4,4,6-Trimethyl-1,3,2-dioxaborinane: A practical reagent for palladium-catalyzed borylation of aryl halides

Article abstract of DOI:10.1055/s-2006-958962

The palladium-catalyzed borylation of aryl iodides with 4,4,6-trimethyl-1,3,2-dioxaborinane is described. The mild reaction conditions employed allow for aryl iodides with a wide variety of functional groups to be tolerated. The products of this borylation were coupled with aryl halides to give biaryls in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958962

PAPER
351
4,4,6-Trimethyl-1,3,2-dioxaborinane: A Practical Reagent for Palladium-
Catalyzed Borylation of Aryl Halides
AM
P
ractica
l
Reagent fo
i
r
Pallad
k
ium-Catalyz
i
edBorylationMurata,* Takeshi Oda, Shinji Watanabe, Yuzuru Masuda
Department of Materials Science, Kitami Institute of Technology, Kitami 090-8507, Japan
Fax +81(157)264973; E-mail: muratamk@mail.kitami-it.ac.jp
Received 20 September 2006; revised 20 October 2006
We thought that 4,4,6-trimethyl-1,3,2-dioxaborinane 1
was a promising borylation reagent because of its high
stability.10 Traditionally, the synthesis of 1 has been ac-
complished by the reduction of 2,2¢-oxybis(4,4,6-trimeth-
yl-1,3,2-dioxaborinane).10b It is interesting to note that 1
can be easily prepared from the borane-methyl sulfide
complex and hexylene glycol by a similar procedure to
that used in the preparation of pinacolborane (Scheme 2).9
Not only is hexylene glycol less expensive, but this reac-
tion also led to a better yield when compared to pinacol.
Thus, using 1 is more economically profitable than using
pinacolborane.
Abstract: The palladium-catalyzed borylation of aryl iodides with
4,4,6-trimethyl-1,3,2-dioxaborinane is described. The mild reaction
conditions employed allow for aryl iodides with a wide variety of
functional groups to be tolerated. The products of this borylation
were coupled with aryl halides to give biaryls in good yields.
Key words: boron, palladium, catalysis, cross-coupling, aryl ha-
lides
Arylboronic acids and their esters are useful intermediates
in organic synthesis, particularly in carbon–carbon bond
formations using the palladium-catalyzed Suzuki–
Miyaura cross-coupling reaction.1 Various methods are
now available for their preparation. Palladium-catalyzed
cross-coupling reactions of tetra(alkoxo)diborons2 or
dialkoxyboranes3–8 with organic electrophiles have
emerged as a general and powerful method in carbon–bo-
ron bond formation. We have demonstrated the first ex-
amples of palladium-catalyzed borylation using
commercially available 4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane (pinacolborane) and 1,3,2-benzodioxaborole
(catecholborane) to give the corresponding arylbor-
onates.3 Pinacolborane has become one of the most popu-
lar borylation reagents, predominantly because the
resulting pinacol boronates display excellent aqueous and
chromatographic stability. It can be synthesized simply by
reaction of equimolar amounts of borane and pinacol;9
however, pinacol is extremely expensive. Consequently,
we have sought an alternative borylation reagent; in this
paper, we wish to report a palladium-catalyzed borylation
of aryl iodides 2 using 4,4,6-trimethyl-1,3,2-dioxabori-
nane (1) (Scheme 1).10
Me
Me
HO
Me
BH3⋅SMe2
1 (78% isolated yield)
+
OH
CH2Cl2
0 °C to r.t.
Scheme 2
In order to optimize reaction conditions, 4-iodoanisole
(2a) was used as the substrate in the palladium-catalyzed
borylation using 1. Table 1 lists the phosphine ligands
tested and the subsequent results. Although the combina-
tion of PdCl2(MeCN)2 and phosphine ligands, (PPh3,
DPPF3 and DPEphos,7 Table 1, entries 1, 3 and 4), gave
the desired arylboronate 3a in moderate to good yields
(74–84%, by GC analysis), there was also considerable
amounts of anisole 5a (15–20%). We recently reported
the use of bis(2-di-tert-butylphosphinophenyl)ether (4,
t-Bu-DPEphos) as a supporting ligand for a palladium-
catalyzed borylation using pinacolborane,8 which also
proved to be an efficient catalyst system here and gave
smaller amounts of 5a (3% yield, Table 1, entry 5). Exam-
ining a variety of bases showed that the use of a tertiary
amine was essential for this borylation and that triethyl-
amine proved to be the most effective base. A good result
was obtained using toluene as a solvent, while the use of
1,4-dioxane resulted in lower selectivity. Thus, the opti-
mized conditions were determined to be 4-iodoanisole
(2a, 1.0 equiv), 1 (1.5 equiv), Et3N as base (3.0 equiv) and
3 mol% of palladium catalyst prepared in situ from
PdCl2(MeCN)2 and t-Bu-DPEphos 4, in toluene at 80 °C
under a nitrogen atmosphere.
