Intermolecular Radical Addition to Ketoacids Enabled by Boron Activation

Article abstract of DOI:10.1021/jacs.9b09099

The intermolecular radical addition to the carbonyl group is difficult due to the facile fragmentation of the resulting alkoxyl radical. To date, the intermolecular radical addition to ketones, a valuable approach to construct quaternary carbon centers, remains a formidable synthetic challenge. Here, we report the first visible-light-induced intermolecular alkyl boronic acid addition to α-ketoacids enabled by the Lewis acid activation. The in situ boron complex formation is confirmed by various spectroscopic measurements and mechanistic probing experiments, which facilitates various alkyl boronic acid addition to the carbonyl group and prevents the cleavage of the newly formed C-C bond. Diversely substituted lactates can be synthesized from readily available alkyl boronic acids and ketoacids at room temperature merely under visible light irradiation, without any additional reagent. This boron activation approach can be extended to alkyl dihydropyridines as radical precursors with external boron reagents for primary, secondary, and tertiary alkyl radical additions. The pharmaceutically useful anticholinergic precursors are easily scaled up in multigrams under metal-free conditions in flow reactors.

Full text of DOI:10.1021/jacs.9b09099

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Intermolecular Radical Addition to Ketoacids Enabled by Boron
Activation
Shasha Xie,† Defang Li,†,‡ Hanchu Huang,† Fuyuan Zhang,†,‡ and Yiyun Chen*,†,‡
†State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
‡School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
S
* Supporting Information
Scheme 1. Alkyl Radical Addition to Ketoacids Enabled by
Lewis Acid Activation
ABSTRACT: The intermolecular radical addition to the
carbonyl group is difficult due to the facile fragmentation
of the resulting alkoxyl radical. To date, the intermolecular
radical addition to ketones, a valuable approach to
construct quaternary carbon centers, remains a formidable
synthetic challenge. Here, we report the first visible-light-
induced intermolecular alkyl boronic acid addition to α-
ketoacids enabled by the Lewis acid activation. The in situ
boron complex formation is confirmed by various
spectroscopic measurements and mechanistic probing
experiments, which facilitates various alkyl boronic acid
addition to the carbonyl group and prevents the cleavage
of the newly formed C−C bond. Diversely substituted
lactates can be synthesized from readily available alkyl
boronic acids and ketoacids at room temperature merely
under visible light irradiation, without any additional
reagent. This boron activation approach can be extended
to alkyl dihydropyridines as radical precursors with
external boron reagents for primary, secondary, and
tertiary alkyl radical additions. The pharmaceutically
useful anticholinergic precursors are easily scaled up in
multigrams under metal-free conditions in flow reactors.
he carbonyl group is a readily available building block for
1
Tthe synthesis of substituted alcohols.
While the
nucleophilic addition to the carbonyl group is favorable and
widely studied, the radical addition to the carbonyl group is
difficult, as the resulting alkoxyl radical undergoes β-
fragmentation readily to reverse the reaction, especially for the
radical addition to ketones (Scheme 1a).2 To date, the
intermolecular radical addition to ketones,3,4 which is valuable
to construct quaternary carbon centers,5 remains a formidable
synthetic challenge. Lactates are important biological metabo-
lites, which are precursors of poly-α-hydroxy acids for targeted
drug delivery,6 and include many prescription drugs such as
anticholinergic Oxybutynin and Glycopyrrolate (see Scheme 3b
for structures).7 The α-ketoacid is a readily available synthetic
building block to prepare lactates by nucleophilic additions with
alkyllithiums or Grignard reagents.8 However, these reactions
are susceptible to air and moisture, and the strong nucleophil-
icity of these reagents unavoidably result in undesirable side
reactions.9 To this end, the new synthetic approaches to lactates,
especially from different mechanistic manifolds, are in high
demand.
