Radial hexadehydro-Diels-Alder reactions

SUMMARY

Polycyclic, highly fused and, perforce, highly conjugated aromatic organic compounds (PACs) have been of interest to chemists since the discovery of naphthalene in 1821. In modern decades these have attracted ever-growing attention because of their architectures, properties, and wide-ranging practical applications (cf. The Bigger Picture). Given the unabated interest in such molecules, the development of new methods and strategies for the practical synthesis of PACs having new structural motifs is important. Here we describe one-pot, purely thermal cyclizations of substrates containing sets of independent triynes, each arrayed upon a common core structure. This produces topologically unique products through sequential generation/trapping of a series of benzyne intermediates. More specifically, these all conform to processes that can be considered as radial-hexadehydro-Diels-Alder (HDDA) reactions. The late-stage and de novo creation of multiple arenes in these multi-benzyne processes constitutes a fundamentally new synthetic strategy for constructing novel molecular topologies.

Graphical Abstract

eTOC blurb

Polycyclic, highly fused/conjugated aromatic organic compounds (PACs) have intrigued chemists since the discovery of naphthalene in 1821. Given the unabated interest in such molecules, the development of new methods and strategies for the practical synthesis of PACs having new structural motifs is important. Here we describe one-pot, purely thermal cyclizations of substrates containing multiple sets of independent triynes, each arrayed upon a common core structure. This produces topologically unique products through sequential generation/trapping of a series of benzyne intermediates.

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INTRODUCTION

Polycyclic aromatic compounds (PACs), of which polycyclic aromatic hydrocarbons (PAHs) are a subset, include both all-carbocyclic as well as mixed carbo- and heterocyclic subunits. These have attracted considerable attention as novel molecules having new properties and/or functions¹ or to serve as precursors to new graphitic materials, including nanotubes and belts.^2,3 Benzyne/aryne chemistry⁴ has been utilized by researchers as a strategy for the synthesis of various classes of arenes.^5,6,7 Reactive benzyne (and aryne) intermediates have long been recognized for the versatile array of products they can afford when produced in the presence of suitable, in situ trapping agents. The thermal (or photochemical⁸) intramolecular cycloisomerization of substrates containing a conjugated 1,3-butadiyne and a tethered third alkyne (the diynophile) produces benzyne intermediates^9,10 (cf. multi-yne to benzyne (n = 1) in Figure 1A); we have termed this process the hexadehydro-Diels-Alder (HDDA) reaction.¹¹

Figure 1. Generic radial-HDDA reactions.

(A) A general formulation of the sequential polycyclization of multi-ynes containing two to six independent, tethered triyne units; the benzyne from each successive cycloisomerization event is rapidly captured by an in situ trapping agent to produce elaborated benzenoid products (gray balls). (B) General structural representations of the products arising from bi-, tri-, tetra-, and hexa-HDDA cyclization/trapping events. HDDA, hexadehydro-Diels-Alder

HDDA chemistry has served as a platform for new strategic developments. Examples include the pentadehydro-DA,¹² domino-HDDA,¹³ and aza-HDDA¹⁴ reactions. We now show that radial-HDDA reactions, related in part to the strategy of “expanding [polyphenylenes] in all directions,”¹⁵ constitute a new facet of this chemistry. Our studies were designed to establish the principles of this process rather than being motivated by targeting a particular set of structures or structural classes. We considered what opportunities might arise by studying substrates having two (or more) independent sets of triyne units that react in, for example, a double-, triple-, quadruple-, or sextuple-barreled fashion (n = 2, 3, 4, or 6; Figure 1B). All these potential multi-yne substrates share the common feature of being templated on and, therefore, radiating from a central aromatic core (blue). We show here that modification of the number of triyne units gives rise to an array of substrates that readily lead to structurally complex PACs in a single operation.

RESULTS and DISCUSSION

Conventions, Preliminary Considerations, and Terminologies.

In this document we have used Roman numerals to indicate presumed intermediates (or transition structures) in a reaction transformation and Arabic numerals for structures of isolable (and characterized) substances. The preparation of all multi-yne substrates is detailed in the Supplementary Information (SI). Because of their inherent symmetry, those with a greater number of triyne subunits are generally no more difficult to synthesize than their simpler analogs. For example, each of the multi-ynes 1, 3, and 5 is made in five reactions (four linear) from bromobenzaldehyde starting materials. Procurement of the yet higher-ynes is similarly straightforward. In reticular chemistry, the term “topicity” is used to describe the number of points of extension in the building units of MOFs or COFs: that is ditopic, tritopic, tetratopic, etc.¹⁶ Similarly, we use here bi-, tri-, tetra-, and hexa-prefixes to denote the topicity of the multi-yne substrates and their respective products.

