Bedford-type palladacycle-catalyzed miyaura borylation of aryl halides with tetrahydroxydiboron in water

Article abstract of DOI:10.1021/acs.joc.7b02771

A mild aqueous protocol for palladium catalyzed Miyaura borylation of aryl iodides, aryl bromides and aryl chlorides with tetrahydroxydiboron (BBA) as a borylating agent is developed. The developed methodology requires low catalyst loading of Bedford-type palladacycle catalyst (0.05 mol %) and works best under mild reaction conditions at 40 °C in short time of 6 h in water. In addition, our studies show that for Miyaura borylation using BBA in aqueous condition, maintaining a neutral reaction pH is very important for reproducibility and higher yields of corresponding borylated products. Moreover, our protocol is applicable for a broad range of aryl halides, corresponding borylated products are obtained in excellent yields up to 93% with 29 examples demonstrating its broad utility and functional group tolerance.

Full text of DOI:10.1021/acs.joc.7b02771

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Article
Bedford-type palladacycle catalyzed Miyaura-borylation
of aryl halides with tetrahydroxydiboron in water
Anna Zernickel, Weiyuan Du, Seema Ghorpade, Dinesh Nanaji
Sawant, Arwa A. Makki, Nagaiyan Sekar, and Jörg Eppinger
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02771 • Publication Date (Web): 09 Jan 2018
Downloaded from http://pubs.acs.org on January 10, 2018
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Bedfordꢀtype palladacycle catalyzed Miyauraꢀborylation of aryl halides with
tetrahydroxydiboron in water
Anna Zernickel†, Weiyuan Du†, Seema A. Ghorpade†,‡, Dinesh N. Sawant†,§*
,
Arwa A. Makki†, Nagaiyan Sekar‡ and Jörg Eppinger †*
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†King Abdullah University of Science and Technology (KAUST), Division of Physical Sciences & Engineering,
KAUST Catalysis Center (KCC), Thuwal 23955ꢀ6900, Saudi Arabia.
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‡Department of Dyestuff Technology, Institute of Chemical Technology (Deemed University), N. Parekh Marg,
Matunga, Mumbaiꢀ400019, Maharashtra, India
§Current address (D.N.S): LeibnizꢀInstitut für Katalyse e.V. an der Universität Rostock, AlbertꢀEinsteinꢀStraße
29a, 18059 Rostock, Germany
Eꢀmail: jorg.eppinger@kaust.edu.sa (J. E.); dinesh.sawant@catalysis.de (D.N. S), dinesh1.sawant@gmail.com
Abstract:
A mild aqueous protocol for palladium catalyzed Miyaura borylation of aryl iodides, aryl
bromides and aryl chlorides with tetrahydroxydiboron (BBA) as a borylating agent is
developed. The developed methodology requires low catalyst loading of Bedfordꢀtype
palladacycle catalyst (0.05 mol %) and works best under mild reaction conditions at 40 °C in
short time of 6 hours in water. In addition, our studies show that for Miyaura borylation using
BBA in aqueous condition, maintaining a neutral reaction pH is very important for
reproducibility and higher yields of corresponding borylated products. Moreover, our protocol
is applicable for a broad range of aryl halides, corresponding borylated products are obtained
in excellent yields up to 93% with 29 examples demonstrating its broad utility and functional
group tolerance.
Keywords: Miyauraꢀborylation, Palladacycle, Tetrahydroxydiboron, Arylboronic acids
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Introduction
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Arylboronic acids provide a unique combination of stability, mild Lewis acidity, low
toxicity and distinct reactivity profile, therefore a tremendous interest in synthesis and
applications of arylboronic acids, and their corresponding intermediates exists.1 Notably
arylboronic acids and their corresponding esters and trifluoroborates are widely explored as a
substrate for numerous organic transformations. In last decade arylboronic acids are well
explored for various crossꢀcoupling reactions, such as SuzukiꢀMiyaura coupling, the Hosomiꢀ
Sakurai allylation2 and the oxidative ChanꢀLam coupling.3 Moreover, other applications
includes 1,4ꢀadditions4 and 1,2ꢀadditions5 of boronic acids to Michael acceptors and
aldehydes, e.g. the Petasis boronoꢀMannich reaction6. Particularly in bioorganic and
medicinal chemistry, arylboronic acids serve as valuable tool for a broad range of applications
including sensors molecules,7 enzyme inhibitors or in vivo alteration of cellular functions.8
Recently many catalytic protocols for amide or peptide synthesis have been reported using
various arylboronic acid derivatives as catalysts.9 Therefore due to their wide applications in
synthetic chemistry, as well as in biology, there are numerous methods reported for the
synthesis of arylboronic acids (Scheme 1).
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Scheme 1. Metal based borylation protocols
Traditionally arylboronic acids were prepared by a metalꢀhalogen exchange approach using
stoichiometric amount of organolithium10 or Grignardꢀreagents11, but offers only limited
tolerance to functional groups and also generates stoichiometric amount of toxic waste
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(Scheme 1, A). To address these issues several research groups, including those of Smith,12
Hartwig,13 Miyaura14 and Marder15 have recently reported efficient catalytic borylation
protocols by CꢀH activation of aromatic compounds using iridium or rhodium catalysts, but
regioselectivity is determined by steric and electronic factors, which represents a major
drawback (Scheme 1, B). Currently, transitionꢀmetalꢀcatalyzed Miyaura borylation of aryl
halides therefore provide the most versatile access to arylboronic acids,16 as it combines high
functional group tolerance and selectivity. Yet, most of these reported catalytic borylation
methods typically require the use of expensive pinacolatoꢀboron precursors. In addition,
reaction of pinacolatoꢀboron with aryl halide gives arylboronic ester as a product instead of
arylboronic acid, necessitating an additional deprotection step which ultimately generates
additional stoichiometric amount of waste (Scheme 1, C). In this regard Molander et al.
