Visible-Light-Promoted Synthesis of 1,4-Dicarbonyl Compounds via Conjugate Addition of Aroyl Chlorides

Article abstract of DOI:10.1002/asia.201701738

A facile visible-light photocatalytic conjugate addition to prepare 1,4-dicarbonyl compounds has been developed by employing readily available aroyl chlorides as aryl radical sources. This operationally simple method shows a broad scope with regard to both aroyl chlorides and Michael acceptors. As a result, a variety of 1,4-diketones were efficiently synthesized in moderate to good yields.

Full text of DOI:10.1002/asia.201701738

CHEMISTRY
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Accepted Article
Title: Visible-Light-Promoted Synthesis of 1,4-Dicarbonyl Compounds
via Conjugate Addition of Aroyl Chlorides
Authors: Chao-Ming Wang, Dan Song, Peng-Ju Xia, Jing Wang, Hao-
Yue Xiang, and Hua Yang
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To be cited as: Chem. Asian J. 10.1002/asia.201701738
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10.1002/asia.201701738
Chemistry - An Asian Journal
COMMUNICATION
Visible-Light-Promoted Synthesis of 1,4-Dicarbonyl Compounds
via Conjugate Addition of Aroyl Chlorides
Chao-Ming Wang,† Dan Song,† Peng-Ju Xia, Jing Wang, Hao-Yue Xiang,* Hua Yang*
Abstract: A facile visible-light photocatalytic conjugate addition to
prepare 1,4-dicarbonyl compounds has been developed by
employing readily available aroyl chlorides as aryl radical sources.
This operationally simple method shows broad scope with regard to
both aroyl chlorides and Michael acceptor. As a result, a variety of
aroyl chlorides are inexpensive, abundant and important
intermediates for the assembly of complex molecules.[11]
However, only rare examples have been reported using aroyl
chlorides as aryl radical source in the preparation of 1,4-
dicarbonyl compounds. In 2010, Wan group reported a Michael-
1,4-diketones were efficiently synthesized in moderate to good yields. addition-type reaction between aroyl chlorides and chalcones in
the presence of samarium powder.[12] We were curious about the
performance of aroyl chloride as radical source in the synthesis
1,4-Dicarbonyl compounds are intriguing motifs and versatile
of 1,4-dicarbonyl compounds. More importantly, the substrate
precursors in numerous heterocyclic compounds and bioactive
gap in the conjugate addition of acyl radical and α,β-unsaturated
carbonyl substrates needs to be filled in (Scheme 1). Herein, we
natural compounds.[1] Undoubtedly, they have gained
considerable attention in respect to their synthetic pathways.[2]
describe an efficient and practical method to construct 1,4-
Of all the reported methods, conjugate addition of acyl radicals
dicarbonyl compounds from commercially available aroyl
to α,β-unsaturated carbonyl compounds is considered as the
chlorides with broad functional group tolerance.
most straightforward and efficient synthetic route.[3] Traditional
approaches to generate acyl radical mostly rely on harsh
reaction conditions - UV irradiation or high temperature with
relatively low yield.[4] In this context, generation of acyl radical
under mild conditions would be highly desirable to overcome the
hurdle of this attractive methodology.
Over the past years, photoredox catalysis has emerged as a
promising route to construct complex scaffolds that are
otherwise difficult to be prepared by traditional methods.[5] To
date, a number of radicals have been effectively generated via
visible-light photoredox catalysis to participate in a wide range of
chemical transformations, giving birth to effective solutions for
the synthesis of challenging and complex compounds.[6]
Recently, much attention has been directed to the conjugate
Scheme 1. Different strategies to hydroacylations of electron-deficient
alkenes.
