Palladium-Catalyzed Oxidative Synthesis of α-Acetoxylated Enones from Alkynes.

We report a palladium-catalyzed oxidative functionalization of alkynes to generate α-acetoxylated enones in one step. A range of functional groups are well-tolerated in this reaction. Mechanistic studies, including the use of (18) O-labeled DMSO, revealed that the ketone oxygen atom in the product originates from DMSO.

Reactions involving C−H functionalization have been widely recognized as highly demanding methodologies for the direct introduction of new functional groups into molecules. For several decades, these reactions have been comprehensively studied in the realm of late‐transition‐metal catalysis, most recently with the assistance of some directing groups.1, 2 In the absence of directing groups, the reaction outcome is mainly determined by its intrinsic reactivity and/or selectivity. In the n>an class="Chemical">palladium‐catalyzed allylic C(sp3)−H acetoxylation reaction, early studies on cyclic alkenes by the Åkermark3 and our group4 showed that in acetic acid, the reaction proceeds via a π‐allylpalladium(II) intermediate. White and co‐workers later found that in the reaction of acyclic terminal olefins, the addition of sulfoxide ligands significantly promoted the allylic C−H oxidation and also allowed the amount of acetic acid to be lowered to 4 equivalents (Scheme 1 a).5

Scheme 1

Palladium‐catalyzed allylic and propargylic C−H functionalization. DMSO=dimethyl sulfoxide.

Following our long‐term interest in palladium‐catalyzed oxidation chemistry, we have actively engaged in the developn>ment of various oxidative carbocyclization reactions.6, 7 In our recent studies of the cyclization of allenynes, we observed an unconventional propn>argylic C−H activation pathway, and the vinylallene products could be formed selectively (Scheme 1 b).8 An interesting question is whether a similar propn>argylic C−H functionalization can also take place with simpn>le n>an class="Chemical">alkynes, via either an allenyl‐ or a propargylpalladium intermediate, which could then undergo a suitable functionalization step, for example, acetoxylation (Scheme 1 c).9, 10 In our evaluation of various acetate sources in the presence of sulfoxides and 1,4‐benzoquinone (BQ), no desired allenyl/propargyl acetates were observed. However, we found that the treatment of alkynes with catalytic amounts of Pd(OAc)2 and (diacetoxyiodo)benzene (PIDA) in DMSO afforded (Z)‐α‐acetoxylated enones with high selectivity (Scheme 1 c).11 To the best of our knowledge, α‐acetoxylated enones were previously only accessible from prefunctionalized starting materials, for example, through the isomerization of propargylic acetates12 or acylation of 1,2‐diketone compounds.13 The use of simple alkynes to directly generate such functionality‐rich structures is unprecedented.14 Herein, we report a palladium‐catalyzed one‐step oxidative protocol for the conversion of alkynes into α‐acetoxylated enones.

We initiated the investigation by using 1‐phenyl‐1‐butyne (1 a) as the model substrate. When alkyne 1 a was treated with n>an class="Chemical">Pd(OAc)2 (5 mol %) and PIDA (1.5 equiv) in [D6]DMSO at 50 °C for 18 h, the α‐acetoxylated enone 2 a was formed in 46 % yield, and the vicinal diketone 3 a was also observed as a side product (7 % yield; Table 1, entry 1).15 No reaction occurred in the absence of either Pd(OAc)2 or PIDA.16 Acetonitrile, chloroform, and toluene could be used as cosolvents, but no increase in yield was observed under these conditions.17 Increased amounts of PIDA improved the reaction outcome, and with 3 equivalents of PIDA, 2 a was generated in 64 % yield (Table 1, entry 3). The addition of ligands, such as 2,2′‐bipyridine and 1,10‐phenanthroline (5 mol %), completely shut down the reaction. Among all the tested additives,18 we found that BQ enhanced the reaction: With 10 mol % of BQ, the yield of 2 a was elevated to 69 % (Table 1, entry 4). The evaluation of quinone analogues, including maleic anhydride, showed that nonsubstituted BQ was optimal (Table 1, entries 5–10). When the reaction was carried out on a 0.3 mmol scale in DMSO, the α‐acetoxylated enone 2 a was obtained in 65 % yield (Table 1, entry 11).

