Branched-selective intermolecular ketone α-alkylation with unactivated alkenes via an enamide directing strategy

Article abstract of DOI:10.1021/jacs.7b08581

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.

Full text of DOI:10.1021/jacs.7b08581

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Communication
Branched-Selective Intermolecular Ketone #-Alkylation with
Unactivated Alkenes via an Enamide Directing Strategy
Dong Xing, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08581 • Publication Date (Web): 17 Sep 2017
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Branched-Selective Intermolecular Ketone α-Alkylation with
Unactivated Alkenes via an Enamide Directing Strategy
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Dong Xing† and Guangbin Dong*,†
†Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
Supporting Information Placeholder
ABSTRACT: We describe
a strategy for intermolecular
branchedꢀselective αꢀalkylation of ketones using simple alkenes
as the alkylating agents. Enamides derived from isoindolinꢀ1ꢀone
provide an excellent directing template for catalytic activation of
ketone αꢀpositions. 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.
αꢀAlkylation of carbonyl compounds is frequently employed to
form C–C bonds in organic synthesis.1 A conventional method for
ketone αꢀalkylation generally involves a SN2 reaction between
enolates and alkyl halides.1 While effective, this approach generꢀ
ally requires strong bases, cryogenic conditions and relatively
expensive/toxic alkyl halides as reagents.2ꢀ4 More importantly,
secondary alkyl halides are not often used in enolate alkylations
due to their reduced electrophilicity for SN2 reactions and enꢀ
hanced vulnerability towards E2 eliminations (Scheme 1A).1 For
example, direct alkylation of cyclopentanone with secondary elecꢀ
trophiles still represents an unsolved challenge to date.5 Hence,
intermolecular ketone αꢀalkylation that can selectively provide
branched products remains highly sought after.
The proposed approach was inspired by the recent advance on
branchedꢀselective hydroarylation of alkenes.9,10 Assisted by suitꢀ
able 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 broadꢀ
ly applicable features. Thus, we decided to adopt iridium as the
metal of choice for the proposed branchedꢀselective αꢀalkylation
of ketones with simple alkenes (Scheme 1B). However, comparꢀ
ing to the aryl C−H activation, the challenge for activating the
alkenyl C−H bonds of electronꢀrich enamines is twoꢀfold: 1) alꢀ
kenes, particularly enamines, are less stable towards oxidants,
electrophiles or hydrolysis; and 2) oxidative addition of a lowꢀ
valent TM into C−H bonds generally becomes more difficult
when the bond becomes more electronꢀrich.12,13 Hence, as a startꢀ
ing point, 5ꢀmember lactams were chosen as the initial directing
template because the resulting enamide intermediate, readily preꢀ
pared from condensation of lactam and ketone (or its equivalent),
is more stable and less electronꢀrich.14 In addition, acetanilide has
been shown by Bower and coworkers11m to be an excellent DG for
an Ir(I)ꢀcatalyzed branchedꢀselective hydroarylation of alkenes.
Our laboratory has been focusing on an enamineꢀtransition
metal (TM) cooperative strategy to realize ketone αꢀalkylation
with simple alkenes as the alkylating agents (Scheme 1B).6,7
When 7ꢀazaindoline was employed as a bifunctional catalyst,
ketone α sp3 C–H bond was converted into a sp2 C–H bond, thereꢀ
fore enhancing the reactivity toward oxidative addition.8 Meanꢀ
while, the directing group (DG), linked to the amine domain, faꢀ
cilitated oxidative addition of TM into the enamine C–H bond to
generate a metalꢀhydride species. By utilizing a Rh(I)/NHC cataꢀ
lytic system, linearꢀselective αꢀalkylation of ketones with various
alkenes has been established.6b As our continuous research efforts,
herein we describe the development of an approach for highly
branchedꢀselective αꢀalkylation of ketones with alkenes through
this unique mode of activation. This strategy offers a distinct and
effective way to access ketones bearing βꢀbranches, which are
highly valuable chiral building blocks but are nontrivial to obtain
through conventional alkylation methods.
Cyclopentanoneꢀbased enamides and 1ꢀoctene 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 comꢀ
plete branched selectivity (entry 1). It is noteworthy that 1ꢀoctene
Scheme 1. Ketone αꢀalkylation reactions
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was considered as a challenging substrate to give branched selecꢀ
The Ir(I)ꢀcatalyzed C−H alkylation can be successfully comꢀ
tivity,11i and often led to olefin isomerization. Enamides derived
from fiveꢀmembered lactams are all competent substrates to give
excellent selectivity, with isoindolinꢀ1ꢀone (DG1) being most
efficient (entries 1ꢀ4). It is interesting that alkylation of enamide
2a occurred siteꢀselectively at the alkene, instead of the arene
ortho position via a fiveꢀmembered metallacycle.
