Regiodivergent Electrophotocatalytic Aminooxygenation of Aryl Olefins

Abstract

A method for the regiodivergent aminooxygenation of aryl olefins under electrophotocatalytic conditions is described. The procedure employs a trisaminocyclopropenium (TAC) ion catalyst with visible light irradiation under a controlled electrochemical potential to convert aryl olefins to the corresponding oxazolines with high chemo- and diastereoselectivity. With the judicious choice of inexpensive and abundant reagents, water or urethane, either 2-amino-1-ol or 1-amino-2-ol derivatives could be prepared from the same substrate. This method is amenable to multigram synthesis of the oxazoline products with low catalyst loadings.

Graphical Abstract

Aryl-substituted 1,2-aminoalcohols of both regioisomeric configurations 1 and 2 are a prevalent architectural motif in many complex molecules, including the bioactive molecules shown in Figure 1A.¹ These structures also commonly occur in natural products,^2,3 chiral auxiliaries,⁴ and ligands for metal catalysis⁵. To construct such motifs, the direct aminooxygenation of alkenes offers one of the most useful modular approaches, and numerous methods to achieve this type of transformation have been developed^6–7,8. After the seminal example reported by Sharpless using osmium catalysis^9,10, many methods have been developed using a variety of other transition metal catalysts^{11–12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33}. However, in recognition of some of the drawbacks of transition metals, there has also been significant effort directed toward the development of methods that utilize non-transition metal reagents or catalysts^{34–35,36,37,38,39,40,41,42,43}. While creative and practical successes have been registered in this area, most of these methods rely on stoichiometric oxidizing agents, which come with their own environmental, safety, and cost issues. In this regard, electrochemistry^{44–45,46,47,48} potentially offers an attractive alternative by obviating the need for traditional chemical oxidants, and indeed Moeller^{49–50,51,52} and Xu⁵³ have reported electrochemical intramolecular olefin aminooxygenation reactions. However, a more general intermolecular protocol remains an open challenge.

Figure 1.

A. Selected examples of biologically active aryl aminoalcohols. B. Goal of access to either aryl aminoalcohol regioisomer. C. Regiodivergent TAC electrophotocatalytic olefin aminooxygenation.

In theory, it should be possible to achieve intermolecular olefin aminooxygenation by the direct electrochemical single-electron oxidation of olefins. However, this strategy is often complicated by selectivity issues because the resulting anodically-generated olefin radical cations are prone to oligomerization or oxidative cleavage^54,55. Lei developed a workaround to this problem by making use of in situ generation of electrophilic chlorine, which achieved oxazoline synthesis via chloronium ion formation followed by trapping with an amide reactant⁵⁶. Still, the highly reactive nature of chlorine is not ideal from a chemoselectivity standpoint, and, apropos of the current work, only provides access to 2-amino-1-alcohol regioisomers. In fact, the divergent synthesis of either 2-amino-1-ol 1 or 1-amino-2-ol 2 derivatives from the same starting material 3 represents an important challenge (Figure 1B), which only a few methods have achieved. In pioneering work, Yoon first reported a catalyst-controlled strategy to selectively access either regioisomeric product from oxaziridine reagents.^25,28 Subsequently, Rovis achieved intramolecular regiodivergent alkene aminooxygenation by ligand-controlled Ir-catalysis.³² Recently, Li reported an iodide-catalyzed intermolecular aminooxygenation strategy, in which simple base or Lewis acid additives were used to control regioselectivity.³⁶ Despite these advances, there remains the need to develop new methods for the regiodivergent aminooxygenation of olefins. In this Communication, we report such a method of aryl olefins using electrophotocatalysis^57,58, in which the regioselection is dictated by the simple choice of either urethane or water (Figure 1C).

Electrophotocatalysis (EPC) involves the combination of electrochemical and photochemical energies to catalyze reactions⁵⁹. We have used trisaminocyclopropenium (TAC) ion 6 as an electrophotocatalyst, which operates by electrochemical oxidation to the radical dication 7 and photoexcitation to the strongly oxidizing species 8. TAC EPC has allowed us to achieve a number of oxidative transformations, including the dioxygenation of aryl olefins with acetic acid⁶⁰ and in another case the diamination of aryl olefin intermediates with acetonitrile.⁶¹ In the latter case, oxyamination products could also be obtained under modified conditions, but these products were formed as mixtures with the diamination adducts. To parlay this reactivity into a selective oxyamination procedure, control of the nitrogen and oxygen nucleophiles and their order of addition must be achieved. We reasoned that control of the first addition should be dictated by the most competent nucleophile in the reaction vessel.

