Four-Component Radical Dual Difunctionalization (RDD) of Two Different Alkenes with Aldehydes and tert-Butyl Hydroperoxide (TBHP): An Easy Access to β,δ-Functionalized Ketones

Article abstract of DOI:10.1021/acs.orglett.9b02264

A convenient Fe-catalyzed four-component radical dual difunctionalization and ordered assembly of two alkenes with aromatic/aliphatic aldehydes and TBHP to provide chain elongated β,δ-functionalized ketones via a one-pot procedure has been developed. Alde

Full text of DOI:10.1021/acs.orglett.9b02264

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Four-Component Radical Dual Difunctionalization (RDD) of Two
Different Alkenes with Aldehydes and tert-Butyl Hydroperoxide
(TBHP): An Easy Access to β,δ-Functionalized Ketones
Chuan-Shuo Wu,† Ren-Xiang Liu,† Da-You Ma,‡ Cui-Ping Luo,† and Luo Yang*,†
†Key Laboratory for Green Organic Synthesis and Application of Hunan Province, College of Chemistry, Xiangtan University,
Hunan 411105, P. R. China
‡Xiangya School of Pharmaceutical Sciences, Central South University, Hunan 410013, P. R. China
S
* Supporting Information
ABSTRACT: A convenient Fe-catalyzed four-component radical dual difunctionalization and ordered assembly of two alkenes
with aromatic/aliphatic aldehydes and TBHP to provide chain elongated β,δ-functionalized ketones via a one-pot procedure has
been developed. Aldehydes were homolytically cleavaged to produce acyl radicals and subsequently allowed for the successive
construction of C(sp2)−C(sp3), C(sp3)−C(sp3), and C(sp3)−O bonds via dual radical insertions and radical−radical coupling,
following the intrinsic nucleo/electrophilic reactivity of both the radicals and alkenes.
centered radical (I) might undergo the second radical addition
irect difunctionalization of simple alkenes by incorporat-
Ding two functional groups across a carbon−carbon to the carbon−carbon double bond of another alkene, to form
the carbon-centered radical (II), which then further reacts
similarly as a radical (I) via radical−radical coupling or an
oxidation−substitution pathway to realize the radical dual
difunctionalization (RDD) of two different alkenes (Scheme
1b).
double bond is of particular interest to the chemical
community, since it converts readily available alkenes into
diversified complex molecules in one step.1 While transition-
metal-catalyzed difunctionalizations of alkenes2 (represented
by epoxidation, dihydroxylation, and aminohydroxylation)
have been well studied and widely applied in organic synthesis,
the radical type difunctionalization of alkenes is expanding and
surging in recent years, to introduce both heteroatoms and
carbon-centered radicals into the products. Mechanistically,
the radical type difunctionalization of alkenes is initiated by a
radical addition to the carbon−carbon double bond to produce
a new carbon-centered radical (I), which could be trapped
directly by another suitable radical (precursor) or oxidized into
a carbocation prior to the subsequent nucleophilic substitution
(Scheme 1a).1 By careful design, the new generated carbon-
To put this RDD of alkenes into practice, the selectivity of
radical addition to carbon−carbon double bond is crucial: (1)
for the first radical addition, the initiating radical (R·) prefers
alkene a, but not alkene b; (2) for the second time radical
addition, the radical intermediate (I) prefers alkene b, but not
alkene a itself to produce oligomers; (3) the radical
intermediate (II) is stable enough or quenched in time to
suppress further copolymerization oligomers. The former two
requirements on selectivity might be achieved by the intrinsic
nucleophilic/electrophilic reactivity of radicals and alkenes, as
exhibited by Ryu and co-workers in the multicompound
cascade reactions of alkyl radicals with carbon monoxide and
alkenes,3 and Cheng et al. in the radical polar crossover
reaction of dioxolanes with two alkenes.4 The third challenge
might be realized by generating a persistent radical (II) for
radical−radical coupling with another transient radical,
following the “persistent radical effect”,5 as revealed by our
recent work on the difunctionalization of styrenes with
aldehydes,6 where a metastable benzyl radical was trapped by
Scheme 1. Radical Difunctionalization vs Dual-
Difunctionalization of Alkenes
6a
t
the BuOO· (from tert-butyl hydroperoxide). In this context,
Received: July 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02264
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Organic Letters
Letter
elegant studies on the acylative-peroxidation type difunction-
alization of styrenes7a or α,β-unsaturated esters7b of aldehydes
have been reported by Z. Li and co-workers, where the radical
reaction was initiated by homolytic cleavage of aldehydes to
acyls radicals in the presence of tert-butyl hydroperoxide
(TBHP). Herein, we report a novel four-component radical
dual difunctionalization (RDD) of two different alkenes with
aldehydes and TBHP.
