Direct Conversion of Carboxylic Acids to Alkyl Ketones

Article abstract of DOI:10.1021/acs.orglett.7b01588

An efficient and mild method for acyl-C_sp3 bond formation based on the direct conversion of carboxylic acids has been established. This protocol is enabled by the synergistic, Ir-photoredox/nickel catalytic cross-coupling of in situ activated c

Full text of DOI:10.1021/acs.orglett.7b01588

Letter
pubs.acs.org/OrgLett
Direct Conversion of Carboxylic Acids to Alkyl Ketones
Javad Amani and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: An efficient and mild method for acyl−Csp3
bond formation based on the direct conversion of carboxylic
acids has been established. This protocol is enabled by the
synergistic, Ir-photoredox/nickel catalytic cross-coupling of in
situ activated carboxylic acids and alkyltrifluoroborates. This
versatile method is amenable to the cross-coupling of
structurally diverse carboxylic acids with various potassium
alkyltrifluoroborates, affording the corresponding ketones with
high yields. In this operationally simple cross-coupling protocol,
aliphatic ketones are obtained in one step from bench stable,
readily available carboxylic acids.
he direct conversion of carboxylic acids to alkyl ketones
represents a fundamental transformation of importance,
the high activation energy barrier associated with the
transmetalation step in the coupling of Csp3-hybridized
nucleophiles.14 In this context and to broaden the range of
electrophiles to which the metallaphotoredox cross-coupling
can be applied, our laboratory has recently developed a visible
light-enabled acylation of alkyltrifluoroborates with both
carboxylic acid chlorides15 and amides16 to access aliphatic
ketones. The MacMillan17 and Doyle18 groups previously
employed related, but mechanistically and operationally
distinct, strategies for the synthesis of ketones using anhydrides.
Those protocols employed mixed anhydrides, formed in situ
from carboxylic acids and acyl chlorides, and symmetrical
anhydrides, respectively, with both methods being focused on
the synthesis of α-amino ketones.
A general, robust method for the direct synthesis of alkyl
ketones from carboxylic acids via Csp3−acyl bond construction
under mild conditions and without the limitations of the more
traditional two-electron protocols would be highly valued. For
realization of this idea and to expand the scope of the
photoredox/Ni dual catalysis cross-coupling strategy, we
investigated the potential of the coupling of carboxylic acids
with alkyltrifluoroborates via in situ activation of the carboxylic
acids (Figure 1).
T
but one that has yet to reach its enormous potential. Carboxylic
acids can be converted directly to alkyl ketones by treatment
with excess organolithium compounds and Grignard reagents,1
but such protocols severely limit functional group incorporation
in both partners. Greater toleration of sensitive functional
groups can derive from reaction of stoichiometric alkylmetallics
(e.g., R-[M], M = Cu,2 Mn,3 Zn,4 Zr,5 B6) with activated
carboxylic acid derivatives such as acyl halides, anhydrides,
thioesters, or amides. Further enhancements can stem from
transition metal-catalyzed protocols, which overcome many
limitations associated with traditional approaches to aliphatic
ketones.7 In particular, palladium- and nickel-catalyzed cross-
couplings of carboxylic acid derivatives such as acyl chlorides,
anhydrides, activated esters, thioesters, and amides have been
developed for the synthesis of alkyl ketones.8 However, only a
few protocols have been reported for the highly desirable, direct
conversion of carboxylic acids in transition-metal-catalyzed
synthesis of ketones. Thus, although a number of elegant
protocols, including in situ activation of carboxylic acids, have
been disclosed by Gooßen,9 Yamamoto,10 and Zou,11 they are
largely limited to the synthesis of aromatic ketones. Reductive
coupling of in situ activated carboxylic acids provides another
means to generate aliphatic ketones, but the employment of
superstoichiometric amounts of Zn or Mn as the reductant and,
in some cases, the use of three to four equivalent of carboxylic
acid are distinct disadvantages of these methods.12
Initial investigations to explore the feasibility of the proposed
transformation began with the coupling of hydrocinnamic acid
with cyclohexyltrifluoroborate as a model reaction in the
presence of a variety of activating reagents (see Supporting
Information, Figure S1). The investigations revealed the
feasibility of the cross-coupling reaction by using dimethyl
dicarbonate (DMDC) as the activator. It was satisfying to see
Recent efforts have demonstrated that photoredox/transition
metal dual catalysis is a valuable mechanistic protocol that
ameliorates chemical transformations that suffer from limi-
tations in traditional cross-coupling paradigms.13 In these
approaches, a novel concept for transmetalation based on a
single-electron transfer (SET) pathway is applied that lowers
Received: May 26, 2017
© XXXX American Chemical Society
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containing Boc- and Cbz-protected nitrogen atoms (2i−k) and
nitrogenous substrates bearing Lewis basic moieties (2h)
reacted efficiently under the reaction conditions to provide
the desired aliphatic ketones with good yields (65%−89%).
