Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Cascade Synthesis of Benzothieno[3,2‑b]indoles under Oxidative Conditions Mediated by CuBr and tert-Butyl Hydroperoxide Xiaoyuan Zhao,† Qiao Li,† Jun Xu,† Donghua Wang,† Daisy Zhang-Negrerie,† and Yunfei Du*,†,‡ †
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Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China ‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China S Supporting Information *
ABSTRACT: A series of biologically relevant compounds of benzothieno[3,2-b]indole derivatives were conveniently synthesized from reactions of N-protected 2-((2-bromophenyl)ethynyl)anilines and potassium ethylxanthate, mediated by cuprous bromide/tert-butyl hydroperoxide. The method features the construction of the pyrrole and thiophene rings in a cascade sequence with the pyrrole ring being formed prior to the thiophene ring via a possible reactive Cu(III)-pyrrole intermediate.
B
quantitate amyloid deposits in human diseases, including Alzheimer’s disease and Down Syndrome.4 Owing to the diverse therapeutic applications of compounds comprising the benzothieno[3,2-b]indole structural element, much effort has been directed at the problem of constructing this special type of heterocyclic skeleton. Existing methods mainly consist of two fundamentally distinct approaches: in one approach, the indole nucleus is annulated onto substrates already containing the benzothiophene moiety;5−7 in the other, the benzothiophene ring is built onto a preexisting indole derivative.8 As illustrated in Scheme 1, method 1 starts from substituted benzothiophenes and forms the corresponding benzothieno[3,2-b]indoles via a Pd-catalyzed intramolecular cyclization of diarylamines (Scheme 1, method a),5a,b or by subjecting N-containing 2-phenybenzo[b]thiophenes to PPh3,6a Cu,6b,c or microwave6d (Scheme 1, method b), or through coupling reactions between 3-N-aryl benzothiophene and dibromobenzenes through Pd-mediated C−N and C−C bond formations (Scheme 1, method c).7 Method 2, however, uses substituted indole substrates as the starting material and achieves the synthesis of the desired benzothieno[3,2-b]indoles over the course of a tandem cross-coupling reaction of K2S and 2-(2-iodophenyl)-1H-indoles mediated by CuI and I2 and involves a sulfur insertion, as well as C−H and C−I bond cleavages.8 Herein, we describe a third strategy, not resembling either of the mainstream approaches, featuring a spontaneous construction of both N- and S-heterocycles in a copperpromoted transformation of a readily available diaryl alkyne. The discovery of this method was a result of our ongoing effort to directly introduce sulfur into organic compounds by the action of readily accessible sulfur reagents and without
enzothieno[3,2-b]indoles are important objectives for synthesis. Their skeleton has not only been adopted in the engineering of pharmaceutical agents exhibiting useful biological activities but also in polymeric materials possessing promising electronic properties.1−4 Listed in Figure 1 are a few
Figure 1. Representative benzothieno[3,2-b]indole compounds of application values.
examples of such compounds that bear the benzothieno[3,2b]indole structure. BTCN, an unsymmetrically substituted dicyanovinyl heterotetracene compound with extra low-lying LUMO (lowest unoccupied molecular orbital), can be adopted in the design of n-type or bipolar organic semiconductors as organic electronics.1 Compound A, which displays high binding affinities to ERα and ERβ proteins, has been used to mimic the effects of estrogen and can thus be useful in medicinal chemistry for developing new treatments of menopausal symptoms and postmenopausal osteoporosis.2 Compound B has potential to be a surrogate for zoxazolamine, which causes paralysis in young rats by stimulating zoxazolamine hydroxylase synthesis.3 Compound C possesses amyloid-binding properties and may be used to detect and © XXXX American Chemical Society
Received: August 15, 2018
A
DOI: 10.1021/acs.orglett.8b02614 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Reaction Conditions Studya
Scheme 1. Mainstream Strategies for the Synthesis of Benzothieno[3,2-b]indoles and the Method Reported Herein
entry
