Borylation of organo halides and triflates using tetrakis(dimethylamino) diboron

Article abstract of DOI:10.1016/j.tetlet.2012.09.009

We report a new in situ borylation method using tetrakis(dimethylamino) diboron, DMA₄B₂, in the presence of a diol. Our method uses standard borylation conditions and readily available Pd-catalysts. The scope of this method includes aryl halides and triflates as well as vinyl halides and triflates. The method successfully works with a broad range of diols, enabling the selection of the best boronic ester for subsequent Suzuki coupling.

Full text of DOI:10.1016/j.tetlet.2012.09.009

Tetrahedron Letters 53 (2012) 6230–6235
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Borylation of organo halides and triflates using
tetrakis(dimethylamino)diboron
⇑
Charles S. Bello, Joachim Schmidt-Leithoff
BASF Corporation, 1424 Mars Evans City Road, Evans City, PA 16033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2012
Revised 3 September 2012
Accepted 4 September 2012
Available online 11 September 2012
We report a new in situ borylation method using tetrakis(dimethylamino)diboron, DMA4B2, in the pres-
ence of a diol. Our method uses standard borylation conditions and readily available Pd-catalysts. The
scope of this method includes aryl halides and triflates as well as vinyl halides and triflates. The method
successfully works with a broad range of diols, enabling the selection of the best boronic ester for sub-
sequent Suzuki coupling.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Borylation
Suzuki-reaction
Pd-Catalysis
C–C-bond formation
Boronic ester
Introduction
(48%) was estimated from the corresponding pinacol ester, in
which the reaction product was transformed separately. Marcuccio
The direct borylation of aryl halides is a very useful reaction in
the organic synthesis toolbox.1 Not only in an academic but also in
an industrial context, Pin2B2 is widely used and esteemed for its
‘‘plug and play’’ utilization.2,3
The transition metal catalyzed borylation is the method of
choice to generate precursors for Suzuki C–C-bond formation in
the later stages of complex organic molecule synthesis. Pin2B2 rep-
resents by far the most prominent borylation reagent. In the last
years, several alternatives4 have been introduced mainly to
circumvent the disadvantages of the pinacolester, for example its
difficult hydrolysis and the often strenuous separation of the pina-
col from the final product.5
and Weigold described the use of DMA4B2 in MeOH with LiOMe as
a base stating that no starting material was detectable via GC after
20 h.13 Molander et al. improved the DMA4B2/MeOH-borylation of
(hetero)aryl halides by using X-Phos-Pd-catalyst.14
DMA4B2 is a liquid15 and shows good solubility in most com-
mon (aprotic) solvents. Since liquids can be pumped and charged
by volume, they are generally preferred over solids on larger scale.
In this paper, we present a new borylation method using
DMA4B2 as the boron source, which is applicable to broad substrate
and solvent scope. Additionally, the in situ borylation with DMA4B2
can be run under solventless conditions, which enables high space-
time yields on larger scale.
Bis(neopentanediolato)diboron has been especially useful deliv-
ering higher yields in borylations of nitriles6 and carbamates.7
Suginome and Iwadate developed BpinBdan, which was used for
the regioselective diborylation of alkynes.8
Borylation with tetrakis(dimethylamino)diboron
In our initial trials, we utilized bisboronic acid, BBA, together
with pinacol or neopentylglycol as the borylation agent. Standard
borylation2 conditions proved to be successful for this reaction
and led to high conversions within 3 h.16
Knowing that an in situ borylation works with BBA as diboron-
agent, we replaced BBA with DMA4B2 for the borylation
reaction(Fig. 1).
Recently, Molander and Trice reported the use of bisboronic acid9
for the borylation of aryl bromides and chlorides.10,11 They devel-
oped an easy-to-use method, with the only drawbacks of a low con-
centration (0.1 M) and expensive Pd ligand requirement. Looking
into alternative borylation agents, our development was focused
on both a broad scope of substrates as well as easy applicability.
Tetrakis(dimethylamino)diboron, DMA4B2, has been sporadi-
cally used for borylations. Miyaura and co-workers12 reported
borylation of phenyl triflate with DMA4B2. The yield of the reaction
This approach provides a more efficient and cost-effective way,
since DMA4B2 serves as starting material for both BBA17 as well as
2
Pin2B2.
