Microwave enhanced formation of electron rich arylboronates

Article abstract of DOI:10.1055/s-2003-39896

Microwave assisted synthesis of eight electron rich aryl boronates (2a-c, 4, 6a-d) via palladium catalyzed reactions of the corresponding aryl bromides with bis(pinacolato)diboron are described. Compared to conventional heating conditions, dramatic rate e

Full text of DOI:10.1055/s-2003-39896

1
204
LETTER
Microwave Enhanced Formation of Electron Rich Arylboronates
M
P
icrowave
E
n
r
hance
d
F
a
o
rmation
o
s
f
E
lectro
n
a
Rich Ary
l
d
boro
n
ates Appukkuttan, Erik Van der Eycken, Wim Dehaen*
Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax +32(16)327990; E-mail: wim.dehaen@chem.kuleuven.ac.be
Received 3 April 2003
combination with the palladium catalysts.7 However,
these ligands are rather laborious to prepare, demanding
sensitive reaction conditions. It has been amply demon-
Abstract: Microwave assisted synthesis of eight electron rich aryl
boronates (2a–c, 4, 6a–d) via palladium catalyzed reactions of the
corresponding aryl bromides with bis(pinacolato)diboron are de-
scribed. Compared to conventional heating conditions, dramatic strated in the literature that the use of microwave irradia-
8
rate enhancements were found for reactions carried out under mi- tion is a very useful and handy tool in organic synthesis.
crowave irradiation, reducing reaction times from hours or days to Microwave irradiation often considerably diminishes the
only minutes.
reaction time and provides a higher yield. As a part of our
Key words: palladium, bis(pinacolato)diboron, arylboronates, mi- research, we were interested in the synthesis of some elec-
crowave irradiation, indoles
tron rich (hetero)arylboronates. Therefore, we decided to
explore the use of microwave enhanced palladium cata-
lyzed boronations of electron rich aromatic substrates. Al-
9
Palladium catalyzed C-C bond forming reactions are of though Fürstner has reported the microwave assisted
extreme interest in present day chemistry. One reason is synthesis of pinacol boronates, the issue of more challeng-
their widespread application in the synthesis of biologi- ing electron rich substrates has not been addressed in this
1
cally active natural product analogues. Among the pleth- strategy. In this communication, we wish to present the
ora of available literature, the Suzuki–Miyaura (S–M) microwave enhanced boronation of some electron rich ar-
2
cross coupling reaction is widely regarded as the best omatic halogenated compounds. A comparison with the
choice because of the ease of handling and mild reaction results obtained under conventional heating conditions is
conditions. Considerable work has been reported in recent presented.
years to develope new strategies for the formation of aryl-
We started our studies on palladium catalyzed borona-
boronates, as they are valuable substrates in S–M cross-
tions of electron rich aryl halides by choosing 4-(N,N-
3
4
couplings and in the selective binding of carbohydrates.
dimethylamino)bromobenzene (1a) as the substrate. The
reported transmetalation methods were low yielding
while the palladium catalyzed boronations, under conven-
tional heating conditions, were slow and also low yield-
There is a vast number of literature available for the syn-
thesis of these boron derivatives via transmetalation reac-
5
tions, i. e. using palladium as the catalyst of choice, a
suitable organodiboron and the corresponding aryl halide
7
ing, except when bulky phosphine ligands were used. We
6
or triflate (Scheme 1). Each method has its specific draw-
therefore decided to investigate the effect of microwave
irradiation on the course of the reaction. All the reactions
backs: transmetalation methods using magnesium or
lithium do not tolerate a wide variety of functional groups
and they often need laborious protection-deprotection
sequences, while the palladium catalyzed boronation
methods are often reported to be slow and low yielding in
the case of electron rich, and ortho-substituted as well as
sterically hindered aromatic halides or triflates.7
were carried out using Pd(dppf)Cl as the catalyst and
2
KOAc as the base at an irradiation power of 150 W (for
DMSO) or 250 W (for DME or Dioxane), the reaction
times varying from 17–27 minutes. Best results were ob-
tained upon microwave irradiation of a solution of 1a in
DMSO for 20 min at a pre-selected temperature of 150 °C.
An efficient method recently described to circumvent The boronate 2a was isolated in 83% yield with minor
these problems is the use of bulky phosphine ligands in decomposition products (Scheme 2, Table 1). This result
Br
O
B
O
O
O
O
+
B
B
Pd(dppf)Cl2/KOAc
O
DMSO, DME or Dioxane
R
R
Scheme 1 General strategy for the palladium catalyzed boronation of aryl bromides.
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,MM,1204,1206,ftx,en;G06903ST.pdf.
©
Georg Thieme Verlag Stuttgart ·New York