recourse to stepwise functionalizations of sulfur-containing substrates.9 Sulfur-containing compounds, in addition to their wide applications in biology,10 material science,11 and food chemistry,12 are key constituents of proteins and, therefore, essential to living organisms. Research efforts aimed at developing new synthetic methods to incorporate sulfur atoms into organic compounds are easily justified, especially nowadays with all of the advances in genetic engineering and material science.13 1,2-Diarylethynes have been widely applied for cascaded synthesis of heterocycles.14 Thus, our study commenced with the reaction of N-(2-((2-bromophenyl)ethynyl)phenyl)-4methylbenzenesulfonamide (1a)15 with potassium ethylxanthate in the presence of Cu(OTf)2, in which the Cu(II) was thought to initially act as an oxidant and, subsequently, in the form of Cu(I), as a catalyst. However, to our disappointment, no reaction occurred when the reaction mixture was conducted at 80 °C for 24 h (Table 1, entry 1). To our delight, however, when Cu(CF3COO)2 was employed, the desired benzothieno[3,2-b]indole, 2a, was formed in 17% yield (Table 1, entry 2).16 The yield of 2a decreased when CuBr was employed (Table 1, entry 3). At this stage, we sought an alternative and more effective oxidative system composed of organic oxidants and copper catalysts. Cu(OTf)2, Cu(CF3COO) 2, CuI, CuSCN, and CuBr were tested17 with TBHP as the oxidant. Our results showed that CuBr gave the best yield of 2a (Table 1, entries 4−8). With CuBr as the catalyst, several oxidants, such as phenyliodine(III) diacetate (PIDA), phenyliodine(III) bis(trifluoroacetate) (PIFA), m-chloroperbenzoic acid (mCPBA), and 2,6-di-tert-butylpyridine (DTBP) were screened; however, none of these reagents outcompeted TBHP (Table 1, entries 9−11). When potassium ethylxanthate was replaced by KSCN, S8, K2S, or KSAc, no product formation or low yields were observed (Table 1, entries 12−16). Temperature-
oxidant
catalyst
1
Cu(OTf)2
none
2
Cu(CF3COO)2
none
3
CuBr
none
4
TBHP
Cu(OTf)2
5
TBHP
Cu(CF3COO)2
6
TBHP
CuI
7
TBHP
CuSCN
8
TBHP
CuBr
9
PIDA
CuBr
10
PIFA
CuBr
11
m-CPBA
CuBr
12
DTBP
CuBr
13 14 15 16 17
TBHP TBHP TBHP TBHP TBHP
CuBr CuBr CuBr CuBr CuBr
18
TBHP
CuBr
19
TBHP
CuBr
20
TBHP
CuBr
S reagent KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt KSCN S8 K2S KSAc KSC(S) OEt KSC(S) OEt KSC(S) OEt KSC(S) OEt
temp ( degC)
yieldb (%)
80
NR
80
17
80
11
80
31
80
35
80
50
80
52
80
78
80
65
80
ND
80
24
80
40
80 80 80 80 rt
NR ND ND 18 NR
40
trace
60
70
100
56
a
Reaction conditions: 1a (1 mmol), oxidant (3 equiv), catalyst (0.2 equiv) and S reagent (2 equiv) in DMSO (4 mL). bIsolated yield.
optimization studies identified the ideal temperature to be 80 °C (Table1, entries 17−20). On the basis of all of the screening results, the optimal reaction conditions were concluded to be 1 mmol of substrate, 3 equiv of THBP, 0.2 equiv of CuBr, and 2 equiv KSC(S)OEt with DMSO as solvent at 80 °C. With the optimal reaction conditions established, we investigated the substituent scope of this reaction. Substrates bearing various R1 substituents (Me, F, Cl, Br) were all converted to the corresponding product in good yields (Table 2, 2a−e) except for 2b, the only substrate carrying an electrondonating group among the series, which was formed in a noticeably lower yield in comparison to the other four products. Concerning R2, both the electron-donating (Me, OMe) and electron-withdrawing (F, Cl, Br, CF3) groups were well tolerated, with the corresponding products in most cases all obtained in high yields (2f−k). Lastly, the impact of the substituent on the nitrogen atom (R3) was also evaluated, which involved the use of substrates containing methanesulfonyl (Ms), benzenesulfonyl, and p-OMe, p-Cl-, and p-BrB
DOI: 10.1021/acs.orglett.8b02614 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Scope of Substituentsa
bond in the reaction of study was not initiated by the sulfur moiety, but the nitrogen moiety. A second control experiment, which investigated the reaction of 1a with CuBr in DMSO at 80 °C for 20 min, revealed that Int-2 was formed in 98% yield (Scheme 2, (ii)), providing further support for the postulate that the nitrogen atom initiates the addition to the alkyne. Furthermore, reacting Int-1 with potassium ethylxanthate under the standard conditions led to no benzothieno[3,2b]indole product (Scheme 2, iii), suggesting that formation of the pyrrole ring precedes the formation of the benzothiophene ring. In addition, no benzothieno[3,2-b]indole product was formed when Int-2 was exposed to potassium ethylxanthate under the standard conditions (Scheme 2, iv), implying that intermediate Int-2 is not on the pathway between the diaryl alkyne starting materials and the bis-heterocyclic products in this process. Lastly, inclusion of TEMPO in the reaction mixture did not affect the outcome of the reaction in any significant way (Scheme 2, v), an observation that rules out a radical mechanism for the double annulation process developed in this study. Based on the above results as well as literature reports,9,18 we propose a mechanistic pathway for this novel cascade process for synthesizing benzothieno[3,2-b]indoles from diaryl alkynes. As depicted in Scheme 3, in the presence of copper(I) Scheme 3. Proposed Reaction Mechanism
a
Reaction conditions: 1 (1 mmol), TBHP (3 equiv), CuBr (0.2 equiv) and KSC(S)OEt (2 equiv) in DMSO (4 mL) at 80 °C. b Isolated yield.