Scheme 3. Scope of (Hetero)aromatic Aldehydes for the
RDD
Based on the above speculation and our recent work, p-
tolualdehyde (1a), methyl acrylate (2a), styrene (3a), and tert-
butyl hydroperoxide (TBHP) were chosen as model substrates
to test the radical dual-difunctionalization strategy (Scheme 2).
Scheme 2. Model Reaction for the Radical Dual
Difunctionalization (RDD) of Two Different Alkenes
a
a
Optimized reaction conditions: 1a (0.8 mmol, 4.0 equiv), 2a (0.2
mmol, 1.0 equiv), 3a (0.4 mmol, 2.0 equiv), TBHP (5.5 M in decane,
1.0 mmol, 5.0 equiv), FeCl2 (0.005 mmol, 2.5 mol %) in CH3CN (1
mL, prepared solution), stirred at 90 °C for 12 h and then DBU (1.5
equiv) was added and stirred at 90 °C for another 12 h.
yields, such as methyl (1a), tert-butyl (1c), methoxy (1d), and
halo (1e−1g). Furthermore, the optimized reaction conditions
could be applied to the aromatic aldehydes with a methyl
group substituted at the para, meta, and ortho position (1a, 1h,
and 1i), and similar yields were obtained, which reveal no
obvious substituent effect and steric hindrance for the
aldehydic unit. Besides substituted benzaldehydes, 2-naph-
thaldehyde (1j), pyrrole-3-carbaldehyde (1k), and thiophene-
2-carbaldehyde (1l) also were suitable substrates for this
radical dual difunctionalization and can be transformed into
the corresponding β,δ-functionalized ketones (4j−4l), respec-
tively.
After investigating the scope of aromatic aldehydes, we next
tested the generality of aliphatic aldehydes on this radical dual
difunctionalization (Scheme 4). Both the linear and branched
aliphatic aldehydes (1m−1p) were tested and compatible with
the optimized conditions. Moreover, the cyclopropane-
Assisted by the peroxide, p-tolualdehyde (1a) can be
transformed into an acyl radical (A) readily by homolytic
hydrogen abstraction.7 The acyl radical (A) is nucleophilic8
and prefers addition onto the electro-deficient carbon−carbon
double bond of methyl acrylate (2a),4,9 to produce another
carbon-centered radical (B). The rate for addition of an acyl
radical to methyl acrylate is around three times faster
(depending on the temperature) than that of styrene.9,10
Obviously, the radical (B) is electrophilic due to its α-electron-
withdrawing group (an ester group),11 so it favors the
subsequent radical addition to styrene (3a) selectively,12 to
provide a metastable benzyl radical (C), which would further
be trapped by the tBuOO· (or its precursor) via radical−radical
coupling to yield the peroxide 4a′. The model reaction did
yield the expected dual-difunctionalization product in the
presence of an iron catalyst. The subsequent detailed
optimization on the iron sources, catalyst loading, ratio of
the four reactants, solvents, and reaction temperature provided
a medium yield of 64%, after a one-pot stepwise conversion of
the peroxide 4a′ into β,δ-functionalized ketone 4a to facilitate
the column isolation (since around 5% of the peroxide 4a′
would undergo Kornblum−DeLaMare rearrangement13 auto-
matically and be transformed into the ketone 4a even without
adding any base.).