A mono-HDDA reaction.

The thermal conversion of 1¹⁷ to 2 in the presence of furan via the benzyne intermediate I constitutes a prototypical mono-HDDA reaction (Figure 2A). There are now dozens of examples of this mono-HDDA process.^18,19,20 The tether between the diyne and diynophile in substrates is nearly always a three-atom linking unit (black dots).

Figure 2. Mono- and bi-HDDA reactions.

(A) A mono-HDDA reaction using furan as the benzyne trap. (B) An “outside-in” bi-HDDA reaction using TPCPD as the trapping reagent; the intermediate bicyclic ketone (not shown) ejects carbon monoxide to provide the aromatized naphthalene derivative under the thermal reaction conditions. (C) An “inside-out” bi-HDDA reaction using TMS-azide as the trapping reagent; the labile TMS group is lost during workup/purification; the desilylated compound 6 was isolable (see Supplemental Information). Note that the three-atoms of the tether (see black dots) are either remote from vs. part of the benzene core in the “outside-in” vs. “inside-out” delineations of these topologically complementary processes. TMS, trimethylsilyl; TPCPD, tetraphenylcyclopentadienone; DA, Diels-Alder; n-hex, normal-hexyl.

Bi-HDDA reactions.

Two complementary types of bi-HDDA reaction can be envisioned: an “outside-in” (Figure 2B) or an “inside-out” (Figure 2C) motif. These differ by the relative orientation of the tether with respect to the central core. Namely, in the hexayne 3 the tethering atoms are remote from that core, whereas in hexayne 5 core atoms make up part of the tether (cf. black dots in 3 vs. 5). An example of the “outside-in” bi-HDDA process is demonstrated by the efficient conversion of hexayne 3 to the bis-fluorenone 4a upon heating 3 in the presence of tetraphenylcyclopentadienone (TPCPD).^21,22 This overall process involves six discrete steps [i)–vi)]; only the second (and penultimate) benzyne, II, is shown in Figure 2B. As a complement, the “inside-out” substrate 5 undergoes cyclization in the presence of trimethylsilyl azide (TMSN₃)²³ to produce the indenofluorenedione 7 (Figure 2C). The discrete benzyne intermediates III and IV are shown following each of the steps in the sequence: i) the (slow) first HDDA reaction, ii) the (rapid) trapping of III by TMSN₃ to give the (isolable) mono-triazole adduct 6, iii) the (slow) second HDDA reaction, and iv) the (rapid) trapping of IV by a second molecule of TMSN₃. Notice the significantly different and complementary topologies of the products arising from these two motifs of bi-HDDA reaction. Namely, 4a has a bis-biaryl skeleton with a non-planar orientation around the core benzene ring whereas 7 is a highly fused heptacycle arrayed in planar fashion around the central benzene ring.

To demonstrate the robustness of the “outside-in” bi-HDDA reaction, we subjected hexayne 3 to an array of benzyne trapping reagents. This produced the collection of products 4b-h (Figure 3A) in generally good to excellent yields. Products include those arising from the use of both symmetrical (4a-d) and unsymmetrical (4e-h) trapping agents. In the case of the latter, the regioselectivity was exclusive, as expected from the high degree of distortion calculated for benzyne II Δ∠_a-b = 13.3°, Figure 2B). That is, the electron-rich center of the trapping agent selectively engaged the more electron-deficient benzyne carbon atom (C_a), as reflected by its larger computed (DFT, see SI) internal bond angle.^24,25,26

Figure 3. Trapping versatility, shown here for “outside-in” bi-HDDA reactions.

(A) Products 4b–4h arising from the hexayne substrate 3, the same precursor used to prepare 4a (see Figure 2B). (B) Products 8a and 8b arising from a hexayne substrate analog of 3 in which the central 1,4-phenylene subunit was replaced by a 1,4-naphthylene moiety (see S5, SI). (C) Trapping of hexayne 9 with 2-pyrone produces, by a multi-stage process in which V is one of the intermediates, the bis-binaphthyl product 10. TBS, (tert-butyl)dimethylsilyl; Ph, phenyl; Et, ethyl; t-Bu, tertiary-butyl.