With this idea in mind, we targeted the use of water in acetonitrile as the best opportunity to achieve the oxygen-first addition. We first examined the conversion of 2-methyl-1-phenyl-1-propene (9) to oxazoline 10 (Table 1). Our initial conditions involved subjecting an acetonitrile solution of 9, water (50 equiv), trifluoroacetic acid (5 equiv), and 8 mol% TAC 6 to a 2.0 V controlled potential in a divided cell (carbon cathode, Pt anode) under visible light irradiation (CFL bulbs) in the presence of LiClO₄. After 18 h, the product 10 was generated (entry 1), but only in 28% yield, along with benzaldehyde as side product. We hypothesized that this side reaction arose from the electrochemical oxidative cleavage of a 1,2-diol intermediate,⁶² which is produced in significant quantities when water is present in large excess. Accordingly, we found that less water led to higher yields (entries 2 – 4), with the optimum being 5.0 equivalents (entry 4). Further reductions in the amount of water were counterproductive, however (e.g. entry 5). When using a lower cell potential of 1.5 V, a reasonable yield of 10 could be achieved (61%, entry 6), but a longer reaction time (30 h) was required. Control experiments indicated that the catalyst, light, and electricity were necessary for high conversion (entries 7–9 and supporting information). Importantly, direct electrolysis using up to 3.0 V constant voltage led to the production of a mixture of aldehyde, ketone, diacetyl acetal, and olefin dimer products with minimal yield of oxazoline 10 (entry 10). ^54,63 The absence of selectivity under the direct electrolysis conditions underscores the unique reactivity of the electrophotocatalytic approach. With the optimized conditions, a 25 mmol scale reaction was conducted using only 3 mol% of TAC catalyst 6 and a longer reaction time (36 h, entry 11).

Table 1.

Optimization studies for regiodivergent aminooxygenation of 2-methyl-1-phenyl-1-propene.^a,b

entry	voltage (V)	NuH (equiv)	other	10 yield (%)	11 yield (%)
1	2.0	H20 (50.0)	-	28	-
2	2.0	H20 (25.0)	-	41	-
3	2.0	H20 (10.0)	-	75	-
4	2.0	H20 (5.0)	-	76 (81)[c]	-
5	2.0	H20 (1.5)	-	39	-
6	1.5	H20 (5.0)	-	61	-
7	2.0	H20 (5.0)	no catalyst	28	-
8	2.0	H20 (5.0)	no light	17	-
9	2.0	H20 (5.0)	no electrolysis	0	-
10	2.0	H20 (5.0)	direct electrolysis at 3.0 V	23	-
11	2.0	H20 (5.0)	25 mmol scale	66[c]	-
12	2.0	H2NC02Et (12)	-	<10	81[c]
13	2.0	H2NC02Et (6)	-	<10	83[c]
14	2.0	H2NC02Et (3)	-	30[c]	35[c|

^aSee SI for detailed procedures.

^bYields determined by

¹H NMR spectroscopy.

^cYield of isolated product.

To access oxazoline products with the opposite regioselectivity, we investigated the use of a reactant in place of water that would achieve nitrogen-first addition, and then oxygen addition via cyclization. With this plan, we found that the addition of 12 equiv. of readily available urethane furnished the alternative product 11 in 81% yield, with less than 10% of 10 observed (entry 12). Understandably, taking care to exclude water from the reaction mixture was necessary to minimize the formation of 10, but with rigorously dried conditions this product could be suppressed to below 5%. Reducing the amount of urethane to 6 equiv. did not diminish the yield of product 11 (entry 13), but 3 equiv. was much less effective (entry 14).

With these optimized conditions in hand, we first explored the substrate scope of the aminooxygenation reaction with water as reagent (Table 2). First, various cyclic alkenes were found to undergo efficient aminooxygenation reactions with high levels of syn diastereoselectivity (12-16). Acyclic stryenic olefins also led to oxazoline products 17–21 in moderate to good yields. The reactions were found to be compatible with carboxy (20) and alkoxy (21) substitution on the aryl ring. Furthermore, trisubstituted aryl olefins with various functional groups, including trifluoromethyl (22), alkyne (23) and fluorine (24), also participated in the reaction efficiently. In addition, adduct 25, bearing a pinacol boronate moiety, could be prepared in high yield with this protocol. Sterically hindered 1,1,2-trisubstituted olefins were successfully transformed to the desired oxazolines 26 and 27 containing a fully substituted carbon center. Although some electron-rich heterocycles are sensitive to oxidative electrochemical processes, this method was compatible with various rings including thiophene (28), benzothiophene (29), dibenzothiophene (30), and pyrazole (31).