PdCl2(MeCN)2 / 4
Et3N
O
O
O
O
B
H
+
I
Ar
B
Ar
toluene, 80 °C
1
2
3
P(t-Bu)2
O
2
4
Scheme 1
To examine the scope of this reaction, borylations of rep-
resentative aryl halides were examined under these condi-
tions (Table 2). Previous borylation reactions using
pinacolborane tolerated various functional groups owing
to the inert nature of the pinacolborane.3,8 As shown in
SYNTHESIS 2007, No. 3, pp 0351–0354
x
x
.
x
x
.2
0
0
7
Advanced online publication: 21.12.2006
DOI: 10.1055/s-2006-958962; Art ID: F15606SS
© Georg Thieme Verlag Stuttgart · New York

352
M. Murata et al.
PAPER
Table 2 Borylation of 2 with 1 (Scheme 1)a
Table 1 Screening of Ligands for Borylation of 2aa
PdCl2(MeCN)2/Ligand (Pd/P = 1/2)
Et3N
Entry
1c
Aryl halide 2
Yield (%)b
1
I
OMe
+
toluene, 80 °C
86 (3a)
I
OMe
NH2
2a
O
O
OMe
B
OMe
+
(2a)
2c
72 (3b)
93 (3c)
78 (3d)
80 (3e)
86 (3f)
3a
5a
I
Entry
Ligand
Yield (%)b
(2b)
3
3a
5a
15
0
I
1c
2c
PPh3
84
23
(2c)
4
PCy2
Ph
I
CO2Et
COMe
(2d)
5
3
4
5
74
83
97
20
15
3
PPh2
PPh2
I
Fe
(2e)
6
DPPF
I
PPh2
CN
O
(2f)
2
7
8
77 (3g)
89 (3h)
DPEphos
4
I
NO2
(2g)
a Reaction conditions: 2a (0.5 mmol), 1 (0.75 mmol), Et3N (1.5
mmol), PdCl2(MeCN)2 (15 mmol), ligand (15 mmol) in toluene (2 mL)
at 80 °C for 4 h.
b GC yields based on 2a.
c 30 mmol of phosphine ligand was used.
I
MeO
(2h)
9
88 (3i)
Me
Table 2, the present procedure using 1 is similarly tolerant
of a variety of common functional groups. Thus, aryl io-
dides 2 containing NH2 (Table 2, entry 2), CO2Et
(Table 2, entry 4), COMe (Table 2, entry 5), CN (Table 2,
entry 6), and NO2 (Table 2, entry 7) were all efficiently
converted to the corresponding products 3. In all cases
listed in Table 2, small amounts of the reduced by-product
I
Me
Me
(2i)
a Reaction conditions: 2 (0.5 mmol), 1 (0.75 mmol), Et3N (1.5 mmol),
PdCl2(MeCN)2 (15 mmol), 4 (15 mmol) in toluene (2 mL) at 80 °C for
were produced, but purification by bulb-to-bulb distilla- 16 h.
b Isolated yields based on 2.
tion or flash column chromatography was simple as the
resulting boronates 3 exhibited excellent stability in aque-
ous workup and chromatography. Both the yield and the
product selectivity were almost independent of the elec-
tronic and steric requirement. The differences in the yields
and the selectivity between substrates bearing electron-
donating (Table 2, entries 1 and 2) or electron-withdraw-
ing groups (Table 2, entries 4–7) were not particularly
large and the sterically hindered 2h and 2i (Table 2, en-
tries 8 and 9) were also coupled with 1 without any diffi-
culty. Accordingly, the present reaction provides a simple
and widely available procedure for the synthesis of aryl-
boronates 3.
c The reaction was carried out for 4 h.
reaction of 2-bromotoluene with 2-(2-methoxyphenyl)-
4,4,6-trimethyl-1,3,2-dioxaborinane (3h) took place
smoothly in N,N-dimethylformamide at 100 °C in the
presence of potassium phosphate and 3 mol% of
Pd(PPh3)4 (Table 3, entry 1). When compared to the cor-
responding pinacol boronate (Table 3, entry 2), the differ-
ence in reactivity between these two compounds was very
small.