In order to determine the optimum reaction conditions for
DMA4B2, we used 4-bromoacetophenone as substrate and neopen-
tyl glycol as diol.
⇑
Corresponding author. Tel.: +1 724 538 1334; fax: +1 724 538 1258.
E-mail address: joachim.schmidt-leithoff@basf.com (J. Schmidt-Leithoff).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.009

C. S. Bello, J. Schmidt-Leithoff / Tetrahedron Letters 53 (2012) 6230–6235
6231
O
B
R
R
R
R
diol, solvent,
base, temp.
O
O
O
O
catalyst, temp.
Br
O
B
B
B
B
O
BBA: R = OH
DMA B : R = NMe2
4
2
O
OH
OH
OH
OH
catalyst: PdCl2(dppf), Pd(PPh3)4
solvent: toluene, THF
diol:
Figure 1. Borylation with DMA4B2 and diol.
Table 1
Influence of solvent on borylation yielda
Me2N
Me2N
NMe2
NMe2
O
O
O
O
O
O
catalyst, temp.
Br
OH OH
KOAc, solvent,
80°C
B
B
B
B
B
O
O
#
Solvent (Temp °C)
Conv.b (%)
#
Solvent
Conv.b (%)
1
3
5
Toluene (80 °C)
EtOH (80 °C)
Heptane (80 °C)
1,4-dioxane (100 °C)
MEK (80 °C)
Acetone (56-57 °C)
99.9
0.0
99.9
99.8
99.8
25.8
2
4
6
THF (65 °C)
99.7
0.0
95.9
96.8
89.7
99.8
iPrOH (80 °C)
THF, H2Od (80 °C)
EtOAc (76 °C)
CH3CN (80 °C)
DMSO (80 °C)
7c
9c
11c
8c
10c
12
a
Reaction conditions: KOAc (3.0 equiv), neopentylglycol (2.4 equiv), DMA4B2 (distilled, 1.2 equiv) in solvent; stirring at 80 °C for 0.5 h; 4-bromo acetophenone, Pd(PPh3)4
(2 mol %).
b
GC-area-%.
C
d
Filtered DMA4B2 (90% in hexanes); 30 min heat soak instead of 2 h.
0.1 equiv H2O.
Influence of solvent
the reaction in acetone (entry 11) failed completely. Evidence sug-
gests that the lower boiling point of acetone cause different bory-
lation results at the lower reaction temperature.19 DMSO also gave
good borylation results (entry 12), which is not surprising, since
DMSO has been reported as an excellent solvent in several
Pin2B2-publications.2
Standard conditions utilizing 3 equiv of KOAc as base, 2 mol % of
Pd(PPh3)4 as catalyst and solvent, showed that borylation was
completed within 22 h (Table 1). Hydrocarbons like toluene (entry
1) or heptane (entry 4) as well as ethers like THF (entry 2, 6) and
dioxane (entry 7) proved to be suitable solvents for the reaction.
The solvents do not need to be completely dry. An experiment
using 10 mol % H2O in THF gave 96% GC-yield after 22 h (entry
6). In contrast to the method developed by Molander and co-work-
ers, the use of alcohols, EtOH or iPrOH does not result in detectible
borylation products. This result can be explained by the competi-
tion of the alcohol with the diol leading presumably to mixtures
of (diol)B-B(OR)2, which does not borylate under our reaction con-
ditions.18 Methyl ethylketone (MEK, entry 9) was suitable, while
Influence of diol
After solvent screening, we explored diols suitable for this pro-
tocol. Figure 2 gives an overview of the results. The in situ forma-
tion of the B2diolato2 from DMA4B2 was complete in all cases.
The reaction with ethylene glycol (1) showed significant lower
conversion after 22 h (38.5%). 1,2-Propylene glycol (2; 91.2%) and
1,3-propylene glycol (4; 90.8%) lead nearly to the same yield and
pinacol gave outstanding conversion (3; 100%). A possible explana-
tion for the differences in reactivity has been given by Bachrach: the
Thorpe-Ingold effect, where increasing the size of two substituents
on a tetrahedral center leads to enhanced reactions.20 Comparison
of ethylene glycol to pinacol shows that the gem-dimethyl groups
of the latter lead to an angle compression resulting in a faster reac-
tion. The same effect – only weaker – can be observed by compar-
ison of neopentylglycol (5; 99.9%) and 1,3-propanediol (4; 90.8%).
