Photoinduced decarboxylative borylation of carboxylic acids

Article abstract of DOI:10.1126/science.aan3679

The conversion of widely available carboxylic acids into versatile boronic esters would be highly enabling for synthesis. We found that this transformation can be effected by illuminating the N-hydroxyphthalimide ester derivative of the carboxylic acid under visible light at room temperature in the presence of the diboron reagent bis(catecholato)diboron. A simple workup allows isolation of the pinacol boronic ester. Experimental evidence suggests that boryl radical intermediates are involved in the process. The methodology is illustrated by the transformation of primary, secondary, and tertiary alkyl carboxylic acids as well as a diverse range of natural-product carboxylic acids, thereby demonstrating its broad utility and functional group tolerance.

Full text of DOI:10.1126/science.aan3679

REPORTS
Cite as: A. Fawcett et al., Science
1
0.1126/science.aan3679 (2017).
Photoinduced decarboxylative
borylation of carboxylic acids
Alexander Fawcett, Johan Pradeilles, Yahui Wang, Tatsuya Mutsuga, Eddie L. Myers, Varinder K.
Aggarwal*
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK..
*
Corresponding author. Email: v.aggarwal@bristol.ac.uk
The conversion of widely available carboxylic acids into versatile boronic esters would be highly enabling
for synthesis. Here we report that this transformation can be effected by illuminating the N-
hydroxyphthalimide ester derivative of the carboxylic acid under visible light at room temperature in the
presence of the diboron reagent, bis(catecholato)diboron. A simple workup allows isolation of the pinacol
boronic ester. Experimental evidence suggests that boryl radical intermediates are involved in the
process. The methodology is illustrated by the transformation of not just primary, secondary, and tertiary
alkyl carboxylic acids but also a diverse range of natural product carboxylic acids, thereby demonstrating
its broad utility and functional-group tolerance.
Carboxylic acids are among the most prevalent of organic carbon centers gives low yields of the desired boronic esters.
molecules found in nature (1). In contrast, the isoelectronic Seeking a complementary method that would allow the
3
boronic acids are scarcely found in nature at all, yet serve as transformation of sp carboxylic acids, we considered N-
precursors to a vast array of molecules containing different hydroxyphthalimide esters, which have recently been used
functional groups (2) through single-step transition-metal- in the decarboxylative functionalization of alkyl groups un-
mediated coupling reactions (3), 1,2-metallate rearrange- der mild conditions (11–15). In the presence of either low-
ments, or deborylative nucleophilic addition (4). Therefore, valent Ni or Fe, or photoexcited Ru(I), these esters are
the conversion of the ubiquitous carboxylic acid group into known to undergo facile single-electron reduction followed
the highly versatile boronic acid moiety would facilitate by rapid decarboxylative fragmentation to an alkyl radical.
more rapid diversification of this important class of feed- The alkyl radical then reacts to form a carbon–carbon bond
stock molecules. Also, boronic acids are important target with either an electrophilic olefin or, through mediation by
molecules in their own right. Specifically, they share a num- a transition metal, a carbon-centered organometallic nucle-
ber of features with carboxylic acids that make them potent ophile, including boronic esters in a Suzuki–Miyaura-type
bioisosteres in medicinal chemistry (5). For example, bo- coupling reaction (16). We wondered whether diboron rea-
ronic acids form hydrogen bonds of similar geometries to gents, such as bis(pinacolato)diboron (B
2
pin ) could take the
2
carboxylic acids (6), despite their lower acidity, and they can place of these carbon-based nucleophiles to instead effect C–
