaction

Mixing of 3-(bromoacetyl)coumarins 1 with sodium arene sulfinates 22 in solid state in the presence of few drops of DMF furnished 3-(2-(phenylsulfonyl)acetyl)coumarin derivatives 23 (Scheme 12).[64,65] Furthermore, the reactions of this type were promoted under solvent-free conditions, as reported in literature.[66,67]

Scheme 12

Alkylation of 3-(bromoacetyl)coumarin derivatives 1via sulfinates metal salts 22.

A facile synthesis (E)-styryl sulfones 25a-k was accomplished via the reaction of 3-(bromoacetyl)coumarin derivatives 1 with sodium sulfinates 24 in the presence of polyethylene glycol (PEG-400) for promoting the reaction at ambient temperature (Scheme 13).[68]

Scheme 13

Synthesis of heteryl (E)-styryl sulfone derivatives 25a-k.

Coupling reactions

Coupling buffered solution of 3-(bromoacetyl)coumarin 1 with benzendiazonium chloride 26 yielded the corresponding 3-(2-bromoacetyl)-4-styryl-2H-chromen-2-one 27 (Scheme 14).[69] While the reaction of 3-(bromoacetyl)coumarin 1 with benzenediazonium chloride 26 under the influence of sodium acetate afforded N-phenylacetohydrazonoyl bromide bearing coumarin moiety 28 (Scheme 14).[70]

Scheme 14

Coupling 3-(bromoacetyl)coumarin 1 with benzendiazonium chloride 26.

Trifluoromethylation reaction

Novak and co-workers showed that trifluoromethylation of 3-(bromoacetyl)coumarin 1 with CHF329 derived CuCF3 at room temperature to give 2-trifluoromethylcoumarin 30 in yield 57% (Scheme 15).[71]

Scheme 15

Trifluoromethylation of 3-(bromoacetyl)coumarin 1.

Phosphorylation reaction

3-(Bromoacetyl)coumarin 1 was transformed to 2-oxophosphonates 32 in xylene via Arbuzov reaction conditions with triphenyl phosphite 31 (Scheme 16).[72-75]

Scheme 16

Formation of 2-oxophosphonates 32.

Wang et al. synthesized triphenylphosphonium 34via the treatment of 3-(bromoacetyl)coumarin 1 with triphenylphosphine 33 in benzene or chloroform (Scheme 17).[76]

Scheme 17

Treatment of 3-(bromoacetyl)coumarin 1 with triphenylphosphine 33.

Cyanation reaction

3-(Cyanoacetyl)coumarin 36 was prepared based on cyanation of 3-(bromoacetyl)coumarin 1 by treatment with potassium cyanide (KCN) 35 under ethanolic condition (Scheme 18).[70]

Scheme 18

Treatment of 3-(bromoacetyl)coumarin 1 with potassium cyanide 35.

Reaction with active methylene compound

2-Hydroxy-1-(2-oxo-2H-chromen-3-yl-ethylidene)malononitrile 39 was obtained through Knoevenagel condensation of 3-(bromoacetyl)coumarin 1 with cyanoacetonitrile, 37 in the presence of ammonium acetate 38 (Scheme 19).[70]

Scheme 19

Formation of 2-hydroxy((2H-chromen-3-yl)ethylidene)malononitrile 39.

Synthetic approach toward heterocyclic hybrids

Synthesis of three-membered rings with one heteroatom

Oxirane

Oxirane phosphonates 41 were obtained via Michaelis–Becker reaction of 3-(bromoacetyl)coumarin 1 and dialkyl phosphites 40 using N-benzyl-N,N,N-triethylammonium chloride (BTEAC) as a phase-transfer catalyst (Scheme 20).[77]

Scheme 20

Synthesis of enol phosphate 41.

Synthesis of five-membered rings with one heteroatom

Pyrroles

An efficient synthesis of poly functionalized coumarin bearing pyrrolo[2,1-a]isoquinoline derivatives 44 was achieved via a multi-reaction of 3-(bromoacetyl)coumarin derivatives 1, isoquinoline 42, and dimethyl acetylenedicarboxylate 43 under the influence of triethylamine as catalyst (Scheme 21).[78]

Scheme 21

Synthesis of coumarin bearing pyrrolo[2,1-a]isoquinolines 44.

Pal et al.[79] reported an eco-benign methodology for the preparation of coumarin-pyrrol hybrids 46via three-component reactions of 3-(bromoacetyl)coumarin derivatives 1, an alkyl/arylamine 13, and acetylacetone 45 in the presence of optimized molarity of alum catalyst in water–PEG 400 (Scheme 22).