In the borylation using in situ formed bis(hexylene glycola-
to)diboron (from 6) the reactivity of the Pd-catalyst becomes
Pd(PPh3)4 (A) or
PdCl2dppf (B) or
PdCl2 + PPh3 (C)
O
B
diol, KOAc,
Me2N
Me2N
NMe2
NMe2
O
O
O
O
(2 mol-%)
Br
O
B
B
B
B
toluene,
80°C, 2 h
O
O
important due to
a
less reactive borylation agent.21 Using
HO
OH HO
OH HO
OH
OH OH
OH OH
OH OH
Pd(PPh3)4 shows a lower conversion (A: 18.8%) than the more ac-
tive PdCl2(dppf) (B: 87.3%).
1
2
3
6
4
5
38.5% (A)
91.2% (A)
100% (B)
18.8% (A)
87.3% (B)
90.8% (A) 99.9% (A)
99.9% (B)
Reactions with catechol or (+)-diisopropyl-L-tartrate did not
give desired borylation product, although bis(catecholato)dibo-
99.4% (C)
rane22 and bis(diisopropyl-
as borylation reagents.
L
-tartrateglycolato)diboron4 are known
Figure 2. Influence of diol on borylation with DMA4B2.

6232
C. S. Bello, J. Schmidt-Leithoff / Tetrahedron Letters 53 (2012) 6230–6235
Table 2
In general, our protocol allows borylations with high flexibility
with regard to the resulting boronic ester, opening up new possi-
bilities for borylation reactions on commercial scale.
Borylation of aryl bromidesa
#
1
2
Aryl bromide; Borylation Product
Catalyst
Conversionb
(%)
Influence of base
4-Bromo-benzaldehyde;
O
B
O
Pd(PPh3)4
98.0
The standard experiment without any base, did not result in
product formation. 1.5 equiv of KOAc lead only to 76% conversion
after 22 h, while two equivalents of KOAc gave full conversion.
Other potassium bases like K3PO4 or K2CO3 resulted in lower con-
version (65% and 11.3%). KOtBu gave no borylation product at all,
instead showing an incomplete B2diolato2-formation (56%). Pheno-
lates had been successfully used as bases in borylations23, how-
ever, NaOPhÁ3H2O showed only 10.4% conversion after 22 h. NEt3
was the only organic base tested and resulted in about 10% conver-
sion after 22 h.
O
Pd(PPh3)4
PdCl2(dppf)
PdCl2 + PPh3
96.7
99.9
99.4
4-Bromo-acetophenone;
O
B
O
O
Ethyl-4-bromobenzoate;
EtO
O
3
4
Pd(PPh3)4
99.6
B
O
O
Pd(PPh3)4
PdCl2(dppf)
77.3
99.6
1-Bromo-4-t-butyl benzene;
O
B
O
Consequently, at least two equivalents of KOAc are necessary
for the in situ borylation.
4-Bromo-benzotrifluoride;
Borylation of aryl halides
O
5
6
PdCl2(dppf)
99.3
F
B
O
With neopentylglycol as diol and toluene as solvent, we inves-
tigated substrate scope and limitations of the in situ borylation
by DMA4B2.
O
O
Pd(PPh3)4
PdCl2(dppf)
85.6
100c
F3C
B
1-Bromo-3,4,5-trifluorobenzene;
F
Aryl bromides
O
7
PdCl2(dppf)
99.1
F
B
The broad range of aryl bromides applicable for the borylation
with Pin2B2 can be used with our new method (Table 2). The bory-
lation of 4-bromo benzaldehyde (entry 1) works very well with
Pd(PPh3)4. Interestingly, the dimethylamine present in the reaction
mixture from the alcoholysis of DMA4B2, does not lead to forma-
tion of the corresponding iminium compound.
