Condensation reactions to form oxazoline-substituted potassium organotrifluoroborates

Article abstract of DOI:10.1021/ol901395c

A library of oxazoline-substituted potassium organotrifluoroborates was prepared via the condensation of various potassium formyl-substituted aryl- and heteroaryltrifluoroborates with tosylmethyl isocyanide under basic conditions. The efficient Suzuki-Miy

Full text of DOI:10.1021/ol901395c

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3830-3833
Condensation Reactions To Form
Oxazoline-Substituted Potassium
Organotrifluoroborates
Gary A. Molander,* Wilma Febo-Ayala, and Ludivine Jean-Ge´rard
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received June 19, 2009
ABSTRACT
A library of oxazoline-substituted potassium organotrifluoroborates was prepared via the condensation of various potassium formyl-substituted
aryl- and heteroaryltrifluoroborates with tosylmethyl isocyanide under basic conditions. The efficient Suzuki-Miyaura cross-coupling of products
thus formed to various aryl bromides was achieved in good yields. The method allows the facile preparation of oxazole-containing triaromatic
products in two steps from simple potassium formyl-substituted aryl- or heteroaryltrifluoroborates.
Oxazolines are important intermediates used in the synthesis
of bioactive compounds (e.g., ꢀ-hydroxy-R-amino acids),
amino alcohols, hydroxy amides, imidazoles, and oxazoles,
among others.1 Oxazolines also find applications as chiral
ligands in a wide range of asymmetric catalytic processes.1
4,5-Disubstituted oxazolines are of interest because they are
found in marine alkaloids, such as ulicyclamide (Figure 1),
which possess high bioactivity. Relatively few methods have
been reported for their preparation.2,3
Figure 1. Ulicyclamide.
(1) Wong, G. S. K.; Wu, W. 2-Oxazolines. In The Chemistry of
Heterocyclic Compounds; Palmer, D. C., Eds.; Oxazoles: Synthesis,
Reactions and Spectroscopy, Part B; John Wiley: Hoboken, 2004; Vol. 60,
pp 331-513.
Potassium organotrifluoroborates are tetracoordinate boron
species that are effortlessly prepared by adding inexpensive
aqueous KHF2 to tricoordinate organoboron intermediates.
They are crystalline solids that are easily purified by
precipitation or crystallization. The lack of an empty p-orbital
on boron makes them very stable, yet they are effective
nucleophiles when used in reactions such as Suzuki-Miyaura
cross-couplings. Until recently, the number of potassium
organotrifluoroborate structures that contain heterocycles has
been limited.4-6 Currently, the available potassium organ-
(2) Wipf, P. Chem. ReV. 1995, 95, 2115–2134
.
(3) (a) Hayashi, T.; Uozumi, Y.; Yamazaki, A. Tetrahedron Lett. 1991,
32, 2799–2802. (b) Soloshonok, V. A.; Hayashi, T. Tetrahedron Lett. 1994,
35, 2713–2716. (c) Le Merrer, Y.; Gravier-Pelletier, C.; Gerrouache, M.;
Depezay, J.-C. Tetrahedron Lett. 1998, 39, 385–388. (d) Benito-Garagorri,
D.; Bocokiæ, V.; Kirchner, K. Tetrahedron Lett. 2006, 47, 8641–8644. (e)
Shinada, T.; Ikebe, E.; Oe, K.; Namba, K.; Kawasaki, M.; Ohfune, Y. Org.
Lett. 2007, 9, 1765–1767. (f) Gosiewska, S.; Herreras Mart´ınez, S.; Lutz,
M.; Spek, A. L.; van Koten, G.; Klein Gebbink, R. J. M. Eur. J. Inorg.
Chem. 2006, 4600–4607. (g) Reetz, M. T.; Wu¨nsch, T.; Harms, K.
Tetrahedron Lett. 1989, 30, 3877–3880. (h) Ortuno, J.-C.; Langlois, Y.
Tetrahedron Lett. 1991, 32, 4491–4494
.
10.1021/ol901395c CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