reported a palladiumꢀcatalyzed borylation protocol, which employed economical and greener
bisꢀboronic acid (BBA) also known as tetrahydroxydiboron as a boron source in ethanol as a
solvent. The resulting diethyl boronic esters converted in situ into the more stable
trifluoroborates or even directly applied in crossꢀcoupling reactions (Scheme 1, D).17 This
represents a major step towards more atom economic and sustainable synthesis of organoꢀ
boronic acids. Thereafter many other transition metals based catalytic protocols were
reported for borylation of aryl halides.18 Recently nice progress has been made in
photoinduced borylation18b,19, as well as organoꢀcatalytic borylation18b,20 protocols. However
overall most of the reported borylation protocols requires use of toxic and environmental
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o
hazardous organic solvents, high catalyst loading, higher temperature (reflux or >80 C) and
longer reaction time, which limits its wide applications. Nevertheless, it would be more
economically and industrially appealing to develop a water based, greener borylation protocol
for direct synthesis of aryl boronic acids using tetrahydroxydiboron (BBA) with lowest
possible catalyst loading, in shorter time, under mild reaction conditions.21 Particularly
compared to toxic organic solvents, water is safe to handle, greener, economically and
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environmentally friendly solvent. Therefore, in the last decade there is growing interest for
water based crossꢀcoupling reactions and many water based catalytic protocols have been
reported particularly with major contributions by Beller,22 Plenio,23 Shaughnessy,24
Leadbeater25 and Lipshutz.26 However the water based protocol under mild reaction
conditions for a Miyauraꢀborylation is rarely explored. In this regard, we believe that
Bedfordꢀtype catalysts has good potential for developing aqueous protocols with low catalyst
loading.27 Recently, we reported a new Bedfordꢀtype palladacycle as effective catalyst for
aqueous Sonogashira and Suzuki crossꢀcoupling reactions.28a, 28b Therefore in continuation
with our interest for development of aqueous catalytic protocols,28 herein we report
application of our developed Bedfordꢀtype palladacycle catalyst (Table 1, Cat. A) for
Miyauraꢀborylation of aryl halides with tetrahydroxydiboron (BBA) in water, notably
reactions proceed under mild reaction conditions, in short time with lowest catalyst loading
(0.05 mol %) (Scheme 1, E).
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Result and Discussion
We started our initial optimization study with borylation of 4ꢀiodophenol (1a) with
tetrahydroxydiboron (2) in presence of 0.2 mol % of Bedfordꢀtype palladacycle catalyst (Cat.
A) and sodium acetate as base in water at 40 °C (Scheme 2) under argon atmosphere. To our
surprise almost 83% yield of borylated product 3a was obtained in 6 hours (Table 1, entry 1).
Scheme 2. Test experiment for borylation using Bedfordꢀtype palladacycle Catalyst A
It should be noted that the direct quantification of borylated product (4ꢀ
hydroxyphenyl)boronic acid (Scheme 2, 3a*) from aqueous phase is difficult and suffers from
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low reproducibility. Therefore, the product 3a* was subsequently converted into the
respective pinacol ester 4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenol (Scheme 2, 3a)
and then GC yield of 3a was measured. This conversion of 3a* into 3a tremendously reduced
the fluctuations of GC yields therefore same procedure is followed throughout our studies.
Next test reaction was performed in air atmosphere and result in a significant drop in yields of
3a to around 20 % (Table 1, entry 2). Therefore, for next studies all the reactions were
performed under argon atmosphere and with degassed water. Subsequently effect of addition
pattern and preꢀstirring were checked and it’s noteworthy to mention that there is no effect of
addition pattern or preꢀstirring observed. Near quantitative yields of borylated product 3a
were obtained in all cases up to 83% yield. Encouraged by our initial test experiments, we
investigated the influence of catalyst loading of Catalyst A on borylation (Table 1, entries 1ꢀ5)
and it was observed that 0.05 mol % of Catalyst A is sufficient to get 96% yield of 3a (Table
1, entry 4).
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Table 1. Catalyst screening for borylationa
entry
1
2
catalyst (mol %)
Cat. A (0.20)
Cat. A (0.20)
yield (%)b
83, (5)c
20d
3
Cat. A (0.10)
99, (1)c
4
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6
Cat. A (0.05)
Cat. A (0.01)
Cat. B (0.10)
96
67
0
7
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Na2PdCl4 (0.10)
K2PdCl4 (0.10)
Pd(NO3)2 (0.10)
Pd(OAc)2 (0.10)
PdCl2 (0.10) / L1 (0.10)
0
0
0
0
0
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PdCl2 (0.10) / L2 (0.10)
PdCl2 (0.10) / L3 (0.10)
Pd(OAc)2 (0.10) /XPhos (0.30)
0
0
0
aReaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), Pdꢀcatalyst, NaOAc (1.5 mmol), degassed
b
c
water (5 mL), 40 °C, 6 h under argon atmosphere. GC yield of 3a. Dehalogenated product
(phenol). dUnder air atmosphere.
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Next to select the best catalyst for borylation, we screened various other palladium catalysts
(Table 1, entries 6ꢀ14), including Davis’ catalyst B8h and surprisingly, only catalyst A found
to be the best catalyst under aqueous conditions.
