Phenoxy-Dialkoxy Borates as a New Class of Readily Prepared Preactivated Reagents for Base-Free Cross-Coupling

Article abstract of DOI:10.1002/ejoc.201900993

One of the most useful chemical transformations of organoboronic acids is the Suzuki–Miyaura cross-coupling reaction. Although it has vast application, it possesses some limitations: boronic acids can be difficult to quantify accurately due to their tendency to form oligomeric anhydrides and they must be activated under basic conditions. To address these problems, a new class of boronic acid derivatives is described. Phenoxy-dialkoxy borates are prepared under mild conditions and show good solubility in common organic solvents. These adducts can be used in base-free metal-catalysed cross-coupling reactions, including orthogonal reactions with MIDA boronates and trifluoroborates.

Full text of DOI:10.1002/ejoc.201900993

DOI: 10.1002/ejoc.201900993
Communication
Base-Free Cross-Coupling
Phenoxy-Dialkoxy Borates as a New Class of Readily Prepared
Preactivated Reagents for Base-Free Cross-Coupling
Marco Paladino,[a] Michele Boghi,[a] and Dennis G. Hall*[a]
Abstract: One of the most useful chemical transformations of a new class of boronic acid derivatives is described. Phenoxy-
organoboronic acids is the Suzuki–Miyaura cross-coupling reac- dialkoxy borates are prepared under mild conditions and show
tion. Although it has vast application, it possesses some limita- good solubility in common organic solvents. These adducts can
tions: boronic acids can be difficult to quantify accurately due be used in base-free metal-catalysed cross-coupling reactions,
to their tendency to form oligomeric anhydrides and they must including orthogonal reactions with MIDA boronates and tri-
be activated under basic conditions. To address these problems, fluoroborates.
Introduction
Several types of organoboron compounds can be employed as
nucleophilic carbon-based reagents in transition metal-cata-
lyzed processes, such as the popular Suzuki–Miyaura cross-
coupling reaction.[1] Typically, the nucleophilic nature of the
carbon-boron bond is revealed upon in situ formation of a
tetrahedral boron species during the transition-metal-catalyzed
reaction. Although many variants of this activation strategy
have been exploited successfully, most notably with boronic
acids, it still possesses limitations: 1. Often the tetrahedral bor-
onate ion is a transient entity that is not isolated and requires
strongly basic conditions in order to form; 2. Some boronic
acids are sensitive to oxidation or protodeboronation, therefore
they require careful handling and storage; 3. Boronic acids tend
to exist as mixtures containing various proportions of de-
hydrated anhydrides, such as as the 6-membered boroxines,
which makes it challenging to determine their accurate
stoichiometry. To address these problems,
a number of
′masked′ boronic acids or preactivated adducts have been pro-
posed (Figure 1). For example, air- and bench-stable trifluoro-
borate salts M[RBF3] (M = K or NR4) are solids that are easy to
prepare, handle, and quantify.[2] On the other hand, they tend
to display low solubility in many common organic solvents.[3]
Use of aqueous base is still required for their activation and
coupling, and corrosive HF is released in the coupling process.
Likewise, MIDA boronates are a stable class of protected bor-
onic acid derivatives but they also require the use of a stoichio-
metric quantity of base as part of a slow-release mechanism.[4,5]
In 2006, Cammidge and co-workers reported the preparation
and characterization of discrete trihydroxy borate sodium salts
Figure 1. Organoboron compounds for Suzuki–Miyaura cross-coupling reac-
tion.
concept of direct base-free Suzuki–Miyaura cross-coupling.[6]
The absence of base is advantageous, however it is not known
whether trihydroxyborate salts are orthogonal with other boron
adducts such as trifluoroborate salts. Subsequently, Miyaura
and co-workers reported the preparation and characterization
of cyclic trialkoxyborates that can also be employed directly in
base-free Suzuki–Miyaura cross-couplings and other C–C bond-
forming reactions (Figure 1).[7,8]
–
(RB(OH)3 Na+) as isolable and stable reagents for use in the
Whereas the reaction conditions for the cross-coupling are
mild, the synthesis of the requisite trialkoxyborates from free
boronic acids requires high temperatures (refluxing toluene)
and a strong base (KOH), which is not ideal for thermosensitive
and highly functionalized boronic acids. Consequently, there is
[a] Department of Chemistry, 4-010 CCIS,University of Alberta,
Edmonton, Alberta, T6G 2G2, Canada
E-mail: dennis.hall@ualberta.ca
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900993.