otrifluoroborate-containing heterocycles have been synthe-
sized using two different strategies. The first involves the
addition of aqueous KHF2 to commercially available boronic
acids (eq 1).5 The second strategy allows the assembly of
the heterocycles from intermediates that already incorporate
the potassium organotrifluoroborate moiety. For example, the
synthesis of organo[1,2,3]triazol-1-yltrifluoroborates was
achieved from the copper-catalyzed 1,3-dipolar cycloaddition
of azidoalkyltrifluoroborates with alkynes (eq 2).6 The latter
approach allows the preparation of complex heterocycles
from readily available components.
Table 1. Aryl-Substituted Oxazolinesa
Herein, we report the use of the second tactic in the first
preparation of oxazoline-containing organotrifluoroborates
from the condensation of formyl-substituted aryl- and het-
eroaryltrifluoroborates with tosylmethyl isocyanide (TosMIC).
This approach fulfills a goal of our program to expand the
versatility of potassium organotrifluoroborates by incorpora-
ting nitrogen-, oxygen-, and sulfur-containing rings in their
substructures, taking advantage of the relative resistance of
the trifluoroborate moiety to a variety of reaction conditions
that are not tolerated by the corresponding boronic acids.
van Leusen et al. were the first to report the one-pot
preparation of oxazolines from the condensation between
tosylmethyl isocyanide and an aldehyde under basic condi-
tions.7 In addition, oxazoles were obtained upon elimination
of the toluenesulfonyl group under basic conditions at high
temperatures. In this report, a series of 4,5-disubstituted
trifluoroborato-containing oxazolines were prepared follow-
ing van Leusen’s method (eq 3).
a Reaction conditions: aldehyde (1 equiv), TosMIC (1 equiv), DBU-PS
(1 equiv), CH3CN (0.5 M), rt.
After exploring various reaction conditions, it was deter-
mined that the condensation of different formyl-substituted
aryl- and heteroaryltrifluoroborates with TosMIC was best
achieved in the presence of equimolar amounts of DBU in
acetonitrile at rt.8,9 Commercially available polystyrene-
bound DBU (DBU-PS) was used because it could be
conveniently removed from the product via filtration and
reused indefinitely (>10 times) after washing with methanolic
NaOH without lowering the yield.10 For example, 11b was
prepared in 89% yield with brand new resin and in 82% yield
with resin that had been recycled once. Also, 9b was prepared
in 73% yield with brand new resin and in 89% yield with
resin that was used and washed approximately five times as
described above. The optimal solution concentration was
found to be 0.5 M. Lower concentrations required a longer
reaction time, while 1 M reactions resulted in a thick slurry
that was inefficiently stirred.
(4) (a) Darses, S.; Geneˆt, J.-P. Chem. ReV. 2008, 108, 288–325. (b)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286.
(5) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009,
74, 973–980, and references cited therein.
(6) Molander, G. A.; Ham, J Org. Lett. 2006, 8, 2767–2770.
(7) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron
Lett. 1972, 23, 2369–2372.
With the optimized conditions in hand, we reacted different
potassium formyl aryltrifluoroborates (Table 1). The substitu-
(8) DBU stands for 1,8-diazabicyclo[5.4.0]undec-7-ene
(9) Other bases and reagents screened included K2CO3, KOt-Bu, NEt3,
.
DIPEA, guanidine, DABCO, and KCN. Other solvents tested were methanol,
(10) Tomoi, M.; Kato, Y.; Kakiuchi, H. Makromol. Chem. 1984, 185,
2117–2124.
ethanol, DME, and DMSO, but they resulted in very impure product
.
Org. Lett., Vol. 11, No. 17, 2009
3831

