Direct α-Tertiary Alkylations of Ketones in a Combined Copper–Organocatalyst System

Article abstract of DOI:10.1002/anie.202016051

Herein, we report an efficient method for the tertiary alkylation of a ketone by using an α-bromocarbonyl compound as the tertiary alkyl source in a combined Cu-organocatalyst system. This dual catalyst system enables the addition of a tertiary alkyl radical to an enamine. Mechanistic studies revealed that the catalytically generated enamine is a key intermediate in the catalytic cycle. The developed method can be used to synthesize substituted 1,4-dicarbonyl compounds containing quaternary carbons bearing various alkyl chains.

Full text of DOI:10.1002/anie.202016051

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 10620–10625
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doi.org/10.1002/anie.202016051
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Synthetic Methods
Direct a-Tertiary Alkylations of Ketones in a Combined Copper–
Organocatalyst System
Ayako Kurose, Yuto Ishida, Goki Hirata, and Takashi Nishikata*
Dedicated to Professor Ilhyong Ryu on the occasion of his 70th birthday
Abstract: Herein, we report an efficient method for the tertiary
alkylation of a ketone by using an a-bromocarbonyl com-
pound as the tertiary alkyl source in a combined Cu-organo-
catalyst system. This dual catalyst system enables the addition
of a tertiary alkyl radical to an enamine. Mechanistic studies
revealed that the catalytically generated enamine is a key
intermediate in the catalytic cycle. The developed method can
be used to synthesize substituted 1,4-dicarbonyl compounds
containing quaternary carbons bearing various alkyl chains.
arylations of carbonyl compounds,[4,5] whereas the a-alkyla-
tion of a ketone with an a-halocarbonyl compound is rare.
The nucleophilic substitution step can be accomplished using
primary or secondary alkyl halides (not a-halocarbonyls and
mainly haloalkanes or benzylic halides) (Figure 1b).[6] Ter-
tiary alkyl halides are poorly reactive due to steric hindrance;
therefore, the corresponding reaction with an a-halocarbonyl
compound, as the electrophile, is challenging.
Another promising methodology involves the alkyl rad-
À
ical addition to a reactive C C double bond (Figure 1c). This
methodology uses enol ethers and their derivatives, including
S
ubstituted 1,4-dicarbonyl compounds are very important
structures that are often found in natural or related com-
pounds.[1,2] Retrosynthetically disconnecting such a compound
reveals two direct synthesis routes from readily available
carbonyl compounds: a) the cross-enolate coupling of two
different ketones or related enolates, and b) the nucleophilic
substitution of a ketone or an enolate with an a-halocarbonyl
compound (Figure 1). Cross-enolate coupling is an area that
has developed recently, and the number of reports in this field
appear to be increasing each year.[3] This methodology
provides a direct approach for the construction of a 1,4-
dicarbonyl structure, but it is sensitive to steric hinderance at
silyl enol ethers,[7] stannyl enolates,[8] enamines,[9,10] ace-
tates,[11] and vinyl ethers,[12] as C C double-bond sources.
À
Despite the importance of substituted 1,4-dicarbonyl com-
pounds, the direct tertiary alkylation of a ketone has not yet
been established because it is difficult to control the reactivity
of a tertiary alkyl radical (a-radical) due to steric hindrance; it
also requires pre-formed highly reactive enolates or their
derivatives.
Recently we reported that the reactions of styrenes and a-
haloesters involve tertiary alkylative olefinations through
atom-transfer radical addition (ATRA) followed by dehy-
drohalogenation.[13] Although the a-tertiary alkylations of
enamides to produce aldehydes has been accomplished,[14] the
direct a-tertiary alkylation of a ketone has, to the best of our
knowledge, not yet been achieved because the a-carbon of
ketone is not directly reactive toward tertiary alkyl radicals.