Entry 2 highlights that the reaction gave equally high yield with
PdII-catalysts (e. g. PdCl2 and PPh3) and does not require highly ac-
tive, expensive catalysts. In order to convert less reactive aryl bro-
mides, like 1-bromo-4-tert-butyl benzene (entry 4) or fluorinated
systems (entries 5-7) slightly more reactive catalysts are necessary
(PdCl2dppf).
O
F
2-Bromoanisole;
O
8
9
B
Pd(PPh3)4
81.7
100
O
OMe
3-Bromoanisole;
O
B
PdCl2(dppf)
O
MeO
4-Bromoanisole;
O
All three isomers of bromo anisole (entries 8–10) gave good to
excellent results. The catalyst of choice in this case was PdCl2dppf,
which was also used for the borylation of 4-bromo-N,N-dimethyl
aniline (entry 11).
Entry 12 expands the scope of our method to heteroaryl sub-
strates. While the reaction with 4-bromo-2-methyl pyridine re-
sulted in the desired borylation product, 2-bromopyridine only
gave homocoupling product.24
Sterically hindered aromatics generally gave a lower yield and
require more electron rich catalyst systems, like Pd-S-Phos25 or
Pd-X-Phos. 2-Bromotoluene showed less reactivity (PdCl2dppf:
41.9%; Pd(OAc)2/X-Phos: 60.7%, entry 13). The reaction with 2-
bromo-1,3-dimethylbenzene gave low yields (11.6%, entry 14).
Further optimization of both the reaction conditions as well as
the catalysts seems necessary, but was not within the focus of this
project.
10
11
Pd(PPh3)4
96.6
100d
MeO
B
O
4-Bromo-N,N-dimethylaniline;
O
PdCl2(dppf)
Me2N
B
O
4-Bromo-2-methyl pyridine;
O
12
13
PdCl2(dppf)
99.8
N
B
O
Pd(PPh3)4
PdCl2(dppf)
Pd(OAc)2, X-
Phos
32.7
41.9
60.7
2-Bromotoluene;
O
B
O
Pd(PPh3)4
PdCl2(dppf)
8.8
11.6
2-Bromo-1,3-dimethylbenzene;
O
B
O
14
Borylation of aryl chlorides
a
Since powerful ligands and catalysts have been developed, the
transformation of aryl chlorides came within reach by nearly all
transition metal catalyzed transformations.11,26
We only investigated two aryl chlorides to demonstrate our
borylation method. In addition to ‘standard’ catalysts, we used
Reaction conditions: KOAc (3.0 equiv), neopentylglycol (2.4 equiv), DMA4B2
(distilled, 1.2 equiv), toluene; stirring at 80 °C for 0.5 h; add. of aryl bromide and
catalyst (2 mol %); 80 °C, 22 h.
b
GC-area-%.
After 3 h.
After 3 h: 97.4%.
c
d

C. S. Bello, J. Schmidt-Leithoff / Tetrahedron Letters 53 (2012) 6230–6235
6233
Table 3
Borylation with vinyl- and aryl triflatesa
#
Triflate; borylation product
Catalyst
Conversionb (%)
1-Cyclohexenyl tri-fluoromethanesulfonate;
O
1
2
PdCl2(PPh3)2 (3 mol %), PPh3 (6 mol %)
100
B
O
Phenyl trifluoro-methanesulfonate;
O
B
PdCl2(PPh3)2 (3 mol %), PPh3 (6 mol %)
98.4
O
2-Naphthyl triflate;
3
4
5
Pd(PPh3)4 (2 mol %)
99.6
91.9
99.7
100
O
B
O
p-Tolyl triflate;
O
B
O
Pd(PPh3)4 (2 mol %)
3,5-Dimethoxyphenyl triflate;
MeO
O
Pd(PPh3)4 (2 mol %)
B
O
MeO
2-Pyridyl triflate;
O
B
O
6
7
8
Pd(PPh3)4 (2 mol %)
N
PdCl2(PPh3)2 (3 mol %), PPh3 (6 mol %)
Pd(PPh3)4 (2 mol %)
100
100
1-Bromo-2-methyl-1-propene;
O
B
O
Pd(PPh3)4 (2 mol %)
Pd(PPh3)4 (2 mol %); N2-purge
—
100
4-Nitrophenyl triflate;
O
O2N
B
O
a
Reaction conditions: KOAc (3.0 equiv), neopentylglycol (2.4 equiv), DMA4B2 (distilled, 1.2 equiv) in toluene; add. of triflate, catalyst/ligand; 80 °C, 24 h.
