Preparation of potassium Alkynylaryltrifluoroborates from Haloaryltrifluoroborates via Sonogashira coupling reaction

Article abstract of DOI:10.1021/ol100081v

A novel serles of alkyne-containing potassium organotrifluoroborates were prepared in good yields from the corresponding haloaryltrifluoroborates and various alkynes via Sonogashlra coupling reaction. Also, the Suzuki-Miyaura cross-coupling reaction of alkynylaryltrifluoroborates with aryl and alkenyl bromides was achieved in the presence of 5 mol % of Pd(TPP)₄ and 3.0 equiv of Cs₂CO₃ in aqueous 1,4-dioxane at 150 °C by microwave irradiation.

Full text of DOI:10.1021/ol100081v

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1092-1095
Preparation of Potassium
Alkynylaryltrifluoroborates from
Haloaryltrifluoroborates via Sonogashira
Coupling Reaction
Dong-Su Kim and Jungyeob Ham*
Natural Products Research Center, Korea Institute of Science and Technology,
290 Daejeon-dong, Gangneung 210-340, Korea
ham0606@kist.re.kr
Received January 13, 2010
ABSTRACT
A novel series of alkyne-containing potassium organotrifluoroborates were prepared in good yields from the corresponding haloaryltrifluoroborates
and various alkynes via Sonogashira coupling reaction. Also, the Suzuki-Miyaura cross-coupling reaction of alkynylaryltrifluoroborates with
aryl and alkenyl bromides was achieved in the presence of 5 mol % of Pd(TPP)4 and 3.0 equiv of Cs2CO3 in aqueous 1,4-dioxane at 150 °C
by microwave irradiation.
Potassium organotrifluoroborates have become one of the
most important coupling partners in Suzuki-Miyaura
cross-coupling reactions as a result of their many advan-
tages over the corresponding boronic acids or boronate
esters such as easy preparation and purification, air- and
moisture-stability, and convenient handling.1 Moreover,
the inert property of organotrifluoroborates to a number
of reaction conditions has allowed the synthesis of more
complicated molecules that may not be prepared from
boronic acids or boronate esters. For example, the direct
functionalization of organotrifluoroborates successfully
performed include a variety of epoxidations,2 cis-dihy-
droxylations,3 oxidations,4 olefinations (Wittig reactions),5
nucleophilic substitution reactions,6 metal-halogen ex-
change reactions,7 1,3-dipolar cycloadditions,8 reductive
aminations,9 and condensation reactions.10 Also, Molander
and Sandrock reported the chemoselective transformation
of boryl-substituted organotrifluoroborates via Pd-cata-
lyzed cross-coupling to increase molecular complexity and
diversity.11 Recently, a copper-catalyzed C-N coupling
reaction of organotrifluoroborates for the preparation of
azidoaryltrifluoroborates has been demonstrated by our
(5) (a) Molander, G. A.; Figueroa, R. J. Org. Chem. 2006, 71, 6135.
(b) Molander, G. A.; Ham, J.; Canturk, B. Org. Lett. 2007, 9, 821. (c)
Molander, G. A.; Oliveira, R. A. Tetrahedron Lett. 2008, 49, 1266.
(6) (a) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031. (b) Molander,
G. A.; Canturk, B. Org. Lett. 2008, 10, 2135. (c) Molander, G. A.; Febo-
Ayala, W.; Ortega-Guerra, M. J. Org. Chem. 2008, 73, 6000.
(7) Molander, G. A.; Ellis, N. M. J. Org. Chem. 2006, 71, 7491.
(8) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2767.
(9) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2008, 73, 3885.
(10) Molander, G. A.; Febo-Ayala, W.; Jean-Ge´rard, L. Org. Lett. 2009,
11, 3830.
(1) (a) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49.
(b) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623. (c)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (d) Darses, S.;
Genet, J. -P. Chem. ReV. 2008, 108, 288. (e) Molander, G. A.; Canturk, B.
Angew. Chem., Int. Ed. 2009, 48, 9240. (f) Molander, G. A.; Sandrock,
D. L. Curr. Opin. Drug DiscoVery 2009, 12, 811.
(11) (a) Molander, G. A.; Sandrock, D. L. J. Am. Chem. Soc. 2008,
130, 15792. (b) Molander, G. A.; Sandrock, D. L. Org. Lett. 2009, 11,
2369.
(2) Molander, G. A.; Ribagorda, M. J. Am. Chem. Soc. 2003, 125, 11148.
(3) Molander, G. A.; Figueroa, R. Org. Lett. 2006, 8, 75.
(4) (a) Molander, G. A.; Petrillo, D. E. J. Am. Chem. Soc. 2006, 128,
9634. (b) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2007, 72, 3558.
(12) Cho, Y. A.; Kim, D.-S.; Ahn, H. R.; Canturk, B.; Molander, G. A.;
Ham, J. Org. Lett. 2009, 11, 4330.
10.1021/ol100081v  2010 American Chemical Society
Published on Web 02/11/2010