Based on this background, including our chemistry, we
hypothesized that an enamine catalytically generated through
the reaction of a ketone and an amino organocatalyst will
react with a tertiary alkyl radical to give the corresponding a-
tertiary-alkylated ketone (i.e., a 1,4-dicarbonyl compound
possessing a quaternary carbon center). Progress in radical
chemistry involving catalytically generated enamines has
recently been reported by Melchiorre, Nicewicz, and Mac-
Millan,[15] who showed that a catalytically generated enamine
from a cyclic ketone or aldehyde can be used in radical a-
alkylation chemistry. On the other hand, the reaction involves
a simple ketone and a functionalized tertiary alkyl reagent,
which remains challenging for this chemistry.[16] Herein, we
report the development of a reaction system that combines an
organocatalyst and a transition-metal catalyst; that is, a dual
catalyst system, that facilitates the direct a-tertiary alkylation
of ketones (Scheme 1).
À
hindered a-carbonyl C C bonds, resulting in oxidative
enolate coupling, while it also suffers from enolate homo-
coupling (Figure 1a). There are many reports on the a-
Figure 1. Synthetic approaches to a 1,4-dicarbonyl compound.
[*] A. Kurose, Y. Ishida, Dr. G. Hirata, Prof. Dr. T. Nishikata
Graduate School of Science and Engineering
Yamaguchi University
2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611 (Japan)
E-mail: nisikata@yamaguchi-u.ac.jp
Optimization studies employed a combination of aceto-
phenone (1a, 3 equiv) and 2-bromoester 2a (1 equiv) in the
presence of pyrrolidine (30 mol%), CuI (5 mol%),
PMDETA (5 mol%, N,N,N’,N’’,N’’-pentamethyldiethylene-
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016051.
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ineffective (Runs 15 and 16). It is well known that copper
complexes with PMDETA efficiently generate alkyl radical
species from alkyl halides in ATRP or ATRA chemistry;[17]
however, the addition of an acid did not affect the coordina-
tion of PMDETA to copper. This reaction required the use of
DABCO, a strong base, with 17% yield of 3aa obtained in the
absence of DABCO (Run 12). A dramatically lower yield of
3aa was obtained when K2CO3, i-Pr2EtN, or 4-dimethylami-
nopyridine (DMAP) was used instead of DABCO (for
optimization details, see Supporting Information).
Scheme 1. This work: Dual catalyst system.
triamine), DABCO (1 equiv, 1,4-diaza bicyclo[2.2.2]octane),
and molecular sieves (MS 3A) in hexane at 1008C for 20 h
(Table 1). At this stage, we expected that generating the
enamine from 1a and the tertiary alkyl radical derived from
2a is critical in this catalyst system. Indeed, 3aa was not
obtained in the absence of a Cu catalyst and pyrrolidine, and
the yield of 3aa depended on the amount of pyrrolidine (Runs
1–4). These results revealed that enamine formation affects
the yield of 3aa. Various acids were examined with the aim of
accelerating the formation of the enamine. p-TsOH and
CF3CO2H gave moderate yields of 3aa (Runs 5 and 6), while
the reaction involving AcOH resulted in 64% yield of 3aa
(Run 7). Although we examined some acetic acid derivatives,
no improvement in yield was observed. On the other hand,
phenol derivatives were effective (Runs 8–14), with 80%
yield of 3aa obtained when methyl 4-hydroxybenzoate was
used (Run 11). Other acids with pKa values of around 9 were
The reactivities of various ketones 1 were next examined
under the optimized reaction conditions (Table 2). Although
the alkylation mechanism is discussed later (vide infra), the
formation of the enamine is an important step in the catalytic
cycle. Pyrrolidine reacted smoothly with electron-poor and
sterically less-hindered ketones 1 to produce the enamine
intermediate, which reacted with the tert-alkyl radical gen-
erated from the reaction of the copper catalyst with the a-
bromocarbonyl compound 2. Therefore, relatively electron-
rich ketones 1 (as in 1b, 1c, 1r, and 1s) resulted in lower yields
of 3, while the reactions proceeded smoothly with relatively
electron-poor ketones 1 bearing (pseudo) halogens (i.e., 1d,
1m, and 1q) and esters (i.e., 1 f–1j) to produce 3 in good
yields. Ketones bearing aminocarbonyl groups (as in 1k and
1l), however, resulted in moderate yields. Ketones bearing
electron-poor aryl and phenyl groups (as in 1n, 1o, and 1p)
also provided 3 in good yields. We examined various solvents
with the aim of increasing the yield, with hexane/CPME
(cyclopentyl methyl ether) found to be the better solvent in
the case of 1b. Sterically hindered ketone 1e gave a low yield
of 3ea, but similarly hindered ketone 1r gave a higher yield of
3ra. Higher yields of 3 were obtained when 50 mol%
pyrrolidine was included in the reactions of 1c and 1r.