LETTER
Microwave Enhanced Formation of Electron Rich Arylboronates
1205
prompted us to investigate the boronation of 4-bromo- Boronates derived from mono-, di-, and triphenylamines
aniline 1b, which proceeded very slowly under conven- are very interesting targets as they can selectively bind to
12
tional heating. Applying the same microwave irradiation fluoride ions (Scheme 3). However, the existing proce-
conditions, the reaction proceeded smoothly within 22 dures are rather low yielding affording the boronates in
1
2
min yielding the boronate 2b in 85% yield (Table 1). We only 20–30%. We therefore decided to investigate the
then envisaged the boronation of 2-bromoaniline 1c. The microwave enhanced palladium catalyzed boronation of
synthesis of this compound as described in the literature is tris(4-bromophenyl)amine (3).
rather troublesome, requiring nitration of the phenylbo-
ronic acid and subsequent reduction to the amino deriva-
1
0
tive followed by conversion into the boronate. For the
direct boronation of 2-bromoaniline 1c the use of bulky
phosphine ligands in combination with pinacol borane is
O
O
O
O
B
B
O
O
Br
B
1
1
Pd(dppf)Cl /KOAc
2
also described. We therefore decided to investigate the
reaction under microwave irradiation. Applying the same
conditions as for 1a,b we obtained the boronate 2c in 74%
yield upon irradiation for 22 minutes (Scheme 2, Table 1).
DME/ MW/ 150 °C
N
N
O
O
Br
Br
B
B
3
O
4
O
Table 1 Comparison of the Palladium Catalyzed Boronations under
a
Conventional Heating as well as Under Microwave Irradiation
Scheme 3 Microwave assisted boronation of tris(4-bormophenyl)
Halide Product Conventional Heating Microwave Irradiation
15
amine.
Time (h) Yield (%)
Time (min) Yield (%)
d
1
1
a
b
c
2a
2b
24b
23
20
74
83
Irradiation of a solution of 3 in DME for 17 min at 150 °C
applying the same catalyst and base afforded the tribor-
onate 4 in 89% (Table 1).
e
2
0
18c
63
22
d
e
67
85
2
2
Indole derivatives are extremely valuable in medicinal
chemistry as a large number of biologically active natural
1
3
5
2c
4
24c
12
70
20
22e
17f
22f
74
89
74
13
products display this moiety in their skeleton. Although
palladium catalyzed S–M cross-coupling reactions have
been well investigated on these systems for the formation
of the indole-aryl skeleton, these studies have been mainly
restricted to the 2- and 3-substituted indole derivatives. A
main reason for this is the limited availability of the 4-, 5-
b
a
b
c
6a
35
72
66
c
4
8
b
c
d
5
5
6b
6c
6d
48
45
58
27
27
45
60
e
4
8
,
6- and 7-boronoindoles (Scheme 4). Reports on the syn-
b
c
d
thesis of 4-, and 5-boronoindoles by palladium catalyzed
48
50
57
27
22
63
69
14
e
reactions are very limited while, to the best of our
knowledge, this strategy has never been used for the 6-
and 7- derivatives.
4
2
b
c
d
e
5
d
48
72
75
22
17
70
77
3
9
Rather long reaction times are spotted as a major draw-
back of this method, e.g. 192 hours for the palladium cat-
a
All reactions were carried out with KOAc as the base and
Pd(dppf)Cl as the catalyst under conventional heating conditions.
2
14
alyzed boronation of 5-bromoindole, demanding the
b
1
00° C in dioxane.
c
d
e
f
application of microwave irradiation in this context. Prior
to the microwave irradiation experiments, all reactions
were optimized under conventional heating conditions,
whose details are presented in Table 1.
1
50 °C in DMSO, and upon microwave irradiation.
25 °C in dioxane.
50 °C in DMSO.
50 °C in DME.
1
1
1
O
Br
R
O
O
O
O
B
Pd(dppf)Cl2 /KOAc
Dioxane or DMSO
O
B
B
R1
R1
R
1
1
1
1
a R = H, R = NMe2
2a, 2b, 2c
1
b R = H, R = NH2
1
c R = NH2, R = H
Scheme 2 Palladium catalyzed boronation of bormoanilines (2a–c).
Synlett 2003, No. 8, 1204–1206 ISSN 1234-567-89 © Thieme Stuttgart · New York

