Quaternary ammonium ion-tethered (ambient-temperature) HDDA reactions

Abstract

The hexadehydro-Diels-Alder (HDDA) reaction converts a 1,3-diyne bearing a tethered alkyne (the diynophile) into bicyclic benzyne intermediates upon thermal activation. With only a few exceptions, this unimolecular cycloisomerization requires, depending on the nature of the atoms connecting the diyne and diynophile, reaction temperatures of ca. 80–130 °C to achieve a convenient half-life (e.g., 1–10 h) for the reaction. In this report we divulge a new variant of the HDDA process in which the tether contains a central, quaternized nitrogen atom. This construct significantly lowers the activation barrier for the HDDA cycloisomerization to the benzyne. Moreover, many of the ammonium ion-based, alkyne-containing substrates can be spontaneously assembled, cyclized to benzyne, and trapped in a single-vessel, ambient-temperature operation. DFT calculations provide insight to the origin of the enhanced rate of benzyne formation.

Graphical Abstract

INTRODUCTION

Quaternization of amines, often referred to as the Menschutkin reaction,¹ has been known for at least 170 years following the earliest reports by Hoffman.² Propargylic alcohol derivatives (e.g., sulfonates or halides) are reactive alkylating agents. With our interest in polyynes containing both a 1,3-diyne and a diynophile that are tethered by three-atom linkers [i.e., substrates for the hexadehydro-Diels-Alder (HDDA) reaction³], we wondered what might happen when a secondary amine (I, Figure 1a) was doubly alkylated (i.e., quaternized) upon being exposed to two equivalents of, for example, a 1-bromo-2,4-diyne derivative (cf. II). No reports to date have described the fate of an ionic HDDA substrate such as III. More specifically, we hypothesized that i) this would result in a highly effective strategy for preparing a class of HDDA substrates and ii) the quaternized nitrogen atom within the linker in III might increase the proximity of the alkyne carbons in III (cf. ◆). If so, that would likely result in a faster rate of bond formation between that pair of alkyne carbon atoms to form a diradical intermediate, the most common initial and rate-limiting event in an HDDA cycloisomerization.⁴ To date only a select few HDDA substrates have been shown to cyclize at low (e.g., ambient) temperature.⁵

Figure 1.

(a) Hypothesis: Tertiary amines I are alkylated in situ to produce ammonium ions III, which cyclize to reactive benzynes IV enroute to trapped products V. (b) DFT free energies and geometries for the analogous reactions of the model6 tetrayne ammonium bromide substrate 1-N⁺ leading to the benzyne 3-N⁺ vs. the hydrocarbon analog 1-C to 3-C. [(U)B3LYP/6-311+G(d,p), SMD: CDCl₃]

RESULTS AND DISCUSSION

DFT Underpinnings

We tested the above line of thinking using DFT computations (Figure 1b). The geometries and free energies for the cycloisomerization of the simple, model quaternized dimethylammonium ion 1-N⁺ were explored in parallel with those of the analogous all-carbon analog 1-C.⁶ The first step in the cycloisomerization process to eventually form the benzyne 3-N⁺ or 3-C involves formation of the diradical intermediate 2-N⁺ or 2-C via the transition structure TS1-N⁺ or TS1-C, respectively. As is often the case for computations of similar HDDA cyclizations,⁴ this event represents the rate-limiting step for each of these overall reactions. Each of the diradicals 2, higher in free energy than the starting tetraynes 1, ring-closes in a substantially exergonic event to its benzyne 3 with a lower barrier than its reversion to 1. The lowest energy conformer for each of the the two tetrayne substrates are set to G = 0 kcal mol⁻¹. The reactive tetrayne conformers of 1-N⁺ and 1-C have their conjugated diynes approximately parallel to one another. The shorter distance between the two proximal alkyne carbons in the ammonium ion is noteworthy. Importantly and as highlighted by the gray oval in Figure 1b, the computed energy of activation for the ammonium ion (via TS1-N⁺) is several kcal mol⁻¹ lower than that for the hydrocarbon analog (via Ts1-C).

