Acylboronates in polarity-reversed generation of acyl palladium(II) intermediates

Article abstract of DOI:10.1021/acs.orglett.1c00742

We report a catalytic cross-coupling process between aryl (pseudo)halides and boron-based acyl anion equivalents. This mode of acylboronate reactivity represents polarity reversal, which is supported by the observation of tetracoordinated boronate and acyl palladium(II) species by 11B, 31P NMR, and mass spectrometry. A broad scope of aliphatic and aromatic acylboronates has been examined, as well as a variety of aryl (pseudo)halides.

Full text of DOI:10.1021/acs.orglett.1c00742

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Letter
Acylboronates in Polarity-Reversed Generation of Acyl Palladium(II)
Intermediates
†
†
̌
Alina Trofimova, Aleksandra Holownia, Chieh-Hung Tien, Martynas J. Sirvinskas,
and Andrei K. Yudin*
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ABSTRACT: We report a catalytic cross-coupling process
between aryl (pseudo)halides and boron-based acyl anion
equivalents. This mode of acylboronate reactivity represents
polarity reversal, which is supported by the observation of
tetracoordinated boronate and acyl palladium(II) species by 11B,
31P NMR, and mass spectrometry. A broad scope of aliphatic and
aromatic acylboronates has been examined, as well as a variety of
aryl (pseudo)halides.
Scheme 1. (a) Previous Work on Electrophilic Reactivity of
MIDA Acylboronates; (b) This work: Pd-Catalyzed
Suzuki−Miyaura Cross-Coupling Reaction of Acylboronates
as Acyl Anion Equivalents
olarity reversal (umpolung) allows one to switch the
1
Pnatural polarization of a functional group. A number of
established examples of this phenomenon demonstrate how
electrophilic functional groups can be turned into nucleophiles
and vice versa. Carbonyl compounds, which are electrophiles of
prominence in organic synthesis, react with a broad range of
nucleophilic species.2 An umpolung transformation can reverse
polarization such that the carbonyl functionality is made to
react with electrophiles as an acyl or formyl anion.2
Acylboron compounds, which are a class of functionalized
carbonyl group-containing molecules, have emerged as useful
reagents in organic synthesis.3,4 While effective as boron-
containing building blocks, these molecules are not stable in
their free boronic acid form.5 Synthetic applications of
acylboronates are enabled by the utilization of a MIDA (N-
methyliminodiacetic acid) ligand4c−g,6,7 or potassium organo-
trifluoroborates,4a,b,g,h which provide enhanced stability to
borylated compounds. It is now well understood that
acylboronates display reactivity that is similar to the ketone
functionality.8 The ability of acylboronates to undergo
nucleophilic addition has found application in the synthesis
of valuable boron-containing heterocycles, peptides, and
catalysis has not been realized to date.10 Herein, we report that
readily available MIDA acylboronates4g give rise to boron
α
analogs of -keto acids. The boron-based acyl anion
proteins (Scheme 1a).4,8 -Functionalization of acylboronates
equivalents have been evaluated in the Pd-catalyzed Suzuki−
Miyaura reaction of acylboronates and aryl (pseudo)halides in
the construction of C(sp2)−C(sp2) bonds (Scheme 1b). The
observation of tetracoordinated boronate and acyl palladium-
(II) intermediates provides additional insights into trans-
α
reveals another mode of reactivity, further underscoring the
relative stability of BMIDA under a range of reaction
conditions.4f,8c Acylboronates have been shown to participate
in rearrangement reactions yielding N-, O-, and C-borylated
species that are difficult to prepare by alternate routes due to
facile boron atom migration.8d After derivatization, the MIDA
ligand can be removed,7 leading to the isolation of stable
molecules in free boronic acid form or nonborylated
compounds afforded by protodeboronation.9
Received: March 4, 2021
Published: April 13, 2021
While there are numerous reports on the electrophilic
reactivity of acylboronates, a polarity-reversed application in
https://doi.org/10.1021/acs.orglett.1c00742
© 2021 American Chemical Society
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Table 1. Suzuki−Miyaura Cross-Coupling Reaction Optimization
a
entry
Pd precatalyst
base
additive
solvent
temp (°C)
yield (%)
b
1
2
3
4
5
6
7
8
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
SPhos Pd G2
RuPhos Pd G2
XPhos Pd G2
XPhos Pd G2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl
4:1 DMF/t-amylOH
80
80
80
80
80
80
80
80
60
44
49
47
10
6
30
26
b
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
c
c
c
CuI
c
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
c
c
61
c
9
73 (66%)
a
b
c
1
Determined by H NMR using an internal standard. p-Iodoanisole was used. p-Bromoanisole was used.