Modifications to the core of the multi-yne substrate are tolerated. For example, replacement of the central benzene scaffold in 3 with a 1,4-disubstituted naphthalene leads to the products 8a and 8b when heated in the presence of, for example, n-hexylamine and cyclooctane (dihydrogen redox transfer²⁷), respectively (Figure 3B). Further modification of the exterior of the substrate (and product) is also possible. For example, hexayne 9 (from 1-bromo-2-naphthaldehyde) upon trapping with 2-pyrone and concomitant cheletropic ejection of CO₂,²⁸ leads to product 10, which embodies five non-contiguous naphthalene substructures.

We next speculated that the “inside-out” bi-HDDA cascade could be an efficient tactic to construct more highly conjugated PACs. Incorporation of an intramolecular benzyne trapping unit into the substrate(s) would lead to products of higher planarity having even more π-conjugation. If successful, this approach would be complementary to existing strategies for preparing PACs of potential utility in organic electronics research.²⁹ To that end, we prepared the “inside-out” bi-HDDA substrates 11a-c (Figure 4A), each containing a nucleophilic substituent in the ortho-position of the two terminal aryl groups. When heated in the presence of acetic acid (5 equiv), each yielded the corresponding product 12a-c, containing newly fused benzothiophene, benzofuran, and indole moieties, respectively, adorning the central fluorenedione. The pair of sequential trapping events in each reaction is envisioned to proceed via a zwitterionic onium ion such as that indicated in intermediate VI. The acetic acid serves as an in situ proton source to quench the carbanion in that zwitterion and then to dealkylate the R group. In the case of substrate 11c, the expected n-hexyl acetate byproduct was formed (by ¹H NMR spectroscopy) in nearly stoichiometric amount in an experiment performed in CDCl₃.

Figure 4. Extended π-conjugated PACs arising from “inside-out” bi-HDDA reactions.

(A) intramolecular trapping by a heteroatom in the 2-position of terminal phenyl substituents (cf. VI) results in formation of additional new rings that contain push-pull (donor-acceptor) motifs commonly found in organic semiconductor structures. The absorption spectra shown were recorded as 10⁻⁵ M solutions in THF (ε_{12a (347 nm)} = 1.3x10⁵, ε_{12b (380 nm)} = 1.1x10⁵, ε_{12c (365 nm)} = 1.0x10⁵; L mol⁻¹ cm⁻¹). (B) intermolecular trapping of an analog of 5 (cf. Figure 2), having a 4-t-butyl group (cf. S18, SI), by TPCPD gives 13a, which provides an entry to the bis-alkynyl indeno-fluorene 15, an architecture of interest in organoelectronic applications (see SI for UV-vis data).^{30, 32, 33, 36} (C) One-pot, six-benzyne cascade combining classical [steps i) and ii)] and HDDA benzyne generation [iii)] and intramolecular trapping [iv)] leads to the bis-naphthalene 18. 18-crown-6, 1,4,7,10,13,16-hexaoxacyclooctadecane; S_N2’, substitution, nucleophilic, bimolecular (with “allylic inversion”); o-DCB, ortho-dichlorobenzene; AcOR, alkyl acetate ester; TIPS, tri(iso-propyl)silyl; THF, tetrahydrofuran; RT, room temperature; n-Bu, normal-butyl. Tf, trifluoromethylsulfonyl; DFT, density functional theory (see SI for computational methods).

The nearly planar, crystalline nature of highly fused PACs such as the nonacyclic products 12 often limits their solubilities in common organic solvents.^30,31 Notably, the n-hexyl substituents in analog 12c allowed for reaction monitoring via an NMR experiment in which the cyclization of the bis-aniline substrate 11c was performed in CDCl₃ at a [11c]_t=0 = 7.2 mg mL⁻¹ (7.0 mM). This experiment demonstrated the remarkable cleanliness of this “inside-out” bi-HDDA process (see SI) by allowing direct observation of the crude reaction mixture, which remained homogeneous even after >90% conversion to 12c.

Enlightened by the effectiveness of the bi-HDDA reaction to afford a planar skeleton in a single operation, we pursued the synthesis of an all-carbon PAH motif (Figure 4B). This was demonstrated by preparation of the TPCPD bis-adduct 15, having an embedded indenofluorene skeleton³² (yellow+green substructure), The twisted aryl appendages in each of compounds 13–15 significantly improved their solubility. Lithium acetylide addition to the diketone 13b (from n-Bu₄N⁺F⁻ treatment of 13a) afforded diastereomeric diols 14, which were then reductively deoxygenated (stannous chloride³³) to give the indenofluorene 15 in good yield.