Acetophenones bearing thiophene or pyridine (1t, 1u), which
can poison the catalyst, afforded 3ta or 3ua in 38% or 52%
isolated yield, respectively. In the case of 1u, increasing
amount of pyrrolidine was effective to obtain high yield.
We next examined the reactivities of a-bromocarbonyl
compounds 2 (Table 3). To check functional group compat-
ibility, 2b–2j bearing alkyl, substituted benzyl, ester, bromine,
alcohol, and amino functional groups were examined, with
our alkylation reaction exhibiting good functional group
compatibility. We also checked the reactivities of substrates
2k–2o bearing alkyl chains of various length, including
cyclobutyl, cyclohexyl, ethyl, propyl, butyl, and other longer
chains at the a-position, which revealed that this radical
reaction is basically insensitive to steric bulk at the reaction
site. Therefore, even 2o substituted with both n-octyl and n-
hexyl groups afforded 3jo in 48% yield. Increasing the
amount of pyrrolidine was also effective in the reactions of 2n
and 2o, to give 3jn and 3jm in yields of 62% and 60%,
respectively. 2-Bromolactone 2p gave 53% yield of 3jp. We
found that 2-bromocarboxamide 2q was a limitation of this
reaction. Indeed, we examined various 2-bromocarboxa-
mides, with the corresponding reduction, HBr elimination,
and 1,4-HAT-like (hydrogen-atom-transfer-like) side-reac-
tions observed. Although our radical methodology was not
applicable to primary- and secondary-alkyl halide but sec-
Table 1: Additive effect.[a]
Run
Additive
Yield of 3aa [%][b]
1
none
none
none
none
26
0
59
81
2[c]
3[d]
4[e]
5
p-TsOH
47
6
CF3CO2H
43
7
AcOH
64
8
9
p-MeC6H4OH
phenol
51
55
10
11
12
13
14
15
16
C6F5OH
49
p-MeO2CC6H4OH
p-MeO2CC6H4OH
m-MeO2CC6H4OH
o-MeO2CC6H4OH
2-(benzo[d]oxazol-2-yl)phenol
(S)-binol
80 (70)
17[f]
66
32
48
71
[a] All reactions were conducted with 1a (3.0 equiv), 2a (1.0 equiv),
pyrrolidine (30 mol%), CuI (5 mol%), PMDETA (5 mol%), DABCO
(1.0 equiv), additive (30 mol%) and MS 3ꢀ in hexane for 20 h at 1008C.
[b] Yield determined by 1H NMR spectroscopy, 1,1,2,2-tetrachloroethane
used as internal standard; yield of isolated product shown in paren-
thesis. [c] Without pyrrolidine. [d] 50 mol% of pyrrolidine. [e] 100 mol%
of pyrrolidine. [f] Without DABCO.
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Table 2: Substrate scope I.[a]
Table 3: Substrate scope II.[a]
[a] All reactions were conducted with 1 (3.0 equiv), 2 (1.0 equiv),
pyrrolidine (30 mol%), CuI (5 mol%), PMDETA (5 mol%), DABCO
(1.0 equiv), methyl 4-hydroxybenzoate (30 mol%) and MS 3ꢀ in hexane
for 20 h at 1008C. Isolated yields are shown. Yields in parentheses were
1
determined by H NMR analysis. [b] 50 mol% pyrrolidine was used.
[c] Isolated yield by GPC.
alkenylated ketone (1w) reacted smoothly with 2a to produce
the corresponding product (3wa) in 65% yield in the
presence of methyl 4-hydroxy benzoate that is the optimal
acid. The reactions of acyclic aliphatic ketones (1x and 1y)
can be applied to this reaction and the yields ranged from 42–
68% (3xk, 3yk, and 3ya). Cyclic ketone 1z gave single
alkylated product 3zk in 56% yield. Interestingly, 3-methyl-
cyclohex-2-en-1-one 1aa gave g-alkylated product 3aak in
63% yield (See SI). In this case, a-alkylation was not
observed.