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a need for new types of stable, preactivated adducts that can B–O, and 1.57 Å for C–B)[11a] and pinacol boronic esters (1.31 Å
be prepared with ease under mild reaction conditions, and that for B–O, and 1.57 Å for C–B).[11b] The tetrahedral nature of the
are easy to handle and soluble in most common organic sol- boron atom is clearly depicted in the ORTEP diagram: all of
vents. Herein, we report the design, facile synthesis, and cross- the C–B–O and O–B–O bond angles are relatively close to the
coupling of a new class of phenoxy-dialkoxy adducts (3) of or- expected value of 109 °. Quaternization of the boron center can
ganoboronic acids (1) and triol 2 (Figure 1). These adducts form also be inferred by NMR spectroscopy: 11B-NMR analysis reveals
under ambient conditions, at a significantly lower temperature a characteristic broad signal with upfield chemical shift, ca.
and with a weaker base compared to the conditions required δ = 7.5 ppm, typical of a negatively charged tetrahedral boron
for the preparation of trialkoxyborates.
species.
Results and Discussion
Triol 2 was selected because it possesses several key features
for the purpose of this application: 1. It embeds a hindered 1,2-
alkanediol group that demonstrates a high affinity for boronic
acids; 2. It includes a phenoxy moiety which, with a lower pKa
than a regular aliphatic alcohol, will allow a more facile deproto-
nation and concomitant quaternization of the boron atom;
3. The aromatic ring can help increase the solubility of the re-
sulting adducts in organic solvents. Triol 2 is easily synthesized
from phenol as shown in Scheme 1. To this end, ortho-hydroxy-
alkylation with EtO2CCHO (ethyl glyoxalate) furnishes interme-
diate 4, which is reacted with MeMgCl to give the desired triol
2.[9] The preparation of phenoxy-dialkoxy adducts is also
straightforward, and the conditions were optimized using phen-
ylboronic acid (Scheme 1). Thus, the boronic acid is condensed
with triol 2 at room temperature in acetone, followed by addi-
tion of potassium carbonate to yield the desired triolborate 3a
in high yield. The reaction is presumed to proceed through the
formation of a boronic ester intermediate (e.g. 5a), which is
then converted into the corresponding phenoxy-dialkoxy bor-
ate by deprotonation of the phenol, and concomitant cycliza-
tion with quaternization of the boron atom.
Figure 2. Preparation and X-ray crystal structure (ORTEP representation) of
tetrabutylammonium borate salt 6a.
To test the generality of the formation of phenoxy-dialkoxy
borates, a prototypical set of arylboronic acids 1a–1e with vari-
ous electronic and steric characteristics were condensed with
triol 2 at room temperature in acetone, followed by addition of
potassium carbonate to yield the desired triolborate salts 3a–e
in high yields (Scheme 2). Most of the adducts 3a–3e are sol-
ids[12] that can be recrystallized with ease from diethyl ether.
They are soluble in most organic solvents with the exception of
halogenated hydrocarbons (i.e. dichloromethane and chloro-
form).
Scheme 2. Preparation of a representative set of aryl phenoxy-dialkoxy borate
salts 3a–3e.
The application of phenoxy-dialkoxy boronates in base-free
Pd-catalyzed Suzuki–Miyaura cross-coupling was assessed using
as model substrates the phenyl borate salt 3a and p-iodoanisole
(7) (Table 1). The formation of the expected coupling product
8a was optimized by examining the effect of temperature and
solvent using Pd(OAc)2 as the pre-catalyst. From the results of
Table 1, it is apparent that the reaction does not proceed at
room temperature and requires gentle heating to 45 °C in order
to reach completion within 18 hours when using triphenylphos-
Scheme 1. Preparation of triol 2 and model phenoxy-dialkoxy potassium bor-
ate 3a.