Thereafter we studied the effect of base because it is a known fact that for organic solvent
based borylation protocols, the nature of the added base strongly influences yields of the
corresponding borylated products (3).16a Therefore, we investigated the influence of base type,
concentration and structure of bases on the yield of borylated product 3a in the aqueous
medium (Table 2). We checked the effect of base stoichiometry using sodium acetate
(NaOAc) as base (Table 2, entries 1 to 6). Notably in the absence of base only trace amount of
product 3a was observed, while further addition of excess of BBA without any base improved
the yield up to 60% but requires longer time 48 hours (Table 2 entry 1). However, it was
observed that 3 equivalence of sodium acetate is sufficient for achieving higher yield of 3a up
to 99% in 6 hours confirms the importance of base for borylation in water (Table 2, entry 4).
Interestingly the addition of 2 to 4 equivalence of sodium acetate results in near quantitative
yields of 3a (Table 2, entries 3ꢀ5), while further decrease or increase in base concentrations
only lead to incomplete conversions (Table 2, entries 2 and 6). After knowing the strong
influence of base concentration on borylation secondly, to investigate the effect of structure of
bases we screened various bases such as carbonates, hydroxides, phosphate, amine, borax etc
(Table 2, entries 7 to 20). From overall base screening, we conclude that the nature of base as
well as concentration of the base mainly influences the reaction pH and the reaction pH
mainly determines the yield of boryaltion product 3a (Table 2). From the overall base study, it
was observed that high yields of product 3a were mainly achieved for reactions performed in
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a narrow pH window of 6.7 to 7.7 except few exceptions (Table 2). Interestingly, in a pH
study we observed that addition of the Lewis acid ScCl3 generated high yields of 3a even at
an acidic pH of 5.3 (table 2, entry 8). However, with addition of Zn(OAc)2 alone, without any
base, the pH of reaction becomes 5.6 but did not result in a detectable 3a formation (table 2,
entry 9). Therefore, we further investigated the influence of different additives on the yield of
3a (Table 3). For more details on effect of base and pH please see the supporting information.
Table 2. Influence of base and pH on borylation yieldsa
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entry
1
2
3
4
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8
base (mmol)
No base
NaOAc (0.5)
NaOAc (1)
NaOAc (1.5)
NaOAc (2)
NaOAc (2.5)
KOAc (1.5)
pHb
5.9
6.1
6.2
6.7
6.8
6.9
6.8
5.3
5.6
6.7
7.6
8.4
4.4
8.0
9.2
9.1
9.4
9.4
9.6
9.0
yield (%)c
4, 14d, 60e
42, (2)f
97, (3)f
99
99, (1)f
45, (2)f
47, (1)f
90
NaOAc (1.5) /ScCl3 (1.5)
Zn(OAc)2 (1.5)
NaHCOO (1.5)
9
0
99
99
12
63
49
0
0
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20
.
Na2B4O7.10H2O (0.5)
Na2B4O7 10H2O (1.5)
NaH2PO4 (1.5)
Na2HPO4 (1.5)
Na3PO4 (1.5)
Na2CO3 (1.5)
Cs2CO3 (1.5)
NaOH (1.5)
0, (2)f
0, (1)f
0
NEt3 (1.5)
KOtBu (1.5)
0
aReaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), base, Catalyst A (0.0.5 mol %), water (5
mL), 40 °C, 6 h under argon atmosphere. Initial pH of the reaction measured after 10 min at
b
c
40 °C in a separate vessel, which was prepared with the exception of catalyst addition. GC
d
yield of 3a. 2nd addition of 1.5 mmol of BBA after 24 h; total reaction time 48 h. e2nd and 3rd
f
addition of 1.5 mmol BBA after 24 h and 36 h; total reaction time 48 h. Dehalogenated
product (phenol).
The effect alkali halides as additives (1.5 eq.), along with base sodium acetate (1.5
eq.) were checked, which leads to moderately improved yields of 3a (Table 3, entries 2ꢀ8)
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compare with 1.5 equivalence of sodium acetate alone (Table 3, entry 1). Various phase
transfer catalysts were checked along with sodium acetate (1.5 eq.) (Table 3, entries 9ꢀ11). It
was observed that the addition of phase transfer agents like PEGꢀ2000, αꢀcyclodextrin or
cetyltrimethylammonium chloride (CTMA) has actually a negative effect on borylation of 1a
and results in lower yield of 3a (Table 3, entries 9ꢀ11). Therefore, based on our optimization
studies about effect of base, influence of reaction pH (Table 2) and effect of additives (Table
3) on borylation of 1a, best results were obtained with the use of 3 equivalence of sodium
acetate (pH 6.7) without using any additives (Table 2, entry 4)
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Table 3. Influence of additivesa
entry
1
2
3
4
5
6
7
8
additive (mmol)
ꢀꢀꢀꢀ
KCl (0.75)
NaCl (0.75)
NaBr (0.75)
KBr (0.75)
LiBr (0.75)
NaI (0.75)
NaF (0.75)
yield (%)b
50
53, (1)c
68, (2)c
64, (1)c
82, (1)c
80, (2)c
80, (1)c
57, (5)c
33
9
10
11
PEGꢀ2000 (0.05)
αꢀcyclodextrine (0.05)
CTMA (0.05)
34
47
aReaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), NaOAc (0.75 mmol), additives, catalyst A
b
(0.05 mol %), water (5 mL), 40 °C, 6 h under argon atmosphere. GC yield of 3a.
cDehalogenated product (phenol).