addition of acyl radical to olefins. In 2015, Fu group reported a
We initially began our studies by choosing benzoyl chloride
photoredox-catalyzed decarboxylative coupling, in which α-oxo-
(1a) and 2-cyclohexen-1-one (2a) as a model reaction
carboxylic acids were employed to generate acyl radicals.[7] Ye
under photochemical conditions to synthesize 1,4-
and co-workers used carboxylic anhydrides as the source of acyl
dicarbonyl product 3a (Table 1). Upon using DIPEA as a
radical to prepare 1,4-dicarbonyl compounds.[8] In 2017, Gryko
reductant, the desired product was unobtainable while the
and co-workers reported the application of 2-S-pyridyl thioesters
title reaction was catalyzed by 1 mol% fac-Ir(ppy)3 and
as acyl radical sources by using vitamin B12 derivative as
irradiated by 9 W white LEDs in CH3CN (Table 1, entry 1).
photocatalyst. [9] More recently, Wang described the generation
Pleasingly, the desired product 3a was obtained in 51%
of acyl radicals through Csp2-H activation of aldehydes with
yield with Hantzsch ester (HEH) as the reductant (entry 2).
quinuclidine as co-catalyst. [10] Noticeably, though encouraging
Next, among a series of common photosensitizers, fac-
advance has been achieved in this field, current methodologies
Ir(ppy)3 was found to be the most effective catalyst (Table
frequently suffer from the availability of substrate - requiring
1, entries 3-7).[13] Furthermore, effects of solvent were also
multistep synthesis for their preparation or costly large-scale
investigated and the yield of 3a was consistently reduced in
preparation. This dilemma for acyl source would surely restrict
DMF, CH2Cl2, toluene, THF, acetone and MeOH (Table 1,
broad application of this straightforward pathway. As we know,
entries 8-13). To furhter improve the yield, a series of bases
were tested to consume HCl produced in the process of
reaction (Table 1, entries 14-18). Satisfyingly, the yield for
[a] Dr. C.-M. Wang, D. Song, Dr. P.–J. Xia, Dr. J. Wang, Dr. X.-Y. Xiang
Prof. Y. Yang
College of Chemistry and Chemical Engineering
Central South University
Changsha 410083, P. R. China
e-mail: hyangchem@csu.edu.cn; xianghaoyue@csu.edu.cn
[b] † C. Wang and D. Song contributed equally.
3a was improved to 87% upon using NaHCO3 as the base.
Switching white LEDs to blue LEDs (460 nm) resulted in a
slight improvement in the yield (Table 1, entry 19). Control
experiments indicated that visible light and photocatalyst
were essential to this reaction (Table 1, entries 20 and 21).
Ultimately, the optimal conditions were finalized as: 1 (2.0
equiv.) and 2 (1.0 equiv.) in the presence of fac-Ir(ppy)3 (1
mol%), HEH (2.0 equiv.) and NaHCO3 (2.0 equiv.) in
CH3CN (0.2 M) under Ar irradiated by 9 W blue LEDs.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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COMMUNICATION
Table 1. Screening of Reaction Conditions[a]
.
photocatalyst
Yield[b]
(%)
NR
51
43
49
36
35
25
trace
43
36
39
44
NR
87
52
41
60
72
entry
1
2
3
4
5
6
7
8
(1 mol%)
fac-Ir(ppy)3
fac-Ir(ppy)3
Ru(bpy)3(PF6)2
Ir(ppy)2(dtbbpy)PF6
Eosin Y
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
reductant
DIPEA
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
HEH
base
—
—
—
—
—
—
—
—
—
—
—
—
Rhodamin B
Rose Bengal
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
—
9
CH2Cl2
Toluene
THF
10
11
12
13
14
15
16
17
18
19c
20d
21c
Acetone
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
—
NaHCO3
Na2CO3
K2CO3
DIPEA
Et3N
NaHCO3
NaHCO3
NaHCO3
89
NR
NR
[a]Unless otherwise noted, all reactions were performed on 1a (0.4 mmol, 2.0
equiv.), 2a (0.2 mmol, 1.0 equiv.), fac-Ir(ppy)3 (0.002 mmol, 1 mol %),
reductant (0.4 mmol, 2.0 equiv.), base (0.4 mmol, 2.0 equiv.) and CH3CN (1.0
mL) under Ar was irradiated by 9 W white LEDs at r.t. for 24 h. [b]Isolated yield.
