Chapter 5. Oxidative Inter-/Intermolecular Alkene Diamination of Hydroxy Styrenes with
5.4 Control Experiments and Mechanistic Hypothesis
Throughout the course of these exploratory studies for the doubly intermolecular alkene diamination, a number of experiments were directed at the isolation of key intermediates or products along the preferred or competing reaction pathways. Chief among these co-products is bis(oxygenation) product 355. This particular product arose from a control experiment in which 2- vinyl phenol was treated with PhI(OAc)2 and KI alone (no amine). 1H NMR analysis of the crude
reaction mixture showed 3-acetoxydihydrobenzofuran (355) as the major product, and subsequent chromatographic separation provided compound 355 in 69% isolated yield (Scheme 140).
Another key product isolated was that of iodoacetoxylation product 356. Based on our previous success of alkene diamination with electron-rich amines, we wanted to see if electron- withdrawing amines could also be tolerated. When combining 2-vinyl phenol with the PhI(OAc)2/KI combination in the presence of electron-deficient bistosylimide (Ts2NH), iodide 356
was furnished, albeit in low yield (12%) (Scheme 141).
Isolation of bis(oxygenation) and iodoacetoxylation products 355 and 356 enabled further studies that could determine if these compounds indeed serve as intermediates en route to diamination. When 355 and 356 were individually subjected to the standard diamination protocol (PhI(OAc)2, KI, thiomorpholine, and CH3CN) at room temperature, no sign of diamine 338a could
be detected (Scheme 142). Furthermore, neither of those intermediates is observed directly during the conversion of 2-vinyl phenol (336) to diamination product 338a under the same reaction conditions. What has been determined, however, is iodide 356 and 3-acetoxydihydrobenzofuran (355) are united in a common pathway. This was confirmed as phenol 356 converts to 355 when exposed to PhI(OAc)2/KI in the absence of amine or when treated with amine alone.
Scheme 140. Generation of Bis(oxygenation) Product 355
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These intermediates were of interest as they provide useful mechanistic insight. These products appear to collectively arise from electrophile addition to the terminal carbon, followed by nucleophilic addition to the benzylic carbon. It is speculated that carbon-nitrogen bond formation via an electrophilic amine formed in situ is a key aspect of the actual mechanism leading to diamination. Additionally, this speculation of electrophilic amine addition (terminal carbon) and subsequent nucleophilic addition (benzylic position) is reflective of the aminoacetoxylation products depicted in Scheme 139. Non-nucleophilic amines such as Ts2NH did not provide
diamination product, even when applying the protocol developed by Muñiz (Scheme 143).166
Instead, monoamination product 357 was afforded in low yield, perhaps through a pathway analogous to 336 → 356→ 355. This result is also consistent with the unique reactivity of an electrophilic amine using the PhI(OAc)2/KI protocol.
A plausible reaction mechanism is depicted in Figure 24. When KI interacts with PhI(OAc)2, it is believed that the iodide substitutes for one of the acetoxy groups, generating
electrophilic iodinating agent A. This particular iodane (A) can activate the amine (B) through iodamine formation (C). The success of NIS in this transformation further suggests that the formation of an iodamine is key in the reaction pathway. Subsequent attack of the halamine by the
Scheme 142. Other Findings with Bis(oxygenation) and Iodoacetoxylation Products 355 and 356
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alkene moiety of 2-vinylphenol generates intermediate D. The lone pairs of electrons on the hydroxyl unit can resonate in order to break open the aziridinium, resulting in ortho-quinone methide E. This intermediate serves as a suitable electrophile for nucleophilic attack of amine en route to homodiamination (F).
One of the key features in regard to the mechanistic pathway described above is the regeneration of iodide. Because it is hypothesized that iodide is regenerated in situ, it is plausible that diamination can be achieved when employing substoichiometric or catalytic quantities of halide. While previous studies employed a full equivalent of KI in order to apply general conditions
Figure 24. Mechanistic Hypothesis for PhI(OAc)2/KI-Mediated Intermolecular Diamination
Table 22. KI Loading Study
entry catalyst loading yield (%) 1 0 mol% 6 2 1 mol% 34 3 2 mol% 54 4 3 mol% 60 5 4 mol% 68 6 5 mol% 73 7 10 mol% 74 8 30 mol% 86 9 50 mol% 86 10 100 mol% 94 11 120 mol% 96
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to a broad collection of substrates, a series of experiments were designed to vary KI loading in the diamination of 2-vinyl phenol (336) with thiomorpholine.
Starving the reaction conditions of the additive resulted in minimal background reactivity (6% yield) (Table 22, entry 1). Yet, when a 1 mol% loading of KI was used, reactivity increased nearly six-fold as diamination product 338a was isolated in 34% yield (Table 22, entry 2). Progressively increasing the iodide loading led to higher yield (Table 22, entries 3-6). This was reflected through a 10 mol% loading, which correlated to a 74% yield of 338a (Table 22, entry 7). Despite observing sufficient reactivity with catalytic halide loadings, further studies confirmed that substoichiometric and even stoichiometric amounts of KI (Table 22, entries 8-11) were necessary in order to achieve optimal yield (Figure 25).
5.5. Future Work
Although this doubly intermolecular diamination with 2-vinylphenol was met with a high degree of success, other avenues can be explored in order to make this system even more efficient. One particular direction to pursue is heterodiamination of 2-vinylphenol. As described previously, this diamination protocol was tolerant to a wide array of amines. One of the main drawbacks, however, is that the amine moieties are identical at both sites of diamination (i.e. homodiamination). If two different amines, such as aniline and thiomorpholine, can be regioselectively installed at these positions through reaction optimization, a much higher level of generality would be achieved for this reaction system (Scheme 144).
Figure 25. Relative Comparison of KI Loading and Reactivity
0 10 20 30 40 50 60 70 80 90 100 0 20 40 60 80 100 120 isolate d yi e ld (% ) mol% KI
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The enantioselective variation of this system is another route to be taken. This can be probed by subjecting a number of chiral organocatalysts (e.g. PBAM) to the previously developed protocol (Scheme 145). Another plausible approach towards achieving enantioselection would be the use of a chiral hypervalent iodine reagent as employed by Muñiz and Ishihara.164,165 If this strategy proves fruitless, in situ generation of chiral iodine(III) via incorporation of chiral iodoarenes and MCPBA would be another possibility. These investigations are currently ongoing within our laboratory.
Scheme 144. Proposed Heterodiamination of 2-Vinyl Phenol
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