Table 1

Optimization of the reaction conditions.[a]

Entry	PIDA (x equiv)	“BQ”	Yield of 2 a [%][b]	Yield of 3 a [%][b]
1	1.5	–[c]	46	7
2	2.5	–[c]	62	9
3	3	–[c]	64	11
4	3	BQ	69	11
5	3	2,6‐Me2‐BQ	66	13
6	3	2,6‐tBu2‐BQ	64	12
7	3	2,6‐(MeO)2‐BQ	65	12
8	3	2‐Cl‐BQ	65	15
9	3	F4‐BQ	62	16
10	3	maleic anhydride	64	14
11[d]	3	BQ	67 (65)[e]	13[e]

[a] Reaction conditions: 1 a (0.1 mmol), Pd(OAc)2 (5 mol %), PIDA (x equiv), “BQ” (10 mol %), [D6]DMSO (0.5 mL), 50 °C, 18 h. [b] The yield was determined by 1H NMR spectroscopy of the crude mixture with anisole as the internal standard. [c] No quinone or quinone analogue was added. [d] The reaction was carried out on a 0.3 mmol scale in DMSO. [e] Yield of the crude product after workup. The yield of isolated 2 a is given in parenthesis.

Having optimized the reaction conditions, we continued to explore the scope of the reaction, first by examining different substituents at the propargylic position of the substrate (Scheme 2). Variation of the length of the alkyl chain at the propargylic position had a minor influence on the yield of the corresponding α‐acetoxylated enone 2 b–e. n>an class="Chemical">Alkyne 1 f containing a benzyl substituent underwent the reaction smoothly to deliver 2 f in 68 % yield. In sharp contrast, substrate 1 g bearing an allyl group on the alkyne was converted into the desired product 2 g′ in only 14 % yield, which implies poor compatibility of the reaction with olefins. We were delighted to find that the propargyl ether 1 h was well‐tolerated, as well as a number of other functional groups, including alkyl halides (substrate 1 i) and protected heteroatoms, such as phthalimides (substrate 1 j) and silyl ethers (substrate 1 k). Notably, the products 2 a and 2 c–k were detected as only the Z isomers.19 As for propargylic disubstituted alkynes, the isopropyl alkyne 1 l gave the tetrasubstituted olefin 2 l in a diminished yield of 46 %. More importantly, we noticed that substrates incorporating a cycloalkyl group differed significantly in their reactivity. The cyclopentyl‐ and cyclobutyl‐substituted alkynes 1 m and 1 n were converted into the corresponding cycloalkylidene products 2 m and 2 n in good yields. However, in the case of the cyclopropyl alkyne 1 o, the expected cyclopropylidene product was not formed. The reaction was dominated by a ring‐opening pathway and provided the α‐acetoxylated dienone 2 o′ in 42 % yield (Z/E=10:1).

Scheme 2

Acetoxylation of substrates with different propargylic substituents. Reactions were carried out on a 0.3 mmol scale. Yields are for the isolated product. [a] Reaction time: 24 h. [b] For the detailed X‐ray crystal structure of 2 j, see the Supporting Information. Bn=benzyl, NPhth=phthalimido, TBS=tert‐butyldimethylsilyl.

Acetoxylation of substrates with different propargylic substituents. Reactions were carried out on a 0.3 mmol scale. Yields are for the isolated product. [a] Reaction time: 24 h. [b] For the detailed X‐ray crystal structure of 2 j, see the Supporting Information. Bn=benzyl, NPhth=n>an class="Chemical">phthalimido, TBS=tert‐butyldimethylsilyl.

Following these encouraging results for different propargylic substituted alkynes, we investigated the scopn>e of the reaction with respn>ect to the n>an class="Chemical">arene unit (Scheme 3). Both electron‐donating and electron‐withdrawing groups, such as alkyl groups, alkoxyl groups, and halides, were compatible with the reaction conditions. Moreover, the ketone‐ and ester‐containing substrates 1 t and 1 u reacted smoothly, and these carbonyl groups are valuable handles for subsequent transformations. Alkyne 1 v with an olefin moiety underwent the reaction poorly to give the desired α‐acetoxylated enone 2 v only in 25 % yield. For synthetically attractive heteroarenes, we were delighted to find that an electron‐rich thiophene group (substrate 1 w) was well‐tolerated, and no side products arising from potential arene C−H oxidation were detected. Similarly, indole moieties could also be incorporated; the α‐acetoxylated enone 2 x could be utilized as a precursor in the synthesis of indole‐type natural products.

