Synthesis and Applications of Benzothiazole Containing Cyanine Dyes

DOI 10.1515/hc-2013-0012 Heterocycl. Commun. 2013; 19(1): 1–11

Review

Maged Henary* , Shirish Paranjpe and Eric A. Owens Synthesis and applications of benzothiazole containing cyanine dyes

Abstract: Heterocyclic compounds are of immense inter- centers joined by a conjugated chain of odd number of est due to their extensive occurrence in nature as well as methine carbons or a conjugated system of double bonds. their applicability in the pharmaceutical industry. Benzo- This polymethine bridge connects an electron acceptor thiazole and its derivatives encompass an attractive heter- group at one end and an electron donor group at the other. ocyclic class that displays practical applications ranging Conjugation between the electron donor and acceptor from medicine to photography and agriculture, among groups results in delocalization of π electrons and hence other things. This review focuses on the synthesis and positive charge over the two nitrogen atoms. specific applications of various benzothiazole cyanine Examples of related cyanine dyes are shown in dyes. Benzothiazole-containing heterocyclic structures Figure 2. Common names of the cyanine dyes are based are prominent throughout the literature and it is very on the number of methine carbons present in the poly- important to acknowledge their efficacy and applicability methine chain. In Figure 2 , the polymethine cyanine dyes as we discuss herein. are designated as mono-, tri-, penta-, and heptamethine cyanines for n = 0, 1, 2, and 3, respectively. The absorp- Keywords: benzothiazole; cyanine dyes; DNA binding; tion/emission wavelengths of the cyanine dyes depend semiconductors; sensitizers; synthesis. upon the length of the polymethine chain and the nature of the terminal groups. The monomethine and trimethine cyanine dyes usually absorb in the visible region (500– 600 *Corresponding author: Maged Henary , Department of Chemistry, nm) of the electronic spectrum with each added (CH = CH) Georgia State University, Atlanta, GA 30303, USA, e-mail: [email protected] methine unit inducing a bathochromic shift of approxi- Shirish Paranjpe and Eric A. Owens: Department of Chemistry, mately 100 nm in the electronic spectrum resulting in Georgia State University, Atlanta, GA 30303, USA an absorption wavelength of 700– 800 nm for penta- and heptamethine cyanines. The 4-pyrilium, 4-thiopyrilium, and benz[c,d ]indolium heterocyclic end groups extend Introduction absorption/emission wavelength well into the near-infrared region, whereas the presence of the benzoxazole end group results in a hypsochromic shift in the electronic Structural characteristics of carbocyanine spectrum. Polymethine cyanine dyes are generally classi dyes fied based on the nature of the end groups present on the polymethine chain. Dyes with two heterocyclic terminal Cyanine dyes are a unique class of compounds that have groups are referred to as closed chain cyanine dyes or a wide range of applications in numerous fields. The first generally referred to as cyanines. The two heterocycles in member of this type was reported by Williams in 1856 [ 1 ]. the cyanines can either be identical or different. Hemicya- The name cyano was given due to the beautiful blue (blue nines are characterized by the presence of one heterocy- – kyano in Greek) color of the dye. This dye was obtained clic and another non-cyclic end group. Dyes without a ter- by treatment of quinoline and 4-methylquinoline with minal heterocyclic moiety are defined as streptocyanines amyl iodide followed by reaction with ammonia. Vogel or open chain cyanines as shown in Figure 2 . in 1873 found that cyanine dyes can be used to increase Cyanine dyes are structurally classified as symmetric sensitivity of the photographic plate [2 ]. It was the turning or asymmetric cyanine dyes as depicted in Figure 3 . These point in the history of the cyanine dyes. symmetric and asymmetric cyanine dyes are quite differ- Cyanine dyes are a subclass of polymethine dyes. As ent with respect to spectral characteristics and nucleic shown in Figure 1, polymethine dyes consist of two nitrogen acid binding behavior [ 3 ]. 2 M. Henary et al.: Benzothiazole containing cyanine dyes