Scheme 4. Scope of Aliphatic Aldehydes for the RDD
The generality of this radical dual difunctionalization of two
different alkenes with aldehydes was subsequently investigated
under the optimized conditions. The scope of aromatic
aldehydes on this cascade reaction is listed in Scheme 3.
Various aromatic aldehydes bearing electron-donating or
-withdrawing substituents on the phenyl moiety (1a−1l)
underwent this four-component cascade reaction smoothly to
afford the desired β,δ-functionalized ketones in moderate
B
DOI: 10.1021/acs.orglett.9b02264
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Organic Letters
Letter
carbaldehyde (1q) and 3-methylbut-2-enal (1r) could also be
used as the suitable substrates, with the three-member ring of
cyclopropane and the carbon−carbon double bond of enal
intact, which might facilitate the further transformation and
potential application of these products. To our delight,
substrate 1r (3-methylbut-2-enal) is also a radical Michael
acceptor, but it did not compete with methyl acrylate (2a) in
this radical dual difunctionalization, maybe due to its more
hindered β-carbon compared with methyl acrylate.
Scheme 6. Scope of Electron-Deficient Alkenes for the RDD
Encouraged by the above results on the wide substrate scope
of this radical dual difunctionalization for both aromatic and
aliphatic aldehydes, the effect of substituents on the styrene
moiety was studied and listed in Scheme 5. Various styrene
Scheme 5. Scope of Styrene Derivatives for the RDD
from the acylative peroxidation of the single alkene (styrene or
methyl acrylate), as demonstrated in Scheme 7.
Scheme 7. Mechanistic Experiments
derivatives bearing electron-donating or -withdrawing sub-
stituents on the phenyl moiety (3b−3j) smoothly underwent
this four-component cascade reaction to afford the desired β,δ-
functionalized ketones in moderate yields after the one-pot
procedure. However, for the α-disubstituted alkenes such as α-
methylstyrene (3k) and 1,1-diphenylethene (3l), where the
Kornblum−DeLaMare rearrangement (showed in Scheme 2)
was impossible for the lack of an α-proton of peroxide motif,
the radical dual difunctionalization provided the peroxide 5k
and 5l, respectively, overriding the DBU-promoted rearrange-
ment procedure.
Then, the scope and limitation of electron-deficient alkenes
for this radical dual difunctionalization was tested (Scheme 6).
Besides methyl acrylate (2a), similar α,β-unsaturated esters
such as n-butyl acrylate (2b), benzyl acrylate (2c), methyl
methacrylate (2d), acrylonitrile (2e), N,N-dimethyl acrylamide
(2f), and diethyl vinylphosphonate (2g) all underwent this
cascade reaction with p-tolualdehyde (1a), styrene (3a), and
TBHP to yield the targeted ketone successfully under the
optimized conditions. It is a pity that currently the chemo-
selectivity for the radical addition to the two different alkenes
was not satisfactory enough, which lowered the yields for this
radical dual difunctionalization and produced the byproducts
Several mechanistic experiments were carried out to
understand this radical dual difunctionalization. First, the
model reaction of 1a, 2a, 3a, and TBHP was completely
inhibited in the presence of 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO); instead, the 4-methylbenzoyl radical was
captured as 2,2,6,6-tetramethylpiperidin-1-yl 4-methylbenzoate
7, which was characterized and isolated in 70% yield (Scheme
7a). Second, by shortening the reaction time to 1 h (from the
optimized 12 h and overriding the DBU-promoted Korn-
blum−DeLaMare rearrangement step at the same time) and
carefully isolating the reaction mixture, three main-products (8,
4a′, and 9) were obtained and characterized, and their yields
1
were determined by the H NMR using the nitromethane as
the internal standard (Scheme 7b). These results supported
our speculation (Scheme 2) that the radical cascade reaction
was initiated by the 4-methylbenzoyl radical (A-a, Scheme 8),
which not only was able to add onto the carbon−carbon
double bond of methyl acrylate (2a) to produce radical
intermediate (B-a), but also reacted with the styrene (3a)
similarly. Under the reduced reaction time and in the absence
of DBU, the Kornblum−DeLaMare rearrangement of these
peroxides to the ketones was almost negligible and indeed the
yields of each ketone were below 1% by HPLC analysis, so the
C
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Organic Letters
Letter
Scheme 8. Proposed Mechanism for the Cascade Reaction
Scheme 9. Synthetic Utility of This Radical Dual
Difunctionalization
two different alkenes has amplified this effect by realizing the
difunctionalization and ordered assembly of two different
alkenes, to introduce three functionalities and elongate the
carbon chain by a one-pot procedure, with TBHP playing a
triple role of radical initiator, terminal oxidant, and radical
coupling partner. The application of an environmentally
benign iron catalyst, cheap and readily available starting
materials, wide substrate scope, and versatile synthetic utilities
of radical dual-difunctionalization products would render this
cascade reaction attractive for organic synthesis and medicinal
chemistry.