Lastly, we explored a hybrid strategy integrating both HDDA and traditional benzyne generation, recognizing its potential to provide highly conjugated, polycyclic, planar frameworks. Specifically, we capitalized on the 1,2-benzdiyne tactic pioneered by Li and coworkers³⁴ to access the nonacyclic PAC 18 (Figure 4C). Treatment of the bis-benzyne equivalent 16 with mild base in the presence of the bis-triflamide 17 generated, first, the benzyne intermediate VII. Nucleophilic attack by a sulfonamide anion in 17 initiated a net S_N2’ event, generating intermediate VII. HDDA cyclization produced a transient naphthyne (not shown),³⁵ which was captured intramolecularly by the strategically placed methoxy group (cf. 11b to 12b). Repetition within the second half of 17 led to the (U-shaped PAC) 18. This overall process proceeds via the intermediacy of six, discrete, independently formed benzyne intermediates (green, then blue, then red).

Tri-HDDA reactions.

To further demonstrate the rapid complexity-building capacity of the radial-HDDA approach, we first elected to explore substrate 19. This nonayne is built upon a 1,3,5-trisubstituted benzene template (Figure 5A). We quickly learned that these three arms did not behave independently. That is, upon heating 19 to typical reaction temperatures and times for cyclization of fluorenone precursors analogous to those in 19 (e.g., 85 °C for 24 h or 130 °C for 8 h), we observed formation of products in which two, but not the third, of the independent triyne subunits had cyclized. Long-range steric interactions were manifesting themselves in this reaction. Specifically, we speculated that at the stage of the doubly cyclized intermediate, cartooned as IX, the top and bottom faces of the core phenyl ring are blockaded by the substituents (blue and green) arrayed along the twisted biaryl bonds (magenta) in IX so as to greatly retard the rate of the third cyclization. The triynyl TBS group (gray oval) needs to enter the volume partially occupied by the meta-disposed, bulky biaryl substituents. Accordingly, upon heating a reaction mixture of 19 and 2-pyrone to substantially higher temperature – namely, 240 °C (in o-DCB) – we achieved clean conversion to the tri-HDDA product 20a (Figure 5A, left). The NMR spectrum of this product was challenging to fully assign because of hindered rotation about not only the three biaryl bonds, but the C_Ar–Si_TBS bonds as well. Desilylation, however, smoothly gave the 1,3,5-triarylbenzene derivative 20b, the spectroscopic characterization of which was straightforward.

Figure 5. Tri-, Tetra-, and Hexa-HDDA.

(A) The nonayne 19 requires heating to ≥200 °C to effect the third HDDA cyclization. (B) The dodecayne 22, having an expanded core structure of considerable larger volume, sequentially cyclizes four times [cf. i) – iv)] at 130 °C. (C) The octadecayne 24 smoothly cyclizes six times to the hexa-fluorenone derivative 25. naph, naphthalene.

In an interesting twist, we also showed that it was possible to differentially trap the three benzyne intermediates when the reaction was performed in the presence of a mixture of two different trapping agents, themselves of inherently different reactivity. For example, heating the nonayne 19 (at 200 °C) in the presence of essentially one equivalent of 2,5-dimethylfuran, a very fast trap of arynes, and an excess of cyclooctane, which engages benzynes by a relatively slow dihydrogen-transfer reaction,²⁷ afforded the unsymmetrically substituted, tri-HDDA product 21a (Figure 5A, right). Again, this structure was more easily characterized following desilylation to the analog 21b.

Tetra-HDDA reactions.

To widen the scope of classes of radial-HDDA reactions, we pursued a substrate that could undergo four-fold cyclization. In view of the accumulating steric inhibition toward cyclization observed with substrate 19 (cf. IX), we designed the dodecayne 22 [Figure 5B, prepared by a 5-(linear)step reaction sequence from tetraphenylethylene]. We expected that this expanded core would remove any difficulties in the later-stage HDDA cyclizations. Indeed, when 22 was heated in the presence of either cyclooctane or 2-pyrone at 130 °C (cf. ≥200 °C for 19 to effect the final HDDA cyclization), it was smoothly and exhaustively cyclized to the tetra-HDDA product 23-HH or 23-naph, respectively, affirming the underlying principles of the design. As can be judged from the single crystal x-ray diffraction structure of 23-naph, the biaryl bonds are sufficiently distant from one another to allow for uninhibited rotation, consistent with the observed sharp resonances in its ¹H NMR spectrum. It is also noteworthy that even though the substance has a high melting point 365–372 °C (and thermal stability; no observed decomposition), it readily dissolves in common organic solvents, a property owing to its multiple biaryl rotational degrees of freedom and associated array of conformational isomers.

