Branched-Selective Direct α-Alkylation of Cyclic Ketones with Simple Alkenes

Article abstract of DOI:10.1002/anie.201900301

Herein, we describe an intermolecular direct branched-selective α-alkylation of cyclic ketones with simple alkenes as the alkylation agents. Through an enamine-transition metal cooperative catalysis mode, the α-alkylation is realized in an atom- and step-economic manner with excellent branched selectivity for preparing β-branched ketones. Employment of a pair of bulky Br?nsted acid and base as additives is responsible for enhanced efficiency. Promising enantioselectivity (74 % ee) has been obtained. Experimental and computational mechanistic studies suggest that a pathway through alkene migratory insertion into the Ir?C bond followed by C?H reductive elimination is involved for the high branched selectivity.

Full text of DOI:10.1002/anie.201900301

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Accepted Article
Title: Branched-Selective Direct α-Alkylation of Cyclic Ketones with
Simple Alkenes
Authors: Dong Xing, Xiaotian Qi, Daniel Marchant, Peng Liu, and
Guangbin Dong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900301
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10.1002/anie.201900301
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Branched-Selective Direct -Alkylation of Cyclic Ketones with
Simple Alkenes
Dong Xing, Xiaotian Qi, Daniel Marchant, Peng Liu*, and Guangbin Dong*
Abstract: Herein, we describe an intermolecular direct branched-
selective -alkylation of cyclic ketones with simple alkenes as the
alkylation agents. Through an enamine-transition metal cooperative
catalysis mode, the -alkylation is realized in an atom- and step-
economic manner with excellent branched selectivity for preparing -
branched ketones. Employment of a pair of bulky Brønsted acid and
base as additives is responsible for enhanced efficiency. Promising
enantioselectivity (74% ee) has been obtained. Experimental and
computational mechanistic studies suggest that a pathway via
alkene migratory insertion into the Ir–C bond followed by C–H
reductive elimination is involved for the high branched selectivity.
nevertheless needs to be first installed and later removed in
separate steps. Clearly, direct, one-step approach for
a
branched-selective ketone-olefin coupling without pre-installation
and post-removal of directing groups (DGs) would be more
attractive. Herein, we describe the initial development of a direct
branched-selective α-alkylation of cyclic ketones via enamine-
transition metal cooperative catalysis (Scheme 1B).[11] This
method allows for a straightforward synthesis of -branched
ketones in a single-step and byproduct-free manner from simple
ketones and alkenes.[12]
Enolate alkylation is one of the fundamental organic
transformations;[1] however, direct alkylation with secondary alkyl
halides remains problematic due to their relatively low
electrophilicity for SN2 reactions and increased instability under
strong basic conditions.[2] In order to access the β-branched
ketones, indirect approaches have been developed. The use of
more nucleophilic (and more basic) metalloenamines, generated
via imine formation followed by deprotonation,[3,4] or an aldol
condensation-Michael addition sequence has been frequently
utilized (Scheme 1A).[5] Although effectively, these approaches
typically require multi-step operations and stoichiometric metallic
reagents. In addition, the expense of alkyl halides and
consequently generated halogen-containing byproducts could
not be neglected. Hence, it would be highly desirable to realize a
direct ketone α-alkylation[6] with suitable alkylating agents that
would 1) selectively provide branched products, 2) avoid
Scheme 1. Methods for synthesizing -branched ketones
The challenge to realize such a direct alkylation is two-fold.
First, enamines are considerably less stable towards hydrolysis
than the corresponding enamides. The instability would
inevitably cause a low concentration of the active enamine
intermediate, which would lead to low catalytic efficiency.
Second, learned from our previous Rh-catalyzed linear-selective
alkylation,[13] coupling with non-ethylene olefins were inefficient
with the enamine intermediates. Hence, it is not trivial to identify
a catalytic system that can afford both high branched selectivity
and high reactivity.
stoichiometric metals or halogens, and 3) operate in
a
byproduct-free fashion. Clearly, readily available olefins become
one almost ideal choice of such alkylating agents.[7]
Stimulated by the challenge of ketone alkylation with alkenes
for yielding -branched products, our laboratory has recently
devised a stepwise enamide-based strategy that enables a net
ketone -alkylation with simple alkenes in high branched
selectivity.[8,9] In this approach, 5-membered lactams were
employed as the directing template to pre-form enamides with
ketones, which further undergo Ir-catalyzed branched-selective
coupling with alkenes.[10] Further hydrolysis of the enamide-
alkylation products affords ketone-alkylation products. While
this is a feasible strategy, the enamide directing template
By choosing cyclopentanone 1a and 1-octene 2a as the
model substrates, a variety of bifunctional directing templates, Ir
precatalysts, ligands and additives were extensively examined.
