Visible Light Promoted β-C—H Alkylation of β-Ketocarbonyls via a β-Enaminyl Radical Intermediate

Article abstract of DOI:10.1002/cjoc.201700785

A 5πe carbonyl activation mode is reported on the basis of photo-induced single-electron-transfer (SET) oxidation of a secondary enamine. The resultant β-enaminyl radical intermediate was trapped by a wide range of Michael acceptors, producing β-alkylation products of β-ketocarbonyls in a highly efficient manner.

Full text of DOI:10.1002/cjoc.201700785

Visible Light Promoted β-C-H Alkylation of β-Ketocarbonyls via a
β-Enaminyl Radical Intermediate
Dehong Wang,a Long Zhang ab and Sanzhong Luo*ab
ABSTRACT A 5πe carbonyl activation mode is reported on the basis of photo-induced SET oxidation of a secondary enamine. The resulted β-enaminyl
radical intermediate was trapped by a wide range of Michael acceptors, producing β-alkylation products of β-ketocarbonyls in a highly efficient manner.
KEYWORDS secondary enamine, β-enaminyl radical, C-H alkylation, photoredox catalysis, β-ketocarbonyls
stoichiometric organometallic reagents,5 and the strategy of direct
Introduction
β-alkylation developed by MacMillan is restricted to aldehydes4b.
Based on our previous works on secondary enamine carbonyls,6
As electron rich species, enamine is also redox-labile and can
be readily oxidized to radical cation upon single electron transfer.
we have explored 5πe carbonyl activation with preformed
1,2
secondary enamine carbonyls under photoredox catalysis7. The
MacMillan and others have successfully demonstrated the
application of enamine cation radical in asymmetric catalysis,
expected transient β-enaminyl radical intermediate, formed via an
enamine oxidation/C-H deprotonation sequence, could be
intercepted by a Michael acceptor, thus generating the direct
β-alkylation products of β-ketocarbonyls .
termed as SOMO catalysis.3 Recently, the same group introduced
a unique 5πe carbonyl activation mode via β-enaminyl radical
intermediate, generated upon SET (single-electron-transfer) with
enamine and a subsequent proton loss.4 Stoichiometric amount of
base such as 1, 4-diazabicyclo [2.2.2] octane (DABCO), was
required in these cases to facilitate the generation of β-enaminyl
Results and Discussion
radical and the resulted β-functionalizations. On the other hand,
5πe carbonyl activation mode with secondary enamine, derived
from the equally prevalent primary amine, has surprisingly
remained underdeveloped (Scheme 1).4d One easily conceived
issue would be the competitive C-H cleavage vs N-H cleavage,
while only the former proton loss would be productive for
β-enaminyl radical process.
Results
To substantiate our hypothesis, enamine 1a was synthesized
beforehand. Indeed, with appropriate choice of photocatalyst and
base, the expected β-alkylation is feasible. Methyl acrylate was
initially selected as the electrophilic coupling partner. To our
delight, we obtained the desired β-alkylation in nearly
quantitative yield (table 1, entry 1), when employing
Ir(ppy)2(dtbbpy)PF6 as photocatalyst and a catalytic amount of
quinine as base. Among the photocatalysts screened, only
Ir[(dFCF3(ppy)2)]dtbbpy could promote the coupling reaction
efficiently (entries 5-7). Without the photocatalyst or light, no
products were observed (entries 2-3), highlighting the
photoresponsive nature of this reaction. Catalytic amount of
quinine was suffice to effectively promote the reaction and the
reaction even worked to give the desired alkyaltion product in 34%
yield without any added base (entry 4). Likely, the enamine itself
may serve as a base to assist in proton abstraction. The use of
other organic bases such as DABCO, quinulcidine, pyridine, 2,
6-lutidine led to diminished productivity (entries 11-14). On the
other hand, the use of ethyl protected quinine resulted in
comparable results, indicating the catalysis was mainly related to
the tertiary amine moiety, but not the free OH group (entry 15).
The reaction generally worked well in aprotic polar solvent and
THF was identified as the optimal solvent (entries 8-10)
Scheme 1. Direct β-alkylation of secondary enamine carbonyls
I. -Enaminyl radical (5 e) with tertiary enamine
N
N
N
SET
5
e
-H+
well-known
II. -Enaminyl radical (5 e) with secondary enamine: this work
R
R
R
H
H
NH
N
N
-H+
SET
EWG
EWG
EWG
only one example
H
Issue: C-H vs N-H proton loss
Bn
H
N
Bn
O
NH
O
EWG
OEt
[Ir] photoredox catalyst
OEt
Base
EWG
-Alkylation of Enamine Carbonyls
The β-alkylation of saturated ketones or aldehydes typically
requires the use of unsaturated carbonyl substrates and
a Key Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing, 100190 (China); College of Chemistry
and Chemical Engineering, University of Chinese Academy of Sciences, Beijing,
100490
E-mail: luosz@iccas.ac.cn
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin, 300071 (China).