R R Electron N N Electron Synthesis and applications of benzothiazole n Acceptor R R Donor Polymethine cyanine dyes Chain The synthesis of the first benzothiazole cyanine dye was Figure 1 General structure of polymethine dyes. reported in the late 18th century [ 9 ]. It was synthesized by heating N -amylbenzothiazolium iodide and 2-methylbenzothiazole in the presence of ammonia. To date, a large R R R N N N N N N number of symmetric and asymmetric benzothiazole n n n R R R R R R cyanine dyes have been synthesized [10 – 12 ]. Streptocyanine Hemicyanine Cyanine Benzothiazole cyanine dyes are commonly classi- Figure 2 Classification of cyanine dyes. fied into four categories of mono-, tri-, penta-, and heptamethine cyanine dyes. The spectral range for these dyes extends approximately between 450 and 750 nm in the electronic spectrum. In the past few years, many syn- In the literature, it is recognized that in 1926, Koenig thetic routes to benzothiazole cyanine dyes have been identified the chromophoric nature of the polymethine developed. structure of the cyanine dye and reported the synthesis of the first chiral polymethine dye [ 4 , 5 ]. Since then many diffe rent types of cyanine dyes have been synthesized. The first bridged cyanine dye synthesis was published in Monomethine cyanine dyes 1933 where trimethine chain formed a part of cyclopen- tadiene ring [4 ]. In a review by Behera et al., it was dis- Monomethine benzothiazole cyanine dyes typically cussed that some naturally occurring cyanine dyes have absorb in the visible region (450 – 470 nm) of the elec- been isolated from Beta vulgaris and Amanita muscaria tronic spectrum depending on the substituents attached [ 5 ]. Cyanine dyes possess some characteristic properties to the benzothiazole core structure. These dyes are which include structure-dependent photochemical stabil- charac terized by a narrow absorption peak and high ity, narrow absorption band, high molar absorption coeffi- fluorescence intensity. They are best known for their cients (~105 m -1 cm -1 ), tendency to form aggregates in solu- nucleic acid binding properties. The oldest method tion, and relatively high fluorescence intensity. A large for the synthesis of the monomethine cyanine dyes number of cyanine dyes have been synthesized using dif- involves condensation of an N -alkyl-2-(methylthio)ben- ferent heterocycles such as indolenine, quinoline, benzo- zothiazolium salt with another alkylated heterocycle xazole, and benzothiazole. with an activated methyl group [ 13 ]. This method was Benzothiazoles have a planar structure, which is an adopted for the synthesis of β -cyclodextrin functional- essential criterion for nucleic acid binding and hence for ized benzothiazole cyanine dye 1 (Equation 1) [ 14 ]. β - their applications as an effective biological marker [ 6 , 7 ]. Cyclodextrin possesses both a hydrophobic cavity and The use of benzothiazole compounds as in vivo imaging hydrophilic surface and is used for molecular recogni- agents for Alzheimer’ s disease is considered to be a major tion as a drug delivery agent in pharmaceutics [15 ]. The breakthrough for benzothiazole studies [8 ]. medicines containing vitamins are generally unstable to light, heat, and oxygen, whereas the formation of inclusion complexes of vitamins with β -cyclodextrin Symmetrical cyanine dyes Asymmetrical cyanine dyes enhances the stability, solubility, and bioavailability of Me the drug [ 16 ]. Analysis of such inclusion interactions of S Me S S vitamins are commonly conducted by means of spec- N N N N 3 Me trophotometric titration using external agents such as TsO 2 Me Me Me dyes as spectral probes. The incorporation of the dye Me N molecule as host compound provides an option to easily Me Me recognize colorless guest molecules by direct titration. N N S Compound 1 was used to study supramolecular interac- I N tions of β-cyclodextrin directly by visible spectroscopy, TsO Me which is otherwise impossible due to an insufficient Figure 3 Classification of cyanine dyes. chromophore system. M. Henary et al.: Benzothiazole containing cyanine dyes 3

S N 4-chloropyridinium or quinolinium substrate in a basic S N Me Me medium [ 19 ]. This synthetic procedure has been used I Me TsO to synthesize dicationic and tricationic benzothiazole cyanine dyes (Equation 4). In this particular case, the

N S (1) increased cationic charge helps increase water solubility N of the dye. I Me 1 Cl S The synthetic procedure shown above involves a Me major drawback of producing methyl mercaptan, which is N N I Me a toxic pollutant. Researchers have overcome this problem 2Br by developing a new procedure that uses 2-iminobenzothiazoline instead of 2-methylthiobenzothiazolium salt N [ 17 ]. This method can be used to synthesize symmetric and I N asymmetric cyanine dyes. In this procedure, cyanine dyes 1. Et3N, MeOH S N (4) are prepared by melting 2-iminobenzothiazoline with qua- 2. KI ternary heterocyclic salt containing 2- or 4-methyl groups, N as depicted in Equation 2. I Me 4 O2N S NH Several homodimeric benzothiazole cyanine dyes N Me N with polycationic charge on the overall cyanine dye have Me Me MeSO4 been published (Equation 5) [ 20].

O2N I

KI S N (2) S Me N NMe -NH 2 2 3 N N N Me I Me I Me 2

Deligeorgiev et al. described a novel procedure for the synthesis of benzothiazole monocyanines, which involves NS Me S N Me heating a sulfobetaine salt of N -alkylbenzothiazolium compound with the quaternary salt of a heterocyclic com- Me Me Me Me (5) pound containing a reactive methyl group, as illustrated N N N N in Equation 3 [ 18 ]. These reactions are usually carried out 4I without solvent by heating the mixture to approximately 5 150 – 200° C. An alternative route to less thermostable com- Compounds 2 – 4 are structural analogs of the thia- pounds involves heating a solution in polar solvent. This zole orange dye which is used extensively for the purpose synthetic procedure is characterized by high yields and of nucleic acid detection, flow cytometry, and gel elec- short reaction times. trophoresis [ 17 ]. Typically, monomethine cyanine dyes S S display almost negligible fluorescence in aqueous solu- SO3 Me N N tions but show multifold fluorescence enhancement upon Me I Me binding to nucleic acids. This phenomenon can be used to detect nucleic acids in the solution up to certain nanomo- S S (3) lar concentrations. The cationic monomethine cyanine -SO,-HO N 2 2 I N dye molecules with planar aromatic rings typically inter- Me Me calate within the two adjacent base pairs of DNA. It has 3 been observed that increasing cationic charges on the Another approach towards the synthesis of dye molecule results in improved binding to the nega- monomethine cyanine dyes involves condensation tively charged nucleic acids. Homodimeric cyanine dye of N -alkyl-2-methylbenzothiazolium salt with 2- or 5 interacts with nucleic acids by bis-intercalation and 4 M. Henary et al.: Benzothiazole containing cyanine dyes

