Multiheterocyclic Motifs via Three-Component Reactions of Benzynes, Cyclic Amines, and Protic–Nucleophiles

Abstract

A broadly general, three-component reaction strategy for the construction of compounds containing multiple heterocycles is described. Thermal benzyne formation (by the hexadehydro-Diels–Alder (HDDA) reaction) in the presence of tertiary cyclic amines and a protic nucleophile (HNu) gives, via ring-opening of intermediate ammonium ion/Nu^– ion pairs, heterocyclic products. Many reactions are efficient even when the stoichiometric loading of the three reactants approaches unity. Use of HOSO₂CF₃ as the HNu gives ammonium triflate intermediates, which can then be ring opened by an even wider variety of nucleophiles.

Graphical Abstract

The rapid construction of complex products from simple starting materials has driven the development of numerous synthetic strategies. These include a wide variety of multicomponent reactions that allow for the modular generation of structural complexity and diversity.¹ One example is initiated by the nucleophilic addition of tertiary amines to benzyne (1, Scheme 1a).² This is thought to proceed by initial 1,3-zwitterion formation (cf. 3),³ which then engages either a carbonyl compound^2c-e or a proton source (cf. 4).^2a,b,f Cyclic amines, when strained [cf. aziridines and azetidines 2], lead to adducts 5 in the presence of acetonitrile^2a or carboxylic acids^2f in a process involving nucleophilic opening of the ion pair 4.

Scheme 1.

Three-component Reactions of Benzynes, Tertiary cyclic Amines, and Protic Nucleophiles (H-Nu)

The thermal cycloisomerization of tethered tri- and tetra-ynes⁴ leads to benzynes under neutral conditions in a process we have termed the hexadehydro-Diels–Alder (HDDA) reaction.⁵ These can then participate in myriad novel trapping processes, including three-component reactions (TCRs) initiated by cyclic sulfide addition⁶ or alkaloidal natural products.⁷ We now report that a diverse array of multiheterocyclic products can be efficiently assembled in a single, thermally driven operation. Substrate 6 (Scheme 1b) cyclizes in a rate-limiting event to the benzyne 7 that, in the presence of a cyclic amine 8 and proton source 9, gives the ion pair 10, which ring-opens to the three-component product P#. There is considerable breadth in each of the three classes of reactants that readily participate: the benzyne precursors [6a-f, Figure 1, panel i)], the cyclic tertiary amines [8a-j, Figure 1, panel ii), non-bicyclic; and 8k-n, Figure 3, panel i), bicyclic], and the protic nucleophiles (9a-m, H–Nu, Figure 1, panel iii). We note that in the absence of a tertiary amine, most of the protic nucleophiles 9 are capable of engaging HDDA benzynes, indicating that the reaction rate of addition of the cyclic amine 8 is considerably faster than that of 9.

Figure 1.

The three classes of reactants [i)-iii)] used to prepare the TCR products P# in Figures 2–4.

Figure 3.

Three-component reactions of HDDA-generated benzynes with bicyclic amines and protic nucleophiles^a.

We did not undertake an exhaustive survey of every possible combination, but rather chose to explore a representative subset to display the versatility of this strategy. The tri- or tetrayne precursors 6 cyclize to produce the benzynes 7 with convenient half-lives of reaction of a few hours at temperatures ranging from 80–130 °C. One limitation is that triynes containing an ynoate or an ynone subunit gave variable results; presumably because these electron deficient alkynes reacted prematurely with some of the more nucleophilic tertiary amines.⁸ This could be mitigated by using ynoates and ynamides containing a bulky TBS group on the terminus of the conjugated alkyne (cf. 6b and 6f).

We describe here three categories of TCR. These differ in the use of: monocyclic tertiary amines (including N-arylpyrrolidines and -piperidines, Figure 2), bicyclic amines with a bridgehead nitrogen atom (Figure 3), and arylammonium triflates (10, Nu^– = TfO^–).

Figure 2.

Three-component reactions of HDDA-generated benzynes with monocyclic tertiary amines and protic nucleophiles^a,b.

We have elected to identify the structures of each product of a TCR in this manuscript by a preceding “P” followed by a unique number, in sequence throughout. Thus, P1-P17 are the products in Figure 2. The three-letter code in parentheses indicates the first (poly-yne 6), second (amine 8), and third (nucleophile 9) components used to prepare each product. Each benzyne intermediate in this study was unsymmetrical; as such, each could react in two different ways with the nucleophilic amine. The major constitutional isomer of the product is shown (see supporting information (SI) for characterization of both isomers); the regioselectivity of the reaction is given in parentheses as the ratio of major to minor products. For example, P5 (acb, 96%, 3:1) arose from the TCR of 6a, 8c, and 9b to give a 3:1 ratio of isomers in 96% yield (of chromatographically purified material).

