Tetrahedron Letters 55 (2014) 5808–5812

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Tetrahedron Letters

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An efficient protocol for the synthesis of benzoheterocycliccompounds via solid-state melt reaction (SSMR)

http://dx.doi.org/10.1016/j.tetlet.2014.08.0840040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Fax: +91 44 22352494.E-mail address: bhakthadoss@yahoo.com (M. Bakthadoss).

Manickam Bakthadoss a,b,⇑, Raman Selvakumar a, Jayakumar Srinivasan a

a Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, Indiab Department of Chemistry, Pondicherry University, R. V. Nagar, Pondicherry 605 014, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 12 July 2014Revised 22 August 2014Accepted 24 August 2014Available online 29 August 2014

Keywords:Benzoheterocyclic compoundsSolid-state melt reactionAnti-tumor agents

An efficient protocol for the synthesis of biologically active benzoheterocyclic compounds such as benzo-thiazoles, benzimidazoles, benzospirothiazoles, and quinoxaline scaffolds have been accomplished viasolid state melt reaction (SSMR) with excellent yields. The new protocol does not require any catalyst,solvent, and workup. Two anti-tumor agents have been prepared to demonstrate the application of thisnew method.

� 2014 Elsevier Ltd. All rights reserved.

Heterocyclic compounds1 such as benzothiazoles, benzimidaz- derivatives such as benomyl, carbendazim, chlorfenazole, deba-

oles, and quinoxalines are unique and multipurpose scaffolds foractive drug design in pharmaceutical industry. Benzoheterocyliccompounds are found to be an integral part of various naturalproducts, drugs, food flavors, biocides, and industrial chemicals.Some of the benzoheterocycles such as 2-mercaptobenzothiazole,cambendazole, and thiabendazole1c were used as rubber vulcani-zation accelerators. Benzothiazoles are effectively used in multipleways in many industries as rubber additive (2-mercaptobenzothi-azole (MBT)),1d slimicides1e in the paper and pulp industry, fungi-cides,1f,2a herbicides,2b–d and anti-algal agents.3a It has been foundthat the benzothiazole has been distributed in the aroma fractionof tea leaves3b and heated cow’s milk.3c Benzothiazole also occursas a flavor compound produced by the fungi Polyporus frondosusand Aspergillus clavatus.3d Furthermore, benzothiazole is presentin the volatile components of oak wood which is used for agingof wines.3e Other applications of benzothiazole derivatives includethe treatment of Alzheimer’s disease,4a selectively targeting lym-phomas,4b potential breast cancer radiopharmaceuticals,4c efficientsensitizers of europium luminescence,4d and dipole alignment ininorganic–organic hybrid films.4e Due to the above mentioned rea-sons, the chemists are attracted to find newer synthetic methods toaccess them.

Benzimidazole moiety is known for antiviral, antiulcer, antihy-pertension, anticancer,5a,b and anti HIV5c,d activities. Some of thebenzimidazoles are used as vermicides or fungicides as they inhibitthe action of certain microorganisms. For example, benzimidazole

carb, fuberidazole, furophanate, thiabendazole and thiophanateare known for their good action against the fungi or fungal spores.6

Quinoxalines exhibit antiviral,7a antibacterial properties7b andare also used as dyes. Some of the quinoxaline derivatives haveshown very good antitumoral properties.7c Recently, quinoxalineand its analogues have been investigated as a ligand for catalysts.7d

D-Luciferin (I),8a Violatinctamine (II),8b Kealiinine A (III),8c

Liarozole (IV),8d Lumazine (V),8e and Spirobrassinin (VI)8f are natu-ral products which contains the thiazole, imidazole and pyrazinemoieties are shown in Figure 1.

Although a number of methods are available for the synthesis ofbenzoheterocyclic compounds, a literature survey revealed thatthe reported synthetic procedure was not more economical andecologically favorable.9a–h Moreover, there is no general methodavailable for making the important benzothiazoles, benzimidaz-oles, benzospirothiazoles, and quinoxaline scaffolds. Therefore,there is a need for making these privileged scaffolds in an environ-mentally benign and economically viable manner. Based on ourexperience in the solid-state melt reaction (SSMR),10 it occurredto us that there are possibilities for making all these importantmotifs via the solid-state melt reaction.

