Cobalt-Catalyzed Markovnikov-Selective Radical Hydroacylation of Unactivated Alkenes with Acylphosphonates

Article abstract of DOI:10.1021/jacs.1c02629

Acylphosphonates having the 5,5-dimethyl-1,3,2-dioxophosphinanyl skeleton are developed as efficient intermolecular radical acylation reagents, which enable the cobalt-catalyzed Markovnikov hydroacylation of unactivated alkenes at room temperature under mild conditions. The protocol exhibits broad substrate scope and wide functional group compatibility, providing branched ketones in satisfactory yields. A mechanism involving the Co-H mediated hydrogen atom transfer and subsequent trapping of alkyl radicals by acylphosphonates is proposed.

Full text of DOI:10.1021/jacs.1c02629

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Cobalt-Catalyzed Markovnikov-Selective Radical Hydroacylation of
Unactivated Alkenes with Acylphosphonates
Benxiang Zhang,§ Jiayan He,§ Yi Li, Tao Song, Yewen Fang,* and Chaozhong Li*
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ABSTRACT: Acylphosphonates having the 5,5-dimethyl-1,3,2-dioxophosphinanyl skeleton are developed as efficient
intermolecular radical acylation reagents, which enable the cobalt-catalyzed Markovnikov hydroacylation of unactivated alkenes
at room temperature under mild conditions. The protocol exhibits broad substrate scope and wide functional group compatibility,
providing branched ketones in satisfactory yields. A mechanism involving the Co−H mediated hydrogen atom transfer and
subsequent trapping of alkyl radicals by acylphosphonates is proposed.
ydroacylation of alkenes represents a highly attractive
protocol for ketone synthesis owing to the easy
Biacetyl has been reported as a radical acceptor, but its
efficiency and generality are both far from satisfactory.81,82
Acylphosphonates,83−85 acylgermanes,86 and thio- and seleno-
esters87 have been tested as radical acylating agents by the
groups of Kim, Curran, and Zard. However, only intra-
molecular acylation reactions have been achieved, while
analogous intermolecular acylation has proved unsuccess-
ful.83,88,89 As an alternative, sulfonyl oxime ethers have been
used as surrogates for an indirect radical acylation approach,
which requires acid hydrolysis in the last step.88,89 It is
therefore highly desirable to develop stable, highly reactive,
and preferably nonmetallic reagents for direct, intermolecular
radical acylation. Herein we report that, through structural
modifications, a novel class of acylphosphonates are identified
to exhibit a significantly enhanced reactivity toward alkyl
radicals, thus enabling the cobalt-catalyzed intermolecular
Markovnikov hydroacylation of unactivated alkenes to proceed
with high efficiency (Figure 1).
H
availability and low cost of alkenes. These processes can be
catalyzed by a variety of transition metals such as rhodium,
ruthenium, cobalt, nickel, and iridium complexes.1−4 However,
a serious limitation is that most intermolecular hydroacylation
reactions exhibit anti-Markovnikov selectivity to form linear
ketones. Markovnikov-selective hydroacylation to provide
branched ketones is generally limited to activated alkenes
(e.g., styrenes,5−12 enones,13,14 and 1,3-dienes15,16) or alkenes
with a directing group17−21 (e.g., allylic alcohols, homoallylic
sulfides, and 1,5-dienes) and often suffers from undesired
chain-walking side-reactions.10,13,15 Meanwhile, acyl radical
mediated intermolecular alkene hydroacylation also leads to
the exclusive formation of anti-Markovnikov products.22,23 In
fact, there have been no reports to date of general methods for
Markovnikov hydroacylation of unactivated alkenes.
On the other hand, metal hydride (MH, M = Co, Fe, Mn,
etc.) catalyzed hydrogen atom transfer (HAT) processes24−27
have enabled the successful implementation of a number of
radical hydrofunctionalizations of alkenes with Markovnikov
selectivity, as developed by the groups of Mukaiyama,28
Carreira,29−37 Boger,38−40 Shigehisa,41−45 Baran,46−50 Her-
zon,51,52 Shenvi,53−60 and others.61−66 In particular, the
nickel−copper-catalyzed hydroacylation of vinylarenes with
acyl fluorides and hydrosilanes was reported by Sawamura et
al.6 Inspired by these studies, we speculated that the
Markovnikov hydroacylation of unactivated alkenes could
also be realized in a similar manner. However, our initial
attempts using in situ generated acyl-NiII intermediates67−80 as
acylating agents failed to give any hydroacylation products.