Scheme 22

MCR of coumarins 1, an alkyl/arylamine 13, and acetylacetone 45.

Pyrrole bis-coumarins 47 as fluorescent probes have been synthesized from the treatment of corresponding 3-(bromoacetyl)coumarin derivatives 1 with aniline 13 under catalytic condition (Zn–I2) (Scheme 23).[80]

Scheme 23

Reaction of corresponding 3-(bromoacetyl)coumarins 1 with aniline 13.

Dihydrofurans

The synthesis of coumarin substituted dihydrofurans 50a-i in good yields was performed via refluxing 3-(bromoacetyl)coumarins 1, dimedone 48, and aromatic aldehydes 49 in a mixture of acetonitrile and pyridine as a solvent containing a catalytic amount of triethylamine (Scheme 24).[81]

Scheme 24

Synthesis of coumarin bearing dihydrofurans.

Thiophenes

Triethylamine-catalyzed heterocyclization of the ketene N,S-acetals 51 with 3-(bromoacetyl)coumarin 1 in ethanol has been employed to synthesize the corresponding 4-amino-2-phenylamino thiophenes 52a-c (Scheme 25).[82]

Scheme 25

Heterocyclization of the ketene N,S-acetals 51.

Treatment of 3-(bromoacetyl)coumarin 1 with sulfur 53 and either malononitrile 37 or ethyl cyanoacetate 54 in the presence of triethylamine furnished the corresponding 2-amino thiophene derivatives 55a and 55b, respectively (Scheme 26).[70]

Scheme 26

Formation of thiophene derivatives 55.

Synthesis of five-membered rings with two heteroatoms

Oxazoles

Eco-friendly approach to accesses 3-methyl-1-(2-(4-(2-oxo-2H-chromen-3-yl)oxazol-2-yl)acetyl)-1H-pyrazol-5(4H)-one 57 was carried out without using any catalyst through the reaction of 3-(bromoacetyl)coumarin 1 with 3-oxopropanamide 56 in ethanol under heating (Scheme 27).[83]

Scheme 27

Synthesis of tetracyclic heterocyclic systems 57.

Imidazole derivatives

A simple one-pot synthesis of novel substituted imidazoles 60 has been accomplished by three-component reaction of 3-(bromoacetyl)coumarin 1, ammonium thiocyanate 58, and phenacyl aniline 59 (Scheme 28).[84]

Scheme 28

Preparation of substituted imidazole derivatives 60.

Boda et al. reported the preparation of fused imidazo[1,2-a][1,8]naphthyridines 62a-g through the solvent-free reaction of 3-(bromoacetyl)coumarin 1 and 2-amino-1,8-naphthyridines 61a-g using 1,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst (Scheme 29).[85]

Scheme 29

Cyclocondensation of compound 1 and 2-amino-1,8-naphthyridines 61.

The coumarin-imidazo[1,2-a]pyrimidine derivatives 64 as pH-sensitive fluorescent compounds were carried out through thermal conventional (CM) or microwave irradiation (MWI) methods. Heating a mixture of 3-(bromoacetyl)coumarin 1 and 2-aminopyrimidine derivatives 63 in the microwave at 200 W at 100 °C afforded corresponding products in yields 5–90% compared by conventional thermal method (5–80%) (Scheme 30).[37]

Scheme 30

Synthesis of coumarin-imidazo[1,2-a]pyrimidines 64.

Rao and Reddy have repeated the cyclocondensation of 3-(bromoacetyl)coumarins 1 with 2-aminothiazoles 5 in refluxing ethanol yielded the corresponding imidazo[2,1-b]thiazol-5-2H-chromen-2-ones 65 (Scheme 31).[86]

Scheme 31

Reaction of bromoacetylcoumarins 1 with thiazole derivatives 5.

3-(2-Cyclohexylimidazo[2,1-b]-[1,3,4]thiadiazol-6-yl)-2H-chromen-2-ones 66a-f was obtained as hydrobromide salt through the reaction of 3-(bromoacetyl)coumarin 1 with 2-amino-5-cyclohexyl-1,3,4-thiadiazole 5 in refluxing ethanol (Scheme 32).[87,88]

Scheme 32

Reaction of 3-(bromoacetyl)coumarin 1 and 1,3,4-thiadiazoles 5.

In refluxing 2-methoxyethanol, the reaction of 6-substituted-3-(bromoacetyl)coumarins 1 with 2-aminobenzo[d]thiazole-6-sulfonamide 5 was achieved, followed by neutralization using ammonia solution afforded corresponding imidazobenzothiazoles 67 (Scheme 33).[89]

Scheme 33

Formation of imidazobenzothiazoles 67.