1
206
P. Appukkuttan et al.
LETTER
(
3) (a) Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami,
S. Org. Lett. 2002, 4, 3371. (b) Uozumi, Y.; Nakai, Y. Org.
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Pd(dppf)Cl2 / KOAc
Dioxane or DMSO
R1
R
N
H
N
H
1
O
O
O
O
6a R = 4-B(pin)
6b R = 5-B(pin)
c R = 6-B(pin)
d R = 7-B(pin)
5
5
5
5
a R = 4-Br
(
(
(
B
B
1
b R = 5-Br
c R = 6-Br
d R = 7-Br
477. (b) Yang, W.; He, H.; Dreuckhammer, D. G. Angew.
1
6
6
Chem. Int. Ed. 2001, 40, 1714.
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(
b) Wong, K.-T.; Chien, Y.-Y.; Liao, Y.-l.; Lin, C.-C.; Chou,
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M.-Y.; Leung, M.-K. J. Org. Chem. 2002, 67, 1041.
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Microwave irradiation for 17–27 min of a DMSO solution
of 5-, 6-, 7- bromoindoles 5b–d containing Pd(dppf)Cl as
2
the catalyst and KOAc as the base at a pre-selected tem-
perature of 150 °C (150 W irradiation power) afforded the
boronates 6b–d in good yields (Table 1). With 4-bromoin-
dole 5a, the best results were obtained by replacing
DMSO with DME (250 W irradiation power), while the
(
e) Ishiyama, T.; Itoh, Y.; Kitano, K.; Miyaura, N.
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9
1
4
available literature states 66% yield in DMSO under
conventional heating conditions. Applying these micro-
wave irradiation conditions the amount of deboronation
side products could be considerably diminished. The
presence of side products, arising from Suzuki coupling
of the boronates formed with the haloindoles, were not
detected during the course of the reaction.
(
8
R. J. Comb. Chem. 2002, 2, 95. (d) Kappe, C. O. Curr.
Opin. Chem. Biol. 2002, 6, 314. (e) Lidstrom, P.; Westman,
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In conclusion, we have demonstrated that the palladium
catalyzed reactions of some electron rich aryl bromides
a–c, of a triphenylamine 3 and of the 4-, 5-, 6- and 7-bro-
moindoles 5a–d could be dramatically accelerated upon
microwave irradiation. The obtained yields are higher and
in some cases clearly superior to those described in the
literature. For the aryl bromides 1a–c the extent of de-
boronation has been considerably reduced.
1
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2
2
(
(
(
Acknowledgement
We wish to thank the FWO-Vlaanderen and the Katholieke Univer-
siteit Leuven for their financial support, and Dr. G. Garcia of 4SC,
München for providing the bromoindoles.
2
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15) Representative Experimental Procedure. Synthesis of tris{4-
(
4,4,5,5-tetra-methyl-[1,3,2]dioxaborolan-2-yl)-
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(
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2
(
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(
°C and the crude mixture was filtered through a thin plug of
celite. The celite plug was washed with ether (3 ꢀ 5 mL), the
organic fractions were combined and the solvent was
removed under reduced pressure. The resultant crude
product was then washed with methanol (ꢀ 3) and
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(
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1
crystals. m p > 300 °C. H NMR (300 MHz, CDCl ): d = 1.36
3
1
3
(
s, 36 H), 7.10 (d, 6 H), 7.70 (s, 6 H). C NMR (75 MHz,
CDCl ): d = 24.8, 83.6, 123.5, 135.90, 149.8. LR-MS (EI)
3
+
[
M ]: 624 (39), 623 (100), 622 (69), 497 (15), 496 (7). HR-
MS (EI): C H B NO Calcd 623.3760, found. 623.3755.
3
6
48
3
6
Synlett 2003, No. 8, 1204–1206 ISSN 1234-567-89 © Thieme Stuttgart · New York