Preparation of potassium azidoaryltrifluoroborates and their cross-coupling with aryl halides

Article abstract of DOI:10.1021/ol901669k

Potassium azldoaryltrlfluoroborates have been prepared from the corresponding haloaryltrifluoroborates In 73-98% yields. Also, we successfully cross-coupled the azido-functlonallzed organotrifluoroborates and carried out a one-pot sequential cross-couplin

Full text of DOI:10.1021/ol901669k

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4330-4333
Preparation of Potassium
Azidoaryltrifluoroborates and Their
Cross-Coupling with Aryl Halides
Young Ae Cho,† Dong-Su Kim,† Hong Ryul Ahn,† Belgin Canturk,‡
Gary A. Molander,*,‡ and Jungyeob Ham*,†
Korea Institute of Science and Technology, 290 Daejeon-dong,
Gangneung 210-340, Korea, and Roy and Diana Vagelos Laboratories, Department of
Chemistry, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104-6323
ham0606@kist.re.kr; gmolandr@sas.upenn.edu
Received July 22, 2009
ABSTRACT
Potassium azidoaryltrifluoroborates have been prepared from the corresponding haloaryltrifluoroborates in 73-98% yields. Also, we successfully
cross-coupled the azido-functionalized organotrifluoroborates and carried out a one-pot sequential cross-coupling/1,3-dipolar cycloaddition
and a one-pot cross-coupling/azide reduction process.
The azide functional group has been used as an important
moiety for the formation of nitrogen-containing compounds
in fields ranging from synthetic organic chemistry to
pharmaceutical chemistry, materials science, and biology.1
Alkyl and aryl azides have gained prominence in particular
because they may be used for the preparation of [1,2,3]-
triazoles by Cu-catalyzed 1,3-dipolar cycloadditions onto
terminal alkynes (via “Click” chemistry).2 Unfortunately, the
preparation of certain classes of organic azides has presented
considerable challenges. Moreover, to the best of our
knowledge, the Suzuki-Miyaura cross-coupling reaction
with boron reagents bearing the azide functional group has
not been reported, perhaps because of the inherent difficulty
in preparing such bifunctional molecules and the perceived
instability of the azide under cross-coupling reaction condi-
tions.
Recently, organotrifluoroborate salts have been used as
important synthetic reagents in the Suzuki-Miyaura cross-
coupling reaction, providing many advantages over the
corresponding boronic acids or boronate esters.3 The orga-
notrifluoroborates are air- and moisture-stable, crystalline
solids that are inert to various nucleophilic reagents owing
to the tetracoordinate nature of the boron.4
† Korea Institute of Science and Technology (Gangneung Institute).
‡ University of Pennsylvania.
Consequently, it seemed likely that they would be tolerant
of conditions allowing the incorporation of the azide
(1) (a) Sheradsky, T. In Chemistry of the Azido Group; Patai, S., Ed.;
Wiley: New York, 1971. (b) Scriven, E. F. V.; Turnbull, K. Chem. ReV.
1988, 88, 297. (c) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188, and references therein.
(3) (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.
(2) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Chapter 1, p 1. (b) Padwa, A. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 4, p 1069. (c) Gothelf, K. V.; Jørgensen, K. A. Chem.
ReV. 1998, 98, 863. (d) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
(4) (a) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031. (b) Molander,
G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597. (c) Molander, G. A.;
Canturk, B. Org. Lett. 2008, 10, 2135. (d) Ahn, H. R.; Cho, Y. A.; Kim,
D.-S.; Chin, J.; Gyoung, Y.-S.; Lee, S.; Kang, H.; Ham, J. Org. Lett. 2009,
11, 361.
´
Chem., Int. Ed. 2001, 40, 2004. (e) Gil, M. V.; Are´valo, M. J.; Lopez, O.
Synthesis 2007, 11, 1589. (f) Meldal, M.; Tornoe, C. W. Chem. ReV. 2008,
108, 2952, and references therein.
10.1021/ol901669k CCC: $40.75
Published on Web 09/08/2009
 2009 American Chemical Society

functional group. Herein, we describe the first preparation
of azidoaryltrifluoroborates from the corresponding haloaryl-
trifluoroborates and reaction conditions permitting Suzuki-
Miyaura cross-coupling reactions of the azidoaryltrifluoro-
borates thus generated.
B(OiPr)3 using 1.0 equiv of n-BuLi (Table 1). When dibromo
or diiodobenzenes were used as starting materials, the target
compounds were obtained in good yields except when 1,2-
diiodobenzene was used. Interestingly, the reaction of
dibromo pyridines gave the corresponding organotrifluo-
roborates in excellent yields. The reaction of 2,5-dibromo-
p-xylene was also problematic, providing the desired product
in much lower yield (Table 1, 5a 47%) under the same
reaction conditions.
As a starting point, potassium haloaryltrifluoroborates were
generated via the one-pot synthesis of aryl dihalides and
Next, using conditions previously developed for the
preparation of aryl azides with aryl halide and Cu/amine-
ligand,1,5 we attempted the formation of azidoaryltrifluo-
roborates (Table 2).
Table 1. One-Pot Preparation of Potassium
Haloaryltrifluoroborates from Various Aryl Dihalidesa
Table 2. Optimization of Reaction Conditions for the
Preparation of Potassium 4-Azidophenyltrifluoroborate (1b)a
reaction
entry CuX ligand
base
time (h) conversion yield (%)b
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
a
b
c
d
e
f
g
h
f
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
24
5
16
24
15
1
24
48
2
66
98
100
81
100
100 (88)c
trace
68
9
CuId
CuBr
CuBr
CuBr
100 (89)c
100 (92)c
100 (94)c
100
10
11
12e
f
f
f
1
0.5
2.5
a All reactions were performed on a 0.05 mmol scale in 0.5 mL of
b
1
DMSO-d6 in an NMR tube. Percent conversions were determined by H
NMR of the reaction mixtures. The conversion yield was based on the
integration of peaks at 7.14 (1a-I) ppm and 6.85 (1b) ppm, respectively.
c Reactions were performed on a 0.1 mmol scale and isolated yields are
reported. d Five molar percent of CuI was used. e Reaction was performed
in DMF-d7.
We first carried out the reaction of potassium 4-azidophe-
nyltrifluoroborate (1b) generated in situ by treatment of 1a-I
with 1.0 equiv of NaN3 in the presence of 10 mol % of Cu(I)
and various amine ligands.
A number of different amine ligands were screened for
their efficacy in promoting the azidation, and it was found
that N,N′-dimethylethylenediamine (ligand f) provided the
fastest reaction time and the highest converted yield (Table
2, entry 6). Although both CuI and CuBr catalysts generated
the target compound 1b under the same reaction conditions
(Table 2, entries 6 and 10), the isolated yield and purity of
compound 1b using CuBr were better than those of using
a Reaction conditions: aryl dihalide (2.0 mmol), triisopropyl borate (2.0
mmol), and n-BuLi (2.0 mmol) at -78 °C to rt under N2 and then quenched
with 1 N KHF2.
Org. Lett., Vol. 11, No. 19, 2009
4331