These computations reinforced our design of the initial set of experiments described in Figure 2. There, piperidine (4a) was treated with two equivalents of the diynyl propargylic bromide 5 in CHCl₃ at ambient temperature (Figure 2a). After three days, the solvent was removed and the isoindolinium ions 7a (minor) and 8a (major, confirmed by X-ray diffraction analysis), arising from attack of the (soft) bromide ion on the (polarizable) benzyne VI produce carbanions VII and VIII, were isolated as the principal products. Note that the overall reaction of 4a + 5 (2 equiv) to 7a + 8a is a perfectly balanced equation. Not only did this outcome serve as an exciting proof of concept, but it demonstrated that the HDDA cyclization of the presumed intermediate ammonium ion 6-Br was i) not only viable but that ii) it was occurring at ambient temperature!

Figure 2.

(a) One pot, room temperature formation of ammonium ion 6-Br and the in situ production of 7a and 8a involving cyclization of 6-Br to benzyne VI and trapping by bromide ion to proceed via zwitterions VII and VIII. (b) Alternative generation of ammonium ion 6-Br (from pre-formed 9), its conversion by anion exchange to 6-BF₄, and room temperature trapping reactions with furan (to 10a) and methanol (to 11a,b). (c) ¹H NMR spectrum of the reaction in CDCl₃ after 7 days at rt for conversion of 6-BF₄ + furan (2.0 equiv) to 10a; insets show the progress of reaction as reflected by the acetate methyl group resonances and from which the half-life of ca. 30 h is determined.

To further understand this overall reaction, we developed protocols to study some of the individual steps. First, the tertiary amine 9 was readily prepared (and isolated) by treatment of 5 with an excess of piperidine (Figure 2b). Quaternization of that amine with an additional equivalent of 5, now in diethyl ether, gave a precipitated sample of the quaternary ammonium bromide salt 6-Br. When this was then dissolved in CHCl₃ (or CDCl₃) at room temperature (rt, 20–22 °C), products 7a/8a were again formed (along with additional, mechanistically informative byproducts, as discussed below in association with Figure 3). The bromide counterion in 6-Br could also be readily exchanged⁷ to the far less nucleophilic tetrafluoroborate analog 6-BF₄ (see SI). When this salt was exposed to furan (2 equiv) in a homogeneous chloroform solution at room temperature, excellent and clean conversion to the furan adduct 10a was observed. In Figure 2c we have shown the ¹H NMR spectrum of a reaction mixture in CDCl₃ showing the formation of 10a. The full spectrum, after 7 days at room temperature, shows the overall cleanliness of the reaction. The set of four insets shows the progression over time of the acetate methyl region at 1, 17, 41, and 160 h. From these data the half-life for the reaction is judged to be ca. 30 h.

Figure 3.

(a) Formation of 7a/8a accompanied by the neutral rearrangement products 12 and 13, the latter pair from the ammonium ylide intermediate IX. (b) Variation in product ratios among 7a-H/D, 8a-H/D, 12, and 13 depending on the reaction solvent and conditions. (c) Schematic for the formation of the six products observed in CDCl₃.

In a related experiment, the overall reaction between piperidine (4a) and the propargylic bromide 5 (1:2 molar ratio) in CDCl₃ was monitored over time by NMR spectroscopy. We could observe the intermediacy of the tertiary amine 9. Its quaternization to produce 6-Br was competitive with the rate of its formation. This is consistent with the known (and similar) relative rates of alkylations of secondary vs. tertiary amines.⁸ Furthermore, the HDDA cycloisomerization of 6-Br to form 7a and 8a was also seen to be competitive with the rates of both of these alkylation events. Thus, both the tertiary amine 9 and the quaternary ammonium ion 6-Br were metastable intermediates, each present at an approximate steady-state concentration under the reaction conditions.

The results of several additional experiments are worth mentioning. If furan is present at the outset of the reaction of 6-Br in chloroform, competitive formation of both 10a (as its bromide salt) and 7a/8a was observed (ca. 5 h); the proportion of 10a was a function of the concentration of added furan. When 6-BF₄ was dissolved in methanol at room temperature, the methanol-trapped products 11a,b were produced and isolated after two days in 90% yield. When this transformation was monitored by ¹H NMR spectroscopy in a CD₃OD reaction solution, a very efficient formation of the tetradeutero-analogs of 11a,b was seen. Finally, the reaction of 6-Br in CD₃OD (discussed further in Figure 6b) and in D₂O (Figure S4) was seen to have a t_1/2 of ca. 10 and 24 h, respectively.

Figure 6.