The potassium borate 3a was interchanged into the corre- phine as the ligand. A variety of solvents are tolerated, making
sponding ammonium salt 6a, which was recrystallized to pro- this reaction suitable for both hydrophobic as well as more po-
vide crystals suitable for X-ray crystallographic analysis (Fig- lar substrates (entries 5–9). As expected, the presence of water
ure 2).[10] In 6a, the length of the B–O bonds is 1.40–1.53 Å and is crucial for a successful outcome.[7] Presumably, partial hydrol-
1.60 Å for the C–B bond. As expected from the loss of conjuga- ysis to a monohydroxyborate intermediate is required for an
tion with the boron atom, these distances are significantly efficient transmetallation step. Initially, PPh3 was used as the
longer than the values observed in boronic acids (1.36–1.37 Å for ligand and since it gave satisfying results, commercially avail-
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able Pd(PPh3)4 was selected as the catalyst for the substrate
scope study.
Table 2. Substrate scope study with aryl and alkenyl halides.[a]
Table 1. Optimization of the model cross-coupling reaction between phen-
oxy-dialkoxy borate 3a and 7.[a]
Entry
Ligand
T
Solvent
Yield[b]
1
2
3
–
–
–
r.t.
90 °C
90 °C
DMF
DMF
DMF/H2O
5:1
0 %
0 %
trace
4
5
6
7
8
9
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
r.t.
DMF/H2O
5:1
DMF/H2O
5:1
dioxane/H2O
5:1
PhMe/H2O
5:1
MeCN/H2O
5:1
THF/H2O
5:1
trace
89 %
80 %
85 %
79 %
81 %
45 °C
45 °C
45 °C
45 °C
45 °C
[a] Reaction conditions: 7 (0.1 mmol), 3a (0.12 mmol), Pd(OAc)2 (5 mol%),
ligand (11 mol%), solvent (0.10 ), time (18 h). [b] Isolated yields of 8a after
flash chromatography on silica gel.
M
With optimized cross-coupling conditions in hand, different
aryl and alkenyl halides were evaluated. Aryl halides with elec-
tron-withdrawing or electron-donating substituents both led to
a successful cross-coupling with the phenoxy-dialkoxyborate 3a
(Table 2). Notably, more congested ortho-substituted aryl hal-
ides (entry 2 and entry 5) afforded the expected biphenyl prod-
ucts in good yields. Cross-coupling with alkenyl halides and
pseudo-halides was also examined and the corresponding
products were isolated in good yields (entry 7 and 8).
[a] Reaction conditions: 3a (0.12 mmol) aryl–X or alkenyl-halide (0.10 mmol),
Pd(PPh3)4 (5 mol%), solvent DMF/H2O (5:1 v/v, 0.5 ). [b] Isolated yield after
flash chromatography on silica gel. [c] 18 h reaction time. [d] Monitored by
TLC.
M
The same procedure was tested in the cross-coupling of a
variety of aryl borates 3b–e with bromobenzene (Table 3). The
expected biphenyl products were isolated in good yields. Re-
markably, the more sterically hindered ortho-substituted aryl
borates (entry 2 and 3) successfully underwent the cross-cou-
pling reaction in very good yields.
Table 3. Cross-coupling reaction with different borate adducts 3b–e.[a]
One attractive attribute of this new class of adducts of bor-
onic acids is their potential chemical orthogonality with other
boron containing reagents.[13] With this view in mind, we
turned our attention to the para-bromoaryl MIDA boronate 9
and trifluoroborate salt 11, with the goal of evaluating their
chemoselectivity with the phenoxy-dialkoxy borates. To our sat-
isfaction, bifunctional substrates 9 and 11 underwent the cross-
coupling reaction with 3a uneventfully, affording the desired
biaryl boron adducts 10 and 12 in good yields (Scheme 3). The
slower hydrolysis rate of the MIDA boronate and the require-
ment of a base to activate the trifluoroborate moiety enables
chemoselective cross-coupling conditions where these groups
remain unreactive throughout these transformations.
[a] Reaction conditions: 3b–e (0.12 mmol.) bromobenzene (0.10 mmol),
Lastly, with the goal of expanding the application of these
new phenoxy-dialkoxy borates to other transition metal-cata-
Pd(PPh3)4 (5 mol%), solvent DMF/H2O (5:1 v/v, 0.5
after flash chromatography on silica gel.
M), 18 h. [b] Isolated yields
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Scheme 3. Examples of orthogonal cross-coupling with MIDA ate complex 9 and trifluoroborate 11.
Scheme 4. Example of rhodium-catalyzed 1,4-conjugate addition.[14]
porting Information for specific examples and characterization
data).
lyzed transformations, we tested the suitability of aryl borate
3a in a base-free rhodium catalyzed 1,4-conjugate addition.[14]
In the event, the reaction with trans-methylcinnamate (13) pro-
ceeded smoothly under mild conditions, affording the expected
biphenyl product 14 in good yield (Scheme 4).