Scheme 2. Scope of the Pd-Catalyzed Suzuki−Miyaura
Reaction of MIDA Acylboronate 1a with Aryl
(Pseudo)halides
Scheme 3. Scope of the Pd-Catalyzed Suzuki−Miyaura
Reaction of MIDA Acylboronate 1 with Aryl Bromides
a
b
1
Isolated yields. Yield determined by H NMR using an internal
standard.
Table 2. Mechanistic Analysis by 11B NMR Spectroscopy
a
entry
deviations from standard conditions
11B NMR resonances
1
none
0.47 ppm
2
3
4
5
6
7
8
9
no XPhos Pd G2, no 2a
only 1a and Cu(OAc)2
no Cu(OAc)2
only 1a and Cs2CO3
only 1a, Cs2CO3, KOAc
only 1a and CsOAc
only 1a, Cu(OAc)2, CsOAc
only 1a, CuCl2, Cs2CO3
only 1a, CuCl2, CsOAc
only 1a, Cu(OAc)2, K3PO4
0.47 ppm
no conversion
no conversion
no conversion
no conversion
no conversion
no conversion
no conversion
0.47 ppm
0.47 ppm
b
b
a
b
c
Isolated yields. Performed on a 1 mmol scale. Yield determined by
10
11
1H NMR using an internal standard.
a
Standard conditions: 1a (1.5 equiv), aryl bromide (1.0 equiv),
XPhos Pd G2 (10 mol %), Cu(OAc)2 (1.5 equiv), Cs2CO3 (3.0
b
equiv) in DMF (0.1 M), 60 °C, 16 h. Decomposition was observed.
metalation in the Suzuki−Miyaura reaction and complements
the previously published reports about this least understood
step of the catalytic cycle.11 A broad scope of aryl
(pseudo)halides has been investigated, as well as a number
of aryl and alkyl acylboronates.
We hypothesized that the polarity-reversed application of
acylboronates could be examined in the Pd-catalyzed cross-
coupling reaction of aryl halides. As a model for our initial
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Scheme 4. Mechanistic Analysis by 11B NMR Spectroscopy
be benzaldehyde 4a, owing to the protodeboronation of 1a. To
optimize the reaction conditions, solvent, palladium species,
base, additive, and temperature were screened. Omitting
alcoholic cosolvent resulted in a slight increase in yield
(entry 2). Changing p-iodoanisole to p-bromoanisole did not
have a major impact on the yield but limited the formation of
other side-products, such as biaryl derivatives, to <10% (entry
3). Switching the stoichiometric additive to CuCl and CuI had
a negative impact on the reaction (entries 4 and 5). Other Pd
species were inferior compared to XPhos Pd G2 (entries 6 and
7). Cs2CO3 was found to be a more efficient base (entry 8).
Decreasing the reaction temperature to 60 °C led to the
formation of 3a in 73% yield (entry 9).
The scope of the reaction was explored with respect to aryl
bromide utilizing the optimized reaction conditions (Scheme
2). para-, meta-, and ortho-Bromoanisole were employed in the
transformation to afford the corresponding ketones 3a−3c in
good yields. Notably, the reaction producing 3a was
successfully scaled up to 1 mmol under standard conditions.
The amine functional group was tolerated in the reaction (3d).
An arene with increased electron density was a suitable
coupling partner and led to product formation in a good yield
(3e). Reactions with mono-, di-, and trimethylated aryl
bromides provided ketones 3f−i in moderate yields. Ketones
3j and 3k were synthesized in 56% and 43% yield, respectively.
The use of p-bromochlorobenzene afforded the corresponding
ketone 3l. In general, substrates bearing electron-donating
groups reacted more efficiently in the cross-coupling reaction,
whereas the presence of electron-withdrawing groups, such as
trifluoromethyl (3m), cyclic ketone (3n), benzothiophene
(3o), and methoxypyridine (3p), on the arene resulted in
lower yields of the corresponding ketone products. Pyridyl and
methylthiophene provided only a trace amount of the
corresponding ketones (3q and 3r).
Scheme 5. Mechanistic Analysis by 31P NMR Spectroscopy
Next, we investigated the scope of electrophilic partners.
The reaction of iodobenzene afforded the desired ketone 3j in
higher yield compared to the reaction of bromobenzene, albeit
with more side-product formation. The same ketone was
synthesized in 29% assay yield when phenyl trifluoromethane-
sulfonate was used. Only a trace amount of 3j was observed in
the reaction with chlorobenzene.
