Communication pubs.acs.org/JACS
Branched-Selective Intermolecular Ketone α‑Alkylation with Unactivated Alkenes via an Enamide Directing Strategy Dong Xing and Guangbin Dong* Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States S Supporting Information *
ketone α sp3 C−H bond was converted into a sp2 C−H bond, therefore enhancing the reactivity toward oxidative addition.8 Meanwhile, the directing group (DG), linked to the amine domain, facilitated oxidative addition of TM into the enamine C−H bond to generate a metal-hydride species. By utilizing a Rh(I)/NHC catalytic system, linear-selective α-alkylation of ketones with various alkenes has been established.6b As our continuous research efforts, herein we describe the development of an approach for highly branched-selective α-alkylation of ketones with alkenes through this unique mode of activation. This strategy offers a distinct and effective way to access ketones bearing β-branches, which are highly valuable chiral building blocks but are nontrivial to obtain through conventional alkylation methods. The proposed approach was inspired by the recent advance on branched-selective hydroarylation of alkenes.9,10 Assisted by suitable DGs, a range of TM catalysts (e.g., Ru, Ni, Co and Ir) have been utilized to give branched products.11 In particular, a cationic Ir system, first developed by Shibata,11h,i recently advanced by Bower,11l,m Hartwig,11j,k Nishimura11o,p and others, exhibits broadly applicable features. Thus, we decided to adopt iridium as the metal of choice for the proposed branched-selective α-alkylation of ketones with simple alkenes (Scheme 1B). However, comparing to the aryl C−H activation, the challenge for activating the alkenyl C−H bonds of electronrich enamines is 2-fold: (1) alkenes, particularly enamines, are less stable toward oxidants, electrophiles or hydrolysis; and (2) oxidative addition of a low-valent TM into C−H bonds generally becomes more difficult when the bond becomes more electron-rich.12,13 Hence, as a starting point, 5-member lactams were chosen as the initial directing template because the resulting enamide intermediate, readily prepared from condensation of lactam and ketone (or its equivalent), is more stable and less electron-rich.14 In addition, acetanilide has been shown by Bower and co-workers11m to be an excellent DG for an Ir(I)-catalyzed branched-selective hydroarylation of alkenes. Cyclopentanone-based enamides and 1-octene were chosen as the model substrates (Table 1). To our delight, after carefully optimizing various reaction parameters, the desired alkylation product 4a was obtained in 91% (82% isolated) yield with complete branched selectivity (entry 1). It is noteworthy that 1-octene was considered as a challenging substrate to give branched selectivity,11i and often led to olefin isomerization. Enamides derived from five-membered lactams are all competent substrates to give excellent selectivity, with
ABSTRACT: We describe a strategy for intermolecular branched-selective α-alkylation of ketones using simple alkenes as the alkylating agents. Enamides derived from isoindolin-1-one provide an excellent directing template for catalytic activation of ketone α-positions. High branched selectivity is obtained for both aliphatic and aromatic alkenes using a cationic iridium catalyst. Preliminary mechanistic study favors an Ir−C migratory insertion pathway. he α-alkylation of carbonyl compounds is frequently employed to form C−C bonds in organic synthesis.1 A conventional method for ketone α-alkylation generally involves a SN2 reaction between enolates and alkyl halides.1 Though effective, this approach generally requires strong bases, cryogenic conditions and relatively expensive/toxic alkyl halides as reagents.2−4 More importantly, secondary alkyl halides are not often used in enolate alkylations due to their reduced