[a] All reactions were conducted with 1 (3.0 equiv), 2 (1.0 equiv),
pyrrolidine (30 mol%), CuI (5 mol%), PMDETA (5 mol%), DABCO
(1.0 equiv), methyl 4-hydroxybenzoate (30 mol%) and MS 3ꢀ in hexane
for 20 h at 1008C. Isolated yields are shown. Yields in parentheses were
determined by H NMR analysis. [b] Reaction in hexane:CPME (10:1).
[c] 50 mol% pyrrolidine was used. [d] Reaction at 808C. [e] Isolated yield
1
by GPC.
alkyl halides are basically reactive for enamines under
classical ionic conditions.
A plausible organo- and copper-catalyzed tert-alkylation
mechanism is outlined in Figure 2. Enamine 1’ is formed by
the pyrrolidine ([N]H) and ArOH catalysts, and reacts with
A, generated from the reaction of 2 with CuI, to form B. The
reaction in the presence of TEMPO did not result in the
formation of product 3, which suggests that radical species A
exists. B is then oxidized by CuII to produce cationic
intermediate C. Here, ATRA provides an alternative path-
way. Key intermediate E is obtained from D by the
elimination of ArOH with DABCO. Finally, the hydrolysis
of E provides 3 with concomitant formation of pyrrolidine to
We next tried miscellaneous combinations of aliphatic,
and b-functionalized ketones (1v–1aa) under modified opti-
mized conditions. AcOH or TfOH gave smooth enamine
formation (Table 4). The NMR yields of 3 were basically good
but isolated yields were moderate to good because the
isolations were sometimes problematic due to inseparable (or
difficult to separate) side products such as reduction and H-Br
elimination of 2. Although b-ethylated ketone (1v) reacted
with 2k to give 34% yield of 3vk in the presence of TfOH, b-
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Table 4: Substrate scope III.[a]
[a] All reactions were conducted with 1 (3.0 equiv), 2 (1.0 equiv),
pyrrolidine (30 mol%), CuI (5 mol%), PMDETA (5 mol%), DABCO
(1.0 equiv), AcOH (30 mol%) and MS 3ꢀ in hexane for 20 h at 1008C.
Isolated yields are shown. Yields in parentheses were determined by
1H NMR analysis. [b] TfOH was used instead of AcOH. [c] 50 mol%
pyrrolidine and acid were used. [d] Methyl 4-hydroxy benzoate was used
instead of AcOH.
Scheme 2. Control experiments.
unstable or short life-time molecules, such as aliphatic
enamines. Low yields of 3aa were obtained in the absence
of 4-(MeO2C)C6H4OH or DABCO. These results are con-
sistent with those in Table 1 (Runs 1 and 12). We expected 4-
(MeO2C)C6H4OH to play an important role in the formation
of the enamine; however, this result suggests that 4-
(MeO2C)C6H4OH affects or accelerates some of the elemen-
tal steps in the catalytic cycle, for example, by stabilizing
cation C. DABCO is required for the hydrogen-elimination
step in the catalytic cycle.
We also used enamine 1’ as a catalyst instead of
pyrrolidine, which resulted in 65% yield of 3aa (Scheme 2II);
in this case, the reaction did not proceed in the absence of 1’.
Pyrrolidine is consumed to generate 1’ and is reformed after
the addition/elimination reaction.
Figure 2. Proposed mechanism.
An azodicarboxylate (Azo) generates the corresponding
tert-alkyl radical when heated; hence, we used Azo to
determine whether this reaction is a radical chain reaction
or not (Scheme 2III). When the reaction using Azo (as
a catalyst or reagent) was carried out in the presence/absence
of 2a, low yield of 3aa or 3-Me (R = Me) was obtained. This
result suggests that a chain mechanism may be involved, but
as a minor pathway. As a key catalyst, a Cu salt is required to
complete or repeat the catalytic cycle.
The reaction conditions associated with these a-alkyla-
tions can be further exploited for chemoselectivity. Hence, the
alkylation of 4, which possesses two different ketone moieties,
exclusively afforded 5, the singly alkylated product
(Scheme 3A). We next demonstrated that 3aa can undergo
three chemical transformations, as shown in Scheme 3B. The
reaction of 3aa in the presence of p-anisidine, Et3N, and TiCl4
resulted in the formation of lactam derivative 6 in 64% yield,
while the reduction of 3aa with NaBH4 led to cyclization and
complete the catalytic cycle. Cationic intermediate C can also
give 3 through an E1-like elimination reaction.