Table 2. Heteroaryl-Substituted Oxazolinesa
Figure 2
coupling.
. Ligands used in the optimization of the Suzuki-Miyaura
There have been few reports concerning direct incorporation
of boron into oxazolines and oxazoles. To the best of our
knowledge, only one oxazoleboronic acid has been prepared
and cross-coupled.11 The lack of oxazoline and oxazole
substructures possessing boron-based functional groups might
be attributed to the fact that these heterocycles may not be able
to withstand the conditions that are used to install the boronic
acid group.1 Furthermore, oxazoleboronic acids may be unstable
to protodeboronation, as are other heteroarylboronic acids.5,11,12
The method described herein serves as a means to prepare
oxazolines from components that already incorporate the
more robust potassium organotrifluoroborate, circumventing
the harsh conditions normally used to install the boronic acid.
A few Suzuki-Miyaura cross-couplings involving ox-
azoles have been reported. In the vast majority of cases, the
oxazole is used as the electrophile. In one example, an
oxazole boronate ester was employed, and in a second
example an oxazoleboronic acid was utilized as a nucleo-
philic partner.11,13,14
In attempts to carry out the Suzuki-Miyaura cross-coupling
of the synthesized oxazoline-incorporated organotrifluoroborates
described herein, a variety of catalyst/ligand combinations
(Figure 2), solvents, and bases were screened to maximize the
yields.15 None of the conditions tried maintained the integrity
of the sulfonyl group. The use of a base and high temperatures
typically required for the reaction generated oxazoles instead.
We successfully achieved the Suzuki-Miyaura cross-coupling
of the oxazolinyl-substituted aryltrifluoroborates to various
electrophiles using 1 mol % of Pd(OAc)2/2 mol % of DavePhos
a Reaction conditions: aldehyde (1 equiv), TosMIC (1 equiv), DBU-PS
(1 equiv), CH3CN (0.5 M), rt.
tion of the trifluoroborate moiety in the ortho (3a), meta (2a)
or para (1a) position of the aryl ring did not significantly
affect the product yield. However, the meta-substituted
substrate gave the best yield (97%). Electron-withdrawing
(4a) and electron-donating (5a) groups para to the aldehyde
did seem to have an effect, giving higher yields for the former
(94%) than the latter (56%). Also, benzyloxy (6a), methyl
(7a), and methylenedioxy (8a) substitutions were well
tolerated (Table 1).
Next, we extended the developed conditions to potassium
formyl-substituted heteroaryltrifluoroborates (Table 2). The
reaction time increased significantly for most cases when
compared to the aryltrifluoroborates. The 3-, 4-, and 5-formyl-
furan-2-trifluoroborates (10a, 9a, 11a), 5- and 4-formyl-2-
thiophenetrifluoroborates (12a, 15a), 4-formyl-3-thiophene-
trifluoroborate (13a), and 5-formyl-3-methylthiophene-2-
trifluoroborate (14a) were efficiently reacted in good to
excellent yields.
(11) (a) Ferrer Flegeau, E.; Popkin, M. E.; Greaney, M. F. J. Org. Chem.
2008, 73, 3303–3306. (b) Araki, H.; Katoh, T.; Inoue, M. Tetrahedron Lett.
2007, 48, 3713–3717. (c) Inoue, M. Mini-ReV. Org. Chem 2008, 5, 77–84,
and references cited therein.
(12) (a) Tyrell, E.; Brookes, P. Synthesis 2003, 469–483. (b) Knapp,
D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961–
6963
.
(13) For Suzuki-Miyaura cross-couplings of 4,5-disubstituted oxazoles
see: (a) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 2905–2907.
(b) Vachal, P.; Toth, L. M. Tetrahedron Lett. 2004, 45, 7157–7161. (c)
Ferrer Flegeau, E.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006, 8, 2495–
2498. (d) Li, B.; Buzon, R. A.; Zhang, Z. Org. Proc. Res. DeV. 2007, 11,
951–955, and references cited therein
(14) Araki, H.; Katoh, T.; Inoue, M. Synlett 2006, 4, 555–558
.
.
3832
Org. Lett., Vol. 11, No. 17, 2009

Table 3. Cross-Coupling of Various Potassium
Organotrifluoroborates with Various Electrophilesa
Figure 3. Medicinal chemistry targets.
of heteroaryl-containing trifluoroborates, and further optimiza-
tion may be needed to obtain the desired cross-coupled product
in acceptable yields.
Oxazole-containing biaryl structures are well-represented in
natural products. Furthermore, oxazoles with substitution at the
C-4 and C-5 positions are becoming increasingly important in
