Visible-Light-Induced Tandem Radical Addition-Cyclization of Alkenyl Aldehydes Leading to Indanones and Related Compounds

Article abstract of DOI:10.1021/acs.orglett.7b01162

Herein we describe a novel, visible light-induced tandem radical addition-cyclization of alkenyl aldehydes with α-bromocarbonyl compounds. A set of cyclic ketones, including indanones, cyclopentenones, 3,4-dihydronaphthalen-1(2H)-ones, and chroman-4-ones,

Full text of DOI:10.1021/acs.orglett.7b01162

Letter
pubs.acs.org/OrgLett
Visible-Light-Induced Tandem Radical Addition−Cyclization of
Alkenyl Aldehydes Leading to Indanones and Related Compounds
Danyang Lu, Yimei Wan, Lichun Kong, and Gangguo Zhu*
Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China
S
* Supporting Information
ABSTRACT: Herein we describe a novel, visible light-induced
tandem radical addition−cyclization of alkenyl aldehydes with
α-bromocarbonyl compounds. A set of cyclic ketones,
including indanones, cyclopentenones, 3,4-dihydro-
naphthalen-1(2H)-ones, and chroman-4-ones, are synthesized
at room temperature with high efficiency and good functional
group compatibility. It represents the first report on the catalytic 1,2-acylalkylation of unactivated alkenes.
ndanones are found in numerous natural products, drugs,
and bioactive molecules, such as the cytotoxic pterosine B,1
Scheme 1. Summary of This Work
I
antitumor active indenoindolone,2 antiosteoporosis active
(+)-isopaucifloral F,3 and donepezil,4 a drug for the treatment
of Alzheimer’s disease (Figure 1). In addition, they can serve as
nucleophilic carbon radical A′ might favor the intramolecular
addition of carbon radicals to aldehydes, thus permitting the
realization of tandem radical addition−cyclization of alkenyl
aldehydes (Scheme 1b, type II).
Figure 1. Significance of indanones.
versatile intermediates for the synthesis of HIV protease
inhibitor indianavir,5 a drug for the treatment of AIDS disease,
and other pharmaceutical compounds. Consequently, a series of
methods have been developed for the assembly of these
scaffolds, including the Pd-,6 Rh-,7 Ag-,8 or In-catalyzed9
annulation, intramolecular Friedel−Crafts reaction,10 Nazarov
cyclization,11 and others.12 However, efficient and mild
methods, especially those that can be performed at room
temperature, are still in high demand.
We have recently developed a new method for the direct
access to carbonyl compounds via the radical transformation of
unsaturated aldehydes.13 In the case of alkenyl aldehydes, the
remote C−H functionalization of aldehydes has been realized
through an intramolecular 1,n-hydrogen atom transfer (1,n-
HAT) (Scheme 1a, type I).13b,c In contrast, the tandem radical
addition−cyclization of alkenyl aldehydes has not been
achieved. We envisioned that the formation of a more
On the other hand, the visible-light-driven photoredox
catalysis has become a powerful tool for organic synthesis
because of its inherent green and sustainable features.14 The
photocatalytic methods generally proceed at ambient temper-
ature, thereby providing extremely mild alternatives to the
existing protocols. Inspired by these works, we report here a
novel, visible light photocatalyzed tandem radical addition−
cyclization of alkenyl aldehydes with α-bromocarbonyls,15
which successfully generates indanones, cyclopentenones, 3,4-
dihydronaphthalen-1(2H)-ones, chroman-4-ones, and related
cyclic ketones in moderate to high yields at room temperature.
The facile transformation of resultant products into 6−5−6
tricyclic compounds, including 5H-indeno[1,2-b]pyridines and
Received: April 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01162
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Organic Letters
Letter
a
9H-fluorenes, has also been demonstrated. As far as we know, it
is the first report on the 1,2-acylalkylation of unactivated
alkenes.
Scheme 2. Substrate Scope
Initially, the reaction was conducted with 2-allyl benzalde-
hyde (1a) and diethyl bromomalonate (2a) in the presence of 2
mol % of Ru(bpy)3Cl2 under a 15 W blue LED irradiation.