Pyrazoles

3,5-Dimethylpyrazole derivatives 69 have been prepared through a one-pot multi-component reaction of 3-(bromoacetyl)coumarin derivatives 1, acetylacetone 45, and hydrazine hydrate 68 in refluxing ethanol (Scheme 34).[90]

Scheme 34

Multi-component reaction of the synthesis of 3,5-dimethylpyrazoles 69.

Condensation of 3-(bromoacetyl)coumarin 1 with 3-aminopyrazole 70 within DMF/AcOH yielded the corresponding imidazo[1,2-b]pyrazole 71 (Scheme 35).[91]

Scheme 35

Annulation of imidazo[1,2-b]pyrazole 71.

Using grindstone chemistry, the synthesis of 3-(7-methylimidazo[1,2-a]pyridin-2-yl)-2H-chromen-2-one 73 was achieved through the reaction of 3-(bromoacetyl)coumarin 1 with 2-amino-4-methylpyridine 72 under neat condition and catalyst-free (Scheme 36).[92]

Scheme 36

Synthesis of coumarin bearing imidazo[1,2-a]pyridine 73.

Thiazole derivatives

Gouda disclosed the reaction of 3-(bromoacetyl)coumarin 1 with thioacetamide 74 in methanol under reflux furnished 3-(2-methylthiazol-4-yl)-2H-chromen-2-one 75 (Scheme 37).[93]

Scheme 37

Formation of 3-(2-methylthiazol-4-yl)-2H-chromen-2-one 75.

One of the most successful methods for the synthesis of 3-(2-ethoxythiazol-4-yl)-2H-chromen-2-one 76 is the refluxing 3-(bromoacetyl)coumarin 1 with potassium thiocyanate 20 in ethanol (Scheme 38).[78]

Scheme 38

Synthesis of 3-(2-ethoxythiazol-4-yl)-2H-chromen-2-one 76.

The Hantzsch thiazole synthesis of numerous 2-amino thiazolylcoumarins 78 was accomplished by cyclocondensation of 3-(bromoacetyl)coumarin derivatives 1 with various N-substituted thiourea 77 under various conditions (Scheme 39).[54,94-109]

Scheme 39

Hantzsch route for the synthesis of substituted 2-amino thiazolylcoumarins 78.

Analogously, 4-coumarinylthiazole derivatives 79–85 were efficiently prepared under conventional method or ultrasound irradiation in short reaction and high yields via the condensation of various 3-(bromoacetyl)coumarin derivatives 1 with N-substituted thioamide 74 (e.g. 2,4-thioureido benzenesulfonamide, ethyl thiooxamate, dihydrophthalazine carbothioamide, and pyrazole carbothiamides) in refluxing ethanol or tetrahydrofuran under alkaline condition (sodium acetate and sodium carbonate) (Scheme 40).[110-116]

Scheme 40

Treatment of various 3-(bromoacetyl)coumarins 1 with N-substituted thioamides 74.

3-(Bromoacetyl)coumarin 1 was reacted with the appropriate carbothioamides 86 in DMF in the presence of triethylamine to give the corresponding 3,3′-(thiazole-2,4-diyl)bis-chromen-2-ones 87a,b (Scheme 41).[117]

Scheme 41

Synthesis of 3-(thiazol-2-yl)-2H-chromen-2-ones 87a,b.

New sets of hydrazinyl thiazolyl coumarin derivatives 89–99 were accomplished in high and efficient yield from the one-pot Hantzsch reaction; the proposed mechanism of the reaction involves the cyclocondensation of the appropriate thiosemicarbazones 88 with 3-(bromoacetyl)coumarin 1 under various conditions (Scheme 42).[94,118-127]

Scheme 42

Synthesis of series of hydrazinyl thiazolyl coumarin derivatives 89–99.

Utilizing deep eutectic solvent (DES) and ultrasound for the preparation of 2-oxochroman-3-thiazol-2-hydrazono-indolin-2-one 101via the reaction of 1 with hydrazinecarbothioamide 100 (Scheme 43).[94,128]

Scheme 43

The synthesis of 2-oxochroman-3-thiazol-2-hydrazono-indolin-2-one 101.

The bis(thiazole-4,2-diyl)bis(2H-chromen-2-ones) 103 and 104 were obtained via one-pot cyclisation reaction of bis(hydrazinecarbothioamides) 102 with 3-(bromoacetyl)coumarin 1 (Scheme 44).[94,129]

Scheme 44

Formation of bis(thiazole-4,2-diyl)bis(2H-chromen-2-ones) 103 and 104.