Also, N-methylsulfonamides such as N-methylthiophene-2-
sulfonamide (2m) were well tolerated under the reaction
conditions (77% yield). Notably, α-aminoalkyltrifluoroborates
can be incorporated with high efficiency in the protocol to
generate α-amino substituted ketones, widespread in pharma-
ceuticals and nature (2j, 2l, and 2m).22 α-Alkoxymethyltri-
fluoroborates underwent the coupling in excellent yields (2f
and 2g, 86%−90%). Therefore, this new protocol provides a
strategy for direct access to α-alkoxy ketones as valuable and
versatile building blocks in construction of various natural
compounds by the direct use of carboxylic acids.23
Furthermore, the acylation of 2-methylcyclopentyltrifluorobo-
rate generated the trans-diastereomer as the only product (2b,
69%). We found that β-trifluoroboratoketones and -esters were
successfully coupled as well to generate 1,4-dicarbonyl adducts
(2c and 2d), which are useful precursors to generate
substituted pyrroles, furans, and thiophenes by the Paal−
Knorr synthesis.24 The scalable nature of the coupling was
evaluated by performing the reaction on a 7.0 mmol scale with
1.5 mol % of photocatalyst 1 and 3.0 mol % of [Ni(dtbbpy)-
(H2O)4]Cl2, affording product 2a in 70% yield (Table S1).
Next, we focused our attention on an examination of the
scope of the carboxylic acid partner. As illustrated in Scheme 1,
a broad range of carboxylic acids readily participated in this
acylative coupling reaction with great efficiency. Many different
functional groups could be accommodated under the reaction
conditions. N-Boc-protected amino acids exhibited excellent
reactivity in this coupling protocol to afford the corresponding
ketones in high yields (3b−c, 3n, and 3r, 81%−87%).
Carboxylic acids containing reactive functional groups such as
esters (3g and 3r, 78% and 87% yield, respectively) and nitriles
(3m, 70% yield), which are susceptible to side reactions in the
presence of strong, nucleophilic organometallic reagents,
participated in the reaction as well. Somewhat surprisingly, a
carboxylic acid possessing a hydroxyl group such as 6-
hydroxycaproic acid proved to be a useful coupling partner
(3j, 86% yield). Moreover, this protocol could be applied to
carboxylic acids containing aliphatic halides to produce adducts
that could be used for further elaboration. The acylation of 3-
bromoadamantane-1-acetic acid generated the corresponding
aliphatic ketone with 88% yield (3i). The reaction was
insensitive to steric hindrance. The carboxylic acids bearing
bulky groups, 1-adamantanecarboxylic acid (3h) and 3-
oxotricyclo[2.2.1.02,6]heptane-7-carboxylic acid (3s), thus
provided the corresponding ketones with 70% and 83% yield,
respectively. The cross-coupling reaction of oleic acid with 2-
(4-(trifluoroborato)piperidin-1-yl)pyridine generated ketone 3t
with 57% yield. The power of this method is further
demonstrated by the preparation of ketone 3p from the
acylation of a synthetic bile acid, dehydrocholic acid, with
cyclohexyltrifluoroborate in 60% isolated yield.