group.12 Thus, these transformations using palladium or
copper catalyst have proven to be very useful processes
to prepare highly functionalized organotrifluoroborates
without loss of the trifluoroborate group.
Table 1. Optimization of Sonogashira Reaction for the
Preparation of Potassium 4-(Phenylethynyl)phenyltrifluoroborate
(1)a
The Sonogashira reaction13 has been used for the prepara-
tion of natural products, pharmaceuticals, agricultural chemi-
cals, and industrial organic materials and is performed on
terminal alkynes with aryl or alkenyl halides in the presence
of palladium catalysts and a copper(I) halide as a co-catalyst.
Therefore, the Sonogashira reaction would also provide a
powerful method for constructing a C(sp)-C(sp2) bond
between terminal alkynes and haloaryltrifluoroborates as
starting materials.
time (h)/
temp (°C)
conversion
yield (%)b
entry
X
Pd catalyst
ligand
1
2
3
4
5
6
7
8
9
10
11
12f
13f,g
I
PdCl2(TPP)2 none
0.5/rt
0.5/rt
0.5/rt
0.5/rt
0.5/rt
1/rt
1/80
1/80
1/80
1/80
1/80
1/80
1/80
100 (98)c
100 (91)c
48
Although a number of methods have been reported in
the literature for the synthesis of alkynylarylboronate
esters from various terminal alkynes and haloarylboronate
ester through the Sonogashira reaction, these previous
methods still leave the problem of protecting the boronic
acid moiety with a relatively expensive diol reagent such
as pinacol or neopentyl glycol prior to the Sonogashira
reaction, and extant methods require long reaction times
or high reaction temperatures to obtain satisfactory
results.14 Moreover, the coupling of terminal alkynes using
potassium haloaryltrifluoroborates has not been reported
so far to the best of our knowledge.
I
I
I
I
Pd(TPP)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
none
none
TPPd
100 (88)c
54
XPhose
Br PdCl2(TPP)2 none
Br PdCl2(TPP)2 none
trace
22
30
trace
22
74
Br Pd(TPP)4
Br Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
none
none
TPP
XPhos
XPhos
XPhos
92
100 (93)c
a All reactions were performed on a 0.1 mmol scale in 0.5 mL of
DMSO-d6 in an NMR tube. b The conversion yield was based on the
integration of peaks at 7.14 (A), 7.24 (B), and 7.28 (1) ppm, respectively.
cIsolatedyieldof1.dTriphenylphosphine.e2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
f 1.5 equiv of phenylacetylene was used. g Reaction was performed
without CuI.
During the course of our synthetic studies on the
development of novel organotrifluoroborates, we discov-
ered a facile and highly efficient method for the prepara-
tion of potassium alkynylaryltrifluoroborates from the
corresponding haloaryltrifluoroborates and various alkynes
via the Sonogashira reaction. The resulting organotrifluo-
roborates could then be utilized as coupling partners in
cross coupling reactions.
reaction with 4-iodophenyltrifluoroborate (Table 1, entries
1-5). Among them, when PdCl2(TPP)2, Pd(TPP)4, and
Pd(OAc)2/TPP were used, the desired compound 1 was
readily prepared at room temperature within 30 min, and
their isolated yields were 98%, 91%, and 88%, respec-
tively (Table 1, entries 1, 2, and 4). However, when
Pd(OAc)2 and Pd(OAc)2/XPhos were used, the reactions
did not go to completion because 1,4-diphenylbutadiyne
was rapidly produced as a byproduct (Table 1, entries 3
and 5).
Herein, we report our results on the development of
such a transformation and the Suzuki-Miyaura cross-
coupling reaction of these alkynylaryltrifluoroborates by
microwave irradiation.
First, we investigated Pd-catalyzed Sonogashira reaction
of 4-iodo- and 4-bromophenyltrifluoroborate15 with phe-
nylacetylene under various conditions. The reactions were
performed in the presence of several palladium catalysts,
CuI as a co-catalyst, and piperidine as a base in an NMR
tube using DMSO-d6 (0.5 mL) as a solvent. The reaction
conditions explored are summarized in Table 1.
In the reactivity test of 4-bromophenyltrifluoroborate,
although the optimized Sonogashira reaction conditions
of 4-iodophenyltrifluoroborate were used, the reaction rate
was very slow (Table 1, entry 6). Also, we could not
completely obtain the desired compound 1 despite an
increase of the reaction temperature to 80 °C (Table 1,
entries 7-10). By contrast, when using Pd(OAc)2/XPhos
as a catalytic system and increasing the equivalents of
phenylacetylene, the conversion yields of the cross-
coupling reaction remarkably increased (Table 1, entries
11 and 12). Fortunately, a 93% isolated yield of product
1 was successfully obtained in the absence of CuI as a
co-catalyst (Table 1, entry 13).
A number of different palladium catalysts were screened
for their effectiveness in promoting the Sonogashira
(13) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(c) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103, 1979. (d) Tykwinski,
R. R. Angew. Chem., Int. Ed. 2003, 42, 1566. (e) Doucet, H.; Hierso, J.-C.
Angew. Chem., Int. Ed. 2007, 46, 834. (f) Chinchilla, R.; Na´jera, C. Chem.
ReV. 2007, 107, 874.
(14) (a) Schwier, T.; Rubin, M.; Gevorgyan, V. Org. Lett. 2004, 6, 1999.
(b) Perttu, E. K.; Arnold, M.; Iovine, P. M. Tetrahedron Lett. 2005, 46,
8753. (c) Zheng, S.-L.; Reid, S.; Lin, N.; Wang, B. Tetrahedron Lett. 2006,
47, 2331. (d) Nakamura, H.; Kuroda, H.; Saito, H.; Suzuki, R.; Yamori,
T.; Maruyama, K.; Haga, T. ChemMedChem 2006, 1, 729. (e) Yamamoto,
Y.; Hattori, K. Tetrahedron 2008, 64, 847. (f) Matsuda, T.; Kadowaki, S.;
Yamaguchi, Y.; Murakami, M. Chem. Commun. 2008, 2744.
(15) For the preparation of these potassium haloaryltrifluoroborates, see
the Supporting Information of ref 12.
With the optimized conditions for the formation of 1 from
4-iodophenyltrifluoroborate in hand (Table 1, entry 1), we
examined the scope of the Sonogashira reaction for the
Org. Lett., Vol. 12, No. 5, 2010
1093