[c]9 W Blue LEDs (460 nm) were used. [d]Reaction was performed in the
absence of visible light.
With the optimized conditions in hand, the generality of this
reaction was then evaluated. To our delight, a range of electron-
deficient alkenes served as suitable radical acceptors to afford
the corresponding products in good to excellent yields (Scheme
2). Firstly, cyclic enones including C-4 disubstituted
cyclohexenone, cyclopentenone or cycloheptenone were well
tolerated to give the corresponding adducts in good yields (3b-
3d). Secondly, comparable yields were also achieved for linear
enones and 3e and 3f were obtained in 75% and 73% yield
respectively. Finally, the employment of α,β-unsaturated
aldehyde, α,β-unsaturated esters and α,β-unsaturated esters
amide gave much lowered yields (3g, 3h, 3j, and 3k), except for
tert-butyl ester with good yield (3i, 85% yield). Unfortunately, α-
substituted α,β-unsaturated esters (2l and 2m) failed to give the
desired product, which might be due to the demanding steric
effect. Surprisingly, 4-phenyl-3-buten-2-one (2n) was also
ineffective in the title reaction.
Scheme 2. Scope with Respect to Michael Acceptors. Reaction conditions: 1a
(0.4 mmol, 2.0 equiv.), 2a (0.2 mmol, 1.0 equiv.), fac-Ir(ppy)3 (0.002 mmol, 1
mol %), NaHCO3 (0.4 mmol, 2.0 equiv.), HEH (0.4 mmol, 2.0 equiv.) and
CH3CN (1.0 mL) under Ar was irradiated by 9 W blue LEDs at r.t. for 24 h.
Next, we turned our attention to various aroyl chlorides bearing
electron-withdrawing or electron-donating substituents on the
aromatic moiety. Generally, moderate to high yields were
obtained and the results are shown in Scheme 3. It was found
that electron-donating substituent is impactful to the chemical
yield of the reaction. Good yields were consistently obtained with
electron-donating substituent attached (3l and 3r) while the
presence of electron-withdrawing group caused the decrease in
yield of 3. Meanwhile, the substituents on different positions all
gave good yields. In addition, aryl halides such as bromide and
chloride were well tolerated without detecting dehalogenated
Scheme 3. Scope of substituted aroyl chlorides. Reaction conditions: 1 (0.4
mmol, 2.0 equiv.), 2 (0.2 mmol, 1.0 equiv.), fac-Ir(ppy)3 (0.002 mmol, 1 mol %),
NaHCO3 (0.4 mmol, 2.0 equiv.), HEH (0.4 mmol, 2.0 equiv.) and CH3CN (1.0
mL) under Ar was irradiated by 9 W blue LEDs at r.t. for 24 h.
products under photoredox conditions, enabling further
transformation of these products using classic cross-coupling
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strategies. As heteroarenes are prevalent in bioactive molecules,
2-furancarbonyl chloride was also tested in this protocol and
44% yield of 3x was obtained. The acyl chlorides such as
cinnamyl chloride or Cyclohexanecarboxylic acid chloride also
was tested, however, it didn’t afforded the desired product.
Having demonstrated the feasibility of this protocol to construct
1,4-dicarbonyl compounds, we decided to further investigate
synthetic utility of the resulting adduct in the construction of
heterocycles (Scheme 4). A highly substituted pyrrole 4a was
obtained in 92% yield through the condensation of 3e with p-
toluidine (Paal–Knorr synthesis) (eq. a). In addition, the synthetic
operation was further optimized by developing an one-pot
process for the synthesis of 4a. A 0.5 mmol scale reaction for 2e
was conducted, in which the reaction mixture was concentrated
in vacuo upon the completion of photocatalytic conjugate
addition and the crude residue was directly used in the following
Paal–Knorr synthesis without purification. Pleasantly, the
desired pyrrole 4a was obtained in 67% yield over two steps
(Scheme 4, eq. b).
Figure 1. Proposed Mechanism for Constructing 1,4-Dicarbonyl Compounds.