GC-area-%.
b
X-Phos, which previously has been utilized in Pin2B2 borylation by
Buchwald11 and Molander.14 The best borylation product yield for
4-chloroacetophenone was 94.1%.27,28 The borylation with methyl-
4-chloro benzoate gave 60.9% with PdCl2dppf, while Pd(OAc)2-
XPhos gave complete conversion of substrate but the product
decomposed under reaction conditions.
O
O
4
O
O
O2N
O2N
NMe2
46
to
B
B
O2
N
OTf
Me2N
Me2N
NMe2
NMe2
OH OH
B
B
+
+
KOAc,
toluene,
80°C
Pd(PPh3)4,
22 h
O
B
O
H
N
54
Our reaction conditions failed with electron rich alkyl substi-
tuted aryl chlorides, such as chlorotoluene or chloroxylene. More
reactive ligands or different reaction conditions were not
investigated.
Figure 3. Side reaction of the in situ borylation.
Br
Borylation of triflates and vinylhalides
O
B
Me2N
Me2N
NMe2
OH OH ,
O
O
B
B
Since triflates are easily accessible from phenols or ketones,
they were also of interest for our study. Their borylation with
Pin2B2 was first described by Miyaura and co-workers using
PdCl2dppf with additional dppf in dioxane with KOAc at 80 °C.12
For the borylation of cyclohexenyl triflate (Table 3, entry 1), we
applied conditions mentioned in a paper of Miyaura et al..23 Con-
trary to this reference we used KOAc instead of KOPh. The conver-
sion to the desired product was completed within 22 h. Using the
KOAc protocol for phenyl triflate (entry 2) we obtained nearly com-
plete conversion (98.4%). For the other borylation experiments
with triflates (entries 3–8) we successfully utilized Pd(PPh3)4 and
KOAc.29
toluene, Pd(PPh3)4 (2 mol-%),
80°C; 24 h; 99.9%
NMe2
O
Fig. 4. One-pot-one-step in situ borylation.
Borylation of 4-nitrophenyl triflate (entry 8) gave an unex-
pected result. Under standard reaction conditions, we only ob-
served a 54:46 mixture of the desired borylation product and
N,N-dimethyl-4-nitroaniline30 (Fig. 3). The latter can be the result
of either a Buchwald–Hartwig amination31 or a nucleophilic aro-
matic substitution. A control experiment without Pd-catalyst re-
sulted in 98.2% in N,N-dimethyl-4-nitroaniline within 24 h, which
proves the nucleophilic aromatic substitution.
1-Bromo-2-methyl-1-propene also gave complete conversion
within 24 h using the above protocol (entry 7).

6234
C. S. Bello, J. Schmidt-Leithoff / Tetrahedron Letters 53 (2012) 6230–6235
Table 4
Borylation with DMA4B2 in different solventsa
Me2N
Me2N
NMe2
NMe2
O
O
O
O
O
O
cond.
catalyst, temp.
Br
B
B
B
B
B
O
O
#
1
Diol
Time (h)
Conversionb (%)
1,3-Propanediol
1,2-Propanediol
Hexylene glycol
3
22
3
22
3
22
26.1
84.8
99.7
100
45.8
99.9
2
3
a
Reaction conditions: KOAc (3 equiv), diol (2.4 equiv), DMA4B2 (distilled, 1.2 equiv); stirring at 80 °C, 4-bromo acetophenone, Pd(PPh3)4
(2 mol %); 80 °C.
b
GC-area-%.
In order to avoid this side reaction, we purged for 2 h with
nitrogen after alcoholysis of DMA4B2 to reduce the amount of
dimethylamine in the reaction mixture. With this slightly changed
protocol, we obtained quantitative yields of the desired product in
only 3 h.
the subsequent Suzuki-reaction. In addition, the reaction condi-
tions for the in situ borylation are similar to the standard condi-
tions used in the Miyaura-Pin2B2 borylation.