N Me N Br S S S Me Br MeSO4 Me S S N 2 h, reflux N N Ac2O, Et3N, KI I Br 67 SH

Scheme 1

electrostatic interaction, which provides extra stabiliza- resin support [23 ]. The schematic representation of the tion to the dye-nucleic acid complex [20 ]. Remarkably, solid phase synthesis is presented in Scheme 2. The first cyanine dye 5 exhibits approximately a 40-nm difference step involves the attachment of 2-mercaptobenzothia- between fluorescence maxima in the presence of single- zole to the Merrifield resin. This resin-attached benzo- stranded DNA and double-stranded DNA, which could thiazole is then reacted in the next step with 4-methyl- make it useful to differentiate between both species in benzenesulfonate to yield N -methylbenzothiazolium salt solution. 8 . In the final step, condensation of N- methylbenzothia- A novel method for the synthesis of monomeric zolium salt 8 with carboxylic acid derivative of lepidine asymmetric benzothiazole derivatives, such as 7 (Scheme affords cyanine dye 9 . Traceless cleavage of Merrifield 1), containing mercapto and thioacetyl substituents resin is normally carried out during the course of the syn- has been reported [ 21 ]. Compound 7 could be further thesis of the cyanine dye. The presence of a carboxylic modified as suggested by Ishiguro et al. by linking the acid side chain attached to the quinoline ring makes the mercapto group to oligonucleotides [ 22 ]. This method dye available for post-synthetic modification. Attaching would facilitate in vitro transcription and gene expres- an amino acid to the carboxylic end group and modify- sion studies. The synthetic methodology is depicted ing it with folic acid can be used to identify cancer cells in Scheme 1. The preparation of the dye intermediate that have a folacin acceptor on the cellular surface [23 ]. 6 was carried out by heating under reflux a mixture of The most important feature of the solid phase synthesis 2-methylmercaptobenzothiazole with 1,3-dibromopro- is the elimination of the lengthy purification step of the pane for 2 h. Compound 6 was then allowed to react with conventional liquid phase method, which allows the use 1,4-dimethylquinolinium iodide to furnish dye 7 in 95% of synthesized dyes directly for biological screening. overall yield. Adding another vinyl unit to the central linking chain A new method for the synthesis of benzothiazole gives rise to trimethine cyanines. This class of dyes is dis- monocyanines was developed making use of solid phase cussed in the following section.

S K2CO3 S SH CH2Cl S N AcOEt N

MeOTs

S S N TsO Me 8 COOH Me Br(CH ) COOH 8 S 2 2 Br , KI, Et3N N Me N N N 8h COOH I Me HS 9

Scheme 2 M. Henary et al.: Benzothiazole containing cyanine dyes 5

Trimethine cyanine dyes the molecule could result in a longer lifetime of the final charge separated state, which is similar to the natural Benzothiazole trimethine cyanine dyes absorb in the phenomenon. visible region (550– 570 nm) of the electronic spectrum. A new class of phosphonate labeled trimethine benzo- The classical ortho ester method described by Koenig is thiazole cyanine dyes has been published using the ortho the oldest known method for the synthesis of symmetric ester approach [28 ]. Synthetic methodology for the phos- trimethine cyanine dyes [ 24 ]. The general synthetic pro- phonate labeled cyanine dye starts with the synthesis of cedure involves condensation of a quaternary benzothia- compound 12 which is obtained by heating under reflux zolium salt containing an activated methyl group with an 2-methylbenzothiazole with diethyl 3-bromopropylphos- ortho ester under basic conditions [25 ]. The ortho ester phonate in acetonitrile (Scheme 4). Phosphonate salt 12 approach is illustrated in Scheme 3 by the synthesis of a is then converted to cyanine dye 14 using triethyl orthofor- dumbbell-type [60]-fullerene dimer containing a benzo- mate under basic conditions. Conversion of phosphonate thiazole trimethine cyanine dye 11 [26 ]. The first step of salt to phosphonic acid salt is achieved by acidic hydroly- the synthesis involves attachment of [60]-fullerene to sis, which is used in a further step to synthesize dye 13 . the benzothiazole system, which is achieved by heating The presence of phosphonic acid side chain improves a solution of [60]-fullerene, sarcosine, and 5-formyl-2- the water solubility of the dye. In the deprotonated form, methylbenzothiazole under a nitrogen atmosphere. The cyanine dyes 13 and 14 are pH sensitive calcium probes. resulting compound 10 is then treated with dimethyl Employment of the phosphonate group on the side chain sulfate to generate a quaternary salt, which undergoes makes these dyes potent fluorescent labels in complexa- the coupling reaction with triethyl orthoformate in the tion with biological systems [ 28 ]. next step to yield cyanine dye 11 . Fullerene chemistry is Another approach to the synthesis of benzothiazole a rapidly growing division of material science. C60 dyads trimethine cyanine dyes involves the use of N,N -diphe- have been the focus of much attention in recent years nylformamidine or iodoform as a condensing agent. This due to their applicability in artificial photosynthesis and synthetic method also allows the synthesis of asymmet- molecular electronic devices [26 ]. The natural photo- ric cyanine dyes [ 29 ]. Scheme 5 shows the use of N,N - synthesis involves multistep electron transfer reactions diphenylformamidine for the synthesis of benzothiazole achieved through various electron mediators present in trimethine cyanine dye 16 . Alkylated benzoxazole deriva- the matrix which accomplish long lifetime of the final tive is first treated with N,N-diphenylformamidine in the charge separated state [27 ]. Fullerenes have been widely presence of acetic anhydride to furnish half dye 15 . Com- employed as donor/acceptor molecules in dyads to accel- pound 15 in the next step is condensed with 2,3-dimeth- erate photo-induced charge separation to mimic natural ylbenozthiazolium iodide to yield final asymmetric dye 16 photosynthesis. The presence of two or more C60 units in . Different solvents can be used for the synthesis of