Next, we checked the effect of different organic solvents with or without water as coꢀ
solvent (Table 4, column A and column B). Firstly, it was observed that the addition of
organic coꢀsolvent in 1:1 ratio with water, reduces the yield of 3a dramatically in most cases
(Table 4, entry 1 compare with entries 2ꢀ9 for column A). Among the eight organic solvents
tested as coꢀsolvent with water notably only methanol, THF and dichloromethane (biphasic)
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gave good yield of 3a, however, at the expense of noticeable formation of the dehalogenated
phenol as side product (Table 4, column A entries 2, 4 and 5). Secondly it was noticed that in
pure solvents catalyst A shows only very low (Table 4, column B entry 3) or no catalytic
activity (Table 4, column B entries 4ꢀ9) except for water and methanol which gives 99% yield
of 3a. A reduced solubility of the base and BBA in organic solvents may be partially
responsible for the observed loss in activity for borylation in pure solvents. Moreover, water
is nontoxic, economical and greener solvent, therefore it is selected as solvent of choice over
methanol for our next studies on borylation of aryl halides (Table 4, entry 1, coloumn B). Our
study on solvent screening confirms a crucial role of water in promoting the borylation
reaction (Table 4). In addition, effect of water volume was also checked and 5 mL of water
found to be sufficient for achieving higher yields of 3a, while in time study reaction already
completes with in 6 hours.
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Table 4. Influence of solventsa
entry
solvent
[A] solvent + water (1:1)
[B] only Solvent
yield (%)b
ꢀ
yield (%)b
1
2
3
4
5
6
7
8
9
Water
MeOH
EtOH
THF
DCM
ACN
DMSO
Acetone
EtOAc
99
99
18
6
91, (9)c
52, (18)c
87, (13)c
86, (14)c
63, (7)c
31, (1)c
15
0
0, (3)c
0
0
0
0
aReaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), NaOAc (1.5 mmol), catalyst A (0.05 mol
%), solvent (5 mL) or 1:1 solvent and water (2.5 + 2.5 mL), 40 °C, 6 h under argon
atmosphere. bGC yield of 3a. cDehalogenated product (phenol).
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From overall optimization study our final optimized conditions for achieving highest yield for
Miyaura borylation under mild reaction conditions are aryl halide (1, 0.5 mmol),
tetrahydroxydiboron (2, 1.5 mmol), catalyst A (0.05 mol %), sodium acetate (1.5 mmol) under
inert atmosphere and reaction at 40 °C for 6 h.
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After this optimization it is important to eliminate any possibility of inꢀsitu formed
nanoꢀpalladium particles catalyzing the Miyaura borylation. Because the BBA driven
Miyuara borylation occurs under reaction conditions, which are moderately reducing and
hence may prone for the formation of Pd nanoparticles. However, we did not observed
emergence of colour during borylation, which typically is indicative for metallic
nanoparticles. Morever, to answer the question, if in situ formed palladium nanoparticles are
the catalytically active species or Bedfordꢀtype palladacycle catalyst A, a mercury drop test
was performed. A mercury drop test is widely used to test exclude possibility of catalysis by
nanoparticles because amalgamation with mercury should only deactivate heterogeneous
metal particle catalyst, yet is not expected to occur for a ligated homogenous Pd(II) species.29
Interestingly in our test experiment despite the addition of 400 eq. of mercury to the catalytic
reaction 99% yields of 3a was obtained (Scheme 3). Therefore, the possibility of a
nanopartical promoted borylation is ruled out and our test experiment (Scheme 3) confirms
that palladacycle catalyst A is the actual catalyst for the Miyuara borylation reaction under
our optimized reaction conditions.
Scheme 3. A mercury drop test to confirm role of Pdꢀcatalyst
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Finally, under optimized reaction conditions the substrate scope of our Miyuara borylation
protocol to aryl halide substrates is explored to check its wide applicability (Table 5ꢀ7).
Firstly, we started our study with borylation of aryl iodides 1a to 1n (Table 5) and effect of
various functional groups was checked (Table 5, entries 3aꢀ3h). Interestingly various para
substituted functionalities on iodobenzene such as hydroxy (1a), methoxy (1b), methyl (1c),
aldehyde (1d), acid (1e), ester (1f), acetyl (1g), chloro (1h) and cyano (1l) group are well
tolerated and borylated products 3a to 3h and 3l obtained in good to excellent yield up to
93%. It was observed that aryl iodides with electron donating groups or waterꢀsolubilizing
groups are converted smoothly to borylated product 3 with higher yields. However, aryl
iodides with electronꢀwithdrawing groups tend to generate low yields of corresponding
borylated product 3. Next various ortho and meta substituted iodobenzene 1i to 1m were
screened and product 3i to 3l were obtained in good to moderate yields. However, for
iodobenzene derivative 1j and 1m only 21% and 16% yield respectively of product 3j and 3m
was obtained, which was improved further up to moderate 63% and 52% yield by extending
reaction time up to 24 hours. Moreover, borylation of unsubstituted iodobenzene 1n give 60%
yield of product 3n under optimized reaction condition. It was observed that with the
exception of a 2ꢀhydroxy substituent, the steric hindrance, which is introduced by orthoꢀ
substitutents, strongly reduces the reactivity of the aryl idodides for borylation. In addition,
lower yields in some exceptional cases can attribute to the lower substrate solubility of
corresponding aryl iodides in water. We also tried to explore the substrate scope for
heteroaromatic iodides and electronic withdrawing aryl iodides with substituents such as CF3
and NO2 groups but because of very low solubility of these derivatives in water no product
formation was observed (See SI, Table S2).