Cyclization reaction of 3-(bromoacetyl)coumarin 1 with thiosemicarbazides 105 in the presence of a catalytic amount of trimethylamine in ethanol yielded thiazolylcoumarin derivatives 106 (Scheme 45).[130]

Scheme 45

Synthesis of thiazolylcoumarin derivatives 106.

Refluxing of 3-(bromoacetyl)coumarin 1 and coumarinothiosemicarbazides 107a-m in methanol containing drops of acetic acid as catalyst gave bis-coumarin–iminothiazole hybrids 108a-m in good yields (Scheme 46).[131]

Scheme 46

Synthesis of bis-coumarin–iminothiazole hybrids 108a-m.

The multi-component reaction of 3-(bromoacetyl)coumarin derivatives 1, phenylisothiocyanates 109a-h with cyanamide 110 in freshly prepared sodium methoxide yielded annulated 3-(4-amino-2-(phenylamino)thiazole-5-carbonyl)-2H-chromen-2-one derivatives 111a-h in moderate yields (Scheme 47).[132]

Scheme 47

The synthesis of (4-aminophenyl-thiazole-5-carbonyl)-2H-chromenones 111.

Novel series of thiazolylcoumarins 114-117 were prepared via multi-component condensation reaction of 3-(bromoacetyl)coumarin derivatives 1 thiosemicarbazide 112 and aldehydes 113 with different substitution patterns (aryl,[133,134] pyrazole,[134] imidazo[1,2-a]pyridine,[135] indole[136]) in ethanol with a catalytic amount of acetic acid (Scheme 48).

Scheme 48

Formation of annulated thiazolylcoumarins 114–117.

New series of coumarin based thiazoles 119a-n were accomplished via mixing of substituted 3-(bromoacetyl)coumarins 1, aldehydes 49, and thiocarbohydrazide 118 in the presence of a catalytic amount of acetic acid in the microwave for 6–8 min (Scheme 49).[137]

Scheme 49

Synthesis of coumarin based thiazoles 119a-n.

Three-component condensation of 3-(bromoacetyl)coumarin derivatives 1, thiocarbohydrazide 118 and aldehyde 120 were carried out under refluxing condition in ethanol in the presence of a catalytic amount of acetic acid to afford novel series of substituted 1,2,3-triazole-hydrazinyl-1,3-thiazole scaffolds 121a-h (Scheme 50).[138]

Scheme 50

Synthetic route for the formation of 1,2,3-triazole-thiazole systems 121a-h.

A water-mediated MCR protocol has been described for the synthesis of thiazolyl coumarins 123 from a three-component reaction of 3-(bromoacetyl)coumarin 1, aldehydes 113 or ketones 122, and thiosemicarbazide 112 catalyzed by montmorillonite K10 clay at ambient temperature (Scheme 51).[139]

Scheme 51

Formation of thiazolyl coumarins 123.

One-pot, synthesis of thiazolylhydrazone derivatives 125a-f through multi-component condensation of 3-(bromoacetyl)coumarin derivatives 1, thiosemicarbazide 112 and 1,3-indandione 124 in refluxing ethanol using a catalytic amount of acetic acid (Scheme 52).[140]

Scheme 52

Synthesis of novel thiazolylhydrazone derivatives 125.

Multi-component synthesis of 3-(2-amino-4-thiazolyl)coumarins 127a-h have been obtained in good yields by refluxing of 3-(bromoacetyl)coumarin derivatives 1, trimethylsilyl isothiocyanate 126, and different primary amines 13 in ethanol (Scheme 53).[141]

Scheme 53

Synthesis of 3-(2-amino-4-thiazolyl)coumarins 127a-h.

The reaction of 3-(bromoacetyl)coumarins 1 with phenylisothiocyanate 128 and aniline derivatives 13 afforded the thiazole derivatives 129a–d (Scheme 54).[70] On the other hand, an efficient three-component synthesis of 2-arylimino-3-thiazolines 131 by the condensation of 3-(bromoacetyl)coumarin derivatives 1, arylisothiocyanates 128, and amine 130 (Scheme 54).[142]

Scheme 54

Synthesis of 2-arylimino-3-thiazolines 129 and 131.

A one-pot multi-component approach involving different substituted of 3-(bromoacetyl)coumarin derivatives 1, phenyl isothiocyanates 128, and p-phenylenediamine 132 in refluxing DMF have been carried out for getting the new series of bis (phenylimino dihydro thiazolyl-2H-chromene) 133 (Scheme 55).[143]

Scheme 55

Preparation of bis (thiazolyl-2H-chromene) systems 133.

