Letter Cite This: Org. Lett. 2018, 20, 6318−6322
pubs.acs.org/OrgLett
Furo[2,3‑g]thieno[2,3‑e]indole: Application of an Ynamide-Based Benzannulation Strategy to the Synthesis of a Tetracyclic Heteroaromatic Compound Clarissa C. Forneris, Yu-Pu Wang, Galina Mamaliga, Thomas P. Willumstad, and Rick L. Danheiser* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
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ABSTRACT: The first synthesis of the tetracyclic aromatic compound furo[2,3-g]thieno[2,3-e]indole (“FTI”) is described. The synthetic strategy features a photochemical benzannulation based on the reaction of an α-diazo ketone and ynamide which assembles a benzothiophene equipped with substituents that enable subsequent cyclizations to generate the nitrogen and oxygen heterocyclic rings.
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synthesis of furo[2,3-g]thieno[2,3-e]indole (“FTI”, 4), a tetracyclic heteroaromatic compound whose structure incorporates three dif ferent heterocyclic rings. Two general strategies have been deployed in previous syntheses of tetracyclic compounds of type 1. One approach begins with the synthesis of a 1,3,5-triheterosubstituted benzene and employs substitution and cyclization steps to generate the desired tetracycle. An alternative strategy starts with the assembly of a linear array of three heteroaromatic rings via condensation or cross-coupling reactions and then utilizes oxidative 6-π photocyclization13 to generate the tetracyclic system. These approaches can be quite effective for the construction of symmetrical molecules, but are less well suited for unsymmetrical targets such as 4. For the efficient synthesis of furo[2,3-g]thieno[2,3-e]indole, we turned to the benzannulation14 strategy previously developed in our laboratory.15 This powerful method for the regiocontrolled synthesis of multiply substituted benzenes involves the reaction of an alkyne with a vinylketene16 generated in situ either by electrocyclic ring opening of a cyclobutenone or by the photochemical Wolff rearrangement of an α-diazo ketone. Although operationally the benzannulation involves a single synthetic step, mechanistically it proceeds via a “cascade”17 involving up to four discrete pericyclic processes. Scheme 1 outlines the mechanism of the benzannulation for the case involving an α-diazo ketone (5) as a vinylketene precursor and ynamide derivative (6) as the ketenophilic reaction partner. Irradiation of the diazo ketone serves as the triggering step for the cascade, effecting photochemical Wolff rearrangement to produce the transient vinylketene intermediate 8. This vinylketene is immediately intercepted by the ynamide reaction partner in a regioselective [2 + 2] cycloaddition that affords a 4-vinylcyclobutenone, 9. Under the conditions of the reaction,
olycyclic systems in which three heteroaromatic rings are arrayed around a central benzene core have attracted much attention from researchers interested in aromatic systems with desirable electronic and materials properties.1 Molecules of type 1 serve as synthetic building blocks for the construction of “star-shaped” polycyclic aromatic compounds with diverse applications (Figure 1).2 Most research to date
Figure 1. Tetracyclic heteroaromatic compounds.
has focused on the most easily synthesized symmetrical systems (1, X = Y = Z), particularly the well-known tetracyclic compound benzotrithiophene (2).3 Benzotrithiophene and its derivatives have been investigated for applications such as photovoltaic cells,4 supramolecular assemblies,5 liquid crystals,6 and field-effect transistors.7 Recently increased attention has been focused on the synthesis and investigation of the chemistry of benzotrifurans (1, X = Y = Z = O),8 benzotripyrroles (1, X = Y = Z = NR),9 the related triindoles (“triazatruxenes”),10 and their derivatives. To our knowledge, however, dithienoindole 3 is the only previous example of a molecule of this type whose structure includes more than one kind of heterocyclic ring.11,12 Herein, we report the first © 2018 American Chemical Society
Received: September 12, 2018 Published: September 26, 2018 6318
DOI: 10.1021/acs.orglett.8b02920 Org. Lett. 2018, 20, 6318−6322
Letter
Organic Letters
oped in our laboratory. While the known α-diazo ketone 14 has been prepared by reaction of the corresponding acyl chloride with diazomethane,19 we chose to generate 14 by application of our detrifluoroacetylative diazo transfer protocol20,21 to commercially available 2-acetylthiophene. For the synthesis of ynamide 18, we employed the N-alkynylation strategy pioneered in our laboratory22 and the laboratory of Hsung.23 Both methods involve the reaction of amine derivatives with alkynyl bromides, which are themselves readily obtained from terminal alkynes by reaction with NBS in the presence of catalytic silver nitrate.24 Thus, exposure of terminal alkyne 1618,25 to the action of NBS afforded the corresponding alkynyl bromide which reacted with N-allyl carbamate 17 using the Hsung protocol to furnish the ynamide benzannulation partner 18 in good yield (eq 1).