electrophilicity for SN2 reactions and enhanced vulnerability toward E2 eliminations (Scheme 1A).1 For example, direct alkylation of cyclopentanone with secondary electrophiles still represents an unsolved challenge to date.5 Hence, intermolecular ketone α-alkylation that can selectively provide branched products remains highly sought after. Our laboratory has been focusing on an enamine-transition metal (TM) cooperative strategy to realize ketone α-alkylation with simple alkenes as the alkylating agents (Scheme 1B).6,7 When 7-azaindoline was employed as a bifunctional catalyst,
T
Scheme 1. Ketone α-Alkylation Reactions
Received: August 11, 2017 Published: September 17, 2017 © 2017 American Chemical Society
13664
DOI: 10.1021/jacs.7b08581 J. Am. Chem. Soc. 2017, 139, 13664−13667
Communication
Journal of the American Chemical Society Table 1. Selected Optimization Studiesa
entry 1 2 3 4 5 6 7 8 9 10 11c 12 13 14
variations from the “standard” conditionsa None DG2 instead of DG1 DG3 instead of DG1 DG4 instead of DG1 without t-BuNHi-Pr BINAP instead of DIOP dppf instead of DIOP dppb instead of DIOP dppe instead of DIOP dppbz instead of DIOP dFppb instead of DIOP toluene instead of CPME 1,4-dioxane instead of CPME [Rh(COD)2]BArF instead of [lr(COD)2]BArF
Scheme 2. Substrate Scope with Different Alkenesa
yield of 4a (%)b d
91 (82 ) 56 56 21 82 37 70 60 56 61 20:1 >20:1 13:1 5:1 >20:1 17:1 4:1 4:1 17:1 19:1
a
Unless otherwise noted, all reactions were run on a 0.2 mmol scale of 2a and 2 mmol of 3; all yields are isolated yields. bWith precondensed propene. cYield of two steps where the corresponding enamide product was isolated before hydrolysis. dThe crude mixture was treated with Pd/C under H2 (balloon) to convert oxidative olefination products (ca. 10−20%) to the alkylation product.
a
First, the scope of alkenes that can be coupled is broad. Aliphatic alkenes such as 1-dodecene, 1-hexene and 4-methyl-1pentene, all gave α-alkylated cyclopentanones with complete branched selectivity (5b−d).17 An isopropyl substituent was introduced when propene was used (3e). Oxygen-based functional groups, e.g., OMe, OTIPS and OAc, are compatible without compromising the regioselectivity (5f-h). In addition, electronically distinct aromatic olefins bearing different substituents are also tolerated, giving corresponding αalkylation products in moderate to good yields with high to complete branched selectivity (5j−o). Oxidative olefination products were observed in small quantities (10−20%) with certain styrene-type alkenes (3j−l) (vide inf ra, Scheme 4). We then turned our attention to the one-pot α-alkylation of enamides derived from other cyclic or acyclic ketones (Scheme 3). Unsurprisingly, acyclic ketones are much less reactive for direct condensation with lactams; however, using the corresponding dimethyl ketal, the enamides can be formed efficiently (for details, see Supporting Information). First, 3,3dimethyl cyclopentanone was alkylated exclusively at the less sterically hindered C5 position in a good yield albeit with a moderate branched selectivity (6a). Cyclohexanone-derived enamide also underwent the desired branched alkylation, and the low yield was primarily caused by undesired aromatization under the current conditions (6b). In addition, the α-alkylation of acyclic ketones can also be achieved. For example, acetone, 2-pentanone and benzoyl-protected 5-hydroxy-2-pentanonederived enamides all gave corresponding alkylation products 6c−e in good yields and complete branched selectivity. Enamides derived from various acetophenones gave siteselective coupling at the ketone α-position (6f−j), and
Unless otherwise noted, all reactions were conducted with 0.2 mmol of enamide and 2 mmol of 3a. bYield determined by 1H NMR using 1,1,2,2-tetrachloroethane as internal standard. cDetermined by 1H NMR of the crude products. dIsolated yield.