Furthermore, we proved that solventless in situ borylation is
possible for liquid diol substrates and products and proceeds rap-
idly to completion. Overall, this protocol is a very attractive alter-
native to Pin2B2 for borylation reactions at commercial scale.33
Solventless in situ borylation
Further reaction time savings can be achieved by omitting the
premixing of DMA4B2 and diol leading to a one-pot-one-step
in situ borylation with our procedure. All necessary reagents [KOAc
(1.84 g, 18.8 mmol, 3 equiv), DMA4B2 (1.48 g, 6.25 mmol,
1.2 equiv), Pd(PPh3)4 (144 mg, 0.125 mmol, 2 mol %), 4-bromo ace-
tophenone (1.24 g, 6.25 mmol), neopentyl glycol (1.56 g,
15.0 mmol, 2.4 equiv)] were added to the reaction vessel and sus-
pended in toluene (25 ml). The mixture was then stirred at 80 °C
for 24 h. The progress of the reaction was monitored by GC (Fig. 4).
In order to increase space time yield of the reaction, we evalu-
ated a solventless in situ borylation. Since some of the reagents
(base, catalyst, and some subtrates) are solids, the viscosity of
the final mixture was of concern. Hence, a low viscosity of the diol
was critical.
Experimental procedure
Borylation with DMA4B2 (Table 2, entry 2)
KOAc (1.84 g, 18.7 mmol, 3 equiv), neopentylglycol (1.56 g,
15.0 mmol, 2.4 equiv) and DMA4B2 (1.48 mg, 7.50 mmol, 1.2 equiv)
were suspended in toluene (25 ml). The reaction mixture was
heated for 30 min to 80 °C. PdCl2 (22.2 mg, 0.125 mmol, 2 mol %)
and PPh3 (163 mg, 0.50 mmol, 8 mol %) in toluene (5 ml) were stir-
red for 30 min before 4-bromoacetophenone (1.24 g, 6.25 mmol)
was added. The catalyst-substrate solution was then added to the
borylation mixture. The resulting reaction mixture was stirred for
22 h at 80 °C.
The GC-chromatogram of the reaction mixture showed 51.7%
conversion to the product after 3 h and 99.4% after 22 h. The prod-
uct was confirmed by its mass using GC–MS-technology.
Ethylene glycol showed the lowest viscosity of the diols tested
in Figure 2,32 but gave only a low borylation yield (38.5% in toluene
as solvent). 1,2-Propanediol, 1,3-propanediol, and hexylene glycol
were further investigated, see Table 4.
Solventless borylation with DMA4B2
Under the standard protocol (3 equiv KOAc, 2.4 equiv diol,
1.2 equiv DMA4B2, 2 mol % Pd(PPh3)4 and 80 °C) 1,3-propanediol
gave a 84.8% GC-conversion within 22 h, which was the first proof
that a borylation without solvent is possible (Table 4, entry 1). The
reaction with 1,2-propanediol (entry 2) was extremely fast giving
99.3% conversion to the borylated product in just 1 h. Hexylene
glycol (entry 3) required 22 h to reach 100% conversion.
With viscous diols, agitation may become challenging on larger
scale. To reduce viscosity, we investigated the use of excess diol.
Unfortunately, the experiment with 10 equiv 1,2-propane diol gave
only 23% conversion after 22 h. Since we were able to detect com-
plete formation of B2diolato2 after 3 h by GC, the residual excess
diol seems to inhibit the borylation reaction.
All reagents, KOAc (8.35 g, 85.2 mmol, 3 equiv), DMA4B2 (3.87 g,
34.1 mmol, 1.2 equiv), Pd(PPh3)4 (0.66 g, 0.57 mmol, 2 mol %) and
4-bromoacetophenone (5.65 g, 28.4 mmol), were suspended in
1,2-propanediol (5 ml, 5.18 g, 68.2 mmol, 2.4 equiv). The reaction
mixture was stirred at 80 °C for 24 h. The progress of the reaction
was monitored by GC. After 1 h the GC showed 99.3% completion,
after 3 h 99.7% and finally after 22 h 100%. The final product was
confirmed by its mass using GC–MS-technology.
Acknowledgments
We gratefully acknowledge Dr. E. R. Burkhardt and Dr. K. Matos
for helpful discussions. We thank the BASF Corp. for the allowance
to publish our results.