Ultimately, the desired alkylation product was obtained in a 40
turnover number (TON) based on iridium with complete
branched selectivity (Table 1, 3a).[14]
A set of control
experiments revealed that 1) 7-azaindoline L1 is indispensable
for this transformation.[15] The use of a series of other types of
bifunctional ligands were either ineffective or resulting relative
low TON; 2) an acid co-catalyst is essential for improving the
efficiency while the bulky MSA (2-mesitylenesulfonic acid) was
found to be superior to other sulfonic acids; 3) a catalytic amount
of the bulky secondary amine, t-BuNHi-Pr, as an additive was
also important to improve the efficiency, its presence was found
to significantly reduce the self-aldol side reaction of
cyclopentanone thereby facilitating the enamine formation
process; 4) among a series of phosphine ligands tested, BINAP-
[*]
Prof. Dr. D. Xing
Shanghai Engineering Research Center of Molecular Therapeutics
and New Drug Development, School of Chemistry and Molecular
Engineering, East China Normal University
Shanghai 200062, China
Prof. Dr. G. Dong
Department of Chemistry, University of Chicago
Chicago, IL 60637, USA E-mail: gbdong@uchicago.edu
Dr. X. Qi, Mr. D. Marchant, Prof. Dr. P. Liu
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260, USA E-mail: pengliu@pitt.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201900301
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family gave excellent branched selectivity with simple rac-BINAP
good efficiency without compromising the regioselectivity (3g, 3i-
n). Styrene also worked albeit with a lower TON and a slightly
reduced branched selectivity (3o). Di-substituted olefins are
generally not reactive under the current conditions; however,
norbornene was effectively coupled to afford the desired -
alkylation product (3p) in 35 TON.[17] The poor diastereo-
selectivity is likely caused by the enamine hydrolysis that led to
thermodynamic products. Nevertheless, the diastereomeric ratio
(dr) of the product could be improved through forming the
corresponding silyl enol ether followed by a kinetic protonation
with a Lewis acid-assisted chiral Brnsted acid (eq 1).[18,19]
being optimal.[16]
Table 1. Scope of the Ir-catalyzed branched-selective -alkylation of cyclic
ketones with simple alkenes.[a]
L1
SO3H
(0.2 mmol)
N
N
H
O
O
[Ir(COD)2]BArF (2 mol%)
MSA
rac-BINAP (2 mol%)
H
N
R
R
MSA 2H2O (5 mol%)
t-BuNHi-Pr (20 mol%)
neat, 130 oC, 96 h
1
2
3 or 4
t-BuNHi-Pr
O
O
1) TBSCl, Et3N, DMF, 130 o
C
alkenes
with cyclopentanone
C6H13
(1)
C6H13
Me
Me
2) rac-BINOL SnCl4, toluene,
78 oC - rt
3a
3a
1.3:1 dr
C6H13
C10H21
C4H9
93%
6.5:1 dr
3a: TON: 40
b/l >20:1
3b, TON: 38
b/l >20:1
3c, TON: 36
b/l >20:1
3d, TON: 32
b/l >20:1
The ketone scope was also explored. 3,3-Dimethyl
cyclopentanone was alkylated exclusively at the less sterically
hindered C5 position with a moderate branched selectivity (8:1)
(4a). For this substrate, one-pot hydrolysis was required to
completely release the alkylated ketone product. 1-Indanones
also worked well under slightly modified reaction conditions, and
the corresponding -alkylation products (4c-g) were obtained in
moderate to good efficiency. Note that alkylation at the ortho
aromatic C−H bond was not observed. Cyclohexanone also
gave the desired product albeit in a lower efficiency (4h).
