O-Acetyl Oximes as Transformable Directing Groups for Pd-Catalyzed C–H Bond Functionalization

Abstract

O-Acetyl oximes serve as effective directing groups for Pd-catalyzed sp² and sp³ C–H functionalization reactions. The C–H functionalization products can be subsequently transformed into ortho- or β-functionalized ketones, alcohols, amines, and heterocycles.

Over the past decade, palladium-catalyzed ligand-directed C–H functionalization has been extensively exploited to convert unactivated carbon–hydrogen bonds into carbon–heteroatom and carbon–carbon bonds.¹ Despite the rapidly growing arsenal of methods in the field, the synthetic utility of these transformations is limited by the requirement that a directing group be built into the substrate. In particular, many effective directing groups are nitrogen-containing heterocycles that are not easily transformed or removed following the C–H functionalization event.¹

The ideal directing ligand would be sufficiently robust to tolerate C–H activation/functionalization conditions but then readily converted into diverse functional groups. Instances of such directing groups in Pd-catalyzed reactions are relatively rare. Yu and Shi have independently demonstrated C–H functionalization of triflamide^2a- and dimethyl^2b-protected benzyl amines followed by nucleophilic displacement or reduction of the amine directing group. Oxazolines have been used for Pd-catalyzed C–I bond forming reactions followed by H₂SO₄-catalyzed hydrolysis to afford carboxylic acids.³ Carboxylic acids have also been directly employed in Pd-catalyzed C–H arylation and then removed by decarboxylation.⁴ Finally, amides have proven effective for directing Pd-catalyzed C–C and C–halogen bond formation, and have been subsequently transformed into nitriles^5a or carboxylic acids.^5b

Ketones are particularly versatile and widely-used synthetic intermediates.⁶ However, ketones are poor ligands for Pd^II, and thus are generally ineffective directing groups for Pd-catalyzed C–H functionalization.^7,8 We sought to temporarily mask ketones as more coordinating imine or oxime derivatives during C–H functionalization and then subsequently remove this group to reveal the ketone functionality (Scheme 1). This communication describes the development of O-acetyl oximes as versatile and readily transformable directing groups for Pd-catalyzed C–H functionalization.

Scheme 1.

Approach to β-C–H Functionalization of Ketones

Two key challenges exist in the design of a ketone surrogate for Pd-catalyzed C–H functionalization. First, the protecting group must be stable to the catalytic conditions. Second, the group must be readily removed in high yield without affecting the newly installed functional group. Previous studies have shown that oxime ethers such as 1 (eq 1) are effective directing groups for Pd-catalyzed sp² and sp³ C–H acetoxylation reactions with PhI(OAc)₂.^9,10 However, removal of the oxime ether protecting group from β-functionalized products like 2 is problematic. Acid-catalyzed hydrolysis¹¹ is sluggish and produces significant quantities of elimination products 3 and 4 (eq. 1).¹² The use of super-stoichiometric Ti^IIICl₃ is effective in some cases,¹³ but this expensive, air sensitive reagent is not practical for general application.

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Imines would be a versatile alternative to oxime ethers, as they are readily hydrolyzed under mild conditions. Pd-catalyzed imine-directed acetoxylation of an sp² C–H bond has been reported;^9a however, imines have proven too labile for analogous sp³ C–H acetoxylations. For example, reaction of 5 under standard acetoxylation conditions affords the hydrolyzed ketone 6 as the major identifiable product (39% yield, eq 2).

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Simple hydroxyl (OH) oximes are another attractive ketone surrogate. These are readily available, stable, often crystalline starting materials, are known to direct stoichiometric cyclopalladation of both sp² and sp³ C–H bonds,¹⁴ and are much more readily cleaved than their oxime ether counterparts.¹⁵ In addition, they are prepared from NH₂OH•HCl, which is nearly 100-fold less expensive than NH₂OMe•HCl.¹⁶ Despite these advantages, oximes are known to undergo rapid oxidative cleavage in the presence of oxidants like PhI(OAc)₂.¹⁷ For example, subjecting oxime 7 to Pd(OAc)₂ and PhI(OAc)₂ in AcOH resulted in a nearly instantaneous color change from colorless to blue-green, concomitant with regeneration of the parent ketone 6. However, encouragingly, a similar color change was not observed when the solvent was changed from AcOH to AcOH/Ac₂O (1:1). Under these conditions, only traces of ketone 6 (4% by GC) were formed; instead the major product (68% by GC) was the O-acetylated/C–H acetoxylated compound 9 (eq 3).

This initial result suggested that the in situ reaction of 7 with Ac₂O affords a stable O-acetyl oxime (8) that can direct C–H acetoxylation. Further study showed that this in situ O-acetylation occurred quantitatively upon stirring the oxime starting material in AcOH/Ac₂O for 2 h at 25 °C. Subsequent addition of Pd catalyst and oxidant, followed by heating the reaction mixture at 100 °C for 12 h afforded 8 in 70% GC yield (49% isolated).

As summarized in Table 1, a number of dialkyl oximes underwent in situ acetylation/β-acetoxylation in modest to good yields (entries 1–6). The observed trends in reactivity and selectivity were similar to those in sp³ C–H functionalization reactions of related oxime ethers.^9b For example, oxidation occurred selectively at 1° β-sp³ C–H bonds versus the analogous 2° sites (entries 1–4). Acetoxylation of a 2° C–H bond could be achieved in modest yield in the rigid trans-decalone system (entry 6). The reaction conditions were compatible with a number of functional groups, including alkyl chlorides (entry 4) and protected amines (entry 3); furthermore, remote benzylic C–H bonds were well tolerated under the oxidizing reaction conditions (entries 1, 9, 14).¹⁸

Table 1.