In conclusion, 4,4,6-trimethyl-1,3,2-dioxaborinane 1 was
found to promote the palladium-catalyzed borylation of
aryl iodides. From an economical point of view, 1 is a less
expensive borylating reagent than pinacolborane. In addi-
tion, 1 tolerates various functional groups and the result-
ing boronates 3 exhibit good reactivity for converting the
In order to demonstrate the synthetic utility of the arylbo-
ronates 3, we proceeded to examine the palladium-cata-
lyzed Suzuki–Miyaura cross-coupling reaction.1,11 The
results are summarized in Table 3 and show that a variety
of substituted biaryls can be obtained in high yields. The
Synthesis 2007, No. 3, 351–354 © Thieme Stuttgart · New York

PAPER
A Practical Reagent for Palladium-Catalyzed Borylation
353
Table 3 Suzuki–Miyaura Cross-Coupling Reaction of 3a
Palladium-Catalyzed Borylation of Aryl Halides; General Pro-
cedure (Table 2)
In a glove box, PdCl2(MeCN)2 (15 mmol) and t-Bu-DPEphos 4 (15
mmol) were placed in a screw-capped vial and dissolved in 2 mL of
toluene. After being stirred for 30 min, Et3N (1.5 mmol), the aryl io-
dide 2 (0.50 mmol) and 4,4,5-trimethyl-1,3,2-dioxaborinane 1 (0.75
mmol) were successively added. The vial was sealed with a cap and
removed from the glove box. The reaction mixture was then stirred
at 80 °C for 16 h. After the reaction was complete, the mixture was
diluted with Et-2O, washed with brine and dried over Na2SO4. The
solvent was removed under reduced pressure and the residue was
purified by Kugelrohr distillation or flash column chromatography
(hexane–Et-2O) to give the desired arylboronate 3. All products 3
Pd(PPh3)4
K3PO4
O
Br Ar'
+
Ar Ar'
B
Ar
DMF, 80 °C
O
3
Entry Arylboronate
Aryl halide
Yield (%)b
93
1
O
Br
B
O
Me
MeO
(3h)
1
were characterized by H and 13C NMR spectroscopy and HRMS
analysis.
2
97
85
O
Br
3a
B
1H NMR (500 MHz, CDCl3): d = 1.33 (d, J = 6.1 Hz, 3 H), 1.35 (s,
3 H), 1.36 (s, 3 H), 1.57 (dd, J = 6.8, 11.6 Hz, 1 H), 1.84 (dd, J = 2.8,
6.8 Hz, 1 H), 3.81 (s, 3 H), 4.32 (br s, 1 H), 6.86 (d, J = 8.6 Hz, 2
H), 7.75 (d, J = 8.6 Hz, 2 H).
O
Me
MeO
3
4
3h
Me
Me
13C NMR (125 MHz, CDCl3): d = 23.25, 28.41, 31.59, 46.32, 55.29,
65.09, 71.04, 113.23, 135.66, 161.47.
Br
Br
HRMS (EI): m/z calcd for C13H19BO3: 234.1427; found: 234.1399.
90
3b
O
O
COMe
1H NMR (500 MHz, CDCl3): d = 1.33 (d, J = 6.1 Hz, 3 H), 1.34 (s,
3 H), 1.35 (s, 3 H), 1.56 (dd, J = 6.8, 12.2 Hz, 1 H), 1.83 (dd, J = 2.8,
6.8 Hz, 1 H), 3.79 (br s, 2 H), 4.30 (br s, 1 H), 6.65 (d, J = 8.0 Hz,
2 H), 7.62 (d, J = 8.6 Hz, 2 H).
B
(3c)
5
6
3c
3c
97
98
13C NMR (125 MHz, CDCl3): d = 23.29, 28.16, 31.36, 46.10, 64.71,
70.60, 114.11, 135.29, 148.37.
Br
CN
HRMS (EI): m/z calcd for C12H18BNO2: 219.1430; found:
219.1479.
TfO
CO2Et
3c
a Reaction conditions: arylboronate (0.25 mmol), aryl bromide (0.25
mmol), K3PO4 (0.75 mmol), Pd(PPh3)4 (7.5 mmol) in DMF (1 mL) at
1H NMR (500 MHz, CDCl3): d = 1.35 (d, J = 6.1 Hz, 3 H), 1.36 (s,
3 H), 1.37 (s, 3 H), 1.58 (dd, J = 6.8, 11.9 Hz, 1 H), 1.86 (dd, J = 2.8,
6.8 Hz, 1 H), 4.34 (br s, 1 H), 7.33 (t, J = 7.0 Hz, 2 H), 7.4–7.8 (m,
3 H).
100 °C for 2 h.
b GC yields.