Compared to cyclic ketones, linear ketones are much less
reactive probably owing to the difficulty to form corresponding
enamine intermediates.[20]
dr: 1.3:1
dr: 1.6:1
dr: 1.3:1
dr: 1.7:1
Cy
Me
Ph
3e, TON: 42[b,c]
b/l >20:1
3f, TON: 11
b/l >20:1
dr: 1.1:1
3g, TON: 38[d]
b/l >20:1
dr: 1.3:1
3h, TON: 25
b/l >20:1
dr: 1.4:1
CO2Me
7
OMe
7
3i, TON: 24[d]
b/l >20:1
OTIPS
7
3j, TON: 33[d]
b/l >20:1
OAc
7
3k, TON: 24[d]
b/l >20:1
dr: 1.1:1
3l, TON: 30
b/l >20:1
dr: 1.4:1
dr: 1.8:1
dr: 1.1:1
NPhth
7
Ph
7
OH
3m, TON: 37[d]
b/l >20:1
dr: 1.1:1
3n, TON: 21[d]
b/l >20:1
dr: 1.6:1
3o, TON: 10
b/l 18:1
dr: 1.1:1
3p, TON: 35
dr: 1.1:1
ketones
with 1-octene
O
O
O
O
Me
MeO
Me
Me
4b, TON 32[e]
b/l > 20:1
dr: 1.6:1
4c, TON 29[e]
b/l > 20:1
dr: 1.6:1
4d, TON 27[e]
b/l > 20:1
dr: 1.8:1
4a,TON 20[c]
b/l 8:1
dr: 1.8:1
When increasing the [Ir] loading from 2 mol% to 10 mol%
(relative to L1), the reaction gave 2.6 turnovers of L1, indicating
certain catalytic ability of the bifunctional ligand (eq 2).
Encouraged by this result, we next investigated the alkylation
reaction using ketones as the limiting reagent. Gratifyingly, the
addition of bulky 2,6-di-t-Bu-4-methylpyridine was found to be
the key for increasing the reaction efficiency. Upon further
optimizations,[14] the branched product 3a was isolated in 68%
yield with 10 mol% of the iridium catalyst (Table 2). With this
protocol in hand, 1-hexene and several other terminal alkenes
bearing different functional groups as well as norbornene were
tested, and the corresponding alkylation products were obtained
in 39-62% yields with excellent branched selectivities. Using 1-
indanone as the limiting reagent was also successful under
similar conditions. The corresponding alkylated enamine was
found to be stable under the reaction conditions. After a one-pot
hydrolysis, the desired alkylated indanone 4b was isolated in
43% yield. Other substituted 1-indanones were also suitable
substrates.
O
O
O
O
F
Cl
Me
4h, TON 14[c]
b/l >20:1
dr: 2.0:1
4e, TON 22[e]
b/l > 20:1
4f, TON 28[e]
b/l > 20:1
dr: 1.9:1
4g, TON 24[e]
b/l > 20:1
dr: 1.9:1
dr: 2.3:1
[a] Unless otherwise noted, all reactions were run with 0.2 mmol of L1, 0.5 mL
of 1 and 0.5 mL of alkene; loadings are based on L1; TONs were calculated
based on [Ir] with isolated products; selectivities were determined by 1H NMR
or GC-MS of the crude products; b/l = branched:linear ratio. [b] Pre-condensed
propene was used. [c] The reaction mixture was further treated with 6 M HCl
and toluene at 110 oC for 1 h. [d] 2 mmol of alkenes were used. [e] 2 mmol of
the ketone substrate was used with 40 mol% of tert-octylamine (instead of t-
BuNHi-Pr) based on L1 in 0.3 mL of toluene at 150 oC for 48 h. The reaction
was further treated with 6 M HCl at 110 oC for 1 h.