This article has been accepted for publication and undergone full peer review but has not
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may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201700785
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Table 1 Screening and Optimizationa
variation from standard
Entry
Yield(%)b
conditions
none
1
2
99
0
no Ir(ppy)2(dtbbpy)PF6
no light
3
0
4
no quinine
Ru(bpy)3Cl2
Eosin Y
34
0
5
6
0
7
Ir[(dFCF3(ppy)2)](dtbbpy)PF6
CH3CN
90
95
92
61
64
72
45
26
90
8
9
DMF
aReactions were performed at room temperature in 0.5 mL THF with 1a
(0.15 mmol), 2a (0.10 mmol), quinine (20 mol %), Ir(ppy)2(dtbbpy)PF6 (1
mol %) under Ar with 3 W blue LEDs irradiation for 24 h, unless otherwise
noted. Yields shown were of isolated products. Diastereomeric ratios were
determined by 1H NMR analysis.
10
11
12
13
14
15
CH2Cl2
DABCOc
quinuclidine
pyridine
2,6-lutidine
O-Et-quinine
aReactions were performed at room temperature in 0.5 mL THF with 1a
(0.15 mmol), 2a (0.10 mmol), quinine (20 mol %), photocatalysts (1 mol %)
under Ar with 3 W blue LEDs irradiation for 24 h, unless otherwise noted.
bIsolated yield. cWhen conducted with 1 equiv of DABCO, the yield was
61%
We next focused our attention on the scope of the secondary
enamine carbonyls coupling partner (table 3). In cases where
partial hydrolysis of enamine observed, the product mixture was
first worked up with 1 M HCl to give β-alkylation product of
β-ketocarbonyl compounds in one port manner. Enamines with
different ester moieties including those with sterically bulky
tert-butyl ester, benzyl, and allyl groups, afforded the desired
alkylation adducts in good yields (3ba-3ea). The current catalysis
worked well with cyclic enamine esters to give the desired
Having identified optimal conditions for this photoredox
catalyzed β-alkylation reaction, we first investigated the scope of
Michael acceptors (table 2). A broad range of electrophilic olefin
acceptors were identified as effective alkylation partners for this
protocol. Unsubstituted acrylates with different ester groups
were generally tolerated in this direct β-alkylationreaction
(3aa-3ae). Delightfully, ethyl (E)-crotonate also performed well
(3af) with 1.6:1 dr. When the alkene became more
electron-deficient, the reaction worked well with good yields, but
low diastereoselectivity (3ag-3ah). Notably, both crotononitrile
and N, N-dimethylacrylamide were proved to be highly effective
acceptors (3ai-3aj). Among other electron deficient alkenes, cyclic
and acyclic enones, 2-buten-4-olide also worked well to give the
alkylation adducts. Unfortunately, the diastereoselectivity was
poor in these cases (3ak-3ao). 4-Ethenylpyridine and
2-ethenylpyridine have also been examined in the reaction
showing good activity (3ap-3aq).
products with high yields.
The relatively unstable
α-acetybutyrolactone was also amenable to the mild catalytic
conditions, furnishing 3ga in 99% yield. Most delightfully, both
cyclic and acyclic 1, 3-diketones were workable substrates under
the current conditions (3ha-3ia). The enamine 1i was prepared as
a mixture of regioisomers, and the corresponding β-alkylation
product was obtained with regioselectivity of 3.6/1. Enamine
amides with either N-phenyl or N-benzyl amides were also viable
substrates for this reaction (3ka-3la). Additionally, enamine 1m
derived from cyclopentanone-2-carbonitrile can also be
incorporated in the alkylation reaction to give the desired
alkylation adduct 3ma in a quantitative yield. When other types of
enamines derived from isopropylamine, cyclohexylamine and
aniline were employed to the coupling reaction, the results were
also satisfactory, though the yield of 3pa is relatively low (3na-pa).
These results set basis for the development of a catalytic
asymmetric version using chiral primary amine catalysts.