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
Conclusions
This work was funded by the Natural Sciences and Engineering
In summary, we have developed a new class of phenoxy-dialk- Research Council (NSERC) of Canada (Discovery Grant to D. G.
oxy borate adducts that can be employed as coupling partners H.). We thank Dr. Michael J. Ferguson (X-ray Crystallography
in base-free Suzuki–Miyaura cross-coupling reactions. The ease Laboratory, University of Alberta) for X-ray crystallographic anal-
of preparation using a milder base at room temperature along ysis of compound 6a.
with their solubility in many of the commonly used organic
solvents makes these phenoxy-dialkoxy adducts an advanta-
Keywords: Boronates · Biaryls · Boronic acid · Cross-
geous alternative for base-sensitive substrates. Moreover, this
coupling · Orthogonality · Homogeneous catalysis
methodology enables chemoselective cross-coupling reactions
with other boron reagents such as MIDA esters and trifluorobor-
ate salts. Finally, it has also been demonstrated that such boron
complexes can be used for other base-free metal-catalyzed re-
actions, such as the rhodium-catalyzed 1,4-conjugate addition.
We are planning to further expand the scope and applications
of this new and complementary class of boron reagents.
[1] A. J. J. Lennox, G. C. Lloyd-Jones, Chem. Soc. Rev. 2014, 43, 412–443.
[2] a) G. A. Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275–286; b) A. J. J.
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Am. Chem. Soc. 2017, 139, 3805–3821; c) L. Chen, D. R. Sanchez, B. Zhang,
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Experimental Section
General synthesis of aryl triolborate 3a–3e. Triol 2 (364 mg,
1.00 equiv., 2.00 mmol) and the appropriate boronic acid 1a–1e
(1.10 equiv.) were dissolved in acetone (4 mL, 0.50 M). The reaction
mixture was stirred at room temperature for 8 h. Then solid K2CO3
(829 mg, 3.00 equiv., 6.00 mmol) was added in one portion. The
reaction mixture was stirred for a further 18 h at room temperature.
The suspension was then filtered through a small plug of Celite®
(ca. 50 mg) and rinsed with acetone. The filtrate was concentrated
under vacuum to afford the desired aryl triolborate salt (see Sup-
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[6] A. N. Cammidge, V. H. M. Goddard, H. Gopee, N. L. Harrison, D. L. Hughes,
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8, 4071–4074.
[7] Y. Yamamoto, M. Takizawa, X. Yu, N. Miyaura, Angew. Chem. Int. Ed. 2008,
47, 928–931; Angew. Chem. 2008, 120, 942.
[8] See also a) X. Yu, Y. Yamamoto, N. Miyaura, Chem. Asian J. 2008, 3, 1517–
1522; b) X. Yu, Y. Yamamoto, N. Miyaura, Synlett 2009, 994–998; c) S.
Sakashita, M. Takizawa, J. Sugai, H. Ito, Y. Yamamoto, Org. Lett. 2013, 17,
4308–4311.
[9] F. Bigi, G. Bocelli, R. Maggi, G. Sartori, J. Org. Chem. 1999, 64, 5004–5009.
[10] CCDC 1953036 (for 6a) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
[12] See Supporting Information for details.
[13] For other examples of boron reagents for orthogonal functionalization
through Suzuki-Miyaura cross-coupling: a) H. Noguchi, K. Hojo, M. Sugi-
nome, J. Am. Chem. Soc. 2007, 129, 758–759; b) See ref.[4a]; c) H. Noguchi,
T. Shioda, C.-M. Chou, M. Suginome, Org. Lett. 2008, 10, 377–380; d) E. P.
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g) N. Iwadate, M. Suginome, J. Organomet. Chem. 2009, 694, 1713–1717;
h) M. K. Reilly, S. D. Rychnovsky, Synlett 2011, 2392–2396.
[14] General procedure from: R. Itooka, Y. Iguchi, N. Miyaura, J. Org. Chem.
2003, 15, 6000–6004.
[11] a) S. J. Rettig, J. Trotter, Can. J. Chem. 1977, 55, 3071–3075; b) O. C. Ho,
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Received: July 11, 2019
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