Microwave irradiation was reported as a green chemistry method for the synthesis of coumarin-3-yl-thiazol-3-yl-1,2,4-triazolin-3-ones 135 by Shaikh et al.[144]via mixing of 3-(bromoacetyl)coumarin derivatives 1, 1,2,4-triazolone, 134 and aryl isothiocyanate 128 in DMF without using a catalyst (Scheme 56).

Scheme 56

Preparation of poly functionalized heterocyclic hybrids 135.

An efficient synthesis of 3-[2-(arylamino)thiazol-4-yl]coumarins 136a-kvia grinding of 3-(bromoacetyl)coumarin derivatives 1, arylamines, 13 and potassium thiocyanate 20 in the least amount of ethanol as solvent under free catalyst and neat condition (Scheme 57).[109]

Scheme 57

Synthesis of 3-[2-(arylamino)thiazol-4-yl]coumarins 136a-k.

l-Proline catalyzed efficient one-pot three-component route for the synthesis of (2-oxo-2H-chromen-3-yl-thiazol-2-yl)-3-arylacrylonitriles 138a-hvia treating 3-(bromoacetyl)coumarin 1 with numerous aryl/heteryl aldehydes 49 and 2-cyanothioacetamide 137 (Scheme 58).[145]

Scheme 58

Multi-component synthesis of chromen-3-thiazol-2-arylacrylonitriles 138.

Thiazolopyrazolones

A mixture of 3-(bromoacetyl)coumarin derivatives 1, acetophenones 139, and thiosemicarbazide 112 were subjected to a one-pot multi-component Vilsmeier–Haack reaction condition afforded series of substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes bearing coumarin moiety 140 in moderate yields (Scheme 59).[146]

Scheme 59

Vilsmeier–Haack reaction condition for the synthesis of products 140.

4,5-Dihydropyrazolyl–thiazole–coumarin systems 142 were obtained via the reaction of 3-(bromoacetyl)coumarin 1 and 3,5-disubstituted phenyl-4,5-dihydropyrazole-1-carbothioamide 141 in ethanol (Scheme 60).[147]

Scheme 60

Synthesis of 4,5-dihydropyrazolyl–thiazole–coumarin hybrids 142.

5-Hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-4-(coumarin-3-yl)thiazoles 144 were obtained by refluxing of 3-(bromoacetyl)coumarin derivatives 1 with 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides 143 in ethanol (Scheme 61).[148]

Scheme 61

Synthesis annulated 4-(coumarin-3-yl)thiazoles 144.

Synthesis of coumarin-substituted thiazolyl-pyrazolone derivatives 146 was reported by Pavurala et al. via a one-pot reaction of 3-(bromoacetyl)coumarin derivatives 1, thiosemicarbazide 89, aryl aldehyde 49, and ethyl acetoacetate 145 in boiling acetic acid (Scheme 62).[149]

Scheme 62

Synthesis of coumarin bearing thiazol-pyrazolone moieties 146.

Series of pyrazoles bearing coumarin moieties 148 were prepared underwent Hantzsch cyclocondensation of 3-(bromoacetyl)coumarin 1, thiosemicarbazide 112 and various 3-(acetoacetyl) coumarins 147 in refluxing ethanol (Scheme 63).[150]

Scheme 63

Coumarin bearing pyrazole and thiazole hybrids 148.

One pot, three-component reaction of chalcones 149, thiosemicarbazide 112, and different substituted 3-(bromoacetyl)coumarin derivatives 1 in refluxing ethanol containing catalytic amount of aqueous sodium hydroxide was achieved as an effective route for the synthesis of 4,5-dihydro-3,5-diphenylpyrazol-1-thiazol-4-2H-chromen-2-one derivatives 150a-l in one step (Scheme 64).[149]

Scheme 64

Synthesis of binary pyrazol-1-thiazol-4-2H-chromen-2-one derivatives 150a-l.

In the same fashion, Ghodsi et al. have been reported the synthesis of fused substituted thiazolyl-pyrazole-biscoumarin 152 through cyclocondensation of different coumarin chalcones 151, thiosemicarbazide 112, and 3-(bromoacetyl)coumarin derivatives 1 in ethanol in the presence of hydrochloric acid (Scheme 65).[151]

Scheme 65

Formation of (2H-chromen-5-phenyl-1H-pyrazol-thiazol-4-yl) chromenones 152.

Thiazolotriazoles

On the other hand, the reaction of 3-(bromoacetyl)coumarin 1 with 5-phenyl-4H-1,2,4-triazole-3-thiol 153 gave fused thiazolo[3,2-b][1,2,4]triazol-5-chromenone 154 (Scheme 66).[152]

Scheme 66

Treatment of 3-(bromoacetyl)coumarin 1 with 5-phenyl-1,2,4-triazole-3-thiol 154.