The solid-state reactions are important not only due to theirhigh efficiency and selectivity but also for their more economicaland eco-friendly procedures involved in the reaction. Therefore,we planned to synthesize privileged benzoheterocyclic compoundsvia solid state melt reaction10 under a catalyst and solvent-freecondition.

In continuation of our interest in the field of heterocyclic chem-istry,11 we herein report a simple, convenient, efficient, novel, and

Table 1Synthesis of benzothiazoles using various aldehydes with 2-(2-(2-aminophenyl)disulfanyl)benzenamine

OC2H5HO

Br

HO

FeN

S

N

S

N

S

N

S4a, 91%d 4b, 95% 4c, 92% 4d, 95%

4e, 97% 4f, 92% 4g, 93%

4h, 92% 4i,96% 4j, 94%

4k, 92% 4l, 91%

4m, 91% 4n, 98% 4o, 95%

4p, 92% 4q, 94% 4r, 93%

NH

N

SNH

N

SNH

N

SO

O

N

S

Cl

ClN

SCl

N

SOMe

OMe

N

SNCl

N

SN

Me

Me N

SOH

N

S

O2NN

SNO2

N

S

MeO

OHHO

S

NN

S

OO

S

NN

S

R CHO1a-r

+2

NH2

S S

H2N

RS

N4a-r 91-98%

melt,180oC, 1h

a All reactions were carried out on a 1 mmol scale of aldehydes (1a–r) with 0.5 mmol of 2-(2-(2-aminophenyl)dis-ulfanyl)benzenamine by melting at 180 �C for 1 h.b Isolated yields of the pure products (4a–r) obtained after washing with ethylacetate and hexane mixture in a 1:49ratio.d The structure of the molecule was further confirmed by single-crystal X-ray data.12

N

N N

N NH

HN

O

O

O

O

OHN

N

N

HN

ClLiarozole (IV) Lumaazine (V)

N

S

N

S

O

OH

HO

D-Luciferin (I)

N

S N

OH

OH

NMe

Me

Violatinctamine (II)

N

NH

HNOMe

OH

OMe

Me

Kealiinine A (III)

NH

S

N SCH3

O

Spirobrassinin (VI)

Figure 1. Representative examples of natural products containing benzoheterocyclic moiety.

M. Bakthadoss et al. / Tetrahedron Letters 55 (2014) 5808–5812 5809

general protocol for the synthesis of benzothiazole, benzimidazole,benzospirothiazole, and quinoxaline scaffolds with excellent yieldsin a catalyst and solvent-free conditions.

To achieve the desired benzothiazole (4a), we have melted 3-ethoxy-2-hydroxybenzaldehyde (1a) with 2-(2-(2-aminophenyl)disulfanyl)benzenamine (2) in a round-bottom flask at 180 �C for

Table 2Synthesis of benzimidazoles using various aldehydes with o-phenylenediamine

RNH

NNH2

NH2

92-97%3

R CHO

5a-g

+

1a,1f-g,1i,1k ,1m, 1s

melt,180oC, 1h

C2H5OOH N

H

O

O

MeO

MeO

N Cl

NH

N

NH

N

NH

N

NH

N

NH

N

5a, 92% 5b, 97% 5c, 92% 5d, 93%

5f, 95%HO OH

NH

NN

NH

5e, 94%

OPh

NH

N

5g, 92%

a All reactions were carried out on a 1 mmol scale of aldehydes (1a, 1f–g, 1i, 1k, 1m, 1s) with 1 mmol ofo-phenylenediamine by melting at 180 �C for 1 h.b Isolated yields of the pure products (5a–g) obtained after washing with ethylacetate and hexane mixturein a 1:49 ratio.

