Reactions of Diaziridines with Benzynes Give N-Arylhydrazones

Abstract

Reactions of thermally generated benzynes with diaziridines are reported. These trapping reactions follow the same pathway as reported earlier by Heine and coworkers with electron-deficient alkynes. The resulting N-aryl hydrazones were obtained efficiently in a single step. The preference for the mode of addition of the nucleophilic diaziridine nitrogen atom to the more electrophilic benzyne carbon was consistent with what is predicted on the basis of distortion analysis. The feasibility of converting the hydrazone into a Fisher-indole adduct was demonstrated.

Graphical Abstract

Forty-five years ago, Heine and coworkers reported on the reactions of nucleophilic diaziridines with electrophilic alkynes (e.g., 1 + 2 to 3 in Figure 1).¹ Largely as a result of a ¹⁵N-labeling experiment (red atoms), the mechanism of the reaction was deemed to involve initial addition of the alkylated (R¹) nitrogen atom to provide the intermediate zwitterion 4.³ Ring-opening was then invoked to give the iminium ion 5, within which proton transfer would then lead to the adduct 3.

Figure 1.

Reaction of nucleophilic diaziridines with electrophilic alkynes.¹

Arynes, another class of “electrophilic acetylene,”¹ have been trapped with myriad nucleophilic trapping agents.⁴Benzyne derivatives can be formed by simple thermal activation of appropriately tethered triyne substrates ⁵ via a process we have called the hexadehydro-Diels-Alder (HDDA) reaction.⁶ We report here reactions of various diaziridines with a number of electrophilic HDDA-generated benzynes. Gratifyingly, these transformations follow the same reaction course as uncovered in 1973. Namely (and as generically shown in Figure 2), when a substrate 6 is heated in the presence of a diaziridine 2, a hydrazone 7 is formed efficiently. We suggest that this is best rationalized, again, by initial attack of the N-alkylated nitrogen in 2 to the benzyne 8 to produce the zwitterion 9. Secondary amines readily add to electron poor alkynes, so the preferential attack by the more substituted and hindered (albeit also more electron rich) nitrogen atom in 2 to either of the “acetylenes” 1 or 8 may be attainable because of the highly unhindered nature of the electrophilic alkynes, all the more so because of the bent geometry of the sp-carbons in 8. Also, the trapping of an aryne by a nucleophile (here, the diaziridine nitrogen) is often significantly exothermic. Accordingly, the transition state should be reached early on the reaction coordinate and have a relatively long distance between the nitrogen and benzyne carbon atoms. This would further reduce the importance of steric interactions in the initial adduct formation. Further transformation of 9 to 7 requires both a proton transfer and ring-opening event of the strained ring. This could conceivably be a concerted process or occur in either order via intermediate 1,2- or 1,4-zwitterions 10 or 11, respectively.

Figure 2.

Reaction of a generic HDDA-generated benzyne and a monoalkylated diaziridine (this work).

We first examined the reaction of triyne 6a with seven different diaziridines (2a–g, entries 1–7, Table 1). These trapping agents differed in the nature of alkyl/aryl substitution at the 3–position of the diaziridine ring. All bear one N-alkyl group (benzyl), which differentiates the nucleophilicity of the two nitrogen atoms. The products from these seven experiments (7aa-7ag) indicated that the benzyne trapping reactions with diaziridines had followed the same course of reaction as precedented (Figure 1) and projected on mechanistic grounds (Figure 2). They all can be rationalized as resulting from attack by the hindered, N1 nitrogen atom at the more electrophilic sp-hybridized carbon atom in the distorted benzyne intermediate 8a (Figure 3).

Table 1.

Products 7^a from reactions^b between benzyne precursors 6a-f and diaziridines 2a-h.

^aThe structure number of each product contains two letters, the first indicating the poly-yne 6 and the second the diaziridine 2 of origin.

^bAll reactions were performed in benzene having an initial [6] = 0.02 M and [2] = 0.04 M. Solutions were heated at 85–90 °C (external bath T) for 18-19 h, except for the case of the less reactive 6e, where the reaction time was 48 h.

Figure 3.

Internal bond angles (∠) at the two benzyne carbons, reflecting the computed ring distortion of the benzynes 8a-f derived from each of the poly-ynes 6a-f {DFT: [SMD(benzene)//M06-2X/6-311+G(d,p)}.

We proceeded to explore the reactions of other HDDA benzyne substrates, namely 6b–f (entries 8–17). These reacted in similar fashion, demonstrating generality within the benzyne component, leading to various N-arylated hydrazone products. The matching of which two reactants were used in the examples in entries 8–17 of Table 1 (i.e., which benzyne precursor 6 with which diaziridine 2) was arbitrarily chosen. Nonetheless, this representative subset demonstrates the generality of the reaction.

Each of the benzyne species 8a-f derived from the set of poly-yne substrates 6a-f is shown in Figure 3. Their reactions with diaziridines were observed to proceed with exclusive regioselectivity for the cases of 8a, 8e, and 8f; mixtures of constitutional isomers were formed in each of the cases of 8b-d. These selectivities for nucleophilic addition to these benzynes are consistent with those expected either from (i) reported reactions with nucleophiles7 or (ii) the extent and direction of the computed distortion [DFT, Figure 3: 8a-c and f (see SI), 8d,^7a and 8e⁷ⁱ]. Distortion analysis has been used quite successfully to account for the strong preference for addition by a nucleophile at the more electrophilic, obtuse sp-center, which has a greater proportion of p-character.⁸ As the magnitude of the difference in the two internal angles diminishes, subtle differences in steric effects for the two potential modes of addition begin to play a more important role (cf. differences in the isomer ratios among entries 9–12 or of 13 vs. 14).

The reactions using the 3-phenyl-substitued diaziridine 2d gave less efficient formation of the hydrazone products (entries 4, 10, 14, and 17). In one instance (entry 4), we separated and identified the product of the major competing pathway—namely, the (polar and chromatographically poorly behaved) amidine 12ad (Figure 4). Presumably, in this reaction the benzyne 8a undergoes initial attack by the NH rather than the NBn nitrogen atom of the diaziridine leading to the zwitterion 13. This species, now containing a benzylic C–H proton, can undergo internal proton transfer to produce 14 followed by a ring-opening event to give the amidine 12ad.

Figure 4.

Rationale for formation of amidine 12ad via initial attack of the secondary amine in 2d to the benzyne 8a.

Finally, we have also demonstrated two examples in which these hydrazone products can be converted into fused indole derivatives. Specifically, we were inspired by the report of Greaney et al. in which benzyne-derived hydrazones underwent Fischer indole cyclization using Lewis acid catalysis to produce indole adducts.⁹When exposed to ZnCl₂ at elevated temperature in tert-amyl alcohol, the hydrazones 7ae and 7aa produced the corresponding cyclized products 9ae and 9aa, respectively (Figure 5). In both cases Lewis acid mediated desilylation was observed under the reaction conditions.

Figure 5.

Fischer indole adducts, 9ae and 9aa derived from hydrazones, 7ae and 7aa, respectively.

In conclusion, the results presented here demonstrate the generality of trapping thermally generated, polycyclic benzyne species with heteroatom-rich diaziridines. These trapping reactions lead to N-arylated hydrazones in a single step. In some instances, these products can be converted to fused-ring indole derivatives. The mechanism of this trapping reaction with benzynes is consistent with one established earlier with electron deficient acetylenes. The preferred mode of addition was consistent with that suggested by DFT-derived structures of the intermediate benzynes.