isoindolin-1-one (DG1) being most efficient (entries 1−4). It is interesting that alkylation of enamide 2a occurred siteselectively at the alkene, instead of the arene ortho position via a five-membered metallacycle. A set of control experiments were then conducted to understand the role of each reactant. A catalytic amount of bulky secondary amines, i.e., tBuNHiPr, as an additive improved both the yield and the regioselectivity likely through stabilizing the enamide from hydrolysis by adventitious water (entry 5, for further control experiments see Supporting Information). Among a series of bidentate phosphine ligands tested (entries 6−11), DIOP gave the optimal yield and selectivity.15 Consistent with the previous observation,11l ligands with a large bite angle, e.g., dppf and dppb, gave excellent branched selectivity. The dFppb ligand11l,m gave a low conversion for this transformation (entry 11), which is probably due to that oxidative addition into the more electron-rich alkenyl C−H bond requires more electron-rich ligands. Cyclopentyl methyl ether (CPME) as solvent proved to be superior to toluene or 1,4-dioxane (entries 12 and 13). Finally, using the corresponding cationic rhodium analogue as the catalyst resulted in nearly no conversion of the enamide (entry 14), indicating a unique feature with the iridium system. The Ir(I)-catalyzed C−H alkylation can be successfully combined with a one-pot enamide hydrolysis to give the corresponding alkylated ketones in high yields (Scheme 2).16 13665
DOI: 10.1021/jacs.7b08581 J. Am. Chem. Soc. 2017, 139, 13664−13667
Communication
Journal of the American Chemical Society Scheme 3. Substrate Scopes with Different Ketonesa
Scheme 4. Preliminary Mechanistic Study
The deuterium content at DG’s benzylic position and the αmethylene group is >95%.
a
a All yields are isolated yields selectivity was determined by 1H NMR or GC of the crude products. bInternal enamide was used as the substrate. For details, see Supporting Information.
Scheme 5. Mechanistic Proposal
alkylation at the arene ortho positions were not observed. Finally, application of the current method was demonstrated in a rapid and direct synthesis of dihydro-ar-turmerone (6k), a natural sesquiterpenoid with potent AChE inhibitory activity.18,19 To demonstrate the scalability of this transformation, a gram scale reaction was conducted (eq 1), which gave an increased yield with complete branched selectivity. Meanwhile, isoindolin-1-one (DG 1) can be recovered in 81% yield.
To gain some insights into the plausible mechanism for this transformation, the reaction between deuterated enamide d-2a and 4-fluorostyrene was conducted, and stopped after 5 h (Scheme 4A). First, the deuterium content at the enamide vinyl H of the recovered d-2a is reduced. Meanwhile, incorporation of deuterium at both α and β positions of unreacted 4fluorostyrene was observed.11i These D/H scrambling results suggest that (a) oxidative addition into the vinyl C−H bond is reversible11i,l and (b) Ir−H migratory insertion into the alkene does occur in both 1,2 and 2,1-addition fashions and is reversible (Scheme 5A, path a/a′). Moreover, a significant amount of alkenylation product d-7 was isolated with substantial deuterium incorporation at the terminal alkenyl position. Further control experiment (Scheme 4B) demonstrated that the alkenylation product did not come from dehydrogenation of product 4l under the reaction conditions. These observations strongly support that (a) Ir−C migratory insertion into the alkene also occurs (Scheme 5A, path b), and (b) subsequent β-H elimination happens and is reversible.11k Hence, after oxidative addition of Ir(I) into the enamide vinyl C−H bond, both the hydride and the carbon substituent on the Ir(III) intermediate have undergone migratory insertion into
the alkene coupling partner. However, the key question is which pathway leads to the product formation? Inspired by a mechanistic study by Nishimura,11p pure cis-βmethylstyrene was employed as a “probe reagent” (Scheme 5B). Though its reaction with d-2a gave no desired alkylation product, the alkene was recovered as a Z/E mixture (7.5:1) with deuterium incorporation at all α-, β-, γ-positions. This observation indicates that Ir−H migratory insertion into βmethylstyrene did occur and an Ir-alkyl intermediate (II) was likely formed. We rationalize that, if the Ir−H migratory insertion was the productive pathway, a similar Ir-alkyl intermediate (I), generated from styrene, would have undergone reductive elimination to give the desired product (Scheme 5C). By analogy, intermediate II should have also been able to undergo reductive elimination to give the coupling product. Though this is not completely conclusive, the absence of the 13666
DOI: 10.1021/jacs.7b08581 J. Am. Chem. Soc. 2017, 139, 13664−13667
Communication
Journal of the American Chemical Society
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