Table 3Synthesis of benzospirothiazoles using isatin derivatives with 2-(2-(2-aminophenyl)disulfanyl)benzenamine

N

SN

O

H

H7a, 87%

N

SN

O

H

Me7b, 85%

N

SN

O

H

Et7c, 82%

N

SN

O

H

7d, 83%

N

SN

O

H

7e, 84%

O HN

S

7f, 86%

N

O

ON

O

SHN

6a-e 7a-e

R1 R1

+

82-87%2

SS

NH2

H2N

melt,160oC, 1h

a All reactions were carried out on a 1 mmol scale of isatin (6a–e)/dimedone (6f) with 0.5 mmol of 2-(2-(2-aminophenyl)disulfanyl) benzenamine bymelting at 160 �C for 1 h.b Isolated yields of the pure products (7a–f) obtained after column chromatography purification (ethylacetate/hexane-5:45 ratio).

5810 M. Bakthadoss et al. / Tetrahedron Letters 55 (2014) 5808–5812

1 h in solvent and catalyst-free condition which successfully affor-ded benzothiazole (4a) in excellent yield (91%).

Encouraged by this result, we have utilized a variety of alde-hydes (1b–r) with 2-(2-(2-aminophenyl)disulfanyl)benzene-amine and successfully obtained the corresponding benzothiazolesin 91–98% yields (Table 1).

After the successful synthesis of benzothiazole, we turned ourattention toward the synthesis of benzimidazole. Treatment ofaldehyde 1a and o-phenylenediamine (3) via solid state melt reac-tion smoothly lead to the desired benzimidazole (5a) in 92% yield.Delighted by this result, we have utilized a variety of aldehydes(1f–g, 1i, 1k, 1m, and 1s) with o-phenylenediamine (3) which suc-cessfully provided the expected benzimidazoles (5b–f) in 92–97%yields (Table 2).

To check the generality of the methodology and its applicabilityto generate the spiro compounds from isatin derivatives (6a–e), we

melted 2-(2-(2-aminophenyl)disulfanyl) benzenamine (2) withvarious isatin derivatives (6a–e)/dimedone (6f) at 160 �C for 1 hunder SSMR condition which smoothly afforded the desired spiro-thiazole oxindole scaffolds (7a–f) in 82–87% yields (Table 3).

To further extend this methodology, we envisaged to accom-plish quinoxaline frameworks. The treatment of diketo/triketocompounds [isatin derivatives (6a–e), acenaphthoquinone (11)and indenetrione (9)] with o-phenylenediamine (3) under solidstate melt reaction condition successfully afforded the quinoxalinescaffolds (8a–e, 10 and 12) in 80–89% yields (Table 4).

To demonstrate the applications and efficiency of this novelprotocol, we have synthesized two important anti- tumoragents12a–c via solid state melt reaction. The synthesis of anti-tumor compounds such as (2-(benzo[d]thiazol-2-yl)benzenamine(13), N-(2-(benzo[d] thiazol-2-yl)phenyl)-4-methylbenzene–sulfonamide (14), and 4-(benzo[d]thiazol-2-yl)benzenamine (15,

Table 5Synthesis of anti-tumor agents

S

NH2N

NHR

S

N

CHO

NHR

15, 93%2

SS

NH2

H2N melt,180oC, 1h

melt,180oC, 1hR = H (13), 91%

Ts (14), 90% CJM126

H2N CHO

Table 4Synthesis of quinoxaline frameworks

NN

N

80-87%8a-e

NH2

NH2

3

+N

O

O

6a-e

R1

melt,160oC, 1h

R1

O

O

O

OO

N

N

N

N

O

NH2

NH23

9

10, 85%

11

12, 89%melt,

160oC, 1hmelt,

160oC, 1h

N

N

NH

8a, 83%

N

N

NMe

8b, 87%

N

N

NEt

8c, 85%

N

N

N

8d, 84%

N

N

N

8e, 80%

N

N

O

10, 85%

N

N

12, 89%

a All reactions were carried out on a 1 mmol scale of keto derivatives (isatin (6a–e), dione (11), and trione (9)) with 1 mmol ofo-phenylenediamine by melting at 160 �C for 1 h.b Isolated yields of the pure products (7a–e), (8a–e), 10, and 12 obtained after column chromatography purification (ethylacetate/hexane-5:45 ratio).