Summary
An efficient, scalable, and high yielding method for the boryla-
tion of aryl halides and triflates has been developed using tetra-
kis(dimethylamino)diboron and diols. Advantages of this new
method are not only the broad scope of substrates but also flexibil-
ity to choose from a variety of diols and solvents. This enables one
to tailor the borylation-product to improve its performance during
References and notes
1. Reviews: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483; Suzuki, A. J.
Organometallic Chem. 1999, 576, 147–168.
2. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510; Pin2B2-
synthesis: Ishiyama, T.; Murata, M.; Ahiko, T.-a.; Miyaura, N. Org. Synth. 2000,
77, 176–181.

C. S. Bello, J. Schmidt-Leithoff / Tetrahedron Letters 53 (2012) 6230–6235
6235
3. Zhu, L.; Patel, M.; Zhang, M. Tetrahedron Lett. 2008, 49, 2734–2737; Grongsaard,
P.; Bulger, P. G.; Wallace, D. J.; Tan, L.; Chen, Q.; Dolman, S. J.; Nyrop, J.;
Hoerrner, R. S.; Weisel, M.; Arredondo, J.; Itoh, T.; Xie, C.; Wen, X.; Zhao, D.;
Muzzio, D. J.; Bassan, E. M.; Shultz, C. S. Org. Process Res. Dev. 2012, 16, 1069–
1081; Recent patents utilizing Pin2B2: Merck Sharp & Dohme Corp.:Lu, Z.; Chen,
Y.-H.; Smith, C.; Li, H.; Thompson, C. F. WO 2012/058187 A1, 2012.; Novartis
AG: Calienni, J. V.; De La Cruz, M.; Flubacher, D.; Gong, B.; Kapa, P. K.; Karpinski,
P. H.; Liu, H.; Michel, P.; Mose, R.; Testa, M. C.; Waykole, L. M. WO 2012/044727
A2, 2012.
4. Marcuccio, S. M.; Rodopoulos, M.; Weigold, H. US 6,515,160 B2, 2003.;
Marcuccio, S. M.; Moorhoff, C. M. WO 2004/076467 A1, 2004.
5. Bis(1,3-diphenyl-1,3-propanediolato)diboron: Nakamura, H.; Fujiwara, M.;
Yamamoto, Y. J. Org. Chem. 1998, 63, 7529–7530; Bis(1,3-propanediolato)
diboron: Zaidlewicz, M.; Wolan, A. J. Organomet. Chem. 2002, 657, 129–135;
Bis(2,2-dimethyl-1,3-propanediolato)diboron: Jones, M. T.; Schwartz, B. D.;
Willis, A. C.; Banwell, M. G. Org. Lett. 2009, 11, 3506–3509.
or Pd(PPh3)4; 2 mol %] in toluene (5 ml) or THF (5 ml) was added. The resulting
reaction mixture was stirred for 22 h at 80 °C. The reaction was monitored by
GC.
17. Nöth, H.; Meister, W. Chem. Ber. 1961, 94, 509–514; McCloskey, A. L.; Boone, J.
L. J. Am. Chem. Soc 1961, 83, 4750–4754.
18. Using 4 equiv of EtOH without any diol, the borylation of 4-
bromoacetophenone was completed within 22 h with 2 mol % Pd(PPh3)4.
Unfortunately, the product is not stable, see Ref.10 Also compare with Ref.14.
19. In our standard borylation of 4-bromoacetophenone with toluene as solvent,
the conversion dropped to 32.4% at the reaction temperature of 65 °C.
20. Bachrach, S. M. J. Org. Chem. 2008, 73, 2466–2468.
21. Different reactivities of borylation reagents: Bonet, A.; Pubill-Ulldemolins, C.;
Bo, C.; Gulyás, H.; Fernández, E. Angew. Chem., Int. Ed. 2011, 50, 7158–7161.
22. Welch, C. N.; Shore, S. G. Inorg. Chem. 1968, 7, 225–230.
23. Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124,
8001–8006. In this paper, KOPh was used as base for the borylation of alkenyl
halides or triflates. Since KOPh was not commercially available, NaOPh was
used.
6. Tobisu, M.; Kinuta, H.; Kita, Y.; Rémond, E.; Chatani, N. J. Am. Chem. Soc. 2012,
134, 115–118.