Thiazolopyrimidines

Novel fused thiazolo[3,2-a]pyrimidines 156a-g have been obtained in good yields by treatment of 3-(bromoacetyl)coumarin 1 with aryl-3,4-dihydropyrimidin-2(1H)-thiones 155a-g under conventional heating in acetic acid as solvent (Scheme 67).[153,154]

Scheme 67

Synthesis of fused thiazolo[3.2-a]pyrimidine derivatives 156.

The cyclocondensation reaction of 3-(bromoacetyl)coumarin derivatives 1 with 4-phenyl-2-thioxo-indeno[1,2-d]pyrimidinone 157 in boiling acetic acid furnished phenylindeno[1,2-d]thiazolo[3,2-a]pyrimidin-6(5H)-ones 158 in high yields (Scheme 68).[155]

Scheme 68

Synthesis of phenylindeno[1,2-d]thiazolo[3,2-a]pyrimidin-6(5H)-ones 158.

A new version of the Biginelli reaction using new variants was applied for the synthesis of substituted thiazolo[3,2-a]thiochromeno[4,3-d]pyrimidine 160a-d through mixing an equimolar ratio of 3-(bromoacetyl)coumarin 1, thiochromanone 159, substituted benzaldehyde 49a-d and thiourea 77 in one-pot reaction in the presence of [Bmim]HSO4 as a mediated ionic liquid catalyst, leading to the formation of a double electrophilic pyrimidine-2(5H)-thione as an intermediate which cyclized directly to furnish the targeting products 160a-d (Scheme 69).[157]

Scheme 69

One-pot four-component Biginelli reaction.

Thiazoloquinazolines

Biginelli reaction of 3-(bromoacetyl)coumarin 1, aryl aldehyde 49a-j, thiourea 77 and 6-methoxy-1-tetralone 161 in the presence of in poly(4-vinylpyridinium)hydrogen sulfate [P(4-VPH)HSO4] as Brønsted acid catalyst under neat condition afforded aryl-thiazolo[2,3-b]quinazoline derivatives 162a-j (Scheme 70).[156]

Scheme 70

Synthesis of fused thiazolo[2,3-b]quinazoline derivatives 162a-j.

Selenazoles

An efficient synthesis of functionalized selenazoles 164 was achieved via ultrasonic irradiation of 3-(bromoacetyl)coumarin 1 with selenourea 163 at ambient temperature an aqueous medium under ultrasonic irradiation (Scheme 71).[99]

Scheme 71

Formation of 2,4-disubstituted selenazoles 164.

Synthesis of five-membered rings with three heteroatoms

Triazoles

Cu(i)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of 3-(bromoacetyl)coumarin derivatives 1, sodium azide 18, and coumarin propargyl ethers 165 has been employed for the construction of bis-coumarinyl triazoles 166 (Scheme 72).[158]

Scheme 72

Click cycloaddition reaction of 3-(bromoacetyl)coumarins 1a-c.

Synthesis of five-membered rings with four heteroatoms

Tetrazoles

1,5-Disubstituted tetrazole based chromone derivatives 167a-d were synthesized employing four-component condensation of 3-(bromoacetyl)coumarin 1, aldehyde derivatives 49a-d, sodium azide 18, and hydroxylamine 16 in ethanol containing catalytic drops of trimethylamine, the reaction was supported by nanorods of zinc oxide (NRs) and Ag-doped ZnO nanocomposites (NCs) as photocatalysts (Scheme 73).[159]

Scheme 73

Preparation of 1,5-disubstituted tetrazole 167.

Synthesis of six-membered rings with one heteroatom

Pyran derivatives

Mohareb and MegallyAbdo[70] described the preparation of 2-amino-3-cyano-pyran derivatives 168 using three-component reactions of 3-(bromoacetyl)coumarin 1 with malononitrile 37 and aromatic aldehydes 49 in boiling ethanol containing catalytic drops of trimethylamine (Scheme 74).

Scheme 74

Synthesis of 3-cyano-pyran derivatives 168.

Pyridines

On the other hand, repeating the previous reaction using a catalytic amount of ammonium acetate 38in lieu of triethylamine afforded the pyridine systems 169a-d (Scheme 75).[70]

Scheme 75

Formation of pyridine derivatives 169a-d.

Multicomponent condensation of 3-(bromoacetyl)coumarin 1, cyanothioacetamide 137, benzaldehyde derivatives 49 and methyl 4-methyl-3-oxopentanoate 170 led to formation of fused chromeno[3′′,4′′:5′,6′]pyrido[2′,3′:4,5]thieno[3,2-e]pyridine derivatives 171 (Scheme 76).[160]

Scheme 76

Synthesis of pyridines 171.