While speculative, we conducted some control experi-
ments to support of the overall reaction mechanism
(Scheme 2). We examined the reactivity of enamine 1’, with
the desired product 3aa obtained in 89% yield under the
optimized conditions; an 80% yield was obtained even when
one equivalent of 1’ was used (Scheme 2I). Although isolated
enamines are reactive and pyrrolidine is cheap and readily
available, the reaction of a catalytically generated enamine
obtained by reacting a ketone with pyrrolidine is much more
attractive than the reaction involving an isolated enamine.
However, there appear to be no reports of reactions of a-
bromocarbonyls with catalytically generated enamines since
Zhang reported reactions of enamines with a-bromocarbon-
yls in the presence of a Ru catalyst,[9a] which is possibly
attributable to the low reactivities of radical species toward
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efficient synthesis of highly congested organic molecules
through radical chemistry. Further applications, including
asymmetric reactions, are currently being explored.
Acknowledgements
We warmly thank Yamaguchi University, Naito foundation
and JSPS KAKENHI Grant Number JP20H04823 in Hybrid
Catalysis for Enabling Molecular Synthesis on Demand.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkylation · copper · ketones · organocatalysis ·
radicals
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Scheme 3. Synthetic application.
the corresponding lactone in 80% yield. Furthermore, the
reaction of 3aa with hydrazine gave pyridazinone derivative 8
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compound (2b), the corresponding tert-alkyl was incorpo-
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in the previous route,[18] in which tert-alkyl was incorporated
via Friedel–Crafts reaction, 12 was synthesized in five steps.
In summary, we successfully demonstrated the direct a-
tertiary alkylations of ketones with a-bromocarbonyl com-
pounds in a Cu- pyrrolidine combined-catalyst system. This
dual catalyst system realizes the synthesis of tertiary alkylated
ketones bearing quaternary carbons. Control experiments
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intermediate. This combined catalyst system enabled the
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1987; b) P. W. Hickmott, Tetrahedron 1982, 38, 1975 – 2050;
c) P. W. Hickmott, Tetrahedron 1982, 38, 3363 – 3446; d) S. F.
Dyke, The Chemistry of Enamines, Cambridge University Press,
Cambridge, 1973; e) Z. Rappoport, The Chemistry of Enamines,
Pt. 1, Wiley, Chichester, 1994; f) L. Zhu, D. Wang, Z. Jia, Q. Lin,
M. Huang, S. Luo, ACS Catal. 2018, 8, 5466 – 5484.
[16] Reactions with catalytically generated enamines: Reaction with
À
C H bond: a) B. Zhang, S.-K. Xiang, L.-H. Zhang, Y. Cui, N.
Jiao, Org. Lett. 2011, 13, 5212 – 5215; Intramolecular cyclization:
b) N. Vignola, B. List, J. Am. Chem. Soc. 2004, 126, 450 – 451; For
a review on enamine catalysis, see: c) S. Mukherjee, J.-W. Yang,
S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471 – 5569.
[17] a) K. Matyjaszewski, J. Xia, Chem. Rev. 2001, 101, 2921 – 2990;
b) M. Kamigaito, T. Ando, M. Sawamoto, Chem. Rev. 2001, 101,
3689 – 3746; c) M. J. W. Taylor, W. T. Eckenhoff, T. Pintauer,
Dalton Trans. 2010, 39, 11475 – 11482; d) W. T. Eckenhoff, T.
Pintauer, Dalton Trans. 2011, 40, 4909 – 4917.
[18] R. L. Hudkins, A. L. Zulli, R. Reddy Dandu, M. Tao, K. A.
Josef, L. D. Aimone, R. C. Haltiwanger, Z. Huang, J. A. Lyons,
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[11] Selected examples: E. Peralta-Hernꢀndez, E. A. Blꢁ-Gonzꢀlez,
V. A. Gracia-Medrano-Bravo, A. Cordero-Vargas, Tetrahedron
2015, 71, 2234 – 2240.
Manuscript received: December 2, 2020
Version of record online: April 7, 2021
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