The compatibility of other acylboronates with the cross-
coupling conditions was also evaluated (Scheme 3). The
introduction of an electron-withdrawing group, such as
fluorine, to the aromatic ring of acylboronate resulted in
successful reactions with p-bromoanisole and p-bromo-N,N-
dimethylaniline (3s and 3t). The reactions of p-methox-
ybenzoyl boronate with these aryl halides afforded the
corresponding ketones 3u and 3v in 74% and 60% yield,
respectively. We next investigated the compatibility of aliphatic
acylboronates with the cross-coupling reaction. Gratifyingly,
when acetyl boronate was employed, the reactions provided
the desired ketones 3w and 3x. The reaction of cyclohexane-
carbonyl boronate gave the product (3y) in good yield.
Ketones 3z and 3aa were synthesized in 41% and 17% yield,
respectively. The reaction of phenylacetyl boronate provided
only trace amount of the desired ketone 3ab.
investigations, acylboronate 1a and p-iodoanisole were
combined with catalytic XPhos Pd G2, Cu(OAc)2 as the
stoichiometric additive, and K2CO3 as a base in a 4:1 solvent
mixture of DMF/tert-amyl alcohol (t-amylOH). The reaction
afforded the desired ketone product 3a in 44% yield (Table 1,
entry 1). Analysis of the crude reaction mixture by H NMR
and GC-MS revealed the major side-product of the reaction to
In order to gain insight into the mechanism of the reaction
and identify possible intermediates, analysis by in situ NMR
spectroscopy was employed. Due to the poor solubility of
Cs2CO3 and the formation of insoluble byproducts, the
reaction of 1a and 2a in DMF-d7 under standard conditions
1
1
was not homogeneous and signals of the H NMR spectrum
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Scheme 6. Proposed Mechanism of the Suzuki−Miyaura Reaction of MIDA Acylboronates
were too broad to be analyzed. Instead, a series of control
reactions was conducted and monitored by 11B NMR
spectroscopy. The reaction of 1a and 2a under standard
conditions in DMF was monitored over 17 h (Table 2, entry
1). After 1 h, a 11B NMR spectrum consisted of a signal at 5.5
ppm (relative to BF3·Et2O) corresponding to 1a and a new
resonance at 0.47 ppm. The intensity of the latter continued to
rise over the course of the reaction, accompanied by the
disappearance of the resonance of 1a within 11 h. When 1a
was mixed with 1.5 equiv of Cu(OAc)2 and 3.0 equiv of
Cs2CO3 in DMF at 60 °C in the absence of Pd catalyst, the
same signal at 0.47 ppm in the 11B NMR spectrum was
observed (entry 2). Further analysis was required to probe the
intermediacy of the species with the distinct resonance at 0.47
ppm that appeared in the course of both control reactions.
Additional experiments were performed to understand the
appeared after 1 h and its intensity continued to increase, while
the peak corresponding to 1a decreased. Gratifyingly, once 1a
was consumed (∼11 h), the resonance at 0.47 ppm began to
disappear. After 16 h, complete consumption of I was observed
confirming the intermediacy of the species.
We then turned our attention to detecting the hypothesized
intermediacy of an acyl palladium complex. The progress of a
stoichiometric reaction of 1a, 2a, and Pd precatalyst was
monitored by 31P NMR spectrometry over 16 h (Scheme 5).
After 15 min, the signals at 41.9 ppm, which corresponded to
XPhos oxide, and 27.4 ppm appeared. The latter was assigned
to the oxidative addition palladium complex III, which
exhibited a chemical shift consistent with previous literature
reports.15 After 1 h, a new signal at 25.9 ppm appeared and its
intensity continued to rise while the resonance of III slowly
disappeared. This new signal, upfield of 1.5 ppm from that of
complex III, was assigned to the acyl palladium species IV. A
similar upfield shift for analogous carbonylated complexes was
observed by the Moser16 and Yamamoto17 groups in Pd-
catalyzed carbonylation reactions with carbon monoxide.
Moreover, IV was detected by HRMS (ESI+) under
stoichiometric conditions with the expected isotopic distribu-
tion (see Supporting Information).