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During substrate scope study for aryl iodides it was observed that electron rich aryl iodides
gave more than 90% yield of borylated product 3. Therefore, with the aim to develop mildest
conditions, we repeated borylation reactions of 1a, 1b and 1h at only 20 °C, interestingly still
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more than 90% yields of 3a, 3b and 3h was obtained within 6 hours (Table 5, entries for 3a,
3b and 3j). It should be noted that in 2006, Van Aken et al.30 introduced the Ecoꢀscale as a
metrics to evaluate green organic synthesis protocols. A respective analysis establishes an
Ecoꢀscale value of 88.5 points for the borylation of 4ꢀiodophenol (1a), 4ꢀiodoanisol (1b) and
2ꢀiodophenol (1h) by our protocol (See SI, Table S1), which comes already close to the score
of 100 points for an ‘‘ideal’’ reaction. This study confirms the added advantage of our
protocol.
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Table 5. Substrate scope study for borylation of aryl iodidesa
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
aReaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), NaOAc (1.5 mmol), catalyst A (0.05 mol
b
%), water (5 mL), 40 °C, 6 h under argon atmosphere. All yields mentioned in brackets are
c
d
isolated yields of product 3. Reaction carried out at room temperature. Corresponding
arylboronic acid 3* are the actual products in all cases only for analysis purpose they are
converted to pinacol ester 3. eReaction time 24 h.
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Secondly, we extended applicability of Bedfordꢀtype palladacycle catalyzed protocol for aryl
bromides (Table 6). It was observed that hydroxy (4a and 4i), cyano (4l) and methoxy (4o)
substituted aryl bromides gave higher yields of corresponding borylated product 3a, 3i, 3l and
3o. However, in case of acetyl substituted phenyl bromide 4g moderate yield of 3g was
obtained, while for 2,4ꢀdimethyl substituted phenyl bromide 4p lowest yield of product 3p
was obtained. Furthermore, by extending the reaction time to 24 hours for aryl bromides 4c,
4n and 4q good yields of product 3c, 3n and 3q up to 90%.
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Table 6. Substrate scope study for borylation of aryl bromidesa
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
aReaction conditions: 4 (0.5 mmol), 2 (1.5 mmol), NaOAc (1.5 mmol), catalyst A (0.05 mol
b
%), water (5 mL), 40 °C, 6 h. All yields mentioned in brackets are isolated yields of product
c
3. Corresponding arylboronic acid 3* are actual products in all cases only for analysis
converted to pinacol ester 3. dReaction time 24 h.
Finally, aryl chlorides (5), which are known to be economically, but difficult substrates for
catalytic reactions were tested for borylation (Table 7). As expected borylation of aryl
chloride required longer reaction times and excess use of BBA. However, it should be noted
that with our protocol the borylation of aryl chlorides could be performed under very mild
o
reaction conditions, notably with low catalyst loading of catalyst A 0.05 mol % at 40 C in
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water. Interestingly aryl chlorides such as 5a, 5b, 5e, 5f, were smoothly converted into the
corresponding borylated product 3a, 3b, 3e and 3f. However, because of excess use of BBA
and longer reaction time diborylation of 4ꢀchloro iodobenzene (5r) and 2ꢀchloro iodobenzene
(5s) to product 3r and 3s was observed. From overall substrate scope study, it was observed
that our Bedfordꢀtype palladacycle catalyzed borylation protocol has wide applications under
mild reaction conditions.
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Table 7. Substrate scope study for borylation of aryl chlorides.a
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
aReaction conditions: 5 (0.5 mmol), 2 (1.5 mmol), NaOAc (1.5 mmol), catalyst A (0.05 mol
%), water (5 mL), 40 °C, 6 h, under argon atmosphere. bAll yields mentioned in bracket are
c
isolated yields of product 3. Corresponding arylboronic acid 3* are actual products in all
cases only for analysis converted to pinacol ester 3. d2nd and 3rd addition of 3 eq. BBA after 12
and 36 h, total reaction time 72 h.
Mechanism
The precatalyst Cat. A is dimer (A) and as soon as water is added to the reaction flask
containing Cat. A, the dimer A breaks down and convert to Pd (II) intermediate (B). The
bulky isopropyl substituents on the phosphorous center are electron rich and well shielded
against cleavage by nucleophilic attack therefore a wellꢀbalanced steric bulk stabilizes the
palladacyclic motive. Based on our previous mechanistic study on Suzuki coupling we believe
that in situ an undercoordinated, palladacyclic anionic Pd(0) species (C) forms which might
be the active catalytic species. In next step, oxidative addition of arly halide (1) occurs to the
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palladium intermediated C which results in the formation of intermediate D. In next step the
halide group is replaced by acetate and forming intermediate E. Thereafter the transmetalation
occurs forming an intermediated F which undergo the reductive elimination and result in
formation of product arylboronic acid (2) and regenerate the catalytically active intermediate
C which continues the cataltytic cycle.
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Ph
O
O
P
P
H2O
(II) Pd Cl
Pd Cl
OH2
2
B
A (cat. A)
B(OH)2
X
Ph
O
P
Pd (0)
2
1
reductive
elimination
oxidative
addition
C
Ph
O
P
Ph
O
(II)
P
Pd
X
(II)
Pd B(OH)2
E
D
Na OAc
transmetalation
Ph
O
P
O
(II)
Na X
Pd OAc
OH
OH
O
B
HO
OH
OH
B
B
HO
D
Conclusion
We have developed a new Bedfordꢀtype palladacycle catalyzed mild aqueous protocol for
the Miyauraꢀborylation using a waterꢀsoluble boron source tetrahydroxydiboron (BBA). The
developed methodology requires low catalyst loading of (0.05 mol%) and works best under
mild reaction conditions at maximum 40 °C or even at room temperature in short time of
6 hours in water. Our results reveal that good to excellent yields of aryl boronic acids can be
achieved in water, therefore eliminating the need of toxic organic solvents for borylation. In
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addition, our studies show that maintaining a neutral reaction pH is very important for
reproducibility and higher yields of corresponding products. We believe that our reported
studies on the effect of pH, will be very helpful for developing new aqueous borylation
protocols. Nevertheless, our protocol is applicable for a broad range of aryl halides and
corresponding borylated produts were obtained in excellent yields up to 94% with 29 such
examples demonstrating its broad utility and functional group tolerance.