switch reversibly between stable tricoordinate and tetra- B bond formation. Very recently, reaction conditions that
3
2
coordinate forms, thus mimicking the tetrahedral interme- allow the decarboxylative borylation of sp and sp N-
diates involved in, for example, the enzymatic hydrolysis of hydroxyphthalimide esters by using such diboron species
amide groups (7). A straightforward method for converting were disclosed (17–19). Use of a Ni(II) precatalyst in the
libraries of bioactive carboxylic acids into the corresponding presence of a bipyridine ligand, MgBr
boronic acids would lead to enhanced screening libraries activated B pin led the putative alkyl radical intermediate
and would facilitate bioisosteric lead optimization.
to combine with a Ni–boryl intermediate, which underwent
2
.OEt , and MeLi-
2
2
2
Up until very recently, only the decarbonylative boryla- reductive elimination to give the alkyl boronic ester (Fig. 1B)
tion of carboxylic derivatives was known. These transfor- (17). The substrate scope (which encompassed amino-acid-
mations involved the oxidative addition of a catalytically derived and peptidic N-hydroxyphthalimide esters) and
active Ni(0) or Rh(I) species into the C–O (8), C–S (9), or C– functional-group tolerance of these reaction conditions were
N (10) bond of an ester, thioester, or amide derivative, re- very broad. The same transformation can be carried out un-
spectively, and only gave high yields for carboxylic acid de- der visible-light-mediated iridium catalysis by using a large
2
rivatives bearing sp carbon centers (Fig. 1A). Applying these excess of tetrahydroxydiboron (B
2
(OH)
4
) or B
2
pin (18), the
2
3
conditions to simple carboxylic acid derivatives bearing sp
proposed mechanism involving reaction of the putative alkyl
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2
3
radical with nucleophile-activated sp –sp diboron species crucial, and the addition of Cs
2
CO
3
had an inhibitory effect
(20, 21) to give the desired organoboron compound. The (see supplementary materials).
substrate scope for this photoexcited-Ir-mediated process
The substrate scope of the transformation was broad.
was narrower than the Ni-mediated process; B
only be used to form the primary boronic esters, with other substrates bearing heteroatoms, heterocycles (thiophene,
more substituted products requiring the use of B (OH) and indole, pyridine), β-positioned alkenes, alkynes, esters, car-
2
pin could Primary carboxylic acids, including a benzylic substrate and
2
2
4
isolation as the trifluoroborate salts. A similar photomediat- bon–bromine bonds, and perfluoroalkyl chains, were con-
ed process for the decarboxylative borylation of aryl N- verted into the corresponding primary pinacol boronic
hydroxyphthalimides that does not require a transition- esters in good to high yields (Fig. 2A). The isolation of these
metal photocatalyst has also been disclosed (19). For that products was extremely facile, a quick filtration through a
process, LED illumination (400 nm), excess B
equivalents), a catalytic amount of Cs CO , and stoichio- high purity. Secondary carboxylic acids, either appended to
metric amounts of pyridine were required for high yields.
acyclic chains or to a variety of rings (cyclohexyl, cyclopen-
2
pin (3.0 plug of silica gel being sufficient for providing material of
2
2
3
Our exploration of this transformation led us to identify tyl, cyclopropyl, 2,2,2-bridged bicyclic, pyranyl), and paired
much simpler reaction conditions. Specifically, treatment of with functional groups such as difluoromethylene, a carba-
N-hydroxyphthalimide ester 1 with a slight excess of the mate, and an ester, were converted into the corresponding
diboron reagent, bis(catecholato)diboron (B
2
cat ; 1.25 equiv- boronic esters in good to high yield (Fig. 2B). We also inves-
2
alents), in N,N-dimethylacetamide (DMAc) solvent at ambi- tigated carbocyclic substrates containing two stereogenic
ent temperature under illumination by blue LEDs, followed centers, at least one of which bore the carboxylic acid moie-
