Direct Use of Carboxylic Acids in the Photocatalytic Hydroacylation of Styrenes to Generate Dialkyl Ketones

Article abstract of DOI:10.1021/acs.orglett.9b03871

A general protocol for the hydroacylation of styrenes from aliphatic carboxylic acids is reported. These reactions proceed via β-scission of a phosphoranyl radical that is accessed by photoredox catalysis, followed by addition of the resulting acyl radical to the styrenyl olefin. We show that phosphine tunability is critical for efficient intermolecular coupling due to competitive quenching of the photocatalyst by the olefin. Primary, secondary, and structurally rigid tertiary carboxylic acids all generate valuable unsymmetrical dialkyl ketones.

Full text of DOI:10.1021/acs.orglett.9b03871

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Use of Carboxylic Acids in the Photocatalytic Hydroacylation
of Styrenes To Generate Dialkyl Ketones
Jesus I. Martinez Alvarado, Alyssa B. Ertel, Andrea Stegner,† Erin E. Stache,‡ and Abigail G. Doyle*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: A general protocol for the hydroacylation of
styrenes from aliphatic carboxylic acids is reported. These
reactions proceed via β-scission of a phosphoranyl radical that
is accessed by photoredox catalysis, followed by addition of
the resulting acyl radical to the styrenyl olefin. We show that
phosphine tunability is critical for efficient intermolecular
coupling due to competitive quenching of the photocatalyst
by the olefin. Primary, secondary, and structurally rigid
tertiary carboxylic acids all generate valuable unsymmetrical
dialkyl ketones.
While the aforementioned methodologies enable the
synthesis of ketones, the substrates for these reactions are
often derived from carboxylic acids in multistep synthetic
sequences. As a result, the functional group tolerance and step-
and redox-economy of the hydroacylation reactions are
compromised (Figure 1B).7 Given the stability and wide
availability of aliphatic carboxylic acids, their direct use for the
generation of aliphatic ketones represents an attractive area for
development. While the synthesis of ketones from carboxylic
acids via cross-coupling has been reported,8 these reactions use
a prefunctionalized coupling partner. The hydroacylation of
olefins directly with carboxylic acids has been far less
developed, with seminal studies from Buchwald and Wang
that are branch selective.9
With the Rovis group, we recently reported the C−OH
activation of carboxylic acids using phosphines and photoredox
catalysis (Figure 1C).10 This work demonstrated that
nucleophilic trapping of a phosphine radical cation could be
leveraged to release acyl radicals via β-scission from a proposed
phosphoranyl radical.11 We showed that the acyl radical
intermediate could be trapped with a hydrogen atom to afford
aldehydes or trapped with a small subset of intramolecular π-
systems to access cyclized products. Given the mild reaction
conditions and the success of the intramolecular alkene
trapping, we envisioned that translation of this strategy to an
intermolecular hydroacylation would deliver a linear-selective
synthesis of valuable unsymmetrical dialkyl ketones directly
from carboxylic acids and olefin feedstocks. Recent work by
Zhu and co-workers demonstrated the feasibility of this
concept using triphenyl phosphine (PPh3) and aromatic
liphatic ketones are versatile synthetic intermediates and
Acommon functional groups found in natural products and
pharmaceuticals.1 As a result, the development of mild and
general methods for the construction of complex aliphatic
ketones is important. Hydroacylation of olefins is one such
strategy, as it affords ketones from abundant and structurally
diverse feedstocks (Figure 1A). For example, transition metal-
catalyzed hydroacylation of olefins with aldehydes has been
extensively studied.2 Nevertheless, the propensity of aliphatic
aldehydes to undergo decarbonylation has limited the
development of intermolecular hydroacylations. Successful
examples are most often restricted to the use of aldehydes
bearing coordinating functional groups or require the use of
high pressures of carbon monoxide to ensure ketone
formation.3
The addition of acyl radicals to a C−C double bond
provides an alternative strategy for joining carbonyl and olefin
substrates.4 Hydrogen atom abstraction from aldehydes can
furnish acyl radicals that undergo alkene addition. When an
aldehyde possesses multiple weak C−H bonds and a highly
reactive hydrogen atom abstractor is used, competitive
abstractions may occur leading to complex reaction mixtur-
es.4c,5 Additionally, the propensity of aldehydes to undergo
autoxidation limits their synthetic utility.6 To overcome this
issue, researchers have developed hydroacylation reactions
with carbonyl substrates that access acyl radicals via alternative
mechanisms, such as single-electron transfer or direct
excitation (Figure 1B).4c−i For example, hydroacylations have
recently been developed that couple olefins with acyl silanes4c
or α-keto acids,4d−f which undergo oxidative fragmentation to
acyl radicals under photoredox catalysis. Activation of acyl
derivatives via visible light fragmentation pathways have also
been reported.4g−i
Received: October 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03871
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Letter
alkene was inhibiting formation of the phosphine radical
cation, which was leading to poor reactivity.13 Indeed, emission
quenching experiments of the reaction components demon-
strated that diphenyl ethylene quenched the excited state of
the photocatalyst over two times faster than PPh3 or
P(OEt)Ph2 (Figure 2A). Thus, we hypothesized that to
achieve productive reactivity, we would need to use more
electron-rich phosphines with lower oxidation potentials that
could outcompete electron or energy transfer to the alkene
(Figure S1).14 A qualitative trend between yield and electron
transfer rate for different phosphines was observed under
optimized conditions, providing support for this proposal
(Figure 2B).15 Ultimately, commercially available dimethyl
phenyl phosphine accomplished the intermolecular coupling in
16
1
81% H NMR yield in 24 h. Control studies confirmed that
phosphine, light, and photocatalyst were all necessary reaction
components for reactivity (Table S9).