7. Huang, K.; Yu, D.-G.; Zheng, S.-F.; Wu, Z.-H.; Shi, Z.-J. Chem. Eur. J. 2011, 17,
786–791.
8. Iwadate, N.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 2548–2549.
9. Borylation with BBA: Marcuccio, S. M.; Rodopoulos, M.; Weigold, H. US
6,448,433 B1, 2002.
10. Molander, G. A.; Trice, S. L. J.; Dreher, S. D. J. Am. Chem. Soc. 2010, 132, 17701–
17703; Molander, G. A.; Trice, S. L. J.; Kennedy, S. M.; Dreher, S. D.; Tudge, M. T.
J. Am. Chem. Soc 2012, 134, 11667–11673.
11. Borylation of Ar-Cl: Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57,
9813–9816; Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed.
2007, 46, 5359–5363; Yamamoto, T.; Morita, T.; Takagi, J.; Yamakawa, T. Org.
Lett. 2011, 13, 5766–5769.
24. Pd(PPh3)4 lead to the homocoupling product in 43.4% conversion, while
PdCl2dppf resulted in 99.0% conversion in homocoupling product.
25. Rawls, K. A.; Grundner, C.; Ellman, J. A. Org. Biomol. Chem. 2010, 8, 4066–4070.
26. Chinchilla, R.; Nájera, C. Chem. Soc. Rev. 2011, 40, 5084–5121; Fleckenstein, C.
A.; Plenio, H. Chem. Soc. Rev. 2010, 39, 694–711; Maiti, D.; Fors, B. P.;
Henderson, J. L.; Nakamura, Y.; Buchwald, S. L. Chem. Sci. 2011, 2, 57–68.
27. Reaction conditions: KOAc (3.0 equiv), neopentylglycol (2.4 equiv), DMA4B2
(1.2 equiv) in toluene (25 ml); 80 °C, 2 h; add. of aryl chloride, Pd(OAc)2
(2 mol %), X-Phos (4 mol %); 80 °C, 22 h.
28. Borylation with other catalysts [GC-area-%]: Pd(PPh3)4: 18.1%; PdCl2(dppf):
55.3%.
29. Miyashita, K.; Sakai, T.; Imanishi, T. Org. Lett. 2003, 5, 2683–2686.
30. The identity of the product was confirmed by GC–MS, signal of the molecule at
166 m/z.
12. Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447–
3450.
13. Marcuccio, S. M.; Weigold, H. US 6,794,529 B2, 2004 (example 36).
14. Molander G. A.; Trice S. L. J.; Kennedy S. M. Org. Lett.; accepted.
15. Tetrakis(dimethylamino)diboron: bp: 55–57 °C (2 mmHg); density: 0.864 g/
cm3 (20 °C).
16. The borylation of 4-bromoacetophenone with bisboronic acid in presence of
pinacol or neopentylglycol gave GC conversions of 97–99% within 3 h.
Conditions for borylation with BBA: KOAc (1.84 g, 18.7 mmol, 3 equiv),
neopentylglycol (1.56 g, 15.0 mmol, 2.4 equiv) and BBA (672 mg, 7.50 mmol,
1.2 equiv) were suspended in toluene (25 ml) or THF (25 ml). The reaction
31. Lee, B. K.; Biscoe, M. R.; Buchwald, S. L. Tetrahedron Lett. 2009, 50, 3672–3674;
Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 1995, 34,
1348–1350.
32. Dynamic viscosity [mPaÁs]: ethylene glycol: 21.04 (20 °C), 3.090 (80 °C); 1,2-
propanediol: 58.24 (20 °C) 4.258 (80 °C); 1,3-propanediol: 29.44 (20 °C), 4.678
(80 °C); hexylene glycol: 162.24 (extrapolated, 20 °C), 12.42 (80 °C). All
viscosities listed above originate from the BASF database for substance
property data.
33. Commercial quantities of DMA4B2 are available from BASF (www.inorganics.
basf.com).
mixture was stirred at 80 °C for 0.5–2 h, before
a solution of 4-
bromoacetophenone (1.24 g, 6.25 mmol) and Pd-catalyst [either PdCl2(dppf)