by a workup that involved adding pinacol and NEt , so as to ty. Here, the boronic ester products were obtained with var-
3
effect ligand exchange to form the more stable pinacol bo- ying diastereomeric ratios (d.r.), depending on the relative
ronic ester, gave the desired boronic ester 2 in 91% yield position of substituents and ring size. Although the 1,3-
(Fig. 1C, entry 4). A solvent screen revealed that amide- substituted cyclopentane, 18, was obtained with low levels
based solvents were uniquely effective for the transfor- of diastereoselectivity, the 1,2-subsitututed cyclohexane 22
mation, with DMAc performing marginally better than N,N- (derived from the corresponding dicarboxylic acid) and 1,2-
dimethylformamide (DMF) (Fig. 1C, entry 1); the use of oth- disubstituted cyclopropane 16 were obtained in 90:10 and
er standard organic solvents, for example, EtOAc, CH
MeCN, and Et O, did not lead to any of the desired product which the three carbon atoms were tied back into a ring
Fig. 1C, entry 5). Increasing the amount of B cat in incre- structure, for example adamantyl, cubyl, and bicy-
2
Cl
2
,
98:2 d.r., respectively (Fig. 2B). Tertiary carboxylic acids in
2
(
2
2
ments from 1.00 equivalent to 2.00 equivalents revealed that clo[1.1.1]pentyl carboxylic acids, were transformed into the
a slight excess of the reagent (1.25 equivalents; 91% yield; corresponding boronic esters in good yield (Fig. 2C). Gram
Fig. 1C, entry 4 versus 1) was optimal; there was a slight quantities of adamantyl pinacol boronic ester 26 could be
drop in yield with larger amounts. The transformation was prepared in a single reaction. However, the use of N-
promoted by light as a reaction conducted in the dark gen- hydroxyphthalimide esters of more flexible tertiary carbox-
erated the desired product at a much lower rate: 36% yield ylic acids, for example 1-methyl-cyclohexyl carboxylic acid,
after 14 hours, and 63% yield after 70 hours (Fig. 1C, entries did not provide the desired boronic ester, although the
6
and 7). Light from a regular white bulb placed in the vicin- starting material was completely consumed under the reac-
ity of the reaction vessel was equally effective (91% yield), tion conditions. Other substrates that did not lead to the
although ambient light led to a less efficient reaction (43% desired boronic ester included secondary benzylic sub-
yield). The transformation was moderately sensitive to con- strates, allylic substrates, and substrates containing α-
centration (0.1 m being optimal) and investigation of the heteroatoms (including amino acids).
progress of the reaction showed that it was complete within
To showcase the utility of the transformation for diversi-
4
hours (for operational reasons, a reaction time of 14 hours fying natural product carboxylic acids, we prepared a di-
was used for the exploration of substrate scope). Although verse collection of N-hydroxyphthalimide esters and
the reaction was tolerant of small amounts of water, the subjected them to the optimized reaction conditions. Bo-
presence of O
the reaction under an inert atmosphere (N
portant for maintaining high yields. Cognizant of the cost of ate to good yields (Fig. 2D). Transformation of the bis(N-
2
was detrimental and therefore conducting ronic esters derived from stearic, oleic, lithocholic, pinonic,
2
or Ar) was im- gibberellic, and arachidonic acids were obtained in moder-
B
B
2
cat
2
, we discovered that replacing it by a 1:1 mixture of hydroxyphthalimide ester) of succinic acid gave the corre-
and catechol gave similar yields (Fig. 1C, entry 8). sponding 1,2-bis(boronic ester) 40 in 41% yield. To demon-
2
(OH)
4
For our process, the use of the more Lewis acidic diboron strate the utility of the transformation for medicinal
reagent, B cat (Fig. 1C, compare entry 2 with entry 3), was chemistry applications, fenbufen, a protected form of glu-
2
2
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2