After being stirred at room temperature in a 1:4 mixture of
DMF/H2O for 24 h, the 2-alkylated indanone 3aa was obtained
in 45% yield, while no reaction was observed with DMF as the
solvent, suggesting the importance of effects of water solvation
(Table 1, entries 1 and 2). The replacement of Ru(bpy)3Cl2
a
Table 1. Optimization of the Reaction Conditions
entry
[M]
base
none
additive
yield (%)
b
1
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3(PF6)2
[Ir(ppy)2(dtbbpy)]PF6
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
none
none
none
none
none
none
none
none
none
none
none
LiCl
0
2
none
45
39
43
17
21
30
trace
trace
13
55
5
3
none
4
none
5
NaHCO3
K2HPO4
NaH2PO4
Et3N
6
7
8
9
i-Pr2NEt
DBU
10
11
12
13
14
15
16
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
LiBr
46
11
LiI
c
LiBF4
KPF6
81 (77)
trace
a
Reaction conditions: 1a (0.25 mmol), 2a (0.50 mmol), [M] (2 mol
%), base (0.50 mmol), additive (0.25 mmol), DMF/H2O (v/v = 1:4),
b
25 °C, 24 h. Yields of the isolated products are given. DMF was used
c
as the solvent. 5 mmol scale.
with either Ru(bpy)3(PF6)2 or [Ir(ppy)2(dtbbpy)]PF6 led to
comparable yields (entries 3 and 4). To improve the reaction
yield, a variety of bases were examined (entries 5−10). In the
presence of Et3N and i-Pr2NEt, only a trace amount of 3aa was
formed (entries 8 and 9). In contrast, the yield was improved to
55% when pyridine was employed as the base (entry 11). It was
reported that Lewis acid additives might promote the reduction
of carbon−halide bonds via coordination, thus facilitating the
formation of carbon radicals.15b Therefore, an array of additives
were tested, and gratifyingly, full consumption of 1a was
observed with the addition of 1 equiv of LiBF4, and 3aa was
isolated in 81% yield (entries 12−16). Furthermore, the
reaction could be scaled up by 20 times without erosion of
the efficiency.
Having identified the optimized reaction conditions, the
scope and limitations of this reaction were investigated in detail
using a variety of alkenyl aldehydes (Scheme 2). Halides, such
as F, Cl, and Br, were tolerated rather well under the reaction
conditions, thereby offering great opportunities for the
downstream derivations (3ba−3fa). In particular, 2-allyl-4-
chlorobenzaldehyde (1d) afforded 3da in 70% yield, while 2-
allyl-6-chlorobenzaldehyde (1f) was converted into the
corresponding product 3fa in 66% yield, implying that the
a
Reaction conditions: 1 (0.25 mmol), 2 (0.50 mmol), Ru(bpy)3Cl2 (2
mol %), pyridine (0.50 mmol), LiBF4 (0.25 mmol), DMF/H2O (v/v =
b
1:4), 25 °C, 24 h. Yields of the isolated yields are given. dr = 88:12.
c
d
dr > 98:2. dr = 50:50.
steric hindrance near the aldehyde group has little impact on
the reaction. Substrates 1i and 1j, bearing the strong electron-
donating OMe group, were transformed to the desired products
in decreased yields (3ia and 3ja). In comparison, aldehydes
1k−1m, having strong electron-withdrawing substituents such
as CF3, CO2Me, and CN on the benzene ring, were viable
substrates and provided indanones 3ka−3ma in high yields.
These results indicated that the electrophilicity of the aldehyde
group has a significant correlation with the reaction yield.
Pleasingly, 2,3-disubstituted indanones could be synthesized
in a diastereoselective manner. For example, the reaction of 1n
occurred uneventfully to deliver 3na in 75% yield with high
diastereoselectivity (dr = 88:12). In the case of 1o, a single
trans-diastereoisomer 3oa was assembled, presumably owing to
B
DOI: 10.1021/acs.orglett.7b01162
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the increased steric hindrance. Moreover, alkenyl aldehyde 1q,
with a disubstituted terminal C−C double bond, was a
competent substrate for the indanone synthesis, albeit in a
moderate yield (3qa). In contrast, the substrate 1r, possessing
an internal alkene, failed to provide the desired product under
the reaction conditions.