ratio of reaction rate for addition of the 4-methylbenzoyl
radical (A-a) to methyl acrylate (2a) and that of styrene (3a)
could be approximatively calculated as dividing the total yield
of 8 and 4a′ by the yield of 9, to provide a value of 2.9. These
results on relative reacting rates agreed well with the literature
reports, and effectively supported our speculation on radical
dual difunctionalization of two different alkenes. Third, the
deuterated aldehydes were synthesized and the preliminary
isotopic competing experiments gave a KIE value of 5.2
(Scheme 7c), which supported that the cleavage of the
aldehydic C−H bond was the rate-determining step for this
cascade reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02264.
Based on the above mechanistic experiments, our previous
studies6 and literature reports,7,12 a possible reaction pathway
on this radical dual difunctionalization of two different alkenes
is depicted in Scheme 8, with the reaction of p-tolualdehyde
(1a), methyl acrylate (2a), and styrene (3a) as an example.
First, reduction of TBHP by Fe(II) salt produces a tert-butoxy
radical (tBuO·) and Fe(OH)X2. Intermolecular hydrogen
Experimental procedures, detailed optimization, mecha-
nistic studies, compound characterization, and NMR
spectra (PDF)
AUTHOR INFORMATION
■
t
abstraction of p-tolualdehyde (1a) by BuO· generates the 4-
Corresponding Author
*E-mail: yangluo@xtu.edu.cn.
ORCID
methylbenzoyl radical (A-a), which is a nucleophilic carbon
radical that thus preferentially adds to the electron-deficient
and less hindered β-carbon of methyl acrylate (2a) to produce
a radical intermediate (B-a). This new generated carbon
radical (B-a) becomes electrophilic due to its α-electron-
withdrawing group (an ester group), so it favors the
subsequent addition to the electron-rich and less hindered β-
carbon of styrene (3a) selectively, to provide a metastable
benzyl radical (C-a), which would further be trapped by the
tBuOO· (or its precursor) via radical−radical coupling to yield
the peroxide 4a′. On the other hand, reaction of Fe(OH)X2
with TBHP provides the tBuOO· (and water) to regenerate the
Fe(II) catalyst.
Luo Yang: 0000-0002-0061-0816
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21772168), Key Foundation of
Education Bureau of Hunan Province (17A208), and the
Project of Innovation Team of the Ministry of Education
(IRT_17R90).
To extend the synthetic utility of this radical dual
difunctionalization of two different alkenes, the β,δ-function-
alized ketones obtained could be readily cyclized into 2,4,6-
trisubstituted pyridine 10 or reductively coupled into 1,3,4-
trisubstituted cyclopentene 11, following the literature
reported pathway (Scheme 9).14
In conclusion, we have developed a convenient Fe-catalyzed
four-component radical dual difunctionalization of two differ-
ent alkenes with aldehydes and TBHP to provide β,δ-
functionalized ketones via a one-pot procedure. Radical
difunctionalization of alkenes was famous for its ability to
synthesize complex molecules from structurally simple and
readily available alkenes; this radical dual difunctionalization of
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