tamic acid, and indometacin were converted into the corre- the alkyl radical and DMAc-stabilized boryl radical within
sponding boronic esters in moderate to good yields. These the solvent cage (19).
examples highlight that the transformation is also tolerant
of free hydroxy groups, silyl ethers, and ketones.
The requirement of using an amide-based solvent
(DMAc, DMF) is evidence to support the involvement of
Based upon the above results and further control exper- boryl radicals, which are extremely unstable unless coordi-
iments (see below), we believe that the transformation pro- nated to a Lewis base, especially those that allow delocaliza-
ceeds through a radical chain process that is initiated tion of the unpaired electron residing formally on the boron
through either a photochemical event or a less-efficient center (24). A recent computational investigation suggests
thermal event, both of which operate in parallel (Fig. 3A). that Lewis bases, such as DMF and DMAc, do provide sub-
For the photochemical process, the N-hydroxyphthalimide stantial stabilization to boryl radicals (25). Recent investiga-
substrate and a DMAc solvent molecule bind to the boron tions have shown that N-heterocyclic carbenes (26, 27) and
centers of B
This species, which is formed in low concentration, absorbs lizing boryl radicals. We therefore subjected our standard
light to form an excited state that ultimately leads to cleav- substrate, 1, and B cat as a solution in CH Cl (a solvent
2
cat
2
forming heteroleptic ternary complex 42. pyridines (28, 29) are among the best Lewis bases for stabi-
2
2
2
2
age of the B–B bond, thus forming the DMAc-stabilized that does not promote decarboxylative borylation), together
boryl radical 44 and the O-boryl-N-hydroxyphthalimide es- with two equivalents of N,N-dimethylamino pyridine
ter radical 43, which subsequently undergoes rapid decar- (DMAP), to blue LED illumination. We obtained the desired
boxylation to form the alkyl radical 45 and O-boryl pinacol boronic ester 2 in 10% yield (13% yield for the reac-
phthalimide 51. The alkyl radical then reacts with DMAc- tion conducted in the dark), thus strongly suggesting that
ligated B
5
2
cat 47, thus generating the desired boronic ester DMAc solvent takes on the additional role of stabilizing a
0 and DMAc-stabilized boryl radical 44. The resulting boryl radical. That the DMAP-mediated transformation pro-
2
boryl radical can then either propagate a radical chain pro- ceeds equally well in the dark supports thermal fragmenta-
cess, through reaction with one of the imidyl oxygen atoms tion of the doubly-ligated diboron species as a possible
of the N-hydroxyphthalimide ester, thus leading to homolyt- chain-process initiating event. Furthermore, comparing the
1
1
ic decarboxylation, or else terminate the chain, through rad-
ical–radical dimerization with another boryl radical (22). (Fig. 3B), the former shows a single signal at 29.7 ppm,
Alternatively, the 2:1 DMAc/B
cat complex 46, undergoes whereas the latter shows two more upfield signals, one
thermal homolytic fragmentation to give two equivalents of broad (25.4 ppm) and one sharp (13.8 ppm). The upfield
the DMAc-stabilized boryl radical 44, which propagate the shifting and broadening of the peak in going from CH Cl to
B NMR spectrum of B
2
cat
2
2
in CH Cl
2
with that in DMAc
2
2
2
2
chain as described above. That the transformation is not DMAc supports the existence of ligated diboron species (30).
diastereospecific (Fig. 2B, products 16, 18, and 22), sup- Intriguingly, the sharp signal at 13.8 ppm is consistent with
ports the intermediacy of an alkyl radical. This possibility the presence of the previously reported cubically-
−
was probed further by subjecting methyl cyclopropyl N- symmetrical bis(catecholato) boronate B(cat)
2
(31); the
hydroxyphthalimide 53 to the reaction conditions (Fig. 3C); identity of this species was confirmed through independent
the isolation of the homoallylic pinacol boronic ester 10 synthesis. This species could be formed through a process
(56% yield) confirmed the intermediacy of the methylcyclo- initiated by homolytic cleavage of the B–B bond, thus lend-
propyl radical, which is known to undergo rapid ring- ing further credence to the above mechanistic proposal.
8
−1
opening to the homoallylic radical (1.3×10 s , 23). We also
That the transformation was promoted by visible light
prepared 5-hexenyl N-hydroxyphthalimide 54 and subjected was initially intriguing because the independent absorption
it to the reaction conditions, knowing that the putative in- spectra of both the N-hydroxyphthalimide substrate 1 and
termediate, 5-hexenyl radical, undergoes cyclization to the the B
2
cat reagent in DMAc solution show bands exclusively
2
more thermodynamically stable cyclopentyl methyl primary in the UV region (maxima at 314 and 303 nm, respectively),
5
−1
radical with a rate constant of 1.0×10 s (23). We obtained with no features in the visible region. However, a DMAc
a mixture of the 5-hexenyl 56 (linear) and the cyclopentyl solution of a mixture of these components, at the concentra-
methyl boronic ester 55 (cyclic) in a ratio of ca. 1.5:1 (Fig. tion relevant to the process (0.1 m), shows a shoulder on the
3
C). This ratio was dependent on the concentration of the bathochromic side that extends into the region that overlaps
reaction components, the cyclic product being favored un- with the band of wavelengths emitted by the blue LEDs
der more dilute conditions (see supplementary materials). (maxima at 450 nm). These data provide strong evidence
The dependence of the linear/cyclic ratio on concentration supporting the presence of ternary complex 42, which is
supports the operation of a chain process, such as the one proposed to absorb light and undergo fragmentation to the
proposed above, rather than a process where the desired alkyl radical and the DMAc-stabilized boryl radical. It is
boronic ester is formed through radical–radical coupling of conceivable that upon excitation of ternary complex 42 (32)
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ACKNOWLEDGMENTS
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0. T. C. Atack, R. M. Lecker, S. P. Cook, Iron-catalyzed borylation of alkyl
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Research reported in this publication was supported by the ERC, under the award
number 670668, and by the EPSRC under the award number EP/I038071/1.
Y.W. is in receipt of a Marie Skłodowska-Curie Fellowship (EMTECS/652890). A
provisional UK patent application on this work has been filed (application
51. H. Zhang, S. Hagihara, K. Itami, Making dimethylamino a transformable directing
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number: GB 1705897.5).
SUPPLEMENTARY MATERIALS
www.sciencemag.org/cgi/content/full/science.aan3679/DC1
Materials and Methods
Figs. S1 to S7
Tables S1 and S2
References (37–67)
NMR Spectra
3
April 2017; accepted 7 June 2017
Published online 15 June 2017
0.1126/science.aan3679
1
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6