inhibited, and the TEMPO-adduct 518 was detected by the
HRMS analysis (eq 1), implying the involvement of a carbon
radical intermediate. Based on the above results and previous
reports,15b,c a putative mechanism is proposed as described in
Scheme 4. First, the photocatalyst Ru(II) is elevated to its
The reaction of 2-allylnicotinaldehyde (1s) took place
smoothly, forming 3sa in a moderate yield. In addition to 2-
allyl benzaldehydes, other alkenyl aldehydes such as 1t and 1u
were also effective coupling partners and gave polysubstituted
cyclopentenones 3ta and 3ua in good yields. The tandem
radical addition−cyclization of hex-5-enal (1v) was sluggish,
probably because of the absence of conjugation effect between
the carbon radical and the adjacent double bond (see the
intermediate IV of the proposed mechanism). When 2-
homoallyl benzaldehyde 1w was subjected to the reaction
conditions, the 3,4-dihydronaphthalen-1(2H)-one derivative
3wa was assembled in 70% yield. The construction of
chroman-4-one was also feasible, as exemplified by the
production of 3ya. Of note, in all cases we tested, byproducts
derived from the intramolecular hydrogen atom abstraction of
aldehydic hydrogen atom were not observed. Meanwhile, the
bromide component was varied. For instance, the coupling of
1a with ethyl 2-bromo-3-oxobutanoate (2b) occurred efficiently
to produce 3ab in 83% yield. The structure of products 3 was
determined by the H−H COSY, HMBC, DEPT, NOE, and
other NMR measurements (see the Supporting Information).
Unfortunately, substrates 2d−2f were incompatible for the
reaction.
Scheme 4. Proposed Catalytic Cycle
excited state Ru(II)* under blue LED irradiation. The
generated Ru(II)* species may act as a single electron transfer
(SET) reagent and reduce 2a to form an electrophilic carbon
radical I, with the concurrent production of Ru(III) species.
Afterward, the addition of radical I across the electron-rich C−
C double bond of 1a, followed by an intramolecular addition to
aldehyde, produces an alkoxy radical III, which is transformed
to the carbon-centered radical IV via a formal 1,2-hydrogen
atom transfer (1,2-HAT).13a,19 In the presence of pyridine, the
SET oxidation20 of IV by Ru(III) species provides the indanone
product 3aa, together with the regeneration of the Ru(II)
catalyst.
Experiments that illustrate the synthetic utility of this method
were carried out (Scheme 3). Upon treatment of 3ab with 3
Scheme 3. Derivatization of Compound 3ab
In summary, an operationally simple and mild visible light-
induced tandem radical addition−cyclization of alkenyl
aldehydes with activated bromides has been developed. To
the best of our knowledge, it is the first report of 1,2-
acylalkylation of unactivated alkenes. A variety of cyclic ketones,
such as indanones, cyclopentenones, 3,4-dihydronaphthalen-
1(2H)-ones, and chroman-4-ones, are successfully synthesized
in moderate to high yields at room temperature. Various
functional groups, such as F, Br, Cl, OMe, CF3, CO2Me, CN,
and Ac, are compatible for the current process. The resultant
products can be smoothly converted into the synthetically
attractive 6−5−6 tricyclic compounds, including 5H-indeno-
[1,2-b]pyridines and 9H-fluorenes, which may be valuable for
the rapid access to complex molecules.
ASSOCIATED CONTENT
* Supporting Information
■
S
equiv of NH2OH in a 4:1 mixture of EtOH/H2O at reflux for 4
h, the 5H-indeno[1,2-b]pyridine product 4a16 was synthesized
in a good yield. In the presence of catalytic concentrated
H2SO4, the intramolecular condensation of 3ab delivered the
9H-fluorene derivative 4b17 in 72% yield. In addition, the
reaction between 3ab and BnNH2 generated the amino 9H-
fluorene 4c in 58% yield.
Subsequently, a radical trapping experiment was performed
with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 2 equiv) as
the radical scavenger. The formation of 3aa was completely
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01162.
Detailed experimental procedures, characterization data
for new products 1, 3, and 4 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gangguo@zjnu.cn.
C
DOI: 10.1021/acs.orglett.7b01162
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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Gangguo Zhu: 0000-0003-4384-824X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation of China (21672191) and Zhejiang Normal
University.
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