With optimized reaction conditions,17 the scope of this
hydroacylation protocol was explored with commercially
available carboxylic acids (Figure 3A). A variety of electron-
deficient and electron-rich substituted hydrocinnamic acids
were competent substrates (4−9). Of note are hydrocinnamic
acids 4 and 6, since traditional methods for ketone generation,
such as the use of excess Grignard reagent, would afford poor
chemoselectivity due to the pendant nitrile and ester.18 Various
heteroaromatic carboxylic acids were also tolerated. Oxazole
10, indole 11, thiophene 12, and pyrazole 23 underwent
hydroacylation in moderate to good yield. Acetic acid, which is
produced annually on a multimillion-ton scale,19 delivered the
hydroacylated product in 76% yield. The hydroacylation with
acetic acid was easily scaled to a 10 mmol scale, which afforded
the ketone product in 48% yield under solvent-free conditions.
Simple aliphatic carboxylic acids (14−17) showed high
reactivity. Primary acids containing distal internal alkenes like
oleic acid 18 and citronellic acid 20 were coupled in good
yield.
Figure 1. Hydroacylation of olefins with aliphatic carboxylic acids
carboxylic acids.12 However, no reactivity was observed with
aliphatic carboxylic acids.
Our initial attempts to effect the intermolecular hydro-
acylation between hydrocinnamic acid 1 and 1,1-diphenyl
ethylene 2 sought to use the same phosphines that we had
previously reported for the reduction of acids to aldehydes.10
However, both PPh3 and ethyl diphenyl phosphinite (P(OEt)-
Ph2) delivered less than 10% yield of product 3 under our
previously optimized conditions, and optimization of standard
reaction parameters failed to deliver significant improvements
with these phosphines (see SI). Since the primary difference
between our previous study and this work was the presence of
alkene, we reasoned that electron or energy transfer to the
Biotin 21 and an aspartic acid derivative 22 were tolerated in
the reaction, highlighting the potential for the use of this
methodology in late-stage functionalization or bioconjugation
chemistry. Additionally, secondary carboxylic acids were also
amenable to hydroacylation. Three- to six-membered ring
carboxylic acids were coupled in good yield without suffering
decarboxylation (27−30). However, depressed yields were
Figure 2. (A) Emission quenching plot of [Ir(dF-Me-ppy)2dtbppy]PF6 with diphenyl ethylene and phosphines. (dF-Me-ppy) = 2-(2,4-
difluorophenyl)-5-methylpyridine; dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine. DPE = diphenyl ethylene. (B) Reactivity studies with different
phosphines. a1H NMR yield determined using 1-fluoronaphthalene as external standard. KSV = Kqτ0; Kq = bimolecular quenching rate constant, τ0 =
excited state lifetime in the absence of quencher. See ref 16 for information on blue LEDs.
B
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Letter
a
b
Figure 3. Reactions run with 2.4 equiv of PMe2Ph and without Ph2S2. Reactions run with 2.4 equiv of PMe2Ph and at 0.33 M in MeCN.
cReactions run at 0.25 M in MeCN. dReactions run with 2.4 equiv of PMe2Ph, in 0.25 M DMA, on a 0.25 mmol scale with 6 equiv of alkene. e1
NMR yield determined using 1-fluoronaphthalene as external standard. The reaction was run neat.
H
f
observed with tertiary carboxylic acids (Figure S2), due to
decarboxylation and competitive addition of the resulting alkyl
radical into diphenyl ethylene.20 Nonetheless, structurally rigid
tertiary carboxylic acids such as adamantane and norbornane
C
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derivatives (31 and 32) provided the ketone product in good
yield.
In addition to the carboxylic acid scope, various substituted
styrene acceptors were explored (Figure 3B). Both electron-
deficient and electron-rich diphenyl ethylene derivatives
underwent hydroacylation efficiently (33 and 34). Comparable
reactivity was observed using halogenated α-methylstyrene
derivatives (38 and 39), which provide a handle for further
functionalization of the product. Although lower yielding, more
sterically demanding alkene 35 was coupled in 48% yield.