These TCRs of N-alkyl cyclic amines are limited to strained ring compounds since dealkylation of the exocyclic alkyl group is a seriously competitive process (see SI). In contrast, N-arylated piperidines, pyrrolidines, and morpholine (8a–8e) undergo efficient ring-opening to give the three-component adducts P1–P9, P15, and P16. Electron-deficient aniline derivatives were not as effective in capturing the benzyne (e.g., cf. yields of P6 vs. P5). N-Alkylazetidines and -aziridines (8g–8j) are competent TCR partners. Products P7–P9, P12, and P17 demonstrate successful trapping by a variety of nitrogenous nucleophiles; all other products in Figure 2 arose from the use of oxygen-based nucleophiles.

The benzynes from 6a and 6b often proceed with low levels of regioselectivity.⁷,⁹ In contrast the benzynes from 6c–6f give only a single regioisomer (P13–P17), a reflection of both predistortion of the benzyne ring¹⁰ and the added steric congestion adjacent to one of the two benzyne carbons. Various nitrogen-containing heterocycles are compatible with the process, including as a preexisting substituent on cyclic amine (cf. P12, P14, and P17) or as the protic nucleophile (cf. P7, P8, P12, and P17).

We next turned our attention to the use of the bicyclic amines 8k–8n (Figure 3), each containing a bridgehead nitrogen atom. These gave rise to aryl piperazines¹¹ P18–P28 [each from DABCO (8k)] and aryl piperidines¹² P29–P31, motifs often viewed as privileged structures in drug discovery efforts.¹³ As can easily be discerned from the structures in Figure 3, a considerably diverse array of multiheterocyclic products can be efficiently generated by this strategy. The stoichiometric ratio among the three substrates 6:8:9 (ca. 1:≤1.5:≤1.5) is particularly noteworthy, suggesting that any or all of the three participants could be of considerable structural complexity. Note that: i) many different classes of nitrogen-containing heterocycles are compatible with the process; ii) chloride can be introduced by performing the reaction in chloroform solution and in the absence of any additional proton source (P25; we have observed a similar chloride ion transfer from, presumably, Cl₃C^– in a recently reported mechanistic study³) iii) use of the quinuclidinol derivatives 8l–m allows for facile introduction of additional heteroatoms into the products (cf. P29–P31).

All of the single-step TCRs described in Figures 2 and 3 meet the following criteria: i) neither the amine or the protic nucleophile should react with the HDDA precursor faster than its rate of cyclization; ii) the tertiary amine should add to the benzyne faster than does the protic nucleophile; iii) the protic nucleophile (H-Nu) should be acidic enough to protonate the intermediate 1,3-zwitterion;¹⁴ and iv) the conjugate base of H-Nu should be sufficiently nucleophilic to ring open the aryl ammonium intermediate (cf. 10, Scheme 1).

We hypothesized that several of these limitations would be circumvented through a two-step process involving the formation and subsequent nucleophilic ring-opening of stoichiometric ammonium triflates 10-OTf (Figure 4).¹⁵ Indeed, if a benzyne 7 is produced from 6 in a solution containing both free tertiary amine and its ammonium triflate, the triflate salts 10-OTf are produced in stoichiometric fashion.¹⁶ For the examples shown in Figure 4, N-phenylpiperidine, N-phenylmorpholine, or DABCO was the amine component. The triflate was then exposed to a nucleophile to effect a 2-step, 3-component coupling. The examples in Figure 4 use one of 9n–9t as the nucleophile, but these by no means constitute a comprehensive set: i) sodium benzenesulfinate (9n) produced a mixture of sulfone P32 and sulfenic ester P33; ii) sodium amide salts 9p and 9t gave rise to the triazole P35 and indole P40, respectively; iii) a heterocyclic thiol (9q) led to the sulfide P36; iv) dimethyl sodiomalonate (9o) gave esters P34 and P38; v) morpholine (9r) produced the tertiary amine P37; and vi) sodium azide (9s) gave the azides P39. Through this protocol the scope of compatible nucleophiles is significantly broadened.

Figure 4.

The use of ammonium triflate intermediates allows for incorporation of an even broader range of nucleophiles.

Nearly all of the types of products produced through the TCRs described here can, in principle, be further diversified to give a wide range of heterocycle-rich small molecules. We show examples in Figure 5. The newly introduced heterocycles (in green) include: oxazolidinone (P41), benzopyrazole (P42), pyrrolopiperidine (P43), and triazoles (P44–P46). Other similar transformations are easily imagined.

Figure 5.

Examples demonstrating diversification of some of the TCR products to produce multiheterocyclic adducts.

In conclusion, we have developed the three-component reaction of HDDA-generated benzynes, cyclic tertiary amines, and protic nucleophiles. Many amines productively engage the benzyne, including N-aryl and N-alkyl cyclic amines and bicyclic amines containing a bridgehead nitrogen atom (8a–n). Many protic nucleophiles are effective (9a–9s). The use of ammonium triflate intermediates increases the scope of compatible nucleophiles (Figure 4). Facile post-TCR modification allows the introduction of additional heterocycles (Figure 5). This new TCR strategy is quite general and has considerable potential for the rapid construction of multiheterocyclic compounds.