Based on the experimental results, a plausible reaction
mechanism shown in Scheme 6 is proposed. According to this
scheme, acylboronate 1 reacts with Cu(OAc)2 and Cs2CO3 to
generate intermediate I, which was observed by 11B NMR
spectrometry, and 2 equiv of CsOAc. Further transmetalation
affords acyl copper species II. The Pd(0) active catalyst is
generated from the base-mediated reductive elimination from
the Pd(II) precatalyst. Oxidative addition with aryl bromide
affords intermediate III. Subsequent transmetalation with II or
directly with I gives acyl palladium complex IV. Further
reductive elimination provides the desired ketone 3 and
regenerates the active catalyst.
reaction mechanism. No conversion of 1a was observed by 11
B
NMR spectrometry when the reaction was conducted with
only Cu(OAc)2, demonstrating that a base was necessary for
the reaction (entry 3). Cu(II) was also found to play a key role,
as no reaction was observed in the absence of Cu(OAc)2
(entry 4), with only Cs2CO3 (entry 5) or when KOAc was
used as the acetate source (entry 6). Since CsOAc is
potentially generated in situ, we conducted two control
reactions of 1a with only CsOAc (entry 7) and with CsOAc
and Cu(OAc)2 (entry 8) as additives. No reaction was
observed in either experiment. The presence of an acetate
anion was necessary for the formation of the species with the
signal at 0.47 ppm (entries 9−11).
The 11B NMR resonance in the area between 9 and −7 ppm
is typical of tetracoordinated boron compounds bearing −OR
groups.12 A tetracoordinated acylboron intermediate with the
11B NMR chemical shift of 2.32 ppm was recently observed by
Mankad and co-workers in the copper-catalyzed carbonylative
borylation of alkyl halides, as tricoordinated pinacol-acylboron
coordinated with 1 equiv of LiOtBu.4g Bode and co-workers
originally proposed that hydrolysis of MIDA acylboronate
leads to the highly reactive boron-ligated intermediate,8a which
undergoes either ligation with O-Me hydroxylamines or rapid
protodeboronation in the presence of water.9 Based on the
results of the control reactions, we propose that a ligand
exchange between the Cu(II) additive and a base promotes
complexation13 of an acetate anion to activate 1a. The
observed intermediate with the 11B NMR signal at 0.47 ppm
likely corresponds to the tetracoordinated boron species I,
where X is either the acetate anion and/or the MIDA ligand
with a decoordinated nitrogen atom.8d,14
In summary, we have developed a new Pd-catalyzed cross-
coupling reaction between aryl (pseudo)halides and MIDA
acylboronates that serve as acyl anion equivalents. The mild
reaction conditions were found to be compatible with various
aliphatic and aromatic acylboronates. 11B and 31P NMR
mechanistic studies, as well as mass spectrometry, revealed that
the tetracoordinated boron and acyl palladium(II) species are
possible reaction intermediates. Further exploration of boron-
based acyl anion equivalents in chemical synthesis as well as
studies aimed at defining broader utility for the ArC(O)B-
(OH)2 class of molecules are underway in our laboratory.
To assess whether or not I is the reactive intermediate in the
reaction, a substoichiometric amount of 1a was subjected to
the standard conditions (Scheme 4). The signal at 0.47 ppm
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preparation of potassium acyltrifluoroborates (KATs) from aryl- and
heteroarylhalides. Angew. Chem., Int. Ed. 2014, 53, 7604−7607.
(c) He, Z.; Trinchera, P.; Adachi, S.; St. Denis, J. D.; Yudin, A. K.
Oxidative geminal functionalization of organoboron compounds.
Angew. Chem., Int. Ed. 2012, 51, 11092−11096. (d) Taguchi, J.; Ikeda,
T.; Takahashi, R.; Sasaki, I.; Ogasawara, Y.; Dairi, T.; Kato, N.;
Yamamoto, Y.; Bode, J. W.; Ito, H. Synthesis of acylborons by
ozonolysis of alkenylboronates: preparation of an enantioenriched
amino acid acylboronate. Angew. Chem., Int. Ed. 2017, 56, 13847−
13851. (e) Lepage, M. L.; Lai, S.; Peressin, N.; Hadjerci, R.; Patrick,
B. O.; Perrin, D. M. Direct access to MIDA acylboronates through
mild oxidation of MIDA vinylboronates. Angew. Chem., Int. Ed. 2017,
56, 15257−15261. (f) Lin, S.; Wang, L.; Aminoleslami, N.; Lao, Y.;
Yagel, C.; Sharma, A. A modular and concise approach to MIDA
acylboronates via chemoselective oxidation of unsymmetrical geminal
diborylalkanes: unlocking access to a novel class of acylborons. Chem.
Sci. 2019, 10, 4684−4691. (g) Cheng, L.-J.; Zhao, S.; Mankad, N. P.