13C NMR (125 MHz, CDCl3): d = 23.20, 28.13, 31.27, 46.01, 64.93,
70.92, 127.40, 130.29, 133.72.
boron functionality and excellent stability in aqueous
workup and chromatography. Further studies are current-
ly underway to expand the scope of organic halides and
dialkoxyboranes.
HRMS (EI): m/z calcd for C12H17BO2: 204.1321; found: 204.1346.
3d
1H NMR (500 MHz, CDCl3): d = 1.35 (d, J = 6.1 Hz, 3 H), 1.37 (s,
3 H), 1.39 (s, 3 H), 1.40 (t, J = 6.3 Hz, 3 H), 1.60 (dd, J = 7.0, 11.9
Hz, 1 H), 1.88 (dd, J = 3.1, 7.0 Hz, 1 H), 4.36 (br s, 1 H), 4.37 (q,
J = 7.1 Hz, 2 H), 7.86 (d, J = 8.5 Hz, 2 H), 7.98 (d, J = 8.5 Hz, 2 H).
All experiments were carried out under a nitrogen atmosphere using
oven-dried glassware. NMR spectra were recorded on a JEOL
JMN-A500 spectrometer. Mass spectra were obtained at an ioniza-
tion potential of 70 eV with a JEOL JMS-SX102 spectrometer.
Bis(2-di-tert-butylphosphinophenyl)ether (4) was prepared by a
known method.8
13C NMR (125 MHz, CDCl3): d = 14.34, 23.14, 28.17, 31.22, 45.97,
60.89, 65.20, 71.32, 128.34, 131.82, 133.73, 167.03.
HRMS (EI): m/z calcd for C15H21BO4: 276.1533; found: 276.1577.
3e
1H NMR (500 MHz, CDCl3): d = 1.36 (d, J = 6.1 Hz, 3 H), 1.38 (s,
3 H), 1.39 (s, 3 H), 1.61 (dd, J = 7.0, 12.2 Hz, 1 H), 1.89 (dd, J = 2.8,
6.9 Hz, 1 H), 2.61 (s, 3 H), 4.36 (br s, 1 H), 7.88 (d, J = 8.6 Hz, 2
H), 7.90 (d, J = 8.6 Hz, 2 H).
Synthesis of 4,4,6-Trimethyl-1,3,2-dioxaborinane
A flask equipped with a distillation apparatus and an oil bubbler was
flushed with nitrogen, charged with CH2Cl2 (10 mL) and hexylene
glycol (2.6 mL, 20 mmol) through the septum inlet with a syringe
and cooled to 0 °C. Then BH3·SMe2 (2.0 mL, 20 mmol) was added
dropwise leading to effervescence. After the mixture was stirred for
2 h at 0 °C and for 1 h at r.t., distillation under reduced pressure af-
forded 2.0 g (78% yield) of 4,4,5-trimethyl-1,3,2-dioxaborinane (1),
bp 45 °C at 35 mmHg.
13C NMR (125 MHz, CDCl3): d = 23.10, 26.72, 28.13, 31.17, 45.92,
65.19, 71.33, 127.06, 133.90, 138.28, 198.68.
HRMS (EI): m/z calcd for C14H19BO3: 246.1427; found: 246.1416.
Synthesis 2007, No. 3, 351–354 © Thieme Stuttgart · New York

354
3f
M. Murata et al.
PAPER
(0.75 mmol), and Pd(PPh3)4 (7.5 mmol) in DMF (1 mL) was stirred
at 100 °C for 2 h. The resulting mixture was diluted with toluene
and washed with H2O. The GC analysis of the organic layer indicat-
ed the formation of the desired biaryl in 93% yield.
1H NMR (500 MHz, CDCl3): d = 1.35 (d, J = 6.7 Hz, 3 H), 1.37 (s,
3 H), 1.38 (s, 3 H), 1.60 (dd, J = 6.8, 11.6 Hz, 1 H), 1.90 (dd, J = 3.1,
6.8 Hz, 1 H), 4.36 (br s, 1 H), 7.43 (t, J = 7.3 Hz, 1 H), 7.66 (d,
J = 7.3 Hz, 1 H), 8.01 (d, J = 7.3 Hz, 1 H), 8.09 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 23.06, 28.12, 31.42, 45.93, 65.37,
71.60, 111.58, 119.38, 128.03, 133.53, 137.65, 137.91.
Acknowledgment
We would like to thank Professor Akira Suzuki (Professor Emeritus
of Hokkaido University) for his fruitful discussions and sugges-
tions.
HRMS (EI): m/z calcd for C13H16BNO2: 229.1275; found:
229.1304.