Scheme 3

Acetoxylation of substrates with different aryl substituents. Reactions were carried out on a 0.3 mmol scale. Yields are for the isolated product. [a] Reaction time: 40 h.

We carried out additional experiments to gain a deeper understanding of the reaction. When PhI(OAc)2 was replaced with PhI(OPiv)2, a pivalate group could be installed at the α position of n>an class="Chemical">enone 4 in good yield, thus revealing that the carboxylate functionality can be varied by the use of different iodine(III) reagents (Scheme 4 a). When the reaction of alkyne 1 a was carried out with [18O]DMSO (86 % 18O), we observed the incorporation of 18O into the product [18O]2 a (62 % 18O), as determined by ESI‐MS analysis (Scheme 4 b; see also the Supporting Information).20 This result shows that the ketone oxygen atom originates from the sulfoxide.

Scheme 4

Reactions of 1 a with PhI(OPiv)2 or [18O]DMSO.

Reactions of 1 a with pan class="Chemical">PhI(OPiv)2 or pan class="Chemical">[18O]DMSO.

As the propargylic C−H bond is broken in the reaction, we performed some kinetic isotope effect (KIE) studies with the deuterium‐labeled substrate [D3]1 b. In an intermolecular compn>etition expn>eriment, an equimolar amount of 1 b and [D3]1 b gave 2 b and [D2]2 b in a nearly 1:1 ratio (k H/k D=1.05; Scheme 5 a). This observation shows that the cleavage of propn>argylic C−H and C−D bonds occurs after the first irreversible stepn> of the catalytic cycle. When n>an class="Chemical">alkyne 1 b and [D3]1 b reacted separately, a KIE value (k H/k D from the initial rates) of 1.04 was observed (Scheme 5 b).21 Such a negligible isotope effect clearly indicates that propargylic C−H bond cleavage is not involved in the rate‐determining step.22

Scheme 5

Isotope‐labeling experiments.

On the basis of the experimental results, we propose a plausible mechanism for this oxidative alkyne functionalization reaction (Scheme 6). Initially, a Wacker‐typn>e nucleopn>hilic attack23 by n>an class="Chemical">DMSO on the palladium(II)‐activated alkyne provides a vinylpalladium(II) intermediate int‐1.24, 25, 26 This palladium(II) species is oxidized by PIDA to a vinylpalladium(IV) intermediate int‐2,27 which can undergo β‐hydride elimination (path A) or reductive elimination (path B)28 to generate int‐3 or int‐4, respectively. Nucleophilic attack by acetate on int‐3 (path A) would give the desired product 2; alternatively, the cleavage of an allylic C−H bond, followed by double‐bond migration (path B), would also deliver product 2. Dimethyl sulfide is expelled as the by‐product and was detected by GC–MS analysis of the crude mixture.29, 30 Although it is known that BQ can promote different catalytic steps in palladium‐catalyzed oxidation reactions,31 the exact role of BQ in this reaction remains unclear.

Scheme 6

Proposed reaction mechanism.

To demonstrate the synthetic utility of the products, we performed an iridium‐catalyzed asymmetric hydrogenation reaction of the α‐acetoxylated enone 2 b by using a chiral N,P ligand.32 Upon selective reduction of the olefin moiety, the enantiomerically enriched α‐acetoxylated ketone 5, a valuable building block, was obtained in 81 % yield with e.r. 80:20 (Scheme 7).33

Scheme 7

Asymmetric hydrogenation of α‐acetoxylated enones. tAmOH=2‐methyl‐2‐butanol, cod=1,5‐cyclooctadiene.

Asymmetric hydrogenation of α‐acetoxylated pan class="Chemical">enones. pan class="Chemical">tAmOH=2‐methyl‐2‐butanol, cod=1,5‐cyclooctadiene.

In conclusion, we have developed a palladium‐catalyzed oxidative protocol for the synthesis of α‐acetoxylated enones from readily available alkynes. This reaction shows good tolerance of a range of functional groups. Mechanistic studies revealed that DMSO acts as an oxygen nucleophile and propargylic C−H cleavage occurs at a later stage of the reaction, as evidenced by KIE studies. We are currently pursuing further studies on propargylic C−H oxidative functionalization.

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Supplementary

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