synthesis of alkyne-functionalized organotrifluoroborates
using various terminal alkynes. The results are summarized
in Table 2.
the reactivity test of various alkyl alkynes, although using
saturated alkyl alkynes resulted in prolonged reaction
(Table 2, entries 7 and 8), there was no significant
influence by the functional group unit in the alkyl chain
(Table 1, entries 9-12).
Next, the Sonogashira reactions of various bromoaryltri-
fluoroborates with phenylacetylene were explored under
optimized condition (Table 1, entry 13). The results are
collected in Table 3.
Table 2. Preparation of Potassium Alkynylaryltrifluoroborates
with Various Alkynes via the Sonogashira Reactiona
Table 3. Preparation of Potassium Alkynylaryltrifluoroborates
with Various Potassium Bromoaryltrifluoroboratesa
a All reactions were carried out on a 0.5 mmol scale in 1.0 mL of DMSO
according to the optimized conditions of entry 13 in Table 1. b Isolated
yields. c Reaction was performed with potassium 3-iodophenyltrifluoroborate
as a starting material and the optimized conditions of entry 1 in Table 1.
d Conversion yield. e Reaction was performed with 3.0 equiv of pheny-
lacetylene and 1.5 equiv of Cs2CO3 instead of piperidine for 2 h.
a All reactions were carried out on a 0.5 mmol scale in 2.0 mL of DMSO
according to the optimized conditions of entry 1 in Table 1. b Isolated yields.
c Reaction time was 2 h.
In a test of reactivity between o-, m-, and p-bromophe-
nyltrifluoroborates, the yields of the corresponding orga-
notrifluoroborates increased in the order para > meta .
ortho (Table 3, entries 1-3). Indeed, ortho-substituted
trifluoroborate could not be isolated from the reaction
mixture (data not shown). 3-Bromophenyltrifluoroborates
bearing a substituent at the 5-position of the aromatic ring
(Table 3, entries 4 and 5) were converted into the
corresponding alkynylaryltrifluoroborates in moderate
yields. When 6-bromo-2-pyridyltrifluoroborate as a starting
material was used, by increasing the equivalents of
phenylacetylene and using Cs2CO3 as a base instead of
piperidine, the desired product was isolated in excellent
yield (Table 3, entry 6).
As expected, all of the alkynylaryltrifluoroborates were
readily generated from the corresponding terminal alkynes
and obtained in good yields without being contaminated
with byproducts such as alkyne-dimer or piperidine HI
salt. Interestingly, the presence of functional groups at
the para position of phenylacetylene did not affect the
yields of products (Table 2, entries 2-5). However, when
using 3-chlorophenylacetylene as a starting material, the
isolated yield of desired trifluoroborate 6 was slightly
lower than those of p-alkyne-substituted trifluoroborates
under the same reaction conditions (Table 2, entry 6). In
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Org. Lett., Vol. 12, No. 5, 2010