Instead, the hydrogenation of alkenes prevailed along with the
alkene isomerization (see Table S1 in the Supporting
Information (SI) for details). Thus, it appears essential that
the acylating agents suitable for MH-catalyzed hydroacylation
should trap alkyl radicals faster than MH or a silane (as the H
source) does. To our surprise, the long search for radical
acylating reagents other than the above-mentioned unstable
acyl-NiII species remains unsolved and a challenging task.
We commenced our investigations by choosing 4-phenylbut-
1-ene (1a) as the model substrate and the commonly used
salen-cobalt complex 2 as the catalyst. After an extensive
screening on the reaction parameters (Table 1; also see Tables
S2 and S3 in SI for details), we were pleased to find that, with
p-chlorobenzoylphosphonate 3a as the acylating reagent,
Figure 1. Working hypothesis.
Received: March 9, 2021
Published: March 30, 2021
https://doi.org/10.1021/jacs.1c02629
J. Am. Chem. Soc. 2021, 143, 4955−4961
© 2021 American Chemical Society
4955

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Communication
demonstrated the role of cobalt as the catalyst (entry 14, Table
1).
Table 1. Optimization of Reaction Conditions
The unexpected substituent effect on the reactivity of
acylating reagents shown above (entries 1−9, Table 1) is
remarkable. By simply changing the open-chain structures (as
in 3c−3e) to the 1,3,2-dioxophosphinanyl ring (as in 3a), the
reagent reactivity is drastically increased. Compared to the
open-chain structures, the 1,3,2-dioxophosphinanyl ring might
reduce the steric hindrance associated with the carbonyl group
and thus facilitates the attack of alkyl radicals. The gem-
dimethyl substitution in 3a may help to stabilize the chair
conformation of the heterocycle. This is evidenced by the X-
ray crystal structures of 3a and 3b in that the six-membered
heterocycle adopts a chair conformation in 3a but a half-chair
conformation in 3b. The CO and PO groups in 3b are
almost coplanar with a dihedral angle of −176°, indicating that
radical attack to the carbonyl from either face will encounter
the same steric hindrance. In contrast, the CO and PO
groups in 3a have a dihedral angle of −128°, resulting in the
blockade of one face of the carbonyl group but the clearance of
the other. As a consequence, the reaction with 3a exhibits
higher efficiency than that with 3b. These experiments are also
the first examples of intermolecular acylation with acylphosph-
onates. It should also be noted that, in the literature
reports,67−80 the proposed species responsible for acylation
of alkyl radicals are generally unstable organometallic
intermediates such as acyl-NiII intermediates. As a comparison,
acylphosphonates structurally similar to 3a are stable
crystalline solids that are easy to handle. Furthermore, they
can be readily prepared by reaction of acyl chlorides with
trialkyl phosphites in one step83,92,93 or in two steps by dialkyl
phosphite addition to aldehydes followed by Dess−Martin
oxidation in excellent yields (see SI for details). These
characteristics should encourage further applications of
acylphosphonates as radical acylating agents.
With the optimized conditions in hand, we examined the
scope of the method. As shown in Scheme 1, a variety of
terminal alkenes underwent hydroacylation reaction smoothly
leading to the synthesis of branched ketones 4b−4u in
satisfactory yields. Exclusive Markovnikov selectivity was
observed in all cases. Chemoselective hydroacylation was
observed in the case of 4u in which the isopentenyl moiety
remained intact. By lowering the catalyst loading to 5 mol %
and slightly increasing the amounts of TBHP and 3a, the
protocol was also applicable to internal alkenes as exemplified
by the synthesis of 4v−4x from the corresponding cyclo-
alkenes. Similarly, the reaction of methyl cyclopent-3-
enecarboxylate furnished the expected product 4y in 74%
yield. The presence of a wide range of functional groups was
well tolerated by the process. For example, alkyl (or aryl)
halides, amides, sulfonamides, esters, sulfonates, ethers, silyl
ethers, alkylphosphonates, nitriles, furans, and nitroalkanes all
proved to be compatible with the reaction. This excellent
functional group compatibility enabled the late stage
modification of complex molecules or drug derivatives. For
example, the reaction of alkene 1za containing an N-Boc-
protected dipeptide motif afforded product 4za in 52% yield.