With the optimized reaction conditions in hand, the scope of
alkenes was first investigated. Simple alkyl-substituted alkenes
all gave -alkylated cyclopentanones in good efficiency with
complete branched selectivity (3b-d). Propene is an excellent
coupling partner that introduces an isopropyl group (3e). When
vinylcyclohexane was employed, the alkylation product (3f) was
obtained in a low TON, probably owing to the steric hindrance of
the cyclohexyl group. With diene 2h, the reaction occurred
chemoselectively at the mono-substituted alkene. Alkenes
bearing a phenyl group or different oxygen/nitrogen-based
functional groups, e.g. OMe, OTIPS, OAc, ester, phthalic amine
or even free tertiary alcohol, are all compatible in moderate to
The feasibility of developing an enantioselective version of
this transformation was then explored. Employing (S)-BINAP as
the ligand, the coupling between 1-indanone 1c and 1-octene 2a
afforded product 4b in 40% yield with 1.3:1 dr, and a promising
level of enantioselectivity (74% ee) has been obtained for both
diastereomers (eq 3).[10i-l]
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Table 2. Alkylation with ketones as the limiting reagent. [a]
To gain further mechanistic understandings, the reaction
between 2,2,5,5-D4-cyclopentanone (d-1a) and 1-octene was
conducted with N-deuterated 7-azaindoline (d-L1), and stopped
early (Scheme 2A). The deuterium incorporation at both  and 
positions of unreacted 1-octene and the deuterium loss at all the
L1
(60 mol%)
N
N
H
O
O
[Ir(COD)2]BArF (10 mol%)
R
rac-BINAP (10 mol%)
R
α-positions of the product ketone are consistent with
a
MSA 2H2O (5 mol%)
t-BuNHi-Pr (20 mol%)
1
2
3 or 4
hypothesis that oxidative addition into the vinyl C–H bond of the
in situ formed enamine is reversible and Ir–H migratory insertion
into the alkene occurs in both 1,2 and 2,1-addition fashions and
is also reversible. In the generated product d-3a, deuterium was
transferred to both the terminal methyl and its adjacent methine
positions. In addition, the side-by-side reactions of 1a and d-1a
were conducted (Scheme 2B). A low intermolecular kinetic
isotope effect (KIE) of 1.7 was observed, indicating that the
oxidative addition into the enamine vinyl C–H bond is unlikely to
be the rate-determining step.
1 equiv
2,6-di-t-Bu-4-Mepyridine (40 mol%)
toluene, 130 oC, 96 h
O
O
O
C6H13
3a, 68%
b/l >20:1
dr: 1.3:1
C4H9
Ph
3c, 59%
b/l >20:1
dr: 1.3:1
3g, 62%
b/l >20:1
dr: 1.3:1
O
O
O
NPhth
7
3m, 39%[b]
b/l >20:1
dr: 1.2:1
3h,43%
b/l >20:1
dr: 1.3:1
3p, 53%
dr: 1.1:1
O
O
4c, 41%[c]
b/l: >20:1
dr: 1.4:1
C6H13
4b, 43%[c]
b/l: >20:1
dr: 1.4:1
Me
C6H13
O
O
4e, 32%[c]
b/l: >20:1
dr: 1.7:1
4g, 36%[c]
b/l: >20:1
dr: 2.1:1
F
C6H13
C6H13
Me
[a] Unless otherwise noted, all reactions were run with 0.2 mmol of 1, 0.12
mmol of L1, 13 equiv of alkene in 0.1 mL of toluene; all yields are isolated
yields; selectivities were determined by 1H NMR or GC-MS of the crude
products. [b] 3 equiv of 2m was used. [c] The reaction was run at 150 oC and
the mixture was further treated with 6 M HCl at 110 oC for 1 h.
To support the proposed enamine-mediated pathway, pre-
formed enamine 5 derived from 2-indanone was used as the
Scheme 2. Deuterium labelling studies.
testing substrate. Interestingly, dialkylation product
6 was
efficiently formed (eq 4).[21] In addition, an Ir–H complex (7) was
successfully prepared from enamine 5 with [Ir(coe)2Cl]2 and
PMe3 (eq 5).[22,23] Although complex 7 did not react with 1-octene
likely owing to the use of strongly coordinating PMe3 ligand, it
nonetheless shows that a low-valent iridium complex can insert
into enamine vinyl C–H bonds via oxidative addition.[7,9,15]
To understand the origin of the high branched selectivity,
density functional theory (DFT) calculations were performed on
the reaction of ketone 1a and olefin 2c (Figure 1). The
computational results indicate the enamine C(sp2)–H oxidative
addition to form Ir(III)-hydride 10 and the subsequent alkene
migratory insertion into the Ir–H bond (via 15-TS or 15L-TS)
both require relatively low kinetic barriers and are reversible, in
accordance with the deuterium labelling experiments described
above (Scheme 2). However, these Ir–H migratory insertion
pathways cannot lead to the alkylation products because of the
high barriers of the subsequent C–C reductive elimination (> 30
kcal/mol for 17-TS or 17L-TS). The most favorable pathway
involves migratory insertion into the Ir–C bond followed by C–H
reductive elimination (via 11-TS and 13-TS). This mechanism is
consistent with Huang’s recent study of the enamide system.[9]
The regioselectivity is determined in the alkene migratory
insertion step, which favours C–C forming with the internal
carbon of the alkene (via 11-TS). The 2,1-migratory insertion
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Figure 1. Computed reaction pathways for the formation of branched and linear alkylation products. For details, see the supporting information.