Figure 1. Photoredox/Ni dual catalysis cross-coupling of carboxylic
acids with alkyltrifluoroborates.
that DMDC, which is a commodity chemical used as a beverage
preservative, would serve as a nearly ideal activating agent that
generates an activated carbonic anhydride in situ. Upon
reaction, the byproducts of the subsequent acylation include
gaseous CO2 and two equivalents of methanol, neither of which
interferes with the separation of the produced ketones.9d Figure
2 shows the proposed mechanistic cycle for this acyl-sp3
coupling protocol adapted from our studies on cross-coupling
of potassium alkyltrifluoroborates with aryl halides.19
Figure 2. Proposed mechanism for the acyl-sp3 cross-coupling.
Further investigations showed that the presence of any type
of base decreased the yield of the reaction (Figures S1 and S2).
As reported by the MacMillan group,20 the main reason for the
lowering of the yield of the reaction under basic conditions is
likely the single electron oxidation of the carboxylate anion
derived from the deprotonation of the acid to form carboxyl
radicals. The resulting carboxyl radicals undergo CO2 extrusion,
producing the corresponding alkyl radicals that generate side
products. To avoid this phenomenon in the protocol developed
herein, weak proton donor additives were examined (Figure
S5). Interestingly, the use of NH4Cl as an additive afforded
higher yields.
Screening of various reaction parameters (e.g., photocatalyst,
solvent, Ni catalyst, and ligand) via microscale high-throughput
experimentation21 to enhance the yields and improve the
robustness of this transformation revealed that the best
conditions involved treatment of the carboxylic acid with
potassium alkyltrifluoroborate in the presence of 3 mol % of
photocatalyst 1 and 6 mol % of [Ni(dtbbpy)(H2O)4]Cl2, 3.0
equiv of DMDC, and 1.0 equiv of NH4Cl in i-PrOAc/THF
(2:1) as a solvent mixture at room temperature. As expected,
control experiments showed that all parameters were essential
for the reaction to proceed, and the Ir complex 1 was the best
photocatalyst for this cross-coupling reaction (Table S1).
Subsequently, the generality of the cross-coupling reaction
with respect to the alkyltrifluoroborate component was
examined. As illustrated in Scheme 1, a variety of alkyltri-
fluoroborates were acylated under mild conditions with good to
excellent yields. The aliphatic, heterocyclic trifluoroborates
In conclusion, we have established a robust strategy for the
formation of C(O)−Csp3 bonds from carboxylic acids and
potassium alkyltrifluoroborates. This new platform for acyl−sp3
bond construction is enabled by the synergistic Ir-photoredox/
nickel catalytic cross-coupling of in situ activated carboxylic
acids using alkyltrifluoroborates as the coupling partners
through low-barrier, open-shell processes. This new protocol
is amenable to the efficient coupling of a wide array of both
B
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a
Scheme 1. Scope of Potassium Alkyltrifluoroborates in Cross-Coupling with Carboxylic Acids
a
b
See Supporting Information for experimental details. All cited yields are isolated. Reaction performed on 7.0 mmol scale with 1.5 mol % of Ir
photocatalyst 1 and 3.0 mol % of [Ni(dtbbpy)(H2O)4]Cl2.
carboxylic acids and alkyltrifluoroborates under mild conditions
at room temperature.
ACKNOWLEDGMENTS
■
This research was supported by the NIGMS (R01 GM-
113878). Frontier Scientific is thanked for the donation of
boron compounds used in this investigation. Dr. Rakesh Kohli
(University of Pennsylvania) is acknowledged for obtaining
HRMS data.
ASSOCIATED CONTENT
* Supporting Information
■
S
This material is available free of charge on the ACS Publications
Web site at DOI: The Supporting Information is available free
of charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.7b01588.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
ORCID
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