Copper-catalyzed activation of disulfides as a key step in the synthesis of benzothiazole moieties

Article abstract of DOI:10.1002/ejoc.201000174

A convenient synthesis of substituted benzothiazoles has been accomplished by way of a copper catalyzed reaction of aromatic disulfide amines and aldehydes. The process, which involves copper catalyzed activation of disulfide functionality, proceeds in a

Full text of DOI:10.1002/ejoc.201000174

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000174
Copper-Catalyzed Activation of Disulfides as a Key Step in the Synthesis of
Benzothiazole Moieties
Jakub Hyvl[a] and Jiri Srogl*[a]
Keywords: Oxidation / Copper / C-H activation / Disulfides / Imines / N,S heterocycles / Benzothiazole synthesis
A convenient synthesis of substituted benzothiazoles has
been accomplished by way of a copper catalyzed reaction of
aromatic disulfide amines and aldehydes. The process, which
involves copper catalyzed activation of disulfide function-
ality, proceeds in a tandem fashion via C–H bond activation,
followed by aerobic oxidation of a resulting dihydrobenzothi-
azole intermediate. The scope and limitations of the reaction
are demonstrated on a variety of substrates.
Introduction
Molecules featuring the benzothiazole structural motif
play a key part in a wide variety of chemistries. Their di-
verse functions range from electron transfer facilitation in
the firefly luciferine cycle[1] through antitumor[2] and anti-
diabetic activity[3] to Alzheimer disease tracer[4] and anti-
cancer agent in pharmaceutical chemistry.[5] Their pharm-
aco chemistry in particular has witnessed renewed interest
in the past couple of years,[2–5] which consequently secured
an assortment of various synthetic methods for their prepa-
ration, including, for example, direct arylation of benzothi-
azoles, oxidative or metal-mediated cyclization of thioform-
anilides etc.[6]
Scheme 1. Cu-assisted S–S bond scission.
In order to utilize this novel metal-catalyzed process for
the synthesis of benzothiazoles, dihydrobenzothiazole 3 was
treated with air in the presence of a copper catalyst
(Scheme 2). The cursory experiment resulted in quantitative
conversion of the compound 3 into the benzothiazole prod-
uct 2.
Results and Discussion
Here, we would like to present an additional, highly con-
venient method that allows for the preparation of function-
alized benzothiazole species under mild, neutral reaction
conditions from easily accessible substrates. The centerpiece
of the method is the interaction between a disulfide moiety
and a thiophilic metal – an interaction that enjoys growing
attention in synthetic organic chemistry and biological
chemistry alike.[7] In our previous work, we examined the
origin of the above chemistry in the Cu-catalyzed intra-
molecular oxidation of imines by disulfides under anaerobic
conditions.[8] It was found that the substrate 1 smoothly
transformed, under the above conditions, into the products
2 and 3 in 1:1 ratio, and, based on our experiments, corrob-
orated by the gas-phase data, a concise mechanism of the
transformation was suggested, invloving the C–H bond ac-
tivation as the rate-limiting step (see Scheme 1).
Scheme 2. Aerobic oxidation of dihydrobenzothiazole.
Connecting both, anaerobic condition explored in the
previous study, and the aerobic oxidation of dihydrobezo-
thiazole byproduct 2, we have thus been able to obtain de-
sired benzothiazoles in good to excellent yields.
Focusing on the key step of the mechanism, our previous
study was conducted with the preformed Schiff bases.[8] Ad-
dressing the synthetic objectives we now present a simpli-
fied version of the benzothiazole forming process and use
disulfide amine 4 and aldehyde 5 instead (Scheme 3). Lead-
[a] Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic,
Flemingovo nam. 2, 166 10 Prague 6, Czech Republic
Fax: +420-220183578
E-mail: jsrogl@uochb.cas.cz
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000174.
Scheme 3. Benzothiazole formation.
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J. Hyvl, J. Srogl
SHORT COMMUNICATION
ing to virtually the same yields, the current variation has ever, AcOH proved superior to the others. The influence of
thus shown an equal, if greater synthetic efficiency com- moisture in the reaction media was also examined. While
pared to the previous two step process.
the reaction does not proceed in water itself, water content
To demonstrate the synthetic potential and examine the is not detrimental to the synthetic outcome of the transfor-
synthetic scope of the method various substrates were mation as the solvents were used “as is” without any drying.
treated under the reaction conditions. The results of the in-
vestigation are depicted in Table 1.
Visibly missing from the list of substrates in Table 1 are
aldehydes carrying an alpha hydrogen atom. Although a
few cursory experiments were carried to fill this reactivity
void, they did not lead to the desired reaction outcome for
reasons extensively discussed in the literature.[9]