bined with a oneꢀpot enamide hydrolysis to give the correspondꢀ
ing alkylated ketones in high yields (Scheme 2).16 First, the scope
of alkenes that can be coupled is broad. Aliphatic alkenes such as
1ꢀdodecene, 1ꢀhexene and 4ꢀmethylꢀ1ꢀpentene, all gave αꢀ
alkylated cyclopentanones with complete branched selectivity
(5b-d).17 An isopropyl substituent was introduced when propene
was used (3e). Oxygenꢀbased functional groups, e.g. OMe, OTIPS
and OAc, are compatible without compromising the regioselectivꢀ
ity (5fꢀh). In addition, electronically distinct aromatic olefins
bearing different substituents are also tolerated, giving correꢀ
sponding αꢀalkylation products in moderate to good yields with
high to complete branched selectivity (5j-o). Oxidative olefination
products were observed in small quantities (10ꢀ20%) with certain
styreneꢀtype alkenes (3j-l) (vide infra, Scheme 4).
Table 1. Selected Optimization Studiesa
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Scheme 2. Substrate Scope with Different Alkenesa
aUnless otherwise noted, all reactions were conducted with 0.2
b
1
mmol of enamide and 2 mmol of 3a. Yield determined by H
NMR using 1,1,2,2ꢀtetrachloroethane as internal standard.
cDetermined by 1H NMR of the crude products. dIsolated yield.
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 exꢀ
periments see Supporting Information). Among a series of bidenꢀ
tate phosphine ligands tested (entries 6ꢀ11), DIOP gave the optiꢀ
mal yield and selectivity.15 Consistent with the previous observaꢀ
tion,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 electronꢀrich alkenyl
C−H bond requires more electronꢀrich ligands. Cyclopentyl meꢀ
thyl ether (CPME) as solvent proved to be superior to toluene or
1,4ꢀdioxane (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.
aUnless otherwise noted, all reactions were run on a 0.2 mmol
b
scale of 2a and 2 mmol of 3; all yields are isolated yields. With
preꢀcondensed propene. cYield of two steps where the correspondꢀ
ing enamide product was isolated before hydrolysis. d The crude
mixture was treated with Pd/C under H2 (balloon) to convert oxiꢀ
dative olefination products (ca. 10ꢀ20%) to the alkylation product.
We then turned our attention to the oneꢀpot αꢀalkylation of enꢀ
amides derived from other cyclic or acyclic ketones. Unsurprisꢀ
ingly, acyclic ketones are much less reactive for direct condensaꢀ
tion with lactams; however, using the corresponding dimethyl
ketal, the enamides can be formed efficiently (for details, see
Supporting Information). First, 3,3ꢀdimethyl cyclopentanone was
alkylated exclusively at the less sterically hindered C5 position in
a good yield albeit with a moderate branched selectivity (6a).
Cyclohexanoneꢀderived enamide also underwent the desired
branched alkylation, and the low yield was primarily caused by
undesired aromatization under the current conditions (6b). In
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alkenyl position. Further control experiment (Scheme 4B) demonꢀ
addition, the αꢀalkylation of acyclic ketones can also be achieved.
strated that the alkenylation product did not come from dehydroꢀ
genation of product 4l under the reaction conditions. These obserꢀ
vations strongly support that (a) Ir−C migratory insertion into the
alkene also occurs (Scheme 5A, path b), and (b) subsequent βꢀH
elimination happens and is reversible.11k Hence, after oxidative
addition of Ir(I) into the enamide vinyl C−H bond, both the hyꢀ
dride 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?
For example, acetone, 2ꢀpentanone and benzoylꢀprotected 5ꢀ
hydroxyꢀ2ꢀpentanoneꢀderived enamides all gave corresponding
alkylation products 6c-e in good yields and complete branched
selectivity. Enamides derived from various acetophenones gave
siteꢀselective coupling at the ketone αꢀposition (6fꢀg), and alkylaꢀ
tion at the arene ortho positions were not observed. Finally, appliꢀ
cation of the current method was demonstrated in a rapid and
direct synthesis of dihydroꢀarꢀturmerone, a natural sesquiterpeꢀ
noid with potent AChE inhibitory activity.18,19
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Scheme 3. Substrate Scopes with Different Ketonesa
Scheme 4. Preliminary mechanistic study
O
R
[Ir(COD)2]BArF (5 mol%)
DIOP (5 mol%)
DG1
O
H
N
TsOH H2O (2 mol%)
or
O
t-BuNHi-Pr (20 mol%)
CPME, 130 oC, 24 h
then HCl, toluene, 1 h
t-BuNHi-Pr (20 mol%)
toluene, 130 o
MeO OMe
R
C
30-86%
2
5a, 6a-k
n-C6H13
O
O
O
n-C6H13
n-C6H13
Me
Me
6a, 67%
6b, 20%
5a, 71%
branched: linear >20:1
dr: 1.2:1
branched: linear 4:1
dr: 2:1
branched:linear > 20:1
dr: 1.2:1
O
O
O
BzO
n-C6H13
6c, 71%
branched:linear > 20:1
n-C6H13
n-C6H13
6d, 56%b
6e, 63%
branched:linear > 20:1
branched:linear > 20:1
no alkylation
73%, branched:linear > 20:1
57%, branched:linear > 20:1
6f R = H
6g R = 4-F
H
O
here
6h R = 4-Me 71%, branched:linear > 20:1
n-C6H13
R
6i R = 2-Cl
6j R = 3-Me
36%, branched:linear > 20:1
70%, branched:linear > 20:1
O
6k, 64%
branched:linear > 20:1
Me
aThe deuterium content at DG’s benzylic position and the αꢀ
methylene group is >95%.