Ketone 4zb having the sensitive diacetonefructose skeleton was
also achieved under the optimized conditions. Alkenes derived
from ibuprofen, hymecromone, nortropine, and estrone
produced the expected products 4zc−4zf in good yields.
Encouraged by the above results, we went on to test the
hydroacylation of alkene 1a with a number of acylphospho-
a
a
entry
variation from the “standard conditions”
yield (%)
1
2
3
4
5
6
7
8
none
78
52
19
21
28
8
17
11
10
17
trace
60
10
0
3b in place of 3a
3c in place of 3a
3d in place of 3a
3e in place of 3a
3f in place of 3a
3g in place of 3a
3h in place of 3a
3i in place of 3a
(MeO)3SiH in place of PhSiH3
Et3SiH in place of PhSiH3
without Selectfluor
without TBHP and Selectfluor
without 2
9
10
11
12
13
14
a
The reaction was carried out in 0.20 mmol scale in i-PrOH (6.0 mL).
Isolated yield based on 1a.
b
phenylsilane as the hydrogen source, tert-butyl hydroperoxide
(TBHP) as the oxidant, and 1-chloromethyl-4-fluorodiazo-
niabicyclo[2.2.2]octane bis(tetrafluoroborate) (Select-
fluor)90,91 as the additive, the reaction of 1a in isopropanol
at room temperature (rt) delivered the desired ketone 4a in
78% yield (entry 1, Table 1). No anti-Markovnikov hydro-
acylation product or chain-walking product10 could be
detected. Switching the acylating reagent from 3a to its analog
3b also provided ketone 4a in 52% yield (entry 2, Table 1). In
contrast, the use of dimethyl phosphonate 3c or diethyl
phosphonate 3d in place of 3a resulted in a very low (∼20%)
yield of 4a (entries 3 and 4, Table 1). A poor result was also
observed when 3a was replaced by monoacylphosphine oxide
3e or 3f (entries 5 and 6, Table 1). Acylphosphinates 3g and
3h and diacylphosphine oxide 3i proved to be incompetent
acylating reagents (entries 7−9, Table 1). Phenylsilane
exhibited much better performance than trimethoxysilane or
triethylsilane (entries 10 and 11, Table 1). A catalytic amount
of Selectfluor, an additive commonly used in cobalt-catalyzed
hydrofunctionalization reactions, helped to increase the
product yield (entry 12, Table 1). Other additives such as
N-fluoropyridinium salts were less efficient than Selectfluor in
promoting the transformation (see Table S2 in SI for details).
TBHP proved to be an oxidant superior to other peroxides or
hypervalent iodine reagents such as diacetoxyiodobenzene
(also see Table S2). Interestingly, the reaction also took place
in the absence of TBHP and Selectfluor, albeit in a low (10%)
yield (entry 13, Table 1), presumably because of the
contamination of trace O2.27 Finally, the control experiment
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Communication
Scheme 1. Hydroacylation of Unactivated Alkenes with 3a
Scheme 2. Hydroacylation of 1a with Acylphosphonates
a
Conditions: 1a (0.20 mmol), 2 (0.02 mmol), 5 (0.70 mmol),
PhSiH3 (0.40 mmol), TBHP (0.30 mmol), Selectfluor (0.04 mmol),
b
c
and i-PrOH (6.0 mL), rt, 12 h. Isolated yield based on 1a. d.r. =
d
50:50 determined by 1H NMR (400 MHz). d.r. = 50:50 determined
by 13C NMR (100 MHz)
in turn indicated that alkanoylphosphonates were less reactive
than benzoylphosphonates toward alkyl radicals.