M. Bakthadoss et al. / Tetrahedron Letters 55 (2014) 5808–5812 5811

CJM126)12a–c resulted in 91%, 90%, and 93% yields, respectively byfollowing similar strategy described earlier (Table 5).

In conclusion, we have successfully developed a simple, efficient,and novel protocol for the facile synthesis of bioactive benzohetero-cyclic compounds such as benzothiazoles, benzimidazoles, benzo-spirothiazoles, and quinoxalines via a solid-state melt reaction(SSMR) using a variety of aldehydes, isatin, 2-(2-(2-aminophe-nyl)disulfanyl)benzenamine, and o-phenylenediamine. Remark-ably, all the pure compounds are obtained in excellent yieldswithout workup, also most of the pure compounds are obtainedwithout column chromatography purification. Moreover, thismethod does not require any catalyst as well as solvent, even forsolid reactants. To demonstrate the application of this novel meth-odology, we have also synthesized two anti-tumor agents. Finally,this novel protocol also opens a new opportunity to make a library

of a wide variety of diversified benzoheterocyclic scaffolds for bio-logical screening.

Acknowledgments

We thank DST-SERB for the financial support. We also thankDST-FIST for the NMR facility. R.S. and J.S. thank CSIR for theirSRF.

Supplementary data

Supplementary data associated (1H and 13C NMR spectra for allcompounds) with this article can be found, in the online version, athttp://dx.doi.org/10.1016/j.tetlet.2014.08.084.

5812 M. Bakthadoss et al. / Tetrahedron Letters 55 (2014) 5808–5812

References and notes

1. (a) Marcos, A. P. M.; Clarissa, P. F.; Dayse, N. M.; Lilian, B.; Pablo, M. Chem. Rev.2009, 109, 4140–4182; (b) Paul, B.; Ronald, G.; Visuvanathar, S. Chem. Rev.2002, 102, 2607–2624; (c) Zeringue, H. G., Jr. J. AOAC Int. 1997, 80, 341–344; (d)Santodonato, J.; Davis, L. N.; Howard, P. H.; Saxena, J. Investigation of selEctedPotential Environmental Contaminants: Mercaptobenzothiazoles. Final reportcontract No. 68-01-3128, project No. L1255–06, prepared for EPA Office ofToxic Substances, 1976.; (e) Meding, B.; Toren, K.; Karlberg, A. T.; Hagberg, S.;Wass, K. Am. J. Ind. Med. 1993, 23, 721–728; (f) Schlör, H. Spezieller Teil. Chemicder Fungizide. In Chemieder Pflanzenschutz und Schadlingsbekampfungsmittel,2,Fungizide-Herbizidenatu rliche Pflanzenwuchsstoffe—Ru ckstandsprobleme;Wegler, R., Ed.; Springer: Berlin, 1970; pp 45–172.

2. (a) Scheinpflug, H.; Schloer, H.; Widdig, A. In Chemie der Fungizide; Wegler, R.,Ed.; Springer: Berlin, 1977; pp 120–239; (b) Wegler, R.; Eue, J. In Herbizide;Wegler, R., Ed.; Springer: Berlin, 1970; pp 172–400; (c) Cheng, H. H.; Fuhr, F.;Mittelstaedt, W. Environ. Qual. Saf. Suppl. 1975, 3, 271–276; (d) Wegler, R.; Eue,J. In Herbizide; Wegler, R., Ed.; Springer: Berlin, 1977 (e) Haslam, E. ShikimicAcid Metabolism and Metabolites, John Wiley & Sons: New York, 1993.; (f) Bez,G.; Zhao, C.-G. Org. Lett. 2003, 5, 4991–4993; (g) Periasamy, M.; Srinivas, G.;Bharathi, P. J. Org. Chem. 1999, 64, 4204–4205; (h) Goralski, C. T.; Hasha, D. L.;Singaram, B.; Steiner, D. Org. Process Res. Dev. 2007, 11, 776–779.