Finally, we turned our attention to the Suzuki-Miyaura
cross-coupling reaction of these alkynylaryltrifluorobo-
rates.
Table 5. Cross-Coupling Reactions by Microwave Irradiationa
As optimization studies revealed (Table 4), the cross-
coupling compound 18 was formed in a low yield of 21%
Table 4. Optimization of Cross-Coupling Reaction Conditionsa
entry
Pd catalyst/ligand
base
time (h) yield (%)b
1
2
3
4
5
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2/TPP
Pd(OAc)2/XPhos
Pd(TPP)4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
7
7
7
7
7
7
7
7
7
1
1
21
60
46
58
62
54
65
30
42
72
78
6
7
PdCl2(dppf)•CH2Cl2 K2CO3
Pd(TPP)4
Pd(TPP)4
Pd(TPP)4
Pd(TPP)4
Pd(TPP)4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
8c
9d
10e
11f
a All reactions were performed on a 0.1 mmol scale in 1.0 mL of 20%
aqueous 1,4-dioxane at 100 °C in an oil bath. b Isolated yields. c MeOH
was used as a solvent at 80 °C. d Reaction solvent was 20% aqueous toluene.
e Initial microwave irradiation of 80 W was used at 100 °C. f Microwave
temperature was 150 °C.
when the reaction was carried out at 100 °C in an oil bath
for 7 h with use of Pd2(dba)3 and K2CO3 (Table 4, entry
1). However, using Pd(OAc)2 and Pd(TPP)4 under the
same conditions, isolated yields of 18 increased to 60%
and 62%, respectively (Table 4, entries 2 and 5). When
Cs2CO3 was used as a base instead of K2CO3, the product
yield increased slightly (Table 4, entries 5 and 7).
In the survey of solvent effects, 20% aqueous 1,4-
dioxane was the best solvent, since the reactions in other
solvents (methanol or 20% aqueous toluene) gave lower
yields of 18 (Table 4, entries 8 and 9). Interestingly, we
found that changing the heating source from an oil bath
to microwave led to not only increased yield of cross-
coupling product but also decreased reaction time from 7
to 1 h (Table 4, entry 10). Especially, the yield of 18
increased to 78% when the reaction was performed at 150
°C for 1 h with microwave irradiation (Table 4 entry 11).
According to the optimized cross-coupling reaction condi-
tions, we examined the Suzuki-Miyaura reaction of various
alkynylaryltrifluoroborates with aryl and alkenyl bromides
by microwave irradiation. The results are shown in Table 5.
As expected, the coupling reactions were completed in 1 h
at 150 °C and provided the corresponding products in good
yields.
a All reactions were carried out on a 0.25 mmol scale using the optimized
conditions of entry 11 in Table 4 and an initial microwave irradiation of
80 W. b Isolated yields.
In summary, we have successfully prepared novel potas-
sium alkynylaryltrifluoroborates from the corresponding
haloaryltrifluoroborates with various terminal alkynes through
the Sonogashira reaction and performed the cross-coupling
reaction with microwave irradiation. Further applications
using these trifluoroborates are currently in progress.
Acknowledgment. This research was supported by the
KIST Institutional Program (2Z03270) and a grant from
Marine Biotechnology Program funded by Ministry of Land,
Transport and Maritime Affairs, Republic of Korea. We are
grateful to Professor Gary A. Molander (University of
Pennsylvania) for his scientific advice.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL100081V
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