Contrasting and complementary behavior of tetraynes 6 having either (a) a BF₄^– or (b) a Br^– counterion.

^aReagents and conditions: 6-BF₄ (1.0 mmol), or 6-Br (1.0 mmol), CH₃OH (or CD₃OD) (2 mL), rt, 24 to 48 h. Isolated yields are indicated.

Overall, we observed the following half-lives for the rate-determining formation of the benzyne: 6-Br, chloroform (5 h); 6-Br, methanol (10 h); 6-Br, water (24 h); and 6-BF₄, chloroform (30 h). The relative tightness of the ion pairs could explain these differences. Closer association of the counterion ion with the ammonium nitrogen atom is expected for Br⁻ relative to BF₄^– and of the ammonium bromide pair in less polar solvents. In turn, this would result in a compressed C–N–C bond angle and an accompanying closer proximity of the terminal diyne and diynophile sp-carbon atoms, a feature demonstrated to result in faster HDDA reaction rates.^4c,d,9

Mechanistic Aspects

When the reaction of isolated 6-Br was carried out in CDCl₃ solution and monitored by ¹H NMR spectroscopy (Figure S3), the HDDA adducts 7a and 8a were again produced, but, in addition, two new products were seen for the first time. Namely, the neutral piperidine derivatives 12 and 13 were also formed (Figure 3a and entry 1 in Figure 3b). An additional fact, perplexing at first, was that the aryl bromide 8a was predominantly deuterated (~20% 8a-H by ¹H NMR analysis) whereas the isomeric 7 was nearly exclusively proterated¹⁰ (~90% 7a-H)! From where was the hydrogen atom in these products coming? Recognizing that the only obvious source of protium in the reaction mixture was the hydrogen atoms in the starting 6-Br, we deduced the origin of the unusual byproducts 12 and 13. Namely, deprotonation at a propargylic carbon in 6-Br by the carbanionic site in intermediate VII and/or VIII (cf. Figure 3c) would give the 1,2-ammonium ylide IX, from within which competitive 2,3-sigmatropic rearrangement¹¹ (blue arrows) gives 12 and 1,2-migration¹² (red arrow, Stevens rearrangement) gives 13. A roadmap summary of the competing events that lead to the isolated product ratios in this CDCl₃ experiment (Figure 3b, entry 1) is provided in Figure 3c. The higher percentage of deuteration in 8a vs. 7a (80% vs. 10%) can be explained by the relative steric accessibility of the carbanionic sites in VIII vs. VII. In VIII the adjacent acetoxymethyl group sterically shields the carbanion relative to the methylene in the five-membered ring VII. The CDCl₃ donor, being smaller than the propargylic ammonium ion 6-Br, preferentially provides its deuteron to VIII.

Performing this reaction in several other solvents added further support to the above mechanistic explanations. When the reaction was carried out in protio-chloroform the ratio of (7a+8a):(12+13) was seen to be higher than it was in CDCl₃ (Figure 3b, entries 1 vs. 2). This is consistent with faster protonation of the aryl carbanion center by CHCl₃ because of the H/D kinetic isotope effect. To further support the involvement of ylide IX, we performed the reaction in H₂O, as well as D₂O. In those experiments neither of 12 or 13 was observed [Figure 3b, entry 3 (and 4)], presumably because the carbanionic centers in VII and VIII were now being quenched by rapid protonation (deuteronation¹⁰) from the vast amount of the kinetically faster proton (deuteron) donor water.

Variations in the Ammonium Ions

To establish that an expanded array of secondary amines would undergo the one-pot, room-temperature assembly of the types of complex products first demonstrated by the piperidinium example (Figure 2a), we explored the use of a variety of secondary amines, both cyclic and acyclic (Figure 4). The combined isolated yields of 7+8 for each of a-g were excellent. We emphasize that each tansformation is fully balanced (i.e., 100% atom economy¹³). In no case was any of the rearrangment product analgous to 12 or 13 observed. This indicates that the proton donation to the carbanion from the intermediate (steady state) NH-ammonium ions [i.e., (R¹)₂NR²H⁺Br^– (R² = H or propargylic substituent)] is considerable faster than protonation by the intermediate ammonium diyne substrates (cf. 6-Br to IX, Figure 3a).

Figure 4.