Table 2. Scope of the Michael Acceptors a
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Table 3. Scope of the enamines a
Scheme 3 Catalytic and asymmetric version
Bn
NH
O
O
Ph
NH2
(20 mol %)
O
O
Ir(ppy)2(dtbbpy)PF6(1 mol %)
quinine (20 mol %)
THF, 3 W blue LED,
24 h
O
(1)
+
O
O
3aa
2a
4
O
15%
O
Ph
NH
O
Ph
NH
O
O
Ir(ppy)2(dtbbpy)PF6(1 mol %)
quinine (20 mol %)
THF, 3 W blue LED,
24 h
(2)
O
+
O
O
3qa
1q
2a
O
90%,dr: 1:1
O
Scheme 4 Control experiments
aReactions were performed at room temperature in 0.5 mL THF with 1a
(0.15 mmol), 2a (0.10 mmol), quinine (20 mol %), Ir(ppy)2(dtbbpy)PF6 (1
mol %) under Ar with 3 W blue LEDs irradiation for 24 h, unless otherwise
noted. Yields shown were of isolated products. Diastereomeric ratios were
determined by 1H NMR analysis. Compounds 3ba-ea, 3fa, 3ha and 3ja-la
were isolated after working up with 1 M HCl and R3 = Bn
To probe the utility of our method in preparative synthesis, a
subgram-scale reaction of enamine 1b with methyl vinyl ketone 2k
was performed, delivering the alkylation product 3bk in 50% yield
after hydrolysis (Scheme 2). We also examined the direct
alkylation of β-ketoester 4 in the presence of catalytic amount of
benzyl amine (20 mol %). Enamine ester product 3aa was
obtained in only 15% yield, and it seemed turnover of the
enamine intermediate was an issue under the basic conditions
(Scheme 3, eq 1). A chiral enamine 1q was employed to induce
chirality at β position, with unfortunately 1:1 dr for product 3qa
(Scheme 3, eq 2).
To shed light on the mechanism, a radical quenching
experiment was conducted. The yield of alkylation product was
decreased dramatically in the presence of TEMPO (scheme 4).
HRMS analysis of the quenched reaction mixture clearly indicated
radical trapped adducts 5 from TEMPO. This observation provided
direct support to the radical mechanism and the existence of
β-enaminyl radical.
A plausible mechanism for this coupling reaction is proposed
in Scheme 5. With the irradiation of blue LED, the photoexcited
*IrIII acts as a strong oxidant (E1/2*III/II = 0.70 V vs Ag/AgCl in CH3CN)
in a single SET event with 1a, generating radical cation 6 and the
reduced photocatalyst IrII. Stern-Volmer fluorescence quenching
experiments (see the Supporting Information for details) indicated
that enamine 1a could quench photoexcited *IrIII efficiently. It is
known that SET oxidation could significantly increase X-H acidity8.
Initial DFT calculation indicated β-C-H (pKa = 0.47) would be more
acidic than N-H (pKa = 5.96)9, deprotonation of the β-C-H of the
radical cation 6 would be favored, resulting in the formation of
β-enaminyl radical intermediate 7 under the present conditions.
The transiently generated species 7 could be rapidly intercepted
by an electrophilic Michael acceptor, forging the desired C−C bond
while delivering the α-carbonyl radical adduct 8. IrIII is regenerated
upon the oxidation of IrII by 8, completing the photoredox
catalytic cycle. Finally, the alkylation product is obtained by the
protonation of the enolate 9. The measured quantum yield of the
model reaction was Φ=0.35, indicating that a radical chain process
may not be involved in the reaction.
Scheme 2 Subgram-scale and conversion reactions
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Scheme 5. Proposed Mechanism of the β-Alkylation reaction
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Conclusions
In conclusion, we have developed a 5πe β-enaminyl activation
platform based on secondary enamine, which enabled the direct
β-alkylation of β-ketocarbonyls. This method was further
demonstrated to be
a
general approach for direct
β-functionalization of β-ketocarbonyls. Mechanistic studies
provided direct evidence for the existence of enaminyl radical.
Further explorations on developing a catalytic asymmetric variant
are currently underway.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
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R.; Nappi, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135,
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Acknowledgement
We thank the Natural Science Foundation of China (21390400,
21521002, 21572232 and 21672217) and the Chinese Academy of
Science (QYZDJ-SSW-SLH023) for financial support. S. L. is
supported by National Program of Top-notch Young Professionals.
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Entry for the Table of Contents
Table of contents
an unprecedented 5πe β-enaminyl activation platform based on secondary enamine, which enabled the direct β-alkylation of
β-ketocarbonyls has been established.
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