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Experimental section
General Information: NMR spectra were recorded on BrukerBioSpin 400, 500, 600 or 700
MHz spectrometer at 297 K. Chemical shifts in ppm are referenced to the residual signal of
the solvent (CDCl3, δH = 7.26 and δ
C = 77.16 ppm).33a Coupling constants J are given in Hz
and signal multiplicities are abbreviated as: s (singlet), d (doublet), t (triplet), vt (virtual
triplet), q (quartet), m (multiplet) and br (broad). As already known in literature in 13C the
carbon next to the boron tend to be broadened beyond the limits of detection due to the
quadrupolar relaxation of 11B.1 MS: High resolution (HRꢀMS) was measured by the CORE
LABS of King Abdullah University of Science and Technology at a LTQ Orbitrap from
Thermo Scientific. Low resolution (LCꢀMS or MS by direct injection) spectra were recorded
on a TSQ Vantage MS from Thermo Scientific. For the combination of gas chromatography
with mass spectroscopic detection (GCꢀMS), a GC from Agilent 7890 A with an Agilent
5975C instrument for MS detection (inert XL EI/CI MSD with TripleꢀAxis Detector, EI,
70 eV) was used. GC/MS Method (80ꢀ280 °C DBꢀ5MS): Initial 80 °C, 3 min; Ramp
25 °C/min, 280 °C, 6 min; total 17 min. Thin layer chromatography was performed using
SiO2 preꢀcoated glass plates (Merck 60, Fꢀ254). The chromatograms were examined under
UV light at 254 nm and 365 nm and by staining of the TLC plate with a 0.1 mM solution of
10ꢀhydroxybenzo[h]quinolone (HBQ) in ethanol, followed by heating with a heat gun.33b If
not stated otherwise, reactions were run under argon atmosphere in Carousel 12 PlusTM
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Reaction Stations from Radleys, which allow simultaneously stirring and heating of up to 12
reactions. HPLCꢀgrade water was used as the solvent and degassed by prior to use by three
freezꢀpumpꢀthaw cycles. All reagents were obtained from commercial sources and used
without further purification unless stated otherwise. Column chromatography was performed
using silica gel 60 (0.040ꢀ0.063 mm) from Merck, but much like other carboxylic acids the
boronic acid interact strongly with slica gel.25 Thus prolonged exposure to silica has to be
avoided. Solvents were used in HPLC grade.
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Synthesis of the palladacycle catalyst A[27a]
Step 1. ([1,1'ꢀBiphenyl]ꢀ2ꢀyloxy)diisopropylphosphine (Ligand A)27a
In a Schlenk tube 2ꢀphenylphenol (1.70 g, 10.0 mmol, 1.0 eq.) was dissolved in 50 mL of
dry toluene and triethylamine (1.51 g, 14.9 mmol, 1.5 eq.) was added. After stirring the
solution for 15 min at r.t. chlorodiisopropylphosphine (1.51 g, 9.9 mmol, 0.95 eq.) was added.
The reaction mixture was refluxed for 16 h. After cooling to r.t. pentane (50 mL) was added.
A white solid precipitated, which was removed by filtration through a pad of Celite® and
washed with pentane (3 × 10 mL). The combined organic fractions were evaporated to
dryness in vacuoyielding the phosphiniteligand (2.63 g, 92%), which was used without further
purification.
Step II. Synthesis of [{Pd(ꢁꢀCl){κ2ꢀP,CꢀP(iPr)2(OC6H3ꢀ2ꢀPh)}}2] (Catalyst A) 27a
In a Schlenk tube ([1,1'ꢀBiphenyl]ꢀ2ꢀyloxy)diisopropylphosphine (2.63 g, 9.9 mmol, 1.0
eq.) and PdCl2 (1.75 g, 9.9 mmol, 1.0 eq.) were dissolved in dry toluene (50 mL). The
reaction mixture was refluxed for 19 h. After cooling to r.t. the solvent was removed in vacuo.
The residue was extracted with DCM (20 mL) and filtered through a pad of Celite®. The
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product was precipitated from the organic solution by addition of ethanol, collected by
filtration and recrystallized from DCM/EtOH.
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General procedure for the Bedfordꢀtype palladacycle catalyzed Miyauraꢀborylation of
aryl halides with tetrahydroxydiboron in water and identification by Pinacolꢀ
esterification:
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214 µL of a 1.16 mM stock solution of palladacycle 1[16a] in DCM are added to the reaction
tube followed by evacuation of the flask for 5 min to evaporate the solvent. NaOAc (123 mg,
1.5 mmol, 3 eq.), tetrahydroxydiboron (134 mg, 1.5 mmol, 3 eq.) and aryl halide (0.5 mmol)
are added before the flask atmosphere is changed to argon gas. 5 mL of degassed water are
added and the reaction mixture is stirred vigorously (1500 rpm) at 40 °C for 6 h.
Subsequently, 2 mL of 3
M HCl are added to quench the reaction. The acidic aqueous phase is
extracted with EtOAc (3x 5 mL) and dried over MgSO4. Addition of Pinacol (600 mg) to the
organic phase and stirring at 40 °C for 1 h yields the boronic acid pinacolatoꢀester, which was
purified by column chromatography on silica gel (pet ether/ethyl acetate combination) to
1
afford the pure product.. Final Products are confirmed by GCMS, H and 13C NMR
spectroscopic analysis.