Ketoacids currently undergo decarboxylative acyl radical
formations in radical reactions, and their engagement as the
radical acceptors remains unknown (Scheme 1b).10 Organo-
borons are environmentally friendly and readily available, and
are stable synthetic building blocks with Lewis acidity.11 In this
communication, we report the first alkyl boronic acids radical
addition to ketoacids with the Lewis acid activation from
organoborons, which can be extended to alkyl dihydropyridine
radical addition to ketoacids in the presence of external boron
reagents (Scheme 1c).
Received: August 22, 2019
Published: October 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b09099
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Our initial discovery arose from the serendipitous observation
when cyclohexyl boronic acid 1 and p-methoxyphenyl ketoacid
2 were mixed. While the individual solutions of 1 and 2 in
dichloromethane were colorless, a yellow color appeared
simultaneously upon mixing (Scheme 2b). When the dichloro-
We also measured the 11B NMR spectrum of 1 and found an
upfield new peak appearing at 13.5 ppm when mixing with 2,
indicating the changed boron chemical environment (Scheme
2c). From the titration experiments via 19F NMR spectrometry,
the 19F NMR signal of fluorinated ketoacid 6 shifted upfield with
the addition of boronic acid 1 (Scheme 2d). A set of control
spectrometry measurements were next performed with cyclo-
hexyl boronic ester 7, p-methoxyphenyl ketoester 8, or o-
nitrobenzoic acid 9, and the spectrometry characterization
indicated no boron complex formation (see Figures S3−S4).15
In addition, the control reaction under 365 nm UV light
irradiation gave no conversion between p-methoxyphenyl
ketoester 8 and boronic acid 1 (Scheme 2e). Taken together,
the carboxylic acid, boronic acid, and the carbonyl group are all
essential for the boron complex formation and the visible-light-
induced reactions.
Scheme 2. Visible-Light-Induced Reaction between Alkyl
Boronic Acids and Ketoacids, and the Spectrometry Studies
for the Boron Complex Formation
We next investigated if this boron complex formation and
subsequent radical addition to ketoacids are general to other
alkyl boronic acids (Scheme 3a). While there were reports on
the transition-metal-catalyzed aryl or allyl boronic acid additions
to the carbonyl group, the alkyl boronic acids were not viable
substrates due to the facile β-elimination.16 The secondary
cyclopentyl, cyclohexyl, cycloheptyl, and indanyl trifluoroborate
5, 10−12 all reacted smoothly with ketoacid 2 under visible light
irradiation to give isolated 67−80% yields of lactates 4, 10a−12a
after TMSCHN2 treatment. The noncyclic secondary boronic
acids 13 and 14 were compatible to give lactates 13a and 14a in
71% and 75% yields, respectively. The heterocyclic N-
tosylpiperidinyl boronic acids 15 afforded lactates 15a in 79%
yields. The primary phenethyl, benzyl, and ethyl boronic acids
16−18 gave 52−65% yields of lactates 16a−18a in the mixed
solvents with 5% hexafluoroisopropyl alcohol (HFIP).17 The
tertiary boronic acids were unreactive in the reaction, possibly
due to the difficult boron complex formation from the steric
hindrance.
The ketoacid scope was also investigated. The electron-
neutral or electron-deficient substituted ketoacids 19−24
reacted with boronic acid 1 or trifluoroborate 5 to give 45−
66% yields of lactates 19a−24a after TMSCHN2 treatment
(Scheme 3a). The ortho, para, and meta aryl substitutions did
not affect the reaction to give lactates 25a−28a in 60−70%
yields. The electron-donating alkoxyl and N-tert-Boc aryl
substituents gave 83−85% yields of 29a−31a. The heterocyclic
thiophene ketoacid gave 32a in decreased 33% yield, and the
bicyclic naphthalene-derived ketoacids 33−34 reacted smoothly
to give lactates 33a−34a in 51−73% yields. Various
pharmaceutically relevant and chemical biologically useful
functional groups such as trifluoromethoxy and terminal alkynes
were tolerated to give 35a−36a in 78−82% yields. Significantly,
the homoserine-derived ketoacid 37 gave the corresponding
lactate 37a in 90% yield. Such mild reaction conditions indicated
future bioconjugation potentials.18
Next, practical aspects of the reaction were evaluated with a
photochemical flow reactor. This approach has historically
afforded chemists greater control, selectivity, and scalability than
batch reactions.19 We injected the alkyl boronic acid 1 and
ketoacid 2 to the flow reactor under household 23 W CFL lamp
irradiation (Scheme 3b, Figures S18−S19). After 10 h of
reaction in 210 mL of the reaction mixture, the quaternary α-
hydroxy acid 3 could be prepared in 1.69 g in 75% isolated yield.