Bonds by Addition to ,-Unsaturated Carbonyl Compounds in
transition state 11L-TS is destabilized by steric repulsions with
the BINAP ligand.[24]
Methods of Organic Chemistry (Ed. G. Helmchen, R. W. Hoffmann, J.
Mulzer, E. Schaumann), Thieme, Stuttgart, 1995, v E21b, p. 2041.
For a review on C−H functionalization of ketones, see: Z. Huang, H. N.
Lim, F. Mo, M. C. Young, G. Dong, Chem. Soc. Rev. 2015, 44, 7764.
Z. Dong, Z. Ren, S. J. Thompson, Y. Xu, G. Dong, Chem. Rev. 2017,
117, 9333.
D. Xing, G. Dong, J. Am. Chem. Soc. 2017, 139, 13664.
For a DFT calculation, see: X. Li, H. Wu, Y. Lang, G. Huang, Catal. Sci.
Technol. 2018, 8, 2417.
In summary, a direct branched-selective -alkylation of cyclic
ketones has been realized using simple alkenes as the
alkylation agents, which offers a byproduct-free access to -
branched ketones. While the efficiency of the reaction remains
to be further improved, the dual activation mode demonstrated
and mechanistic understanding obtained here should have
implications beyond this transformation.
[6]
[7]
[8]
[9]
[10] For a recent review on branched-selective hydroarylation of alkenes,
see: G. E. M. Crisenza, J. F. Bower, Chem. Lett. 2016, 45, 2. For
examples of iridium-catalyzed branched-selective hydroarylation of
alkenes, see: a) K. Tsuchikama, M. Kasagawa, Y.-K. Hashimoto, K.
Endo, T. Shibata, J. Organomet. Chem. 2008, 693, 3939; b) S. Pan, N.
Ryu, T. Shibata, J. Am. Chem. Soc. 2012, 134, 17474; c) C. S. Sevov,
J. F. Hartwig, J. Am. Chem. Soc. 2013, 135, 2116; d) C. S. Sevov, J. F.
Hartwig, J. Am. Chem. Soc. 2014, 136, 10625; e) G. E. Crisenza, N. G.
McCreanor, J. F. Bower, J. Am. Chem. Soc. 2014, 136, 10258; f) G. E.
Crisenza, O. O. Sokolova, J. F. Bower, Angew Chem Int Ed. 2015, 54,
14866; g) T. Shirai, Y. Yamamoto, Angew. Chem. Int. Ed. 2015, 54,
9894; h) Y. Ebe, T. Nishimura, J. Am. Chem. Soc. 2015, 137, 5899; i)
M. Hatano, Y. Ebe, T. Nishimura, H. Yorimitsu, J. Am. Chem. Soc.
2016, 138, 4010; j) Y. Ebe, M. Onoda, T. Nishimura, H. Yorimitsu,
Angew. Chem. Int. Ed. 2017, 56, 5607; k) D. Yamauchi, T. Nishimura,
H. Yorimitsu, Chem. Commun. 2017, 53, 2760; l) S. Grélaud, P. Cooper,
L. J. Feron, J. F. Bower, J. Am. Chem. Soc. 2018, 140, 9351.
Acknowledgements
Financial supports from NSF (CHE-1254935) (G.D.), NSFC
(21772043) (D.X.) and NIH (R35GM128779) (P.L.) are
acknowledged. D.X. thanks the International Postdoctoral
Exchange Fellowship Program 2015 from the Office of China
Postdoctoral Council (OCPC, document 38, 2015). Mr Ki-Young
Yoon is thanked for the X-ray structure analysis. Ms. Lin Deng is
thanked for checking the experiments.