3g
1H NMR (500 MHz, CDCl3): d = 1.37 (d, J = 6.1 Hz, 3 H), 1.39 (s,
3 H), 1.40 (s, 3 H), 1.62 (dd, J = 7.0, 12.2 Hz, 1 H), 1.91 (dd, J = 3.1,
7.0 Hz, 1 H), 4.38 (br s, 1 H), 7.95 (d, J = 8.6 Hz, 2 H), 8.15 (d,
J = 8.6 Hz, 2 H).
References and Notes
(1) For reviews of the Suzuki coupling, see: (a) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Miyaura, N.
Adv. Organomet. Chem. 1998, 6, 187. (c) Miyaura, N. Top.
Curr. Chem. 2002, 219, 11.
13C NMR (125 MHz, CDCl3): d = 23.04, 28.14, 31.13, 45.89, 65.47,
71.72, 122.13, 134.65, 149.87.
(2) For reviews of the Miyaura borylation, see: (a) Ishiyama,
T.; Miyaura, N. J. Organomet. Chem. 2000, 611, 392.
(b) Ishiyama, T.; Miyaura, N. Chem. Rec. 2004, 3, 271.
(3) (a) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem.
1997, 62, 6458. (b) Murata, M.; Oyama, T.; Watanabe, S.;
Masuda, Y. J. Org. Chem. 2000, 65, 164.
(4) (a) Murata, M.; Watanabe, S.; Masuda, Y. Tetrahedron Lett.
2000, 41, 5877. (b) Murata, M.; Oyama, T.; Watanabe, S.;
Masuda, Y. Synthesis 2000, 778. (c) Murata, M.; Oyama,
T.; Watanabe, S.; Masuda, Y. Synth. Commun. 2002, 32,
2513.
(5) Baudoin, O.; Guénard, D.; Guéritte, F. J. Org. Chem. 2000,
65, 9268.
(6) Wolan, A.; Zaidlewicz, M. Org. Biomol. Chem. 2003, 1,
3274.
(7) Broutin, P.-E.; Čerña, I.; Campaniello, M.; Leroux, F.;
Colobert, F. Org. Lett. 2004, 6, 4419.
(8) Murata, M.; Sambommatsu, T.; Watanabe, S.; Masuda, Y.
Synlett 2006, 1867.
HRMS (EI): m/z calcd for C12H16BNO4: 249.1173; found:
249.1156.
3h
1H NMR (500 MHz, CDCl3): d = 1.34 (d, J = 6.1 Hz, 3 H), 1.37 (s,
3 H), 1.39 (s, 3 H), 1.63 (dd, J = 7.0, 11.9 Hz, 1 H), 1.86 (dd, J = 3.1,
7.0 Hz, 1 H), 3.80 (s, 3 H), 4.38 (br s, 1 H), 6.82 (d, J = 7.3 Hz, 1
H), 6.92 (t, J = 7.3 Hz, 1 H), 7.31 (t, J = 7.3 Hz, 1 H), 7.59 (d,
J = 7.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 23.11, 28.07, 31.18, 45.85, 55.70,
65.06, 71.02, 110.80, 120.18, 131.06, 135.38, 163.43.
HRMS (EI): m/z calcd for C13H19BO3: 234.1427; found: 234.1415.
3i
1H NMR (500 MHz, CDCl3): d = 1.32 (d, J = 6.1 Hz, 3 H), 1.35 (s,
3 H), 1.41 (s, 3 H), 1.63 (dd, J = 6.8, 12.2 Hz, 1 H), 1.91 (dd, J = 3.1,
6.8 Hz, 1 H), 2.21 (s, 3 H), 2.31 (s, 6 H), 4.37 (br s, 1 H), 6.75 (s, 2
H).
(9) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992,
57, 3482.
(10) (a) Woods, W. G.; Strong, P. L. J. Am. Chem. Soc. 1966, 88,
4667. (b) Smith, H. D. Jr.; Brotherton, R. J. Inorg. Chem.
1970, 9, 2443.
13C NMR (125 MHz, CDCl3): d = 21.16, 21.82, 23.20, 28.02, 31.17,
46.24, 65.22, 71.32, 127.13, 137.75, 139.97.
HRMS (EI): m/z calcd for C15H23BO2: 246.1792; found: 246.1830.
(11) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
Palladium-Catalyzed Biaryl Coupling; Typical Procedure
(Table 3)
A mixture of 2-(2-methoxyphenyl)-4,4,6-trimethyl-1,3,2-diox-
aborinane (3h) (0.25 mmol), 2-bromotoluene (0.25 mmol), K3PO4
Synthesis 2007, No. 3, 351–354 © Thieme Stuttgart · New York