Fig. 1. Reaction development. (A) Transition-metal-catalyzed
decarbonylative borylation reactions of aryl carboxylic acid derivatives.
These reactions proceed through oxidative addition of the metal into the
C–X bond, extrusion of CO, σ-bond metathesis with the diboron species,
and reductive elimination to form the C–B bond. (B) Baran’s Ni-
catalyzed decarboxylative borylation. (C) Optimization of reaction
conditions for the visible-light-activated decarboxylative borylation of N-
hydroxyphthalimide ester 1 in the presence of diboron species,
bis(catecholato)diboron (B
2
cat ). The reaction conditions highlighted in
2
yellow (entry 4) are optimal.
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7

Fig. 2. Exploration of substrate scope. Decarboxylative borylation of (A) primary, (B)
secondary, (C) tertiary and (D) drug and natural-product-derived N-hydroxyphthalimide
esters.
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8

Fig. 3. Mechanistic studies. (A) Proposed mechanism for the decarboxylative borylation of N-hydroxyphthalimide
1
1
esters. (B) B NMR spectra of DMAc and CH
cyclopropylmethyl N-hydroxyphthalimide ester 53 leads to homoallyl boronic ester 10. Decarboxylative borylation of
-hexenyl N-hydroxyphthalimide ester 54 leads to a mixture of the 5-hexenyl 56 and the cyclopentyl methyl boronic
ester 55. (D) UV/Vis absorption spectra (normalized) of DMAc solutions of N-hydroxyphthalimide ester 1 (red
trace), B cat (blue trace) and a 1:1.25 mixture of ester 1 and B cat (green trace).
2
Cl
2
solutions of B
2
cat
2
(C) The decarboxylative borylation of
5
2
2
2
2
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9

Photoinduced decarboxylative borylation of carboxylic acids
Alexander Fawcett, Johan Pradeilles, Yahui Wang, Tatsuya Mutsuga, Eddie L. Myers and Varinder K. Aggarwal
published online June 15, 2017
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