substituted benzenesulfonyl as group R3. All substrates afforded the corresponding benzothieno[3,2-b]indole products in satisfactory yields (Table 2, 2l−p). However, when the Ts group in 1a was replaced with a benzyl or methyl group, the corresponding substrates failed to provide the desired cyclized products in each case (not shown). A series of control experiments were carried out to gain insights on the reaction mechanism. When diaryalkyne 3 was subjected to the standard reaction conditions, no formation of 2-phenylthiophene product was observed (Scheme 2, (i)), indicating that the addition across the carbon−carbon triple Scheme 2. Control Experiments for Mechanistic Studies
bromide, 1a undergoes an intramolecular, 5-endo-dig nucleophilic addition of the nitrogen atom to the proximate alkyne, leading to the formation of an indole−copper(I) complex, intermediate A. In the presence of TBHP and potassium ethylxanthate, A may be oxidized to copper(III) intermediate B, which could subsequently undergo reductive elimination of CuBr to give the indole intermediate C.19 Next, the reaction of intermediate C with the ethylxanthate anion could give rise to intermediate D, with the release of bis(ethoxythiocarbonyl)sulfide.20 The reaction of intermediate D with CuBr, for the second time, could then generate Cu(III)complex E via oxidative addition and a simple ligand substitution. From intermediate E, the final carbon−sulfur bond formation would occur in the course of a final reductive elimination with regeneration of cuprous bromide; this final transformation would complete the construction of benzothieno[3,2-b]indole 2a. It is worth mentioning that the p-toluenesulfonyl (Ts) group in the products can be easily removed under basic conditions to afford the unprotected benzothieno[3,2-b]indole, another series of biologically significant compounds. As described in C
DOI: 10.1021/acs.orglett.8b02614 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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Scheme 4, compound 1q could be converted to the biological interesting compound B in a straightforward two-step reaction,
with 2q obtained in 58% yield after applying the newly established method; a final deprotection of the Ts group under basic conditions gave rise to the desired product B in 61% yield. In conclusion, we described a Cu-catalyzed synthesis of benzothieno[3,2-b]indoles from N-protected 2-((2bromophenyl)ethynyl)anilines using TBHP as an oxidant and potassium ethylxanthate as the sulfur source. Convenient deprotection of the Ts group can lead to the synthesis of the unprotected counterpart compounds. A plausible reaction mechanism, supported by a series of control experiments, features two sequential ring closures, with the pyrrole ring being formed prior to that of the thiophene ring. Our efforts to further exploit this direct, new method for synthesizing benzothieno[3,2-b]indoles are underway.
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02614. Experimental procedures, data of compounds characterization (PDF) Accession Codes
CCDC 1851291 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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REFERENCES
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Scheme 4. Application of the Reported Method in the Synthesis of the Biologically Interesting Compound B
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Letter
AUTHOR INFORMATION
Corresponding Author
*Tel: +86-22-27406121. E-mail:
[email protected]. ORCID
Yunfei Du: 0000-0002-0213-2854 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge the National Natural Science Foundation of China (No. 21472136) and the Tianjin Research Program of Application Foundation and Advanced Technology (No. 15JCZDJC32900) for financial support. We also thank Prof. Erik J. Sorensen (Princeton University and Tianjin University) for the helpful suggestions. D
DOI: 10.1021/acs.orglett.8b02614 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters (16) For crystallographic data of compound 2a, see the Supporting Information. (17) (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (b) Reddy, C. R.; Prajapti, S. K.; Ranjan, R. Org. Lett. 2018, 20, 3128. (c) Liu, Y.; Nie, G.; Zhou, Z.; Jia, L.; Chen, Y. J. Org. Chem. 2017, 82, 9198. (d) Aljaar, N.; Malakar, C. C.; Conrad, J.; Strobel, S.; Schleid, S.; Beifuss, U. J. Org. Chem. 2012, 77, 7793. (e) Brassard, C. J.; Zhang, X.-G.; Brewer, C. R.; Liu, P.; Clark, R. J.; Zhu, L. J. Org. Chem. 2016, 81, 12091. (f) Deng, W.; Liu, L.; Guo, Q. X. Chin. J. Org. Chem. 2004, 24, 000150. (g) Wang, Y. F.; Zeng, J. H.; Cui, X. R. Chin. J. Org. Chem. 2010, 30, 181. (h) Wang, M.; Wei, J.-P.; Fan, Q.-L.; Jiang, X. F. Chem. Commun. 2017, 53, 2918. (18) Yu, J.-C.; Zhang-Negrerie, D.; Du, Y.-F. Org. Lett. 2016, 18, 3322. (19) We thank one reviewer for suggesting the synthesis of intermediate C and investigating whether it can be converted to product 2a. However, there is no reported synthetic route to access intermediate C, and our several attempted approaches also proved to be unsuccessful. Further studies are ongoing in our labratory. (20) Castro, E. A.; Meneses, B.; Santos, J. G.; Vega, J. C. J. Org. Chem. 1985, 50, 1863.
E
DOI: 10.1021/acs.orglett.8b02614 Org. Lett. XXXX, XXX, XXX−XXX