(a) Variation of the 2° amines used in the one-pot assembly, cyclization, and bromide ion trapping reactions leading to aryl bromides 7a-g and 8a-g. (b) A different type of HDDA pathway when strained (small ring) amines 4h and 4i are used.

^aReagents and conditions: 5 (2.0 mmol), amine (1.0 mmol), CHCl₃ (2.0 mL), rt (unless otherwise indicated), 3 days or overnight (see SI). Isolated yields are indicated. ^b100 °C, 5 h.

We note that both the electronic character of the ammonium ion (examples b and c) as well as higher reaction temperature (examples e-g) resulted in formation of larger amounts of 8 relative to the slight preference for formation of 7 seen for most of the examples using simple dialiphatic amines at room temperature. This hints of the possibility that the addition of bromide ion to the benzyne VI to form the regioisomeric zwitterions VII and VIII is reversible and that the relative rates of proton transfer vs. benzyne regeneration (cf. Figure 3c) are competive, albeit in sublte and perhaps complex ways. This idea is supported by parallel experiments in which 6-Br was incubated in chloroform solution either i) alone or ii) in the presence of added Et₃N•HBr (5 equiv), the latter to serve as a proton source that presumably would donate its proton faster than a propargylic C–H in 6-Br. The ratio of 7a:8a changed from ca. i) 3.5:1 to ii) 1:2 in the two experiments (cf. entries 1 vs. 5 in Figure 3b), suggesting that the intermediate ion pairs VII and VIII are protonated in the product-determining events at different rates depending on, for example, the steric hindrance of the proton donor. This interpretation requires that the intermediate ion pairs revert, at least partially, to benzyne and bromide ion.

Use of the small-ring analogs ethylenimine (4h) and azetidine (4i) led, at room temperature, to the formation of isolable tertiary amines 14a or 14b containing a 2-bromoethyl or 3-bromopropyl substituent, respectively (Figure 4b). These arise from ring-opening of the intermediate strained ammonium ion by the bromide counterion.¹⁴ Each of these tertiary amines was quaternized rather slowly at ambient temperature, but by treating 4h or 4i with three equivalents of 5 and at higher temperature, we isolated the arylbromide 15 or 16. Formation of the presumed intermediate tris-propargylated, hexayne HDDA ammonium ion substrate was now the rate-limiting event. Finally, we observed that higher temperature was required when using the hindered diisopropylamine enroute to 7g and 8g; the quaternization step was the rate-limiting event driving the need for higher temperature. In situ monitoring (¹H NMR) of this reaction showed no evidence of the intermediate tetrayne, indicating that its HDDA cyclization was much faster than the rate of its formation.

Ring-size Effects on Rates

To probe the effect of the ring-size in the ammonium ion HDDA substrates on the rates of their cycloisomerization, we carried out the experiments summarized in Figure 5. This was done using the tetrafluoroborate salts 17a-e; each of the non-small ring analogs 17a-d were prepared by first synthesizing the bromide salt in diethyl ether and isolating that precipitate. This was then dissolved in dichloromethane (DCM) and immediately shaken with an aqueous solution of NaBF₄. Removal of the DCM gave the solid BF₄ salts 17a-d, which could be stored for later use. The strained ammonium ion 17e was prepared by reaction of bromoalkylamine 14b with AgBF₄ in CHCl₃, which drove the formation of the 4-membered ring as AgBr was precipitating from the reaction mixture.

Figure 5.

^a Effect of ring-size of the ammonium ion on the rate of the HDDA cyclization reaction.

^a[17]₀ = ca. 0.3 M in CDCl₃, furan (2 equiv), rt.

The half-lives for benzyne formation for this series of tetraynes was measured by incubating each substrate in CDCl₃ in the presence of furan as the benzyne trapping agent and using ¹H NMR spectroscopy to monitor the reaction progress (e.g., Figure S1, Supporting Information). Although there is little difference in the rate of cyclization among the 6-, 5-, and 7-membered cyclic substrates (or the diethylated ammonium ion 17d) (Figure 5), the azetidinium substrate 17e reacted dramatically slower (by 10x–16x). This is consistent with the view that the exocyclic CNC bond angle is significantly splayed in this strained-ring substrate, resulting in an increased distance between the two most proximal diyne carbon atoms in the reactive rotamer. This distance parameter is thought to significantly impact the rate of HDDA cyclization reactions.⁹