Table 1. Investigation of the reaction scope.
In analogy with the previous accounts,[7a,8] we suggest
the reaction mechanism is centred around the Cu catalyzed
scission of the S–S bond and the subsequent intramolecular
C–H abstraction. Both, Fehling-like one electron, or two
electron pathways can be involved, as the clear distinction
between the two is, in the open-air system, ambiguous (see
Scheme 4).
Scheme 4. Tentative mechanism of the reaction.
In a set of control experiments we also focused on the
influence of the catalyst on the reaction outcome. From the
variety of copper sources examined [CuI, CuCN, Cu2O,
Cu(OAc)2 and CuI-3-methylsalicylate] leading to virtually
the same results, CuI-3-methylsalicylate was selected as the
catalyst of choice for its solubility in the reaction media.
When, in the separate control experiment, the catalyst was
fully omitted from the reaction mixture, no desired product
was detected.
Conclusions
In conclusion we have presented here a novel synthetic
route to benzothiazoles under relatively mild conditions.
The method is built on copper-catalyzed activation of a di-
sulfide accompanied by C–H bond activation of neighbour-
ing imine functionality. The scope and the limitations of the
process have been demonstrated on the various function-
alized substrates with good to excellent yields.
General procedure: The mixture of aldehyde (0.005 mol)
and amine disulfide (0.0025 mol) in acetic acid (5 mL) was
stirred in presence of CuI 3-methylsalicylate (5%) open to
air and heated to 80 °C.
During optimalization a variety of solvents were ex-
plored (dioxane, THF, toluene, H2O, DMA, AcOH) with
Experimental Section
2,2Ј-Disulfanediyldianiline (0.50 mmol) was dissolved in acetic
acid (2 mL) followed by aldehyde (1.1 mmol) and copper(I) 3-meth-
ylsalicylate (0.025 mmol). The mixture was stirred and heated at
some success. On the basis of the best isolated yield, how- 80 °C for 5 hours open to air. After the reaction was complete, the
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Synthesis of Benzothiazole Moieties
[4] C. Rodrigues-Rodrigues, N. S. de Groot, A. Rimola, A. Alva-
rez-Larena, V. Lloveras, J. Vidal-Gancedo, S. Ventura, J. Vend-
rell, M. Sodupe, P. Gonzalez-Duarte, J. Am. Chem. Soc. 2009,
131, 1436–1451.
mixture was poured into water (75 mL) and the resulting precipi-
tate was collected by filtration. The dry crude product was finally
purified by column chromatography.
[5] S.-T. Huang, I.-J. Hsei, C. Chen, Bioorg. Med. Chem. 2006, 14,
Supporting Information (see also the footnote on the first page of
this article): A complete description of all of the experimental pro-
cedures as well as the characterization of all of the new compounds.
6106–6119.
[6] a) J. Cavinet, J. Yamaguchi, I. Ban, K. Itami, Org. Lett. 2009,
11, 1733–1736; b) D. Subhas Bose, M. Idrees, J. Org. Chem.
2006, 71, 8261–8263; c) K. Inamoto, C. H. Hasegawa, K. Hi-
roya, T. Doi, Org. Lett. 2008, 10, 5140–5150; d) A. J. Blacker,
M. M. Farah, M. I. Hall, S. P. Marsden, O. Saidi, J. M. Wil-
liams, J. Org. Lett. 2009, 11, 2039–2042; e) T. Itoh, T. Mase,
Org. Lett. 2007, 9, 3687–3689; f) T. Itoh, T. Mase, Pure Appl.
Chem. 2008, 80, 707–715; g) N. K. Downer-Riley, Y. A. Jack-
son, Tetrahedron 2007, 63, 10276–10281.
[7] a) N. Taniguchi, J. Org. Chem. 2006, 71,7874–7876; b) R. P.
Houser, J. A. Halfen, V. G. Young, N. J. Blackburn, W. B. Tol-
man, J. Am. Chem. Soc. 1995, 117, 10745–10746; c) S. Itoh, M.
Nagagawa, S. Fukuzumi, J. Am. Chem. Soc. 2001, 123, 4087–
4088; d) Y. Ueno, Y. Tachi, S. Itoh, J. Am. Chem. Soc. 2002,
124, 12428–12429; e) A. J. Blacker, M. M. Farah, M. I. Hall,
S. P. Marsden, O. Saidi, J. M. Williams, J. Org. Lett. 2009, 11,
2039–2042; f) T. Itoh, T. Mase, Org. Lett. 2007, 9, 3687–3689;
g) T. Itoh, T. Mase, Pure Appl. Chem. 2008, 80, 707–715; h)
N. K. Downer-Riley, Y. A. Jackson, Tetrahedron 2007, 63,
10276–10281.
Acknowledgments
The work was generously supported by the Czech Academy of Sci-
ˇ
ences (Z40550506), and a Grantová Agentura Ceské Republiky
(GACR) grant (203/08/1318).
[1] a) E. H. White, F. McCapra, G. F. Field, J. Am. Chem. Soc.
1963, 85, 337–343; b) W. C. Rhodes, W. D. McElroy, J. Biol.
Chem. 1958, 233, 1528–1537.
[2] a) C. G. Mortimer, G. Wells, J.-P. Crochard, E. L. Stone, T. D.
Bradshaw, M. F. G. Stevens, A. D. Westwell, J. Med. Chem.
2006, 49, 179–185; b) M. Chakraborty, K. J. Jin, A. C. Brewer,
H.-L. Peng, M. S. Platz, M. Novak, Org. Lett. 2009, 11, 4862–
4865.
[8] J. Srogl, J. Hývl, A. Révész, D. Schröder, Chem. Commun. 2009,
3463–3465.
[3] M. C. Van Zandt, M. L. Jones, D. E. Gunn, L. S. Geraci, J. H.
Jones, D. R. Sawicki, J. Sredy, J. L. Jacot, A. T. DiCioccio, T.
Petrova, A. Mitschler, A. D. Podjarny, J. Med. Chem. 2005, 48,
3141–3152.
[9] M. R. Crampton, S. D. Lord, R. Millar, J. Chem. Soc. Perkin
Trans. 2 1997, 909–914.
Received: February 6, 2010
Published Online: April 20, 2010
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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