Me S Me N N

S H toluene Me N COOH Me N2, reflux OHC N 10

Me Me N N

1. Me2SO4 S S 2. pyridine, CH(OEt)3, KI N N I Me Me 11

Scheme 3 6 M. Henary et al.: Benzothiazole containing cyanine dyes

pyridine S S CH(OEt)3 N N Br O P O O P O Et Et Et O O 13 Et S Br(CH2)3PO(OEt)2 S Me Me N CH3CN, reflux N Br

O S S Et P O O 1. AcOH-HCl N N Br Et 2. pyridine O 12 CH(OEt)3 P O HO P OH HO OH 14

Scheme 4

S Cl Me Ph Ph N O N N O I Me H H S Me OAc O N N Ac2O N N N I I Ph I Me Me Me Me 15 16

Scheme 5

asymmetric cyanine dyes using the N,N -diphenylforma- N midine approach. The reactions are usually carried out in acetic anhydride but can also be conducted in n -propanol or DMSO at high temperatures for several hours. CHO Park et al. developed novel triazacarbocyanine intra- S Me S 1. piperidine, EtOH molecular charge transfer dye sensor 17 (Equation 6) [ 30 ]. N N 2. NaI, MeOH TsO This dye sensor shows reversible pH induced color switch- Et Et ing effects. Here, a methoxy group acts as a donor group, N whereas the nitro group acts as an acceptor group.

1. HCl, NaNO2 O2N NH2 MeO S 2. S S NH2 (7) N N N MeO Et I Et NO2 18 S (6) N N N N H The pentamethine cyanines are prepared using a similar approach. This class of dyes is discussed next. 17

Equation 7 depicts the synthesis of trimethine cyanine dye with meso substitution in the trimethine chain. The Pentamethine cyanine dyes meso methyl group undergoes condensation reaction with 9-julolidine carboxaldehyde to furnish benzothiazole Pentamethine cyanine dyes generally absorb in the visible derivative 18 [ 31 ]. region (650 – 670 nm) but fluoresce in the near-infrared M. Henary et al.: Benzothiazole containing cyanine dyes 7 region (690– 710 nm) of the electronic spectrum. The clas- tetrakis(triphenylphosphine) palladium(0) to afford com- sical synthetic procedure involves use of bis(phenylimine) pound 23 . This product was alkylated by reaction with hydrochloride of malonaldehyde under basic conditions, methyl iodide in the presence of silver tetrafluoroborate as exemplified in Equation 8 [ 32 , 33 ]. to obtain compound 24 , which on subsequent reaction with 2-fluoromethylbenzothiazole methylene base was Cl transformed into cyclic compound 25 . Alkylation of 25 S PhHN NHPh Me followed by reaction with p -dimethylaminotoluidine fur- N Ac2O or ACN nished pentamethine cyanine dye 26 . It is noteworthy Et N or NaOAc Cl Et 3 that the electronegative fluorine atoms in the pentamethine chain act as electron donating substituents result- S S 26 (8) ing in the shift of absorption maximum for compound N N (691 nm) of 41 nm relative to the non-fluorinated dye. Cl Et Et The synthesis of asymmetric pentamethine ben- 19 zothiazole cyanine dyes can be accomplished utilizing Modification of the trimethine chain in the malo- an aldehyde analog of the benzothiazole moiety [36 ]. naldehyde-derived reagent for the use in synthesis Meguellati et al. adapted the aldehyde strategy to syn- of γ -substituted pentamethine cyanine dye has been thesize the imino pentamethine cyanine dye, as depicted reported, as shown in Scheme 6 [ 34 ]. The new γ -substituted in Scheme 8. These dyes remain stable in the solid state, pentamethine cyanine dyes were synthesized using a whereas in solution within an hour aldehyde and imine three-step procedure. The first step involves synthesis are regenerated [37 ]. Compound 29 was synthesized by of N- pyridinium acetic acid salt 20 by reaction between reacting malonaldehyde bis(phenylimine) hydrochloride 3,5-dimethylpyridine and bromoacetic acid. In the second with a 1,2,3,3-tetramethylindolenine iodide salt. Basic step, compound 20 was formylated in the presence of hydrolysis of the activated hemicyanine derivative 27 in N,N- dimethylformamide and phosphorus oxychloride to sodium hydroxide solution afforded compound 28 in obtain compound 21 . The synthesis of cyanine dye 22 was excellent yield. In the last step, compound 28 was treated carried out by condensation reaction between compound with N -methyl-2-aminobenzothiazolium salt to yield 21 and 2,3-dimethyl benzothiazole tetrafluoroborate in cyanine dye 29 . The cyanine dye 29 is accessible through the presence of sterically hindered Hunig base. The pres- reversible and thermodynamically controlled reaction of ence of the pyridine ring in the pentamethine chain makes amine and aldehyde. the dye more rigid and the cationic charge makes it water A series of benzothiazole fluorophores with substituted soluble. The presence of the pyridinium moiety affects cyclohexene and cyclopentene in the pentamethine chain electron density distribution of the dye molecule. has been described [38 ]. These compounds were studied Benzothiazole cyanine dyes with fluorine substi- as fluorescent probes for nucleic acid and proteins. It is tuted pentamethine chain have been reported (Scheme 7) believed that they act as nucleic acid groove binders. Syn- [35 ]. The Stille reaction was employed in the first step thesis of pentamethine cyanine dyes 34 and 35 containing for coupling of 2-iodobenzothiazole with a fluori- a cyclopentene ring in the pentmethine chain was accom- nated tin reagent in the presence of copper iodide and plished by condensing 2-methylcylcopentane-1,3-diones 30 ,