Table 2.

Scope of electrophotocatalytic aminooxygenation of aryl olefins with water as reagent.^a,b,c

^aSee SI for detailed procedures and general hydrolysis conditions to reveal the aminoalcohols.

^bIsolated yields.

^cDiastereomeric ratio (d.r.) determined by

¹H NMR spectroscopy. 14: 2:1 d.r., 19: 10:1 d.r., 27: 6:1 d.r., 33: 1:1 d.r.

One limitation of many aminooxygenation reactions arises from the difficulties in differentiating between aliphatic and aryl alkenes, and so several substrates with both types of alkenes were tested. The exclusive formation of the products 32–34 shows that this method is highly selective for the aryl-substituted alkene, even in competition with a strained norbornene derivative (32). Interestingly, 1,3-dienes exclusively underwent 1,2-aminooxygenation to furnish 35 and 36, with reaction taking place preferentially at the olefin distal to the aryl ring. Notably, we found that this protocol could also be applied to the formation of more complex products 37–39 bearing diverse functionality.

We next explored the scope of the reaction using urethane as the nucleophile to yield the regioisomeric aminoxygenated products (Table 3). Again, we found that various aryl olefins could participate in this reaction to produce the desired oxazolines with high levels of regio- and diastereoselectivity. For example, a variety of 1,2-disubstituted styrene and stilbene type olefins led to aminooxygenation products 40–49 in moderate to good yields and with high selectivity for the trans diastereomers. Furthermore, trisubstituted olefins of varying structures also worked smoothly (11, 50-54). An alternative carbamate also proved viable, as reaction of 9 with methyl carbamate provided the methyl analog of 11 (see Supporting Information for details). Again, this method was compatible with electron-rich heterocycles which can be sensitive to electrochemical oxidation processes (55–58). Additionally, as with the reaction using water as the reagent, this protocol also displayed high chemoselectivity for reaction of the aryl olefin (59), and distal 1,2-aminooxygenation of 1,3-dienes was observed (60–61). Lastly, we found the probenecid derivative 62 was also formed in good yield. Interestingly, we found a cyclic olefin substrate to be problematic in that it led to substantial amounts of diamination product in addition to the desired oxazole (see Supporting Information for details).

Table 3.

Scope of electrophotocatalytic aminooxygenation of aryl olefins with urethane as reagent.^a,b,c

^aSee SI for detailed procedures and general hydrolysis conditions to reveal the aminoalcohols.

^bIsolated yields.

^cDiastereomeric ratio (d.r.) determined by

¹H NMR spectroscopy. 53: 3:1 d.r., 54: 2:1 d.r.

The mechanistic rationale for these catalytic reactions is shown in Figure 2. As we have previously described, TAC 6 can be electrochemically oxidized at a relatively mild potential (1.26 V vs. SCE) to furnish the deep red TAC radical dication 7. Upon photoexcitation, the very strongly oxidizing 8 (E*_red = 3.3 V vs. SCE) is generated, which can oxidize alkene 63⁶⁴ to radical cation 64. Nucleophilic trapping of 64 by water leads to the radical 65. Further oxidation of this radical (either by 7 or the anode) to cation 66, followed by nucleophilic trapping by acetonitrile then reveals the intermediate 67. After intramolecular addition of the hydroxyl group to the nitrilium ion, oxazoline product 68 is produced. We believe that water can be competitive as the second nucleophile to form diol 69, particularly when present in large equivalencies, as evidenced by the formation of benzaldehyde when too much water is present (see Table 1, entry 1). However, minimizing the amount of water enables selective trapping of 66 with acetonitrile, thus leading to adduct 68.

Figure 2.

Mechanistic rationale for regiodivergent aminooxygenation reactions.

Alternatively, the use of urethane instead of water leads to the formation of radical 70 via the trapping of radical cation 64 with this alternate nucleophile. Oxidation of 70 leads to cyclization by the carbamate carbonyl oxygen, thus furnishing product 71. Obviously, the key to both of these reactions is that the water or urethane outcompetes acetonitrile for the first nucleophilic addition step.

The methods described here offer a convenient strategy to convert aryl olefins to oxazolines of either regioselectivity simply by the choice of two inexpensive reagents: water or urethane. The use of electrophotocatalysis to effect these transformations enables the double nucleophilic addition to aryl olefins without the need for a stoichiometric chemical oxidant. Furthermore, the mild reaction conditions make these methods compatible with various functional groups, heterocycles, and complex structures.