In summary, an operationally simple and mild visible-light
photoredox catalyzed conjugate addition between aroyl chloride
and various Michael acceptors was developed. Using
inexpensive and abundant aroyl chlorides as aryl radical source,
a variety of 1,4-dicarbonyl compounds were obtained in good to
excellent yields. Furthermore, the resulting 1,4-dicarbonyl
compound can be readily transformed into highly substituted
pyrrole, which is of wide interest in materials science and
pharmaceutical industry.
Experimental Section
To an oven-dried 15 mL Schleck flask equipped with a magnetic stir bar,
aroyl chlorides (0.4 mmol, 2.0 equiv.), Michael Acceptors (0.2 mmol, 1.0
equiv.), fac-Ir(ppy)3 (0.002 mmol, 1 mol %), NaHCO3 (0.4 mmol, 2.0
equiv.), HEH (0.4 mmol, 2.0 equiv.) and CH3CN (1.0 mL) were added.
The vessel was evacuated and backfilled with Ar. The tube was screw-
capped and stirred at room temperature under irradiation of blue LEDs (9
W, 460 nm) for 24 h (distance app. 3 cm). After the reaction was
completed (monitored by TLC analysis), the solvent was removed under
reduced pressure, and then the residue was purified by flash column
chromatography (PE/EA:9/1) to afford the desired product 3.
Scheme 4. Synthetic Transformation of 3 to Pyrrole.
To gain further insight into the mechanism, some control
experiments were also conducted (see supporting information
for details). The results of TEMPO trapping experiments
suggested the involvement of radical intermediates. As
determined by Stern–Volmer fluorescence-quenching analysis,
Hantzsch ester effectively quenched the photoexcited of fac-
Ir(ppy)3, but aroyl chlorides did not. Additionally, none of
deuterated product was observed, when D2O was added to the
reaction system. These results proved that the α-H in product 3
came from HEH.[14] Based on the results mentioned above and
previous reports,[8, 15] a plausible mechanism of this reaction is
proposed in Figure.1. Visible-light irradiation of fac-Ir(ppy)3
facilely generates photoexcited state *Ir(ppy)3, which could be
reduced by Hantzsch ester to Ir2+ species. Single electron
transfer from Ir2+ species to benzoyl chloride produces radical A
and thus regenerates the ground state photocatalyst. The acyl
radical conjugate addition with electron-deficient olefin to forge a
new C−C bond with concomitant formation of alkyl radical B,
which ultimately abstracts one hydrogen atom from HEH• to
form product 3.
Acknowledgements
We gratefully acknowledge the financial support from National
Natural Science Foundation of China (21776318, 21676302 &
81703365), Natural Science Foundation of Hunan Province
(2017JJ3401), China Postdoctoral Science Foundation
(2017M610504) and Central South University.
Conflict of interest
The authors declare no conflict of interest.
Keywords: photocatalysis • conjugate addition • 1,4-dicarbonyl
compounds • aroyl chloride • radical reactions
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IV/*III
1/2
[13] The reduction potential: fac-Ir(ppy)3 (E
=
-1.73
V
vs. SCE),
III/II
red
Ru(bpy)3(PF6)2 (E = -0.81 V vs. SCE), Eosin Y (E
= -1.06 V vs.
1/2
1/2
red
1/2
SCE) and benzoyl chloride (E = - 0.972 V vs. SCE).
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Chao-Ming Wang,† Dan Song,† Peng-
Jue Xia, Jing Wang, Hao-Yue Xiang,*
Hua Yang*
Page No. – Page No.
Visible-Light-Promoted Synthesis of
1,4-Dicarbonyl Compounds Using
Aroyl Chlorides
A facile visible-light photocatalytic conjugate addition to prepare 1,4-dicarbonyl
compounds has been developed by employing readily available aroyl chlorides as
aryl radical sources. The operationally simple method shows broad scope with
regard to both aroyl chlorides and Michael acceptor, in which a variety of 1,4-
diketones were synthesized in moderate to good yields.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.