DMF-POCl Me Me Me Me 3 Me Me BrCH2COOH HBF4 2BF4 N N N Br Me2N NMe2 HOOC 20 21

S Me N S S BF4 Me N N Hunig base Me 2BF4 N Me

Me Me 22

Scheme 6 8 M. Henary et al.: Benzothiazole containing cyanine dyes

S S CF2=CF-CF=CF-SnBu3 S MeI CF=CF-CF=CF I CF=CF-CF=CF2 2 N Pd(PPh3)4, CuI, THF N AgBF4 N 23Me 24 BF4

F S -HF F N Me F F 1. MeI, AgBF , glyme 4 S F F 2. p-MeC H NEt , glyme S F F S 6 4 2 F N S F N N N H BF4 Me F F F Me Me 26 25

Scheme 7

Cl Me NHPh Me O Me Me Me Me PhHN NHPh 10% NaOH Me N N N Ac2O I 27 28 I Me Me Me

S NH2 Me N Me I S Me N N N I Me 29 Me

Scheme 8

31 with quaternary salts of 2-methylbenzothiazolium 32 , the two substrates or by heating in benzonitrile at 120– 33 at 210° C in the presence of triethylamine (Equation 9). 130° C, as illustrated in Equation 10. Compound 36 displays Compound 35 exhibits a 15-fold increase and compound 34 an 8-fold increase in the fluorescence intensity in the pres- displays an 8-fold increase in the fluorescence intensity in ence of RNA, but almost negligible fluorescence changes the presence of DNA. Cyanine dyes 34 and 35 can be further in the presence of DNA. Remarkably, compound 36 exhi- modified to increase their binding interactions with DNA. bits an approximately 26-fold increase in the fluorescence

S 210°C, 30 min intensity in the presence of bovine serum albumin [ 38 ]. It Me 36 O O has been suggested that compound could be used as a N Et3N 1 potential fluorescent probe for other proteins. R TsO R

Me Me 30:R=H 32:R1 =Me 31 S 210°C, 30 min :R=Me 33:R1 =Et Me N Et N MeO OMe 3 Et Me I S S (9) N N Me Me X 1 1 R R S S R (10) N N 34 1 I :R=H;R = Me; X = ClO4 Et Me Et 35:R=Me;R1 = Et; X = Br 36 Synthesis of pentamethine dyes with a cyclohexene ring in the pentamethine chain was achieved by condensation of quaternary salts of benzothiazole containing Heptamethine cyanine dyes an active methyl group with 1,5-dimethoxy-1,4-cyclohexadienes or with 1,3-diethoxy-5,5-dimethyl- or 1,3-dieth- Heptamethine cyanine dyes typically absorb and fluo- oxy-2,5,5-trimethyl-1,3-cyclohexadienes either by melting resce in the near-infrared region (750 – 1100 nm) of the M. Henary et al.: Benzothiazole containing cyanine dyes 9 electronic spectrum. The general synthetic method for apparatus [ 45 ]. The major advantage of using this method the synthesis of benzothiazole heptacyanines with a flex- of synthesis is the elimination of a catalyst and the for- ible polymethine chain involves use of glutaconaldehyde mation of final dye 40 in high yield (Equation 13). Benzo- dianil monohydrochloride as a precursor to the heptame- thiazole cyanine dyes similar to compound 40 can be thine linker [ 39 ]. As shown in Equation 11, a number of additionally functionalized at the meso position by reac- benzothiazole heptamethine derivatives with different tion with various nucleophiles. The products have been substituents at the benzothiazole nitrogen atom have examined as sensitizers for zinc oxide solar cells [ 43]. been synthesized [ 40 , 41 ]. nBuOH/benzene Cl S reflux Me PhHN NHPh S N 2 Me I Et N Et3N I R S Cl S (13) R = Me, Et, Bn, CH2CH2OCOMe N N I Et Et S S (11) 40 N N I R R

37 Applications of benzothiazole cyanine dyes Synthesis of another class of benzothiazole hepta- Several applications of cyanine dyes have already been methine dyes containing five- or six-membered cyclic mentioned above. After the discovery of cyanine dyes, systems as a part of the heptamethine linker makes use their first uses were limited to photographic sensiti zers of the Vilsmeier-Haack reagents [42 , 43 ]. The presence of [46 ]. Other than photography, cyanine dyes now also a carbocyclic ring in the heptamethine chain makes dye find applications in several other fields such as recording more rigid, which helps to increase fluorescence quantum media [ 47 ], laser materials [ 48 ], solar cells [ 49 – 51 ], and yield and decrease aggregation of the dye in solution. semiconductors [ 52 , 53 ]. Vilsmeier-Haack reagents are derived from cyclopen- Cyanine dyes have often been regarded as good silver tanone or cyclohexanone in a two-step procedure, as halide photography sensitizers. A silver halide solution shown in Equation 12. possesses limited sensitivity up to 550 nm but when it is O doped with dye its sensitivity extends up to 650 nm and 1. DMF, POCl3 sometimes even into near-infrared region of the electronic 2. PhNH3Cl, EtOH spectrum. Sensitizer dyes show a bathochromic shift when n added to the silver halide solution by up to 20 – 80 nm. n = 1, 2 Benzothiazole dyes 41 and 42 are typical examples of pho- Cl Cl tographic sensitizers [ 54 ]. PhHN NHPh (12)

n MeO S S OMe 38: n = 1 39: n = 2 N N TsO Et Et

The general methodology for the synthesis of hepta- 41 methine cyanines with a rigid polymethine chain involves Et the condensation of Vilsmeier-Haack reagents 38 or 39 S N Et with a heterocycle containing an activated methyl group N in ethanol in the presence of sodium acetate as catalyst