1
([1,1'ꢀBiphenyl]ꢀ2ꢀyloxy)diisopropylphosphine (Ligand A)27a Yield: 92% (2.63 g). HꢀNMR
(500 MHz, CDCl3) δ 7.61ꢀ7.58 (m, 2H), 7.51ꢀ7.43 (m, 3H),7.39ꢀ7.32 (m, 3H), 7.10 (m, 1H, t,
J(H,H)= 7.5 Hz), 1.86 (dvt, 2H, J(P,H)= 2.9 Hz, J(H,H)= 9.1 Hz), 0.06 (dd, 6H, J(P,H)= 11.4
Hz, J(H,H)= 7.0 Hz); 13CꢀNMR (126 MHz, CDCl3) δ 156.2, 138.9, 132.6, 130.8, 130.0,
128.6, 127.8, 126.9, 121.7, 118.2, 28.3, 17.7, 17; 31PꢀNMR (600 MHz, CDCl3) δ 150.8.
27a
1
[{Pd(ꢁꢀCl){κ2ꢀP,CꢀP(iPr)2(OC6H3ꢀ2ꢀPh)}}2] (Catalyst A)
Yield: 43% (1.9 g) HꢀNMR
(500 MHz, CDCl3) δ 7.55 (m, 1H), 7.49ꢀ7.47 (m, 2H), 7.39ꢀ7.36 (m, 2H), 7.30ꢀ7.28 (m, 1H),
7.08ꢀ7.07 (m, 1H), 6.88ꢀ6.86 (m, 1H), 2.45ꢀ2.42 (m, 2H), 1.31ꢀ1.26 (m, 12H); 13CꢀNMR (126
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MHz, CDCl3) δ 161.8, 139.2, 136.3, 136.1, 129.1, 128.3, 128.1, 126.9, 126.8, 122.7, 122.5,
29.7, 17.8, 17.1; 31PꢀNMR (600 MHz, CDCl3) δ 201.4, 200.1.
6
7
8
1
4ꢀ(4,4,5,5ꢀTetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenol (3a):19b Yield: 93% (102 mg). Hꢀ
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NMR (500 MHz, CDCl3) δ 7.70 (d, J = 10 Hz, 2H.), 6.82 (d, J = 10 Hz, 2H), 1.33 (s, 12H);
13CꢀNMR (126 MHz, CDCl3) δ 158.5, 136.9, 114.9, 83.8, 24.9.
2ꢀ(4ꢀMethoxyphenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane (3b):19a Yield: 92% (108 mg).
1HꢀNMR (500 MHz, CDCl3) δ 7.75 (d, J = 10 Hz, 2H.), 6.89 (d, J = 10 Hz, 2H.), 3.83 (s, 3H),
1.33 (s, 12H); 13CꢀNMR (126 MHz, CDCl3) δ 162.2, 136.6, 113.4, 83.6, 55.2, 24.9.
1
4,4,5,5ꢀtetramethylꢀ2ꢀ(pꢀtolyl)ꢀ1,3,2ꢀdioxaborolane (3c):19a Yield: 85% (93 mg). HꢀNMR
(500 MHz, CDCl3) δ 7.86 (d, 2H), 7.29 (d, 2H), 2.46 (s, 3H), 1.43 (s, 12H); 13CꢀNMR (126
MHz, CDCl3) δ 141.3, 135.0, 128.6, 83.6, 24.9, 21.8.
4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)benzaldehyde (3d):19a Yield: 15% (17 mg).
1HꢀNMR (500 MHz, CDCl3) δ 10.04 (s, 1H), 7.96 (d, J = 8 Hz, 2H), 7.86 (d, J = 8 Hz, 2H),
1.36 (s, 12H); 13CꢀNMR (126 MHz, CDCl3) δ 192.8 (s), 138.2 (s), 135.3, 128.8, 84.5, 25.0.
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4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)benzoic acid (3e):32a Yield: 57% (71 mg). Hꢀ
13
NMR (500 MHz, CDCl3) δ 10.01 (s, 1H), 8.10 (d, 2H), 7.91 (d, 2H), 1.36 (s, 12H); CꢀNMR
(126 MHz, CDCl3) δ 172. 3, 134.8, 129.3, 84.4, 25.0.
Methyl 4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)benzoate (3f):19a Yield: 52% (72 mg).
1HꢀNMR (500 MHz, CDCl3) δ 7.93 (d, 3J = 8 Hz, 1H), 7.53ꢀ7.48 (m, 2H), 7.43ꢀ7.38 (m, 1H),
3.90 (s), 1.40 (s, 12H); 13CꢀNMR (126 MHz, CDCl3) δ 168.6, 133.5, 132.3, 131.9, 129.1,
128.9, 84.2, 52.4, 25.0.
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1ꢀ(4ꢀ(4,4,5,5ꢀTetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)ethanone (3g):19a Yield: 68% (84
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mg). HꢀNMR (500 MHz, CDCl3) δ 7.90 (dd, J = 8 Hz, 4H), 2.61 (s, 3H), 1.35 (s, 12H); 13Cꢀ
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NMR (126 MHz, CDCl3) δ 198.6, 139.1, 135.0, 127.4, 84.3, 26.9, 25.0.
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2ꢀ(4ꢀchlorophenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane (3h):19a Yield: 28% (33 mg).1Hꢀ
NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8 Hz, 2H), 7.74 (d, J = 8 Hz, 2H), 1.34 (s, 12H); 13Cꢀ
NMR (126 MHz, CDCl3) δ 137.7, 136.3,128.1, 84.2, 25.0.