One-step synthesis of acylboron compounds via copper-catalyzed
carbonylative borylation of alkyl halides. Angew. Chem., Int. Ed. 2021,
60, 2094−2098. (h) Schuhmacher, A.; Ryan, S. J.; Bode, J. W.
Catalytic synthesis of potassium acyltrifluoroborates (KATs) from
boronic acids and the thioimidate KAT transfer reagent. Angew.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00742.
■
sı
Experimental details, characterization data for all new
compounds, optimization, and mechanistic studies
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Andrei K. Yudin − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
ON M5S 3H6, Canada; orcid.org/0000-0003-3170-
9103; Email: andrei.yudin@utoronto.ca
Authors
Alina Trofimova − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
ON M5S 3H6, Canada
Aleksandra Holownia − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
ON M5S 3H6, Canada
(5) (a) Hillman, M. E. D. The carbonylation of organoboranes. I.
The carbonylation of trialkylboranes. A novel synthesis of
trialkylcarbinols. J. Am. Chem. Soc. 1962, 84, 4715−4720. (b) Hillman,
M. E. D. The carbonylation of organoboranes. II. The carbonylation
of trialkylboranes in the presence of glycols. J. Am. Chem. Soc. 1963,
85, 982−984.
(6) Gillis, E. P.; Burke, M. D. Multistep synthesis of complex boronic
acids from simple MIDA boronates. J. Am. Chem. Soc. 2008, 130,
14084−14085.
Chieh-Hung Tien − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
ON M5S 3H6, Canada
̌
Martynas J. Sirvinskas − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
ON M5S 3H6, Canada
(7) Li, J.; Ballmer, S. G.; Gillis, E. P.; Fujii, S.; Schmidt, M. J.;
Palazzolo, A. M. E.; Lehmann, J. W.; Morehouse, G. F.; Burke, M. D.
Synthesis of many different types of organic small molecules using one
automated process. Science 2015, 347, 1221−1226.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00742
Author Contributions
(8) For papers on applications of acylboronates, see: (a) Noda, H.;
Bode, J. W. Synthesis and chemoselective ligations of MIDA
acylboronates with O-Me hydroxylamines. Chem. Sci. 2014, 5,
4328−4332. (b) Diaz, D. B.; Scully, C. C. G.; Liew, S. K.; Adachi,
S.; Trinchera, P.; St. Denis, J. D.; Yudin, A. K. Synthesis of
aminoboronic acid derivatives from amines and amphoteric boryl
carbonyl compounds. Angew. Chem., Int. Ed. 2016, 55, 12659−12663.
(c) Lee, C. F.; Holownia, A.; Bennett, J. M.; Elkins, J. M.; St. Denis, J.
D.; Adachi, S.; Yudin, A. K. Oxalyl boronates enable modular
synthesis of bioactive imidazoles. Angew. Chem., Int. Ed. 2017, 56,
6264−6267. (d) Lee, C. F.; Diaz, D. B.; Holownia, A.; Kaldas, S. J.;
Liew, S. K.; Garrett, G. E.; Dudding, T.; Yudin, A. K. Amine
hemilability enables boron to mechanistically resemble either hydride
or proton. Nat. Chem. 2018, 10, 1062−1070. (e) Tan, D.-H.; Cai, Y.-
H.; Zeng, Y.-F.; Lv, W.-X.; Yang, L.; Li, Q.; Wang, H. Diversity-
oriented synthesis of α-functionalized acylborons and borylated
heteroarenes by nucleophilic ring opening of α-chloroepoxyboronates.
Angew. Chem., Int. Ed. 2019, 58, 13784−13788. (f) Ivon, Y. M.;
Mazurenko, I. V.; Kuchkovska, Y. O.; Voitenko, Z. V.; Grygorenko, O.
O. Formyl MIDA boronate: C1 building block enables straightfor-
ward access to α-functionalized organoboron derivatives. Angew.
Chem., Int. Ed. 2020, 59, 18016−18022. (g) Deng, X.; Zhou, G.; Han,
X.; Ullah, K.; Srinivasan, R. Rapid access to diverse potassium
acyltrifluoroborates (KATs) through late-stage chemoselective cross-
coupling reactions. Org. Lett. 2021, 23, 1886−1890.
†A.T. and A.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank D. Burns, J. Sheng, and K. Z. Demmans from the
University of Toronto CSICOMP NMR facility for their
assistance with NMR spectroscopic experiments. We thank the
Natural Science and Engineering Research Council of Canada
(NSERC) for financial support. C.-H. T. would like to thank
the Connaught Fund (U of T) for funding.
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