[44 ]. Another approach for the synthesis of heptamethine SO3 cyanine dyes involves heating under reflux a quater- 42 nary salt of benzothiazole and bis-aldehyde in butanol/ benzene solvent mixture with continuous removal of Another important application of benzothiazole dyes the water from the reaction mixture using a Dean-Stark is their use in recording media. At the beginning, most 10 M. Henary et al.: Benzothiazole containing cyanine dyes available CD-Rs used indolenine based cyanines as the Dye-sensitized solar cells have attracted tremendous recording dyes. With the discovery of the modern DVD-R attention within the past decade; this includes cyanine system, which requires a shorter wavelength laser beam, dyes substituted with heavy metal based complexes as benzothiazole trimethine cyanine dyes were found to be sensitizers in solar cells. Advantages of using cyanine dyes better dyes to obtain appropriate reflection and modula- as solar cell sensitizers include cost efficiency and easy tion of the DVD-R. An important advantage of using tri- recycling of solar cells. Several benzothiazole cyanine methine cyanine dyes is their good chemical stability and dyes such as compound 44 have been synthesized and photostability. Compound 43 is an example of a practical studied for their efficiency towards solar sensitization benzothiazole cyanine dye that is used for the purpose of [ 56 ]. recording media [ 55 ]. S Et S N N Me Br S Me COOH HOOC N N 44 ClO4

Me Me Received January 16, 2013; accepted January 20, 2013; previously 43 published online February 16, 2013

References

[1] Williams, C. Cyanine dyes. Trans. R. Soc. Edinb. 1856 , 21 , 377. S. Specific fluorescent detection of fibrillar α -synuclein using [2] Hamer, F. Mainly introductory. In Chemistry of Heterocyclic mono- and trimethine cyanine dyes. Bioorg. Med. Chem. 2008 , Compounds; Hamer, Frances M., Ed. John Wiley & Sons, Inc.: 16 , 1452 – 1459. Hoboken, NJ, USA, 2008; pp. 1 – 31. [12] Deligeorgiev, T.; Kaloyanova, S.; Vaquero J. Intercalating [3] Armitage, B. Cyanine dye-nucleic acid interactions. In cyanine dyes for nucleic acid detection. Recent Patents Mater. Heterocyclic Polymethine Dyes. Strekowski, L., Ed. Springer: Sci. 2009 , 2 , 1 – 26. Berlin, 2008; Vol. 14, pp. 11 – 29. [13] Brooker, L.; Keyes, G.; Williams, W. Color and constitution. V. [4] Katritzky, A.; Fan, W.-Q.; Li, Q.-L. Bridged cyanine dyes. Part The absorption of unsymmetrical cyanines. Resonance as a 1. 1-(N-methyl-4-pyridinio)-3-(N-methylpyridylene)cyclopenta- basis for a classification of dyes. J. Am. Chem. Soc. 1942 , 64 , 1,4-dienes. J. Heterocycl. Chem. 1988 , 25 , 1311 – 1314. 199 – 210. [5] Behera, G.; Behera, P.; Mishra B. Cyanine dyes: self [14] Zhao, J.-L.; Lv, Y.; Ren, H.-J.; Sun, W.; Liu, Q.; Fu, Y.-L.; Wang, aggregation and behaviour in surfactants. A review. J. Surface L.-Y. Synthesis, spectral properties of cyanine dyes-β - Sci. Technol. 2007 , 23 , 1 – 31. cyclodextrin and their application as the supramolecular host [6] Kovalska, V.; Volkova, K.; Losytskyy, M.; Tolmachev, O.; with spectroscopic probe. Dyes Pigments 2013 , 96 , 180 – 188. Balanda, A.; Yarmoluk, S. 6,6′ -Disubstituted benzothiazole [15] Del Valle, E. Cyclodextrins and their uses: a review. Proc. trimethine cyanines – new fluorescent dyes for DNA detection. Biochem. 2004 , 39 , 1033 – 1046. Spectrochim. Acta A Mol. Biomol. Spectr. 2006 , 65 , 271 – 277. [16] Zhu, X.; Sun, J.; Wu, J. Study on the inclusion interactions of [7] Kaloyanova, S.; Trusova, V.; Gorbenko, G.; Deligeorgiev, β -cyclodextrin and its derivative with dyes by spectrofluorimetry T. Synthesis and fluorescence characteristics of novel and its analytical application. Talanta 2007 , 72, 237– 242. asymmetric cyanine dyes for DNA detection. J. Photochem. [17] Deligeorgiev, T.; Gadjev, N.; Drexhage, K.-H.; Sabnis, Photobiol. A Chem. 2011 , 217 , 147 – 156. R. Preparation of intercalating dye thiazole orange and [8] Klunk, W.; Engler, H.; Nordberg, A.; Wang, Y.; Blomqvist, G.; derivatives. Dyes Pigments 1995 , 29 , 315 – 322. Holt, D.; Bergstr ö m, M.; Savitcheva, I.; Huang, G.-F.; [18] Deligeorgiev, T.; Zaneva, D.; Katerinopoulos, H.; Kolev, V. A Estrada, S.; et al. Imaging brain amyloid in Alzheimer ’ s disease novel method for the preparation of monomethine cyanine with Pittsburgh compound-B. Ann. Neurol. 2004 , 55 , 306 – 319. dyes. Dyes Pigments 1999 , 41 , 49 – 54. [9] Mills, W. LIV. – The cyanine dyes. Part IV. Cyanine dyes of the [19] Deligeorgiev, T.; Zaneva, D.; Kim, S.; Sabnis, R. Preparation of benzothiazole series. J. Chem. Soc. Trans. 1922 , 121 , 455 – 466. monomethine cyanine dyes for nucleic acid detection. Dyes [10] Ogul ’ chansky, T.; Losytskyy, M.; Kovalska, V.; Yashchuk, V.; Pigments 1998 , 37 , 205 – 211. Yarmoluk, S. Interactions of cyanine dyes with nucleic acids. XXIV. [20] Timtcheva, I.; Maximova, V.; Deligeorgiev, T.; Gadjev, N.; Aggregation of monomethine cyanine dyes in presence of DNA Drexhage, K.; Petkova, I. Homodimeric monomethine cyanine and its manifestation in absorption and fluorescence spectra. dyes as fluorescent probes of biopolymers. J. Photochem. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2001 , 57 , 1525 – 1532. Photobiol. B Biol. 2000 , 58 , 130 – 135. [11] Volkova, K.; Kovalska, V.; Balanda, A.; Losytskyy, M.; Golub, [21] Deligeorgiev, T.; Gadjev, N.; Vasilev, A.; Drexhage, K.-H.; A.; Vermeij, R.; Subramaniam, V.; Tolmachev, O.; Yarmoluk, Yarmoluk, S. Synthesis of novel monomeric cyanine dyes M. Henary et al.: Benzothiazole containing cyanine dyes 11