The synthetic analogues of 3 were practically one esterification
step away from the racemic forms of anticholinergic drugs
Oxybutynin/Glycopyrrolate. With its mild, metal-free, and
a
Reaction conditions: 1 (0.30 mmol, 3.0 equiv) and 2 (0.10 mmol,
1.0 equiv) in 2.0 mL of CH2Cl2 with light irradiation at room
b
temperature for 5 h, unless otherwise noted. Conversions of ketoacid
2 and yields of α-hydroxy acid 3 were determined by 1H NMR
c
analysis. The alkyl trifluoroborates 5 were used in 1:1 CH2Cl2/H2O.
Isolated yields of lactate 4 after esterification with trimethylsilyl-
diazomethane (TMSCHN2) were in parentheses.
methane solution containing 1 and 2 was irradiated, the α-
hydroxy acid 3 was obtained in 76% yield under the blue LED
irradiation without any additional reagent (entry 1 of Scheme
2a). The use of a 23 W household fluorescence lamp gave a
slightly increased 84% yield of 3 (entry 2). When using light
irradiation with the band-pass at 475 nm, in which neither 1 nor
2 absorbs (Scheme 2b), a 64% yield of 3 was obtained (entry 3).
The alkyl trifluoroborates 5 in aqueous conditions gave an
optimal 95% yield of α-hydroxy acid 3,12 which gave lactate 4
after TMSCHN2 treatment in 80% isolated yield (entry 4).13
The reaction in the darkness gave 3 in only 21% yield (entry 5;
see detailed optimization in Table S1).
We next measured the UV−vis absorption spectra of alkyl
boronic acid 1 and ketoacid 2, with which the Job’s plot revealed
the 1:1 ratio of the boron complex formation (Scheme 2b).14
B
DOI: 10.1021/jacs.9b09099
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Journal of the American Chemical Society
Communication
additional-reagent-free character, we expect this visible-light-
induced alkyl boronic acid addition method will be an attractive
approach to prepare lactates in the pharmaceutical industry.
We further investigated the reaction mechanisms. When the
radical scavenger 1,4-dinitrobenzene 38 was incubated with
boronic acid 1 and ketoacid 2, the formation of α-hydroxy acid 3
was completely inhibited (Scheme 4a, Figure S9). The radical
Scheme 3. Substrate Scope of the Alkyl Boronic Acid
Addition to Ketoacids
Scheme 4. Mechanistic Investigations
a
The combined yields after TMSCHN2 treatment were reported.
clock cyclopropylmethyl boronic acid 39 resulted in the
cyclopropyl ring-opening adduct 39a and subsequent dehy-
dration adduct 39b in 12% and 26% yields, respectively.
Tetrabromomethane 40 was next added to the reaction
conditions of 41 and 2 to trap the potential radical intermediates
(Scheme 4b, Figure S11).20 Other than lactate 41a formation in
22% yield, the tribromomethyl-42a and bromo-42b were
observed in 25% and 28% yields, respectively, deriving from
alkyl boronic acid 41. In contrast, neither the tribromomethyl-
43a nor bromo-43b adduct from ketoacid 2 was observed, which
suggested no ketyl radical was formed from ketoacids during the
reaction.21 We further performed the on−off-light experiment
between boronic acid 1 and ketoacid 2 and observed the
occurrence of the dark reaction (Scheme 4c, Figure S13). These
results suggested the alkyl radical intermediate and the radical
chain reaction mechanism.22
a
The reaction time was 48 h, and 5% HFIP was added as cosolvent.