3. (a) Bujdakova, H.; Kralova, K.; Sidoova, E. Pharmazie 1994, 49, 375–376; (b)Vitzthum, O. G.; Werkhoff, P.; Hubert, P. J. Agric. Food Chem. 1975, 23, 999–1003; (c) Friedrich, J. E.; Acree, T. E. Int. Dairy J. 1998, 8, 235–241; (d) Seifert, R.M.; King, D. A. J. Agric. Food Chem. 1982, 30, 786–790; (e) Pérez-Coello, M. S.;Sanz, J.; Cabezudo, M. D. Chromatographia 1998, 47, 427–432.

4. (a) Veloso, A. J.; Hung, V. W. S.; Sindhu, G.; Constantinof, A.; Kerman, K. Anal.Chem. 2009, 81, 9410–9415; (b) Carpenter, R. D.; Andrei, M.; Aina, O. H.; Lau, E.Y.; Lightstone, C. F.; Liu, R.; Lam, K. S.; Kurth, M. J. J. Med. Chem. 2009, 52, 14–19;(c) Tzanopoulou, S.; Sagnou, M.; Petsotas, M. P.; Gourni, E.; Loudos, G.;Xanthopoulos, S.; Lafkas, D.; Kiaris, H.; Varvarigou, A.; Pirmettis, I. C.;Papadopoulos, M.; Pelecanou, M. J. Med. Chem. 2010, 53, 4633–4641; (d)Shavaleev, N. M.; Scopelliti, R.; Gumy, F.; Bunzli, J. C. G. Inorg. Chem. 2009, 48,6178–6191; (e) Cui, Y.; Qian, G.; Chen, L.; Wang, Z.; Gao, J.; Wang, M. J. Phys.Chem. B 2006, 110, 4105–4110.

5. (a) Gravatt, G. L.; Baguley, B. C.; Wilson, W. R.; Denny, W. A. J. Med. Chem. 1994,37, 4338–4345; (b) Kim, J. S.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.; La Voie, E. J. J.Med. Chem. 1996, 39, 992–998; (c) Porcari, A. R.; Devivar, R. V.; Kucera, L. S.;Drach, J. C.; Townsend, L. B. J. Med. Chem. 1998, 41, 1252–1262; (d) Roth, T.;Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.; Bukheit, R. W.; Michejda, C. J. J.Med. Chem. 1997, 40, 4199–4207.

6. Zhonghua, M.; Michael, A. Y.; Themis, J. M. Appl. Environ. Microbiol. 2003, 69,7145–7152.

7. (a) Harmenberg, J.; Akesson-Johansson, A.; Griislund, A.; Malmfors, T.;Bergman, J.; Wahren, B.; Akerfeldt, S.; Lundblad, L.; Cox, S. Antiviral Res.1991, 15, 193–204; (b) Naylor, M. A.; Stephens, M. A.; Nolan, J.; Sutton, B.;Tocher, J. H.; Fielden, E. M.; Adams, G. E.; Stratford, I. J. Anticancer Drug Des.1993, 8, 439–461; (c) Jean, R.; Patrick, M. Eur. J. Med. Chem. 1981, 16, 545–550;(d) Xianghong, Wu.; Anne, E.; Gorden, V. J. Org. Chem. 2007, 72, 8691–8699.

8. (a) Presiado, I.; Gepshtein, R.; Erez, Y.; Huppert, D. J. Phys. Chem. A 2011, 115,7591–7601; (b) Chill, L.; Rudi, A.; Benayahu, Y.; Kashman, Y. Tetrahedron Lett.2004, 45, 7925–7928; (c) Lima, H. M.; Sivappa, R.; Yousufuddin, M.; Lovely, C. J.Org. Lett. 2012(9), 2274–2277; (d) Mohamed, S. G.; Caroline, E. B.; Ahmed, S. A.;Gareth, J. V.; Christopher, P. F. R.; Andrea, B.; Jane, L. A.; Simons, C. J. Med. Chem.2011, 54, 2778–2791; (e) Gerard, V.; Silvia, C.; Gijsbert, A.; van der, M.;Wolfgang, P.; Jacques, H.; van, B.; Dmitri, V. F. J. Nat. Prod. 2005, 68, 938–941;(f) Jain, R.; Sharma, K.; Kumar, D. Tetrahedron Lett. 2012, 53, 6236.