Reactivity was restored using the less sterically hindered cyclic
alkene 36, which furnished the ketone product in 66% yield. A
current limitation is that electron-rich and neutral unsub-
stituted styrenes provide only moderate yield (30−40%) of the
hydroacylation products under optimized reaction conditions
(Figure S3).
Mechanistically, after acyl radical addition into the olefin,
hydrogen atom transfer or a reduction-protonation sequence
could result in the formation of the product. In our report on
the reduction of carboxylic acids to aldehydes, we proposed
that hydrogen atom transfer to the acyl radical furnished
product. In Zhu and co-workers’ aromatic acid hydroacylation,
they suggest a reduction-protonation mechanism is operative.
To probe these two pathways, we subjected acetic acid and
1,1-diphenyl ethylene to the standard reaction conditions in
acetonitrile-d3 (Figure 4A). No deuterium incorporation was
observed, revealing that hydrogen atom transfer from solvent
does not take place. The use of acetic acid-d1 under the
standard reaction conditions, on the other hand, showed 33%
D-incorporation over 24 h. Deuterium incorporation into the
enolizable C−H bonds of the product was also detected,
indicating that isotope exchange by a polar mechanism likely
decreases the efficiency of D incorporation at the methine site
(see SI). Indeed, after 25 min, 86% D-incorporation at the
methine position was observed. These findings are consistent
with either a reduction-protonation sequence or hydrogen
atom transfer from thiophenol. However, in the absence of
diphenyl disulfide, deuterium incorporation was also observed
at similar levels; taken together, these results suggest that a
reduction-protonation sequence is most likely operative both
in the presence and absence of diphenyl disulfide.21
These experiments and the emission quenching studies
presented at the outset lend support for the mechanism
proposed in Figure 4B. Initial visible light excitation of [Ir(dF-
Me-ppy)2dtbppy]PF6 (41) enables a long-lived excited state
42 that can serve as a one electron oxidant (*E1/2 (III/II) =
+0.97 V vs SCE in MeCN) for dimethyl phenyl phosphine (Ep
= +0.89 V vs SCE in MeCN), generating phosphine radical
cation 43.22 Nucleophilic trapping of the radical cation with
the deprotonated carboxylic acid results in formation of a
phosphoranyl radical 44, followed by β-scission to generate an
acyl radical. Addition into an alkene results in formation of
aliphatic radical 45, which is reduced to the anion with the
reduced form of the photocatalyst (46).23 Subsequent proton
transfer from 47 results in product formation.12,24
Figure 4. (A) Deuterium labeling experiments. Deuterium incorpo-
ration was determined by quantitative 13C NMR. Yield of product was
determined using 1-fluoronaphthalene as external standard. (B)
Proposed mechanism of the hydroacylation of aliphatic acids with
alkenes using phosphines.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03871.
Experimental procedures, optimization data, character-
ization data, and mechanistic data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: agdoyle@princeton.edu.
ORCID
Abigail G. Doyle: 0000-0002-6641-0833
Present Addresses
†California Institute of Technology, Pasadena, California
91125, United States.
In summary, a mild methodology for the hydroacylation of
styrenyl olefins with carboxylic acids has been developed.
Aliphatic acyl radicals are accessed from a phosphoranyl radical
that is generated directly from a phosphine and a carboxylic
acid. Key to the success of this reaction was tuning the
phosphine for efficient electron transfer, which enabled
hydroacylation with a diverse selection of aliphatic acids to
afford valuable dialkyl ketone products.
‡Cornell University, Ithaca, New York 14853, United States.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the MacMillan lab (Princeton University) for access
to their photoreactors and Lotus Separations for assistance
■
D
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up. For optical properties of the photoreactor, see: Le, C.; Wismer, M.
K.; Shi, Z.-C.; Zhang, R.; Conway, D. V.; Li, G.; Vachal, P.; Davies, I.
W.; MacMillan, D. W. ACS Cent. Sci. 2017, 3, 647−653.
with a purification. Financial support for this project was
provided by NIGMS R35 GM126986.
(17) The products from hydroacylation with nonpolar aliphatic acids
were easier to isolate when the reactions were conducted in the
absence of diphenyl disulfide. In these cases, additional phosphine was
added to compensate for the slightly reduced yield.
(18) Ahn, Y.; Cohen, T. Tetrahedron Lett. 1994, 35, 203−206.
(19) Le Berre, C.; Serp, P.; Kalck, P.; Torrence, G. P. Acetic Acid. In
Ullmann’s Encyclopedia of Industrial Chemistry [Online]; Wiley-VCH
Verlag GmbH & Co., 2014; DOI: 10.1002/14356007.a01_045.pub3
(accessed Oct. 7, 2019).
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E
DOI: 10.1021/acs.orglett.9b03871
Org. Lett. XXXX, XXX, XXX−XXX