Keywords: C–C bond formation
• branched-selectivity •
alkylation • iridium catalysis• cyclic ketones
[11] For selected reviews and recent examples on enamine-transition metal
catalysis, see: a) S. Afewerki, A. Córdova, Chem. Rev. 2016, 116,
13512; b) D.-S. Kim, W.-J. Park, C.-H. Jun, Chem. Rev. 2017, 117,
8977; c) Y. Xu, T. Su, Z. Huang, G. Dong, Angew. Chem. Int.
Ed. 2016, 55, 2559; d) R.-R. Liu, B.-L. Li, J. Lu, C. Shen, J.-R. Gao, Y.-
X. Jia, J. Am. Chem. Soc. 2016, 138, 5198; e) C. Yang, K. Zhang, Z.
Wu, H. Yao, A. Lin, Org. Lett. 2016, 18, 5332; f) R. Manzano, S. Datta,
R. S. Paton, D. J. Dixon, Angew. Chem. Int. Ed. 2017, 56, 5834.
[1]
[2]
D. Cain, Carbon-Carbon Bond Formation (Ed.: R. L. Augustine), Marcel
Dekker; New York, 1979; vol. 1, p. 85.
M. B. Smith, J. March, March’s Advanced Organic Chemistry, 7th Ed;
Wiley: New York, 2001.
[3]
[4]
J. K. Whitesell, M. A. Whitesell, Synthesis 1983, 1983, 517.
a) G. Stork, S. R. Dowd, J. Am. Chem. Soc. 1963, 85, 2178; b) E. J.
Corey, D. Enders, Tetrahedron Lett. 1976, 17, 3; c) T. Hatakeyama, S.
Ito, M. Nakamura, E. Nakamura, J. Am. Chem. Soc. 2005, 127, 14192.
a) P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon Press, Oxford, 1992; b) Y. Yamamoto, Formation of C-C
[12] For examples of intramolecular alkylation of ketones with tethered
alkenes that give branched products, see: a) Y.-P. Xiao, X.-Y. Liu, C.-M.
[5]
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Che, Angew. Chem. Int. Ed. 2011, 50, 4937; b) H. N. Lim, G. Dong,
Angew. Chem. Int. Ed. 2015, 54, 15294.
[13] a) F. Mo, G. Dong, Science 2014, 345, 68; b) F. Mo, H. N. Lim, G.
Dong, J. Am. Chem. Soc. 2015, 137, 15518.
[14] For detailed condition optimizations, see the Supporting Information.
[15] For a DFT calculation on the indispensable role of 7-azaindoline, see: Y.
Dang, S. Qu, Y. Tao, X. Deng, Z.-X. Wang, J. Am. Chem. Soc. 2015,
137, 6279.
[16] While excess 1-octene was used to ensure the high TON, only a very
small portion of the alkene isomerized to internal octenes with most
being intact.
[17] The exo/endo selectivity for the norbornene-derived alkylation product
3p is unclear yet.
[18] S. Nakamura, M. Kaneeda, K. Ishihara, H. Yamamoto, J. Am. Chem.
Soc. 2000, 122, 8120.
[19] Attempts to determine the configuration of the major diastereomer by
2D NMR or X-ray analysis of its corresponding 2,4-dinitrophenyl
hydrazone product were unsuccessful.
[20] Both 1- and 2-tetralones also failed to provide desired products.
[21] Dialkylation products were not observed for other cyclic ketones being
tested.
[22] Using the [Ir(COD)2]BArF/BINAP system, a tiny yet clear metal-hydride
peak was observed by in situ 1H NMR analysis. However, attempts to
isolate and characterize this metal-hydride intermediate was unfruitful
yet.
[23] CCDC 1819814 (7) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[24] G. Huang, P. Liu, ACS Cat. 2016, 6, 809.
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Entry for the Table of Contents
Layout 2:
COMMUNICATION
Dong Xing, Xiaotian Qi, Daniel
Marchant, Peng Liu,* Guangbin Dong*
Page No. – Page No.
Branched-Selective Direct -
Alkylation of Cyclic Ketones with
Simple Alkenes
An intermolecular direct branched-selective α-alkylation of cyclic ketones has been
achieved using simple alkenes as the alkylation agents. 7-Azaindoline is employed
as a bifunctional ligand to facilitate enamine formation and guide subsequent C−H
activation with an iridium catalyst. This method offers a straightforward and
byproduct-free means to access ketones with β–stereocenters.
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