containing mercapto and thioacetyl substituents for nucleic [38] Losytskyy, M.; Volkova, K.; Kovalska, V.; Makovenko, I.; acid detection. Dyes Pigments 2006 , 70 , 185 – 191. Slominskii, Y.; Tolmachev, O.; Yarmoluk, S. Fluorescent [22] Ishiguro, T.; Saitoh, J.; Yawata, H.; Otsuka, M.; Inoue, T.; properties of pentamethine cyanine dyes with cyclopentene Sugiura, Y. Fluorescence detection of specific sequence of and cyclohexene group in presence of biological molecules. nucleic acids by oxazole yellow-linked oligonucleotides. J. Fluoresc. 2005 , 15 , 849 – 857. Homogeneous quantitative monitoring of in vitro transcription. [39] Kharitonova, A. Cyanine dyes. J. Org. Chem. USSR 1992 , 28 , Nucleic Acids Res. 1996 , 24 , 4992 – 4997. 2159–2164. [23] Fei, X.; Yang, S.; Zhang, B.; Liu, Z.; Gu, Y. Solid-phase synthesis [40] Brooker, L.; Smith, L. 1,1′ -Diaralkyl-4,4′ -carbocyanine salts. and modification of thiazole orange and its derivatives and Patent A.l. 2,233,511 1941 . their spectral properties. J. Comb. Chem. 2007 , 9 , 943 – 950. [41] Vompe, A.; Ivanova, L.; Meskhi, L.; Monich, N.; Raikhina, R. [24] Koenig, W. Ü ber Indolenino-cyanine. Ber. Dtsch. Chem. Ges. Reactions of polymethine dyes. I. Synthesis of pseudobases of 1924 , 685. polymethine dyes and their reactions. Zh. Org. Khim. 1985 , 21 , [25] Kabatc, J.; P ą czkowski, J. Three-cationic carbocyanine dyes 584 – 594. as sensitizers in very efficient photo-initiating systems for [42] Ramos, S.; Santos, P.; Reis, L.; Almeida, P. Some new symmetric multifunctional monomer polymerization. J. Polymer Sci. A rigidified triheterocyclic heptamethinecyanine dyes absorbing Polymer Chem. 2009 , 47 , 4636 – 4654. in the near infrared. Dyes Pigments 2002 , 53 , 143– 152. [26] Xiao, S.; Xu, J.-H.; Li, Y.-S.; Du, C.-M.; Li, Y.-L.; Jiang, L.; Zhu, D. [43] Matsui, M.; Hashimoto, Y.; Funabiki, K.; Jin, J.-Y.; Yoshida, Preparation and characterization of a novel dumbbell-type [60] T.; Minoura, H. Application of near-infrared absorbing fullerene dimer containing a cyanine dye. New J. Chem. 2001 , heptamethine cyanine dyes as sensitizers for zinc oxide solar 25 , 1610 – 1612. cell. Synth. Metals 2005 , 148 , 147 – 153. [27] Ohkubo, K.; Kotani, H.; Shao, J.; Ou, Z.; Kadish, K.; Li, G.; [44] Makin, V. Cyanine dyes. J. Org. Chem. USSR 1977 , 13 , 2440 – 2441. Pandey, R.; Fujitsuka, M.; Ito, O.; Imahori, H.; et al. Production [45] Narayanan, N.; Strekowski, L.; Lipowska, M.; Patonay, G. A of an ultra-long-lived charge-separated state in a zinc new method for the synthesis of heptamethine cyanine dyes: chlorin-C60 dyad by one-step photo-induced electron transfer. synthesis of new near-infrared labels. J. Org. Chem. 1997 , 62 , Angew. Chem. Int. Ed. 2004 , 43 , 853 – 856. 9387. [28] Maziè res, M.; Duprat, C.; Bellan, J.; Wolf, J. Synthesis and [46] Tani, T. The present status and future prospects of silver halide characterisation of new phosphonate labelled cyanines. Dyes photography. J. Imag. Sci. Technol. 1995 , 39 , 31 – 40. Pigments 2007 , 74 , 404 – 409. [47] Dai, Z.; Qun, L.; Peng, B. Synthesis and characterization of [29] Shi, Q.-Q.; Sun, R.; Ge, J.-F.; Xu, Q.-F.; Li, N.-J.; Lu, J.-M. some stabilized indocarbocyanine dye complex colorants for A comparative study of symmetrical and unsymmetrical optical recording media. Dyes Pigments 1998 , 36 , 243 – 248. trimethine cyanine dyes bearing benzoxazolyl and [48] Reisfeld, R.; Weiss, A.; Saraidarov, T.; Yariv, E.; Ishchenko, A. benzothiazolyl groups. Dyes Pigments 2012 , 93 , 1506 – 1511. Solid-state lasers based on inorganic-organic hybrid materials [30] Park, J.-Y.; Gwon, S.-Y.; Yoon, N.-S.; Son, Y.-A.; Kim, S.-H. Novel obtained by combined sol-gel polymer technology. Polymers triazacarbocyanine dye sensor synthesis: pH switching effect. Adv. Technol. 2004 , 15 , 291 – 301. Fibers Polym. 2011 , 12 , 976 – 978. [49] Zhang, Q.; Dandeneau, C.; Zhou, X.; Cao, G. ZnO [31] Mitekura, H.; No, T.; Suzuki, K.; Satake, K.; Kimura, M. nanostructures for dye-sensitized solar cells. Adv. Mater. Spectroscopic properties of meso-substituted cyanine dyes: 2009 , 21 , 4087 – 4108. evidences for intramolecular charge transfer from a julolidine [50] Liang, M.; Xu, W.; Cai, F.; Chen, P.; Peng, B.; Chen, J.; Li, Z. New moiety as a meso-substituent to the cyanine chromophore. triphenylamine-based organic dyes for efficient dye-sensitized Dyes Pigments 2002 , 54 , 113 – 120. solar cells. J. Phys. Chem. C 2007 , 111 , 4465 – 4472.