10 and 11), and DMSO-d6 appeared to be a better solvent
than DMF-d7 (Table 2, entries 11 and 12). Using these
conditions (Table 2, entry 11), the azidation of various
potassium haloaryltrifluoroborates was examined (Table 3).
As a general rule, isolated yields and reaction rates of the
corresponding azidophenyltrifluoroborates increased in the
order para > meta > ortho under the same conditions (Table
3, 1b-3b). Both mono- and dimethyl-substituted aryltrif-
luoroborates afford the corresponding azidoaryltrifluorobo-
rates in satisfactory yields (Table 3, 4b-5b). Surprisingly,
when organotrifluoroborates 7a, 8a, and13a were used as
starting materials, aminoaryltrifluoroborates were generated
in good yields instead of azidoaryltrifluoroborates.
Table 3. One-Pot Preparation of Potassium
Azidoaryltrifluoroboratesa
On the other hand, the azidation reactions of bromopy-
ridinyl and iodonaphthyl organotrifluoroborates proceeded
readily to give the desired azide compounds in excellent
yields (Table 3, 9b-12b and 16b). Naphthyl organotrifluo-
roborates were not suitable for this azidation because the
resulting products were contaminated with the starting
material or mixtures of azido- and aminoaryltrifluoroborates
(Table 3, 14b and 15b).
We next examined the Suzuki-Miyaura cross-coupling
reaction of 4-azidophenyltrifluoroborate (1b) and various aryl
halides in the presence of Pd catalyst and 3.0 equiv of
Cs2CO3 (Table 4). As expected, the coupling of aryl and
Table 4. Cross-Coupling Reactionsa
a Reaction conditions A: potassium 4-azidophenyltrifluoroborate (1b,
0.2 mmol), aryl bromide (0.2 mmol), 10 mol % of PdCl2(dppf)·CH2Cl2,
Cs2CO3 (0.6 mmol), MeOH (1.5 mL), 80 °C.; B: 1b (0.2 mmol), aryl
chloride (0.2 mmol), 3 mol % of Pd(OAc)2, 6 mol % of XPhos, Cs2CO3
(0.6 mmol), 1,4-dioxane/H2O (10/1, 1.5 mL), 100 °C. Yields are given for
isolated products.
a All reactions were performed on a 1.0 mmol scale in 4 mL of DMSO
and monitored by 1H NMR in D2O. Yields are given for isolated products.
b Reaction was performed on a 3.0 mmol scale. c Products were obtained
as amorphous solids. d Product was contaminated with about 10% of 14a.
e Product was contaminated with about 15% of the azide product.
heteroaryl bromides led to the corresponding target products
in good yields. Aryl chlorides were generally ineffective as
coupling partners.
CuI. A decrease in the catalyst loading from 10 to 5 mol %
effectively doubled the reaction time (Table 2, entries 6 and
9).
When Cs2CO3 was used as a base instead of K2CO3, the
reaction time decreased from 1 h to 30 min (Table 2, entries
Finally, we examined one-pot sequential reactions that
incorporated cross-coupling followed by 1,3-dipolar cycload-
4332
Org. Lett., Vol. 11, No. 19, 2009

dition or NaBH4 reduction to the amine (eqs 1 and 2).6 These
processes provided the desired compounds in good overall
yields.
successfully cross-coupled the azido-functionalized organ-
otrifluoroborates and carried out a one-pot sequential cross-
coupling/1,3-dipolar cycloaddition and a one-pot cross-
coupling/azide reduction process. Further investigations on
transformations of azido-substituted trifluoroborates are cur-
rently underway in our laboratory.
Acknowledgment. This research was supported by KIST
Institutional Program (2Z03270) and a grant from Marine
Biotechnology Program funded by Ministry of Land, Trans-
port and Maritime Affairs, Republic of Korea. Support from
the NIH General Medical Sciences Institute is also acknowl-
edged.
In summary, we have developed a new synthetic method
for the preparation of potassium azidoarytrifluoroborates from
the corresponding haloaryltrifluoroborates. Additionally, we
Supporting Information Available: General experimental
procedures, compound characterization data, and NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(5) (a) Zhu, W.; Ma, D. Chem. Commun. 2004, 888. (b) Andersen, J.;
Madsen, U.; Bjo¨rkling, F.; Liang, X. Synlett 2005, 14, 2209, and references
therein.
(6) For detailed procedures, see Supporting Information.
OL901669K
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