The results in Schemes 1 and 2 clearly demonstrated the
broad substrate scope and wide functional compatibility of the
method. To gain further insight into the hydroacylation, the
following radical clock experiments were designed. The
reaction of vinylcyclopropane (7) with 3a under the above
optimized conditions afforded the ring-opening product 8 (eq
1). 1,6-Diene 9 underwent an addition−cyclization−acylation
a
Conditions: 1 (0.20 mmol), 2 (0.02 mmol), 3a (0.70 mmol),
PhSiH3 (0.40 mmol), TBHP (0.30 mmol), Selectfluor (0.04 mmol), i-
b
c
PrOH (6.0 mL), rt, 12 h. Isolated yield based on 1. 2 (0.01 mmol),
d
3a (0.80 mmol), and TBHP (0.40 mmol) were used. d.r. = 50:50
e
determined by 1H NMR (400 MHz). d.r. = 50:50 determined by 13
NMR (100 MHz).
C
nates other than 3a. As shown in Scheme 2, benzoylphosph-
onates 5a−5k bearing either electron-withdrawing or electron-
donating substituents on the aromatic ring all participated in
the reaction with 1a to give the expected products 6a−6k
under the optimized conditions without further modification.
Taking advantage of their easy availability, structurally complex
benzoylphosphonates also served as ideal acylating reagents, as
evidenced by the efficient synthesis of aromatic ketones 6l
containing a menthol group and 6m having a propranolol
motif. Pyridine-3-carbonylphosphonate 5n also took part in the
hydroacylation with 1a to generate 6n in a moderate yield. In
another case, (cyclopropanecarbonyl)phosphonate 5o led to
the formation of cyclopropyl ketone 6o in 15% yield.
Nevertheless, further extension of the method to alkanoyl-
phosphonates such as heptanoylphosphonate 5p failed, which
sequence to provide cyclopentane 10 as a single diaster-
eoisomer, whose configuration was unambiguously established
by 2D NMR experiments (eq 2).
A tentative mechanism is thus proposed based on the above
results and literature reports, as depicted in Figure 2. The
oxidation of CoII complex 2 by TBHP generates the
43,94
CoIIIO2 Bu species
that is then captured by phenylsilane
t
to give the CoIII−H intermediate.27,95 Selectfluor as a co-
oxidant helps in the oxidation of CoII to CoIII.27 The cobalt
hydride engages in the HAT with an alkene to produce radical
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Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China; orcid.org/0000-0002-
5135-9115; Email: clig@mail.sioc.ac.cn
Authors
Benxiang Zhang − Key Laboratory of Organofluorine
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
Jiayan He − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Figure 2. Proposed mechanism.
Yi Li − Key Laboratory of Organofluorine Chemistry, Center
for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, China
Tao Song − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0003-2088-
8177
A and regenerates the CoII catalyst. Next, the nucleophilic alkyl
radical attacks the carbonyl group of an acylphosphonate to
form alkoxyl radical B. Subsequent β-scission of radical B
delivers the hydroacylation product and the phosphoryl radical
C. The phosphoryl radical is then quenched by phenylsilane
(or CoIII−H) via H-abstraction to offer dialkyl phosphite D.
Indeed, the formation of D was clearly observed by the crude
31P NMR. Note that the dialkyl phosphite D served as the
starting material for the preparations of acylphosphonates (3a
and 5) and could be recycled in theory. Further investigations
on the detailed mechanism are currently underway in our
laboratory.
In conclusion, we have successfully accomplished the
unprecedented cobalt-catalyzed intermolecular Markovnikov
hydroacylation of unactivated alkenes with acylphosphonates
as the acylating agents. As the procedure is mild, tolerant of
sensitive functional groups, and broad in scope, the method
should find applications in ketone synthesis. More importantly,
our finding that the stable and readily available acylphosph-
onates consisting of the 5,5-dimethyl-1,3,2-dioxophosphinanyl
skeleton are capable of intercepting alkyl radicals intermolec-
ularly should inspire further development of new acylation
reactions of important value.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c02629
Author Contributions
§B.Z. and J.H contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China (Grants 21532008, 21871285, and
21971253), by the Chinese Academy of Sciences (Grants
XDB20020000 and ZDBS-LY-SLH026), and by the Zhejiang
Provincial Natural Science Foundation of China (Grant
LY20B020008). This paper is dedicated to Professor Ilhyong
Ryu, a pioneer in free radical chemistry, on the occasion of his
70th birthday.
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AUTHOR INFORMATION
Corresponding Authors
■
Yewen Fang − School of Materials and Chemical Engineering,
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