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2ꢀ(4,4,5,5ꢀTetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenol (3i):32b Yield: 92% (101 mg). Hꢀ
NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H),
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6.90ꢀ6.87 (m, 2H), 1.38 (s, 12H); CꢀNMR (126 MHz, CDCl3) δ 163.7, 135.8, 133.9, 119.6,
115.5, 84.5, 24.9.
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4,4,5,5ꢀTetramethylꢀ2ꢀ(oꢀtolyl)ꢀ1,3,2ꢀdioxaborolane (3j):19a Yield: 68% (69 mg). H NMR
(300 MHz, CDCl3) δ 7.68 (dd, J = 7.7, 1.6 Hz, 1H), 7.23 (td, J = 7.5, 1.6 Hz, 1H), 7.07 (m, 2H),
2.46 (s, 3H), 1.26 (s, 12H).
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2ꢀ(2ꢀchlorophenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane (3k):19a Yield: 5% (6 mg). Hꢀ
NMR (500 MHz, CDCl3) δ 7.72 (d, 1H), 7.33ꢀ3.38 (m, 2H), 7.25 (t, 1H), 1.39 (s, 12H); 13Cꢀ
NMR (126 MHz, CDCl3) δ 139.6, 136.5, 131.9, 129.4, 125.8, 84.1, 24.8.
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3ꢀ(4,4,5,5ꢀTetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)benzonitrile (3l):19b Yield: 64% (73 mg). Hꢀ
NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 8.00 (d, 3J = 5 Hz, 1H), 7.72 (d, 3J = 5 Hz, 1H), 7.47
(t, 3J = 7.6 Hz, 1H), 1.35 (s, 12H); 13CꢀNMR (126 MHz, CDCl3) δ 138.8, 138.5, 134.5, 128.5,
119.0, 112.15, 84.6, 24.9.
2ꢀ(2ꢀmethoxyphenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane (3m):32c Yield: 52% (61 mg).
1H NMR (300 MHz, CDCl3) δ 7.60 (dd, J = 7.3, 1.8 Hz, 1H), 7.31 (ddd, J = 8.4, 7.3, 1.9 Hz,
1H), 6.86 (td, J = 7.3, 0.9 Hz, 1H), 6.80 – 6.74 (m, 1H), 3.75 (s, 3H), 1.27 (s, 12H).
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4,4,5,5ꢀTetramethylꢀ2ꢀphenylꢀ1,3,2ꢀdioxaborolane (3n):19a Yield: 60% (61 mg). HꢀNMR
(500 MHz, CDCl3) δ 7.82 (d, J = 8 Hz, 2H), 7.47 (t, J = 8 Hz, 1H), 7.38 (t, J = 8 Hz, 2H),
1.36 (s, 12H). 13CꢀNMR (126 MHz, CDCl3) δ 135.2, 131.7, 128.2, 84.2, 25.3.
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2ꢀ(3,5ꢀdimethoxyphenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane (3o):32c Yield: 90% (119
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mg). HꢀNMR (500 MHz, CDCl3) δ 6.95 (d, 2H), 6.57 (t, 1H), 3.81 (s, 6H), 1.34 (s, 12H);
13CꢀNMR (126 MHz, CDCl3) δ 160.4, 111.6, 104.6, 84.0, 55.5, 24.9.
2ꢀ(2,4ꢀdimethylphenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane (3p):32d Yield: 16% (19 mg).
1HꢀNMR (500 MHz, CDCl3) δ 7.78 (d, 1H), 7.08 ( d, 2H), 2.62 (s, 3H), 2.41 (s, 3H), 1.42 (s,
12H); 13CꢀNMR (126 MHz, CDCl3) δ 145.0, 140.9, 136.2, 130.8, 125.6, 83.2, 24.9, 22.2,
21.5.
2,6ꢀDimethylꢀ4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenol (3q):32e Yield: 68% (84
mg). 1HꢀNMR (500 MHz, CDCl3) δ 7.46 (s, 2H), 2.24 (s, 6H), 1.33 (s, 12H); 13CꢀNMR (126
MHz, CDCl3) δ 155.2, 135.6, 131.0, 83.6, 24.9, 15.7.
1,4ꢀbis(4,4,5,5ꢀTetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)benzene (3r):19a Yield: 30% (50 mg). 1Hꢀ
NMR (500 MHz, CDCl3) δ 7.81 (s, 4H), 1.35 (s, 24H); 13CꢀNMR (126 MHz, CDCl3) δ 134.0,
84.0, 25.0.
1,2ꢀbis(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)benzene (3s):32f Yield: 16% (26 mg). 1Hꢀ
NMR (600 MHz, CDCl3) δ 7.64 (q, J = 3.0 Hz, 2H), 7.37 (q, J = 3.0 Hz, 2H), 1.37 (s, 24H);
13CꢀNMR (151 MHz, CDCl3) δ 133.5, 129.2, 84.0, 25.0.
Acknowledgment:
This work was supported by the King Abdullah University of Science and Technology
(KAUST baseline funding and GCR grant FIC/2010/07). Authors are gratefully
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acknowledging support from King Abdullah University of Science and Technology
(KAUST), Saudi Arabia.
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Supporting Information: Copies of GCMS, 1H and 13C NMR of the products. This material
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is available free of charge via the Internet at http://pubs.acs.org.
Author Information
Corresponding Authors
*(Jorg Eppinger) EꢀMail: jorg.eppinger@kaust.edu.sa
* (Dinesh Nanaji Sawant) Eꢀmail: dinesh.sawant@catslysis.de; dinesh1.sawant@gmail.com;
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