Counterion Effects

As mentioned earlier, the reaction of the BF₄^– salt 6-BF₄ in methanol solution allowed for an efficient trapping reaction to give the isomeric ethers 11a and 11b (Figures 6a and S2). This outcome is in distinct contrast with what is observed when 6-Br is allowed to react in methanol (Figure 6b). The progression of a complex series of events was deduced from monitoring this experiment by ¹H NMR spectroscopy in CD₃OD over time (Figure S5). First, an almost immediate (and surprising), exhaustive exchange of all four propargylic protons adjacent to the quaternized nitrogen atom for deuterons was observed. More slowly, deacetylation of the esters (by transesterification with methanol), competitive with HDDA cyclization and trapping by bromide ion, was seen. The spectroscopic signatures for this highly complex mixture of intermediates yet more slowly (over several days) simplified to that of largely a single species: namely that of 20-D₁₀. The protio version 20-H was isolated in 65% yield from the analogous reaction performed in CH₃OH. This same material could also be accessed cleanly by treating the isolated diacetate ester 7a with methanol containing a small amount of methoxide ion at room temperature.

In retrospect, we can explain the complicated sequence leading to 20 as follows. The initial rapid H/D exchange could arise from the fact that even the first small portion of 6-Br to undergo benzyne formation and trapping by bromide ion concomitantly generates low levels of methoxide anion. This is sufficient to rapidly catalyze H/D exchange of the acidic propargylic protons. The deacetylation, also methoxide-catalyzed, was slower but gained momentum as the percent conversion to benzyne progressed, increasing the concentration of catalyst throughout. Conversion to the deacetylated diol 19 proceeds to high conversion over the course of 24 h. Finally, the cyclization of that penultimate intermediate to produce the benzofuran derivative 20, also base-catalyzed,¹⁵ was the slowest of all events. Additionally consistent with this interpretation, the methoxy analogs 11 derived from the tetrafluoroborate 6-BF₄ did not give rise to observable deacetylated materials during their formation (Figure 6a) because no appreciable amount of methoxide ion was generated in the absence of bromide ion; alcohols are thought to add to HDDA benzynes by a concerted addition of an alcohol dimer via a six-atom TS rather than a 1,3-oxonium/carbanion zwitterion.¹⁶

Dequaternizing Reactions

We were also interested in post-HDDA polishing reactions that would remove one of the substituents on the quaternary nitrogen atom to render neutral rather than zwitterionic products. Two reactions that nicely achieve that outcome are shown in Figure 7. First (Figure 7a), using N-methylethanolamine (4j) as the secondary amine and by way of the one-vessel spontaneous substrate assembly and ambient temperature HDDA reaction introduced in Figure 4, we observed the efficient formation of the aryl bromides 21a/b. Following their separation, each was exposed to methanolic KOH and underwent several events: deacetylation, cyclization to the dihydrobenzofuran (cf. 20), and ethylene oxide extrusion¹⁷ to produce 22a or 22b, respectively. The assignment of Z-configuration of the alkene in each of 22a/b (and, by extrapolation, in 20-H) was made based on a DP4⁺ analysis¹⁸ of the computed NMR chemical shifts (¹³C and ¹H, see SI for details). Second (Figure 7b), the triyne substrate 23 was prepared (by quaternization of the tertiary amine 9 with 4-bromobut-2-ynyl acetate, see SI) and, not surprisingly,^3,4a observed to undergo the HDDA cyclization considerably more slowly than the analogous tetrayne 6-Br. At 100 °C in chloroform (in the presence of Et₃N•HBr to thwart ammonium ylide formation), the adduct 24 was smoothly formed, notably now as essentially a single regioisomer of the aryl bromide. Upon exposure to methanolic KOH, this diacetate was smoothly cleaved and cyclized to the neutral dihydroisobenzofuran 25.¹⁹ As further side notes, i) it was interesting that upon heating 23 in CD₃OD, also at 100 °C, the H/D exchange at the propargylic site of the monoyne was essentially not occurring, whereas the diynyl propargylic hydrogens, as before, exchanged very quickly and ii) triyne 23 represents a rare example of an HDDA substrate bearing a distal propargylic hydrogen atom on a monoyne diynophile. In our experience, these types of triynes are typically susceptible to entering into competitive propargylic ene reactions.²⁰

Figure 7.