C
DOI: 10.1021/jacs.9b09099
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Journal of the American Chemical Society
Communication
With the detailed mechanistic investigation, we propose the
reaction is initiated by the boron complex formation between
alkyl boronic acid A and ketoacid B, which is represented either
as the Lewis acid−base pair I or as the boron anhydride II
(Scheme 4d).23 This boron complex can be photoexcited to
generate the alkyl radical R· for radical initiation, which then
yields the cyclic boron radical intermediate III. The delocalized
radical intermediate III is stabilized by the boron complex to
prevent the C−C bond cleavage reaction and undergoes the C-B
bond cleavage reaction to eliminate the alkyl radical R· for chain
propagation.24 The intermediate IV then undergoes an ester
exchange reaction with alkyl boronic acid A to yield the resulting
cyclic boron complex V, which was suggested by the NMR
spectrometry (Figures S7−S8).25 The intermediate V then
undergoes hydration to yield the quaternary α-hydroxy acid
product C and releases the alkyl boronic acid A for the next
boron complex formation.26
After the successful alkyl boronic acid addition to ketoacids
with boron complex formation, we were curious if other alkyl
radical precursors could engage in radical carbonyl additions
with this approach. The alkyl-substituted dihydropyridines
(DHPs) are readily available alkyl precursors and can be
prepared from aldehydes in one step.27 While visible light
irradiation of cyclohexyl-DHP 44 (E1/2ox = +0.65 V vs Fc+/Fc in
DMSO) and ketoacid 2 gave no conversion,28 the addition of
external boron reagents significantly affected the reaction
outcomes (Scheme 5a). The trimethyl borate B(OMe)3 45
next measured the UV−vis absorption spectrometry of ketoacid
2 with different boron reagents and found the bathochromic
shift to be similar to that for the addition of alkyl boronic acids
(Scheme 5a, Figure S5). The 11B NMR spectrometry of
B(OMe)3 45 and ketoacid 2 also showed a clear upfield shift
at 10.2 ppm, indicating the new boron complex formation.
We then tested different alkyl-DHP derivatives under visible
light irradiation and observed primary and secondary alkyl-
DHPs 44, 50−54 engaged in the ketoacid additions smoothly, in
which 60−94% yields of lactates were obtained (Scheme 5b).
Gratifyingly, the tertiary alkyl-DHPs 55 and 56 reacted well to
give lactates 55a−56a with two adjacent quaternary carbon
centers in 62−92% yields, which were steric-crowded lactates
and synthetically challenging. These results indicated that the
boron complex formation with external boron reagents may
overcome the steric hindrance limitation imposed by the use of
tertiary alkyl boronic acids.29
In conclusion, we have reported the first visible-light-induced
alkyl radical addition to ketoacids enabled by Lewis acid
activation. The boron complex formation between boronic acids
and ketoacids facilitates the alkyl radical addition to the carbonyl
group and prevents the cleavage of the newly formed C−C
bond. The dihydropyridines engage in radical additions to
ketoacids with external boron reagents to enable the primary,
secondary, and tertiary alkyl radical addition reactions. This
reaction is readily performed in photochemical flow reactors to
enable the multigram synthesis of pharmaceutically important
lactates under metal-free conditions.
Scheme 5. Radical Addition to Ketoacids by Alkyl-DHPs with
External Boron Reagents
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b09099.
■
S
Complete mechanistic experiments, optimization tables,
experimental methods, and additional experimental data
(PDF)
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*yiyunchen@sioc.ac.cn
■
ORCID
Yiyun Chen: 0000-0003-0916-0994
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by National Natural Science
Foundation of China 91753126, 21622207, 21602242, and
Strategic Priority Research Program of the Chinese Academy of
Sciences XDB20020200.
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