dihydro-ar-turmerone
aAll yields are isolated yields; selectivity was determined by 1H
Inspired by a mechanistic study by Nishimura,11p pure cisꢀβꢀ
methylstyrene was employed as a “probe reagent” (Scheme 5B).
While its reaction with dꢀ2a gave no desired alkylation product,
the alkene was recovered as a Z/E mixture (7.5:1) with deuterium
incorporation at all α, β, γꢀpositions. This observation indicates
that Ir−H migratory insertion into βꢀmethylstyrene did occur and
an Irꢀalkyl intermediate (II) was likely formed. We rationalize
that, if the Ir−H migratory insertion was the productive pathway, a
similar Irꢀalkyl 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.
While this is not completely conclusive, the absence of the alkylaꢀ
tion product with cisꢀβꢀmethylstyrene does not imply a successful
C−C reductive elimination, therefore not favoring Ir−H migratory
insertion (path a/a’) to be the main productive pathway. Moreover,
these experimental results are also consistent with the proposal of
a recent DFT study by Huang and Liu on the Irꢀcatalyzed hyꢀ
droarylation of alkenes,20 which supports the Ir−C migratory inꢀ
sertion pathway (path b).
b
NMR or GC of the crude products. Internal enamide was used as
the substrate. For details, see Supporting Information.
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, isoindolinꢀ
1ꢀone (DG 1) can be recovered in 81% yield.
To gain some insights into the plausible mechanism for this
transformation, the reaction between deuterated enamide dꢀ2a and
4ꢀfluorostyrene was conducted, and stopped after 5h (Scheme 4A).
First, the deuterium content at the enamide vinyl H of the recovꢀ
ered dꢀ2a is reduced. Meanwhile, incorporation of deuterium at
both α and β positions of unreacted 4ꢀfluorostyrene was obꢀ
served.11i These D/H scrambling results suggest that (a) oxidative
addition into the vinyl C−H bond is reversible11i,11l and (b) Ir−H
migratory insertion into the alkene does occur in both 1,2 and 2,1ꢀ
addition fashions and is reversible (Scheme 5A, path a/a’). Moreꢀ
over, a significant amount of alkenylation product dꢀ7 was isolatꢀ
ed with substantial deuterium incorporation at the terminal
In summary, by utilizing a preꢀinstalled enamide DG, we have
realized an initial approach for highly branchedꢀselective αꢀ
alkylation of ketones with simple olefins. Encouraged by the
broad substrate scope and mechanistic understanding, efforts on
developing a more efficient catalyst system that can use catalytic
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Scheme 5. Mechanistic proposal
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AUTHOR INFORMATION
Corresponding Author
gbdong@uchicago.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial supports from NSF (CAREER: CHEꢀ1254935) is
acknowledged. D.X. thanks the International Postdoctoral Exꢀ
change Fellowship Program 2015 from the Office of China Postꢀ
doctoral Council (OCPC, document 38, 2015). Mr. Jianchun
Wang is thanked for checking the experiments.
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(16) Attempts to further combine enamide formation with the C–H alꢀ
kylation in one pot or use of catalytic DG1 remained unsuccessful yet.
(17) Vinyl ether type olefins, such as vinyl nꢀbutyl ether, gave a low
yield (<30%). 1,1 and 1,2ꢀdisubstituted olefins were not reactive under the
current conditions.
(18) Fujiwara, M.; Yagi, N.; Miyazawa, M. J. Agric. Food Chem. 2010,
58, 2824.
(19) For other syntheses of dihydroꢀarꢀturmerone, see: (a) Crawford, R.
J.; Erman, W. F.; Broaddus, C. D. J. Am. Chem. Soc. 1972, 94, 4298. (b)
Shono, T.; Ishifune, M.; Kinugasa, H.; Kashimura, S. J. Org. Chem. 1992,
57, 5561. (c) Solabannavar, S. B.; Wadgaonkar, P. P.; Desai, U. V.; Mane,
R. B. Org. Prep. Proced. Int. 2003, 35, 418.
(20) Huang, G.; Liu, P. ACS Cat. 2016, 6, 809.
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