[32] Renikuntla, B.; Rose, H.; Eldo, J.; Waggoner, A.; Armitage, B. [51] Ehret, A.; Stuhl, L.; Spitler, M. Spectral sensitization of TiO2 Improved photostability and fluorescence properties through nanocrystalline electrodes with aggregated cyanine dyes. polyfluorination of a cyanine dye. Org. Lett. 2004 , 6 , 909 – 912. J. Phys. Chem. B 2001 , 105 , 9960 – 9965. [33] Kaur, G.; Zhan, W.; Wang, C.; Barnhill, H.; Tian, H.; Wang, Q. [52] Nasr, C.; Hotchandani, S.; Kamat, P.; Das, S.; Thomas, K.; Crosslinking of viral nanoparticles with “ clickable ” fluorescent George, M. Electrochemical and photoelectrochemical crosslinkers at the interface. Sci. China Chem. 2010 , 53 , 1287. properties of monoaza-15-crown ether linked cyanine dyes:

[34] Mehranpour, A.; Hashemnia, S.; Maghamifar, R. Synthesis and photosensitization of nanocrystalline SnO 2 films. Langmuir characterization of new γ -substituted pentamethine cyanine 1995 , 11 , 1777 – 1783. dyes. Synth. Commun. 2010 , 40 , 3594 – 3602. [53] Tang, X.; Gan, F. Optical storage performance of cyanine-doped [35] Yagupolskii, L.; Chernega, О .; Kondratenko, N.; Chernega, A.; ormosil film. Proc. SPIE Int. Soc. Opt. Eng. 1997 , 3136 , 210–214. Vlasenko, Y.; Nedelkov, R.; Yagupolskii, Y. Synthesis of the first [54] Li, Q.; Lin, G.-L.; Peng B.-X.; Li, Z.-X. Synthesis, representative of dicarbothiacyanine dyes with completely characterization and photographic properties of some new fluorinated polymethine chain. J. Fluorine Chem. 2010 , 131 , styryl cyanine dyes. Dyes Pigments 1998 , 38 , 211 – 218. 165 – 171. [55] Tian, H.; Meng, F. Cyanine dyes for solar cells and optical [36] Nesterenko, Y.; Briks, Y.; Kachkovskii, A.; Tolmachev, A. data storage. In Functional Dyes; Sung-Hoon, K., Ed. Elsevier Synthesis and spectral properties of pyran-based heterocyclic Science: Amsterdam, 2006, pp. 47 – 84. polyene vinylogs. Khim. Geterotsikl. Soedin. 1990 , 2, 252 – 255. [56] Ehret, A.; Stuhl, L.; Spitler, M. Variation of carboxylate- [37] Meguellati, K.; Spichty, M.; Ladame, S. Reversible synthesis functionalized cyanine dyes to produce efficient spectral and characterization of dynamic imino analogues of trimethine sensitization of nanocrystalline solar cells. Electrochim. Acta and pentamethine cyanine dyes. Org. Lett. 2009 , 11 , 1123– 1126. 2000 , 45 , 4553 – 4557.