Demonstrations of neutralization of the ammonium ion by hydroxide ion-promoted intramolecular dealkylation reactions: (a) Ethylene oxide extrusion or (b) intramolecular ring-opening by a pendant alcohol hydroxy group.

One-pot HDDA Substrate Self-assembly and Cyclization with External Trapping

Finally, we designed capstone experiments by amalgamating a number of the individual elements we had uncovered. These are shown in Figure 8. They were designed to minimize or eliminate entirely the formation of the bromoarene products that prevailed in many of the earlier experiments. If successful, such strategies would open the way for use of a much wider array of trapping reactions³ for implementation into this facile, one-pot HDDA substrate preparation, cyclization, and trapping sequence.

Figure 8.

(a) A two-phase reaction mixture allows for exchange of the nucleophilic bromide anion with the non-participating tetrafluoroborate counterion, leading to preferential formation of the furan adduct 10a. (b) Use of 5-OMs allows for efficient in situ trapping of the benzyne intermediate by the external agent (furan, giving 10a-OMs) because the mesylate counterion is an innocent bystander.

In the first protocol (Figure 8a) we designed a two-phase experiment in which piperidine (4a), the propargylic bromide 5, and furan were dissolved in chloroform and stirred under an aqueous solution of NaBF₄. When a 2:1 molar ratio of bromide 5 to amine 4 was used, the major HDDA product 10a, the fluoroborate salt of the furan-benzyne adduct, was indeed formed. However, a surprisingly large amount of unreacted bromide 5 remained in the otherwise fairly clean crude product mixture following simple evaporation of the volatiles from the organic phase and NMR analysis. Surmising that the piperidine was being partitioned preferentially into the aqueous phase as its hydrobromide salt, we changed the ratio of 5:4a to 1:1, and still observed a small amount of recovered 5. Finally, using a 1:1.2 ratio, we isolated crude 10a in 90% mass recovery with an estimated purity of ≥80%. Trace amounts (<5%) of resonances consistent with the presumed bromoarenes 7a-Br and 8a-Br were observable.

In what proved to be a superior “single-operation” approach, we changed the propargylic leaving group from the bromide in 5 to the mesylate anion by using 5-OMs. (Figure 8b). Again, with a 2:1 molar ratio of 5-OMs:4a, we obtained both the mesylate salt of the furan adduct 10a-OMs but with a significant amount of unreacted 5-OMs along with piperidinium mesylate (4a•HOMs). This established that the mesylate anion proved to be an innocent bystander, allowing the furan to intercept the benzyne (the mesylate analog of VI). Again, changing the starting ratio of 5-OMs:4a to 1:1.2 allowed for essentially full conversion to 10a-OMs in excellent yield. It is notable that, overall, this final pair of experiments represent three-component reactions in which the HDDA substrate is assembled and cyclized, and the intermediate benzyne is trapped with a third, external species. This serves as a promising harbinger of additional new opportunities and directions for future exploitation of HDDA-enabled strategies.

CONCLUSIONS

Ammonium ions containing two conjugated 1,3-diyne units can be assembled by alkylation of secondary amines. These function as HDDA substrates and will cyclize to benzynes even at room temperature and with rates similar to that of their formation. When the anionic counterion is the softly nucleophilic bromide ion, it adds efficiently to the benzyne, which is then protonated by a donor in the reaction mixture: for example, chloroform, added Et₃N•HBr, or another molecule of the starting propargylic ammonium ion. In the last instance, the resulting ammonium ylide proceeds to products of Stevens rearrangements. If the counterion is a non-nucleophilic species such as a tetrafluoroborate or methanesulfonate, the benzyne can be trapped by other external agents (e.g., furan or methanol).

The dependency of the rate of the HDDA cyclization on the structure of the ammonium ion (ring size or other substituent effects) was measured. The feasibility of conversion of the initial ammonium ion products to neutral tertiary amines was also demonstrated. Time courses for the competing events in several reactions were mapped using in situ monitoring by ¹H NMR spectroscopy. Parallel DFT calculations comparing an ammonium ion- vs. all hydrocarbon-tethered tetrayne suggest that the rate enhancement in these ammonium ion HDDA reactions results from the shorter distance of the proximal pair of alkynes in the reactive conformation of the substrates. Finally, two one-pot protocols for substrate self-assembly, cyclization, and trapping was demonstrated. This facile variant of the HDDA reaction opens the way for related investigations.