Synthesis of six-membered rings with two heteroatoms

Fluoroquinolone derivatives

Nucleophilic substitution reactions of fluoroquinolones 172 (GTFX, CPFX, and 8-OCH3CPFX) with 3-(bromoacetyl)coumarin derivatives 1 in dimethylformamide, in the presence of NaHCO3, provide fluoroquinolone derivatives 173 (Scheme 77).[62]

Scheme 77

Formation of various fluoroquinolone derivatives 173.

3-(Quinoxalin-2-yl)-2H-chromen-2-ones

3-(Quinoxalin-2-yl)-2H-chromen-2-ones 175-177 have been synthesized via substituted 3-(bromoacetyl)coumarins 1 and substituted o-phenylenediamines 174 in the presence of a catalyst such as PEG-600 or pyridine or without catalyst through microwave irradiation (Scheme 78).[161-163]

Scheme 78

Synthesis of 3-(quinoxalin-2-yl)-2H-chromen-2-ones 175–177.

Synthesis of six-membered rings with three heteroatoms

Thiadiazin derivatives

One-pot condensation reaction between 3-(bromoacetyl)coumarin 1 and thiocarbohydrazide 118 as bishydrazide in ethanol and in the presence a catalytic amount of acetic acid afforded 2-hydrazino[1,3,4]thiadiazin-5-chromenone 178 (Scheme 79).[164]

Scheme 79

Formation of 3-(2-hydrazino-6H-[1,3,4]thiadiazin-5-yl)-chromen-2-one 178.

Pyrazolyl-thiadiazine derivatives

Refluxing of an equimolar mixture of substituted 3-(bromoacetyl)coumarins 1, acetylacetone 45, and thiocarbohydrazide 118 in ethanol furnished pyrazolyl-thiadiazinyl-2H-chromenones 179a–i (Scheme 80).[165]

Scheme 80

Synthesis of pyrazolyl-thiadiazinyl-2H-chromenone derivatives 179a–i.

Triazolo[3,4-b]thiadiazines

Series of functionalized 4-amino-4H-1,2,4-triazole-3-thiols 180 on reaction with substituted 3-(bromoacetyl)coumarins 1 under simple reaction conditions formed the title products coumarin-substituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids 181–185 in good to excellent yields (Scheme 81).[47,166-1,2,4]Triazolo [3,4-b][1,3,4]Thiadiazin-6-yl)-2H-Chromen-2-Ones. J. Heterocycl. Chem.. 2016 ">169]

Scheme 81

Synthesis of coumarin[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids 181–185.

Triazolo[3,4-b]thiadiazine 187 was produced from the treatment of 3-(bromoacetyl)coumarin 1 with 4-aminotriazole-3-thiol 186 under both conventional and microwave conditions (Scheme 82).[170]

Scheme 82

Formation of triazolo[3,4-b]thiadiazines 187.

Bis coumarinyl bis triazolothiadiazinyl ethane derivatives 189 were synthesized through the reaction of ethane-1,2-diyl bis-4-amino-4H-1,2,4-triazole-3-thiols 188 with different substituted 3-(bromoacetyl)coumarin derivatives 1 in the presence of ethanol solvent (Scheme 83).[165]

Scheme 83

Synthesis of bis coumarinyl bis triazolothiadiazinyl ethane derivatives 189.

A one-pot, multi-component reaction of 3-(bromoacetyl)coumarins 1, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol 190 and various ethyl 2-(2-(aryl)hydrazono)-3-oxobutanoate dervatives 191 in acetic acid in the presence of sodium acetate provide a direct route for the synthesis of corresponding triazolothiadiazinyl-pyrazolone 192a-h (Scheme 84).[171]

Scheme 84

Synthesis of triazolothiadiazinyl-pyrazolone 192a-h.

Pavurala and Vedula[172] disclosed multi-component one-pot synthesis of pyrazolyl triazolo thiadiazinyl chromen-2–ones 193 was achieved via the multi-component reaction of 3-(bromoacetyl)coumarins 1, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol 190 and acetylacetone 45 in absolute ethanol (Scheme 85).

Scheme 85

One-pot synthesis of series of fused pyrazolyl triazolo thiadiazinyl chromenones 193.

Thiadiazinyl-phthalazine-1,4-diones

Rao Chunduru and Rao[173] reported the synthesis of thiadiazinyl-phthalazine-1,4-dione derivatives 195via one-pot condensation reaction of 3-(bromoacetyl)coumarins 1, thiocarbohydrazide 118, and phthalic anhydride 194 in ethanol containing a catalytic amount of acetic acid (Scheme 86).