Scheme 1. Pericyclic Cascade Mechanism of the Vinylketene-Based Benzannulation
As outlined in Scheme 3, the key benzannulation step was achieved by irradiating a degassed solution of ynamide 18 and
this intermediate undergoes reversible 4-electron electrocyclic ring opening to generate the dienylketene 10, which rapidly cyclizes via a 6-π electrocyclic ring closure to furnish the desired benzannulation product 7 after tautomerization. Scheme 2 outlines our retrosynthetic plan for the application of this variant of our vinylketene-based benzannulation to the
Scheme 3. Construction of the Tetracyclic System
Scheme 2. Retrosynthetic Plan for Synthesis of FTI
synthesis of FTI. Use of the diazo derivative of 2acetylthiophene (14) would furnish a benzothiophene annulation product with the requisite 1,3,5 relationship of oxygen, nitrogen, and sulfur substituents on the benzenoid ring. For the alkyne reaction partner, we selected the ynamide 15 which incorporates two latent formylmethylene (CH2CHO) substituents. Sequential unveiling of the aldehyde moieties would allow for successive cyclization reactions to generate the remaining two heterocyclic rings. The nitrogen heterocycle would be formed under the basic conditions developed in our previous application of the benzannulation strategy to the synthesis of highly substituted indoles,18 and the furan ring would then be generated by cyclization under acidic conditions. Synthesis of the requisite benzannulation partners was conveniently accomplished using methods previously devel-
1.2 equiv of diazo ketone 14 with a 450-W medium-pressure Hanovia lamp until TLC analysis indicated complete consumption of the diazo ketone.26 At that point the reaction mixture consisted of the desired phenolic annulation product and some intermediate vinylcyclobutenone (i.e., 9 in Scheme 1). As we have noted in prior photochemical benzannulations, the buildup of colored polymers on the walls of the reaction tube sometimes impedes the complete conversion of vinylcyclobutenone to product even on prolonged irradiation. In these cases we simply heat the crude product in toluene to complete the conversion of all intermediates to phenol. In this reaction we also found it essential to employ strictly anhydrous conditions for the photochemical benzannulation.27 If present, trace amounts of water can intercept the ketene intermediates 6319
DOI: 10.1021/acs.orglett.8b02920 Org. Lett. 2018, 20, 6318−6322
Letter
Organic Letters
key reagent. As outlined in Scheme 4, reaction of 22 with excess Me3SiOTf and HMDS in dichloromethane at room
to generate carboxylic acids that catalyze undesired reactions at the acetal moiety. At this point the product of the benzannulation reaction (19) was subjected to column chromatography to furnish material of 90−95% purity. Protection of the phenolic hydroxyl as the TBDMS ether was then carried out under standard conditions to afford the silyl ether 20 in 55−57% overall yield for the two steps beginning with ynamide 18. Protection of the phenolic hydroxyl group was necessary to prevent attack on the methyl acetal moiety during the subsequent oxidative cleavage step. Since a free phenolic hydroxyl group is required for the base-promoted cyclization that generates the indole system, it was important to avoid such premature formation of the cyclic acetal. A silyl group was selected as the protective group anticipating that deprotection could later be effected in the same operation as the base-promoted cyclization step. Oxidative cleavage of the terminal alkene was best achieved under modified Lemieux−Johnson conditions28 and furnished the desired aldehyde 21 in good yield. Our original plan for generation of the nitrogen heterocyclic ring called for treatment of the phenol corresponding to 21 with K2CO3 or DBU followed by addition of HCl, conditions developed in our previous application of the benzannulation to the synthesis of highly substituted indoles.18 Unfortunately these conditions provided the desired indole in poor yield. After considerable experimentation, we were able to devise a protocol that achieved cleavage of the silyl ether and formation of both the nitrogen and oxygen heterocyclic rings in an efficient one-flask operation. The success of this process required the careful choreography of reagent additions according to the protocol outlined in Scheme 3. First, exposure of 21 to the action of 1.1 equiv of TBAF in isopropanol at room temperature for 90 min effected silyl ether cleavage, after which excess K2CO3 was added to the reaction mixture which was then heated at 40 °C. The use of isopropanol is crucial, as cleavage of the carbamate was observed when methanol was employed as solvent. After heating for 2 h, the product consisted of a mixture of the hydroxyindoline from cyclization of the aldehyde and the corresponding indole resulting from elimination of water from this intermediate. Addition of anhydrous HCl in methanol then completed the elimination and also brought about transacetalization to form the oxygen heterocyclic ring. Under the initial conditions employed, however, the product 22 was found to be contaminated with 20−50% of a byproduct formed by acid-catalyzed acetal exchange with the isopropanol solvent. This byproduct, the isopropyl acetal corresponding to 22, was difficult to separate and was resistant to elimination in the next step in the synthesis. Fortunately, the formation of this byproduct could be suppressed simply by diluting the reaction mixture with methanol before the addition of HCl. The optimized one-pot “double cyclization” protocol provided tetracycle 22 in excellent yield with