9. (a) Patil, A.; Ganguly, S.; Surana, S. Rasayan J. Chem. 2008, 3, 447–460; (b)Gupta, A.; Rawat, S. J. Curr. Pharm. Res. 2010, 3, 13–23; (c) Roy, P.; Binay, K. G.Beilstein J. Org. Chem. 2010, 6, 52; (d) Dowlatabadi, R.; Khalaj, A.; Rahimian, S.;Montazeri, M.; Amini, M.; Shahverdi, A.; Mahjub, E. Syn. Commun. 2011, 41,1650–1658; (e) Allam, Y. A.; Nawwar, G. A. M. Heterocycl. Chem. 2002, 13(3),207–210; (f) Bahrami, K.; Khodaei, M. M.; Naali, F. J. Org. Chem. 2008, 73, 6835–6837; (g) Fei, W.; Shangjun, C.; Zhipeng, W.; Chanjuan, X. Org. Lett. 2011, 13,3202–3205; (h) Liu, S.; Xiangqian, L.; Hui, Z.; Yongwen, J.; Dawei, M. J. Org.Chem. 2011, 76, 4200–4204.

10. (a) Bakthadoss, M.; Sivakumar, G.; Kannan, D. Org. Lett. 2009, 11, 4466–4469;(b) Bakthadoss, M.; Kannan, D. RSC Adv. 2014, 4, 11723–11731; (c) Bakthadoss,M.; Sivakumar, G. Tetrahedron Lett. 2014, 55, 1765–1770; (d) Kaupp, G.;Schmeyers, J.; Kuse, A.; Atfeh, A. Angew. Chem., Int. Ed. 1999, 38, 2896–2899; (e)Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J. L. J. Am. Chem. Soc. 2001,123, 8701–8708; (f) Toda, F.; Tanaka, K.; Iwata, S. J. Org. Chem. 1989, 54, 3007–3009; (g) Alizadeh, A.; Rezvanian, A. C. R. Chimie. 2014, 17, 103–107; (h) Toda,F. Acc. Chem. Res. 1995, 28, 480–486.

11. (a) Bakthadoss, M.; Kannan, D.; Selvakumar, R. Chem. Commun. 2013, 10947–10949; (b) Bakthadoss, M.; Murugan, G. Eur. J. Org. Chem. 2010, 5825–5830; (c)Bakthadoss, M.; Devaraj, A.; Kannan, D. Eur. J. Org. Chem. 2014, 1505–1513; (d)Bakthadoss, M.; Kannan, D.; Sivakumar, G. Synthesis 2012, 44, 793–797; (e)Bakthadoss, M.; Srinivasan, J.; Selvakumar, R. Synthesis 2012, 44, 755–766; (f)Bakthadoss, M.; Sivakumar, N.; Sivakumar, G.; Murugan, G. Tetrahedron Lett.2008, 49, 820–823; (g) Bakthadoss, M.; Murugan, G. Synth. Commun. 2009, 39,1290–1298.

12. (a) Shi, D.-F.; Bradshaw, T. D.; Wrigley, S.; McCall, C. J.; Lelieveld, P.; Fichtner, I.;Stevens, M. F. G. J. Med. Chem. 1996, 39, 3375–3384; (b) Bradshaw, T. D.;Wrigley, S.; Shi, D-F.; Schultz, R. J.; Paull, K. D.; Stevens, M. F. G. Br. J. Cancer1998, 77, 745–752; (c) Bradshaw, T. D.; Shi, D.-F.; Schultz, R. J.; Paull, K. D.;Kelland, L.; Wilson, A.; Garner, C.; Fiebig, H. H.; Wrigley, S.; Stevens, M. F. G. Br.J. Cancer 1998, 77, 421–429.