Scheme 86

Multi-component reaction for the synthesis of thiadiazinyl-phthalazine-1,4-diones 195.

Thiadiazino[2,3-b]quinazolin-6(2H)-ones

An efficient one-pot synthesis of chromenyl[1,3,4]thiadiazino[2,3-b]quinazolin-6(2H)-ones 197 in high yields through cyclocondensation of 3-(bromoacetyl)coumarins 1 with 3-amino-2mercapto-3H-quinazolin-4-one 196 under the conventional and microwave conditions in the presence of potassium carbonate (Scheme 87).[174]

Scheme 87

Synthesis of chromenothiadiazino[2,3-b]quinazolin-6-ones 197.

Applications

Biological activities

3-(Bromoacetyl)coumarins are being employed as privileged building blocks for the production of several bioactive heterocyclic compounds with a broad spectrum of medicinal agents including antibacterial, antifungal, antioxidant, anticancer, anti-inflammatory, anti-hepatocarcinoma, and antiproliferative agents (Table 1). Moreover, many approaches have also been explored for the construction and synthesis of a diverse range of inhibitors of metalloproteinase with significant inhibitory effects. These as a versatile scaffold include, for example, alkaline phosphatase,[131] aldose reductase,[110] alpha-glucosidase,[91] and MMP-13 (ref. 40) inhibitors (Fig. 6).

Examples of a vast array of biologically active molecules towards some diseases

Structures	Activities	Ref.
	Antibacterial activity against: (E. coli, S. aureus and P. aeruginosa)	175
	Antifungal activity against: (A. flavus, C. keratinophilum, and C. albicans)
	Antioxidant activity: (moderate potency in scavenging DPPH radical (approximately 65%)
	Antibacterial activity (zone of inhibition, ZI) against: S. aureus, ZI = 36.8 ± 0.6 mm	176
	• S. mutans, ZI = 25.4 ± 0.5 mm
	• K. pneumoniae, ZI = 27.2 ± 0.5 mm
	• E. coli, ZI = 26.3 ± 0.5 mm
	Anti-influenza A virus H1N1: IC50 = 4.84 μg mL−1 in MDCK cells	108
	Antimicrobial agents: M. tuberculosis (MIC = 15 μM)	177
	Anti-Alzheimeractivity: anti-cholinesterases (IC50 = 43 nM)	178
	Anticancer activity against	144
	• Breast cancer
	• Lung cancer
	• Leukemia
	• Human cervical cancer
	Anticancer activity against human gastric cancer NUGC	70
	• 168a: Ar = 2-furyl, IC50 = 29 nM (against human gastric cancer NUGC)
	• 168b: Ar = 4-Cl-C6H5, IC50 = 89 nM (against MCF)
	Anticancer activity (against MCF-7, HepG2 and SW480 cells): IC50 = 7.5–16.9 μg mL−1	132
	Anticancer activity (against Hela cell line)	146
	• R = 6,8-diCl, R1 = 4-MeC6H4, IC50 = 5.75 μM
	• R = 6,8-diBr, R1 = 4-MeC6H4, IC50 = 6.25 μM
	Anticancer activity (against Melanoma tumor cell line): 55.75% GI	99
	Anti-inflammatory agents: 73–86% of inhibition after 1 h	148
	Antiproliferative activity: IC50 = 10.364 ± 0.270 μM	170
	Anti-hepatocarcinoma activity: IC50 = 2.33 ± 0.004 μM	145

Fig. 6

Representative inhibitors of metalloproteinase with significant inhibitory effects.

Analytical applications

3-(Bromoacetyl)coumarin and 3-bromoacetyl-7-methoxycoumarin were used for the analysis of an emerging contaminant, perfluorinated substances.[179,180] 3-(Bromoacetyl)coumarins are versatile scaffolds with pivotal templates which have a vast array of applications in the field of fluorescent chemosensors towards metal cations, anions, and biomolecules[181-184] (Fig. 7).

Fig. 7

Fluorescent chemosensors towards metal cations, anions, and biomolecules.

Conclusion

This review has illuminated different aspects of 3-bromoacetylcoumarin 1 and its derivatives chemistry up to the beginning of 2021. It implies many sections on the synthesis of bromoacetylcoumarin derivatives. Besides different chemical reactions of bromoacetylcoumarins with various reagents, their biological evaluations and analytical application have been presented. Eventually, we hope that showcasing information accumulated over the years in developing 3-(bromoacetyl)coumarins core ranging from chemistry to applications will supplement the ongoing and forthcoming efforts towards the advancement of new functional molecular materials in the industry, biochemistry, and the environment.

Conflicts of interest

There are no conflicts to declare.