O-Acetyl Oxime-Directed Acetoxylation of C–H Bonds^a

entry	starting material	product	yieldb
1c			49% (70%)d
2c			61%
3c			65%
4c			33%
5c			66%
6			41%
7e			61%
8e			86%
9e			72%
10			77%d
11e			77%
12e			79%
13e			80%
14			55%

^aConditions: 0.12 M in AcOH/Ac₂O (1:1), 2 h, 25 °C; then 5 mol % Pd(OAc)₂, 1–3 equiv PhI(OAc)₂, 80 or 100 °C, 4–12 h.

^bThe remaining mass balance (as determined by GC of the crude reaction mixtures) was generally unreacted O-acetyloxime (analogous to 8 in eq 3).

^cStarting material and product consisted of a mixture of oxime E/Z stereoisomers.

^dGC yield.

^eProduct consisted of a mixture of oxime E/Z stereoisomers.

O-Acetyl ketoximes were also effective directing groups for Pd-catalyzed acetoxylation at sp² C–H sites. Both electron poor and electron rich aryl rings underwent mono-ortho-oxygenation in high yields (entries 7 and 11). Further, aryl bromides (entry 8) and silyl-protected phenols (entry 12) were compatible with the reaction conditions. One notable limitation of this method is that O-acetyl aldoximes (for example, entry 10) were susceptible to elimination of AcOH to generate nitriles.¹⁹

The C–H acetoxylation products in Table 1 were obtained in yields comparable to those previously reported with oxime ether derivatives.^9b,d However, the O-acetyl oxime directing group is significantly more readily deprotected. In general, β-hydroxy ketones are accessible via alcoholysis of both acetate groups (to afford β-hydroxy oximes) followed by removal of the oxime functionality. The first step can be accomplished by treatment of starting materials like 9 with K₂CO₃ in MeOH to afford 10 in 91% isolated yield.

While numerous methods exist for the second step (conversion of an oxime to a ketone), many of our substrates are susceptible to competing formation of side products (e.g., via alcohol oxidation, isoxazoline formation, or elimination). After extensive experimentation, we identified the use of NaHSO₃ in EtOH/H₂O²⁰ as the most general and high yielding method to transform these oximes into β-hydroxy ketones, while circumventing undesired side reactions and persistent byproducts. Under these conditions, substrate 10 was converted cleanly to 11 in 80% yield. Compound 11 was obtained in pure form by a simple extraction, obviating the need for chromatography.

The two deprotection steps could also be combined to provide an operationally simple, high yielding, one-pot route from O-acetyl oxime C–H oxidation products to β-hydroxy ketones (eq 4). For example, treatment of 9 with K₂CO₃ in MeOH, followed by addition of NaHSO₃ and H₂O provided 11 in 80% yield after a simple extractive work-up (eq 4). As shown in Table 2, this one-pot deprotection could also be achieved with other substrates. Under these conditions elimination products were not observed, and isoxazoline formation was limited to ≤5%.

Table 2.

Deprotection to β- and ortho-Hydroxy Ketones^a

entry	starting material	product	yield
1			80%
2			56%
3			83%
4			89%

^aConditions entries 1–3 (one pot): K₂CO₃ (3 × 0.15 equiv/2.5 h), MeOH, 25 °C, then 3.5 equiv NaHSO₃, H₂O, 80 °C, 3 h; Conditions entry 4 (two steps): (i) 0.15 equiv K₂CO₃, MeOH, 25 °C, 1 h, then (ii) 3.5 equiv NaHSO₃, H₂O, EtOH, 90 °C, 12 h.

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An important characteristic of the O-acetyl oxime directing group is that it enables access to a variety of additional structural motifs from a common synthetic intermediate. As exemplified with 12 in Scheme 2, K₂CO₃-catalyzed methanolysis of the acetyl groups provided oxime 13 in quantitative yield. Product 13 could then be converted to the corresponding acetophenone 14, to oxazoline 15 (via Beckmann rearrangement²¹ followed by intramolecular condensation), to amino phenol 16 (via reduction),²² and to diol 17 (via oxime hydrolysis followed by reduction).²³

Scheme 2.

Diverse Transformations on C–H Functionalization Product 12

Preliminary results indicate that these O-acetyl oximes are also effective directing groups for other Pd-catalyzed C–H functionalization reactions. For example, as shown in Scheme 3, the Pd-catalyzed iodination of 18 and chlorination of 19 proceeded to form aryl halides 20 and 21 in modest to good yields.²⁴ Interestingly, under standard Pd-catalyzed C–H arylation conditions with PhI and AgOAc in TFA,²⁵ 19 underwent in situ Beckmann rearrangement/C–H phenylation to afford acetamide 22.

Scheme 3.

Other Pd-Catalyzed C–H Functionalization Reactions of O-Acetyl Oximes

In conclusion, this letter describes the use of in situ generated O-acetyl oximes as effective directing groups in Pd-catalyzed C–H functionalization reactions. These directing groups are stable under the catalytic reaction conditions but can then be readily manipulated to afford ketones, alcohols, amines, and heterocycles.