Hexa-HDDA reactions.

Finally, to push the radial-HDDA cascade to yet another level, we designed a six-fold HDDA reaction. An expanded core was again enlisted to accommodate the cyclization of now six sets of pendant triyne units. Specifically, the octadecayne 24, having six triyne units (spokes) arrayed on a 1,3,5-triphenylbenzene core (hub) was devised. Heating 24 with cyclooctane afforded the hexa-cyclized product 25, having six new fluorenones symmetrically arrayed about the core structure. An analogous reaction of 24 using pyrone as the trapping agent proceeded efficiently to provide what we judge to be the hexabenzo-analog of 24 (benzo-fusions at the six red bonds; cf. 23-HH vs. 23-naph), although slow rotation about the hindered biaryl bonds in that analog precluded full analysis of its NMR spectral data (see S25 in the SI). Processes that allow the construction of such a high degree of structural complexity, accompanied by a high level of atom economy, in a single operation are rare.

Conclusion.

The radial-HDDA (i.e., bi-, tri-, tetra-, hexa-) reaction described here constitutes a fundamentally new strategy for the creation of structurally complex and topologically unique polycyclic aromatic compounds (PACs). The reaction substrates have multiple (2, 3, 4, or 6) independent sets of triyne units (6 to 18 alkynes) and can be synthesized in straightforward fashion, starting from symmetrical starting materials. Simple heating of a solution of the multi-yne substrate and benzyne trapping partner, absent the need for any additional reagents or catalysts, induces a cascade of sequential HDDA reactions that rapidly builds structural complexity. The radial-HDDA approach, capitalizing on the de novo (and, here, late-stage) construction of arene rings, contrasts and complements many existing strategies for the synthesis of PACs.

The examples shown here were selected to demonstrate the variety of new architectural topologies that can be accessed by a radial-HDDA approach. These include both highly conjugated/fused polycyclic frameworks as well as skeletons with multi-fold symmetry. The work establishes a basis upon which future research aimed at the synthesis of specifically targeted, functional compounds and materials (e.g., in one or more of the MOF, COF, or organoelectronic arenas) can be fashioned.

EXPERIMENTAL PROCEDURES

Resource availability

Lead contact

Requests for further information and data should be directed to the corresponding author (hoye@umn.edu).

Materials availability

This study did not generate new materials (other than, of course, the new chemical compounds for which experimental details for their preparation are described in the Supplemental Information.

Data and code availability

The NMR spectra can be accessed and manipulated in the .mnova file uploaded to the SI as S2.

General procedure for the radial HDDA reactions.

An oven-dried, threaded, glass culture tube containing the multi-yne precursor in organic solvent (initial concentration of 0.01–0.05 M, in, e.g., (ethanol-free) CHCl₃) and the indicated number of equivalents of trapping reactant(s) was closed with a Teflon-lined cap and the solution was heated at 85–130 °C for 8–24 h. The products were separated and purified by chromatography on silica gel.

Bigger Picture.

We report hexadehydro-Diels-Alder (HDDA) reactions in which the substrates are designer multi-ynes arrayed upon a common, central template. These undergo sequential, multiple cycloisomerization (termed here radial-HDDA) reactions to produce architecturally novel polycyclic compounds in a single operation.

Diverse product topologies are accessible, ranging from highly fused, polycyclic aromatic compounds (PACs) to architectures having structurally complex arms adorning central phenylene or expanded phenylene cores.

Members of some of these structural classes are well known to play important roles in fields of, for example, organic electronic/photonic devices, organomagnets, and as building blocks in reticular chemistry [metal-organic and covalent-organic frameworks (MOFs and COFs)]. Hence, new strategic advances that complement existing approaches and/or that provide access to novel structural topologies are significant.

Highlights.

• Multi-triynes undergo cascade HDDA reactions to afford polyaromatic compounds (PACs)

• New strategy for constructing structurally complex molecular architectures

• Up to 24 new bonds and eight new rings in a single-vessel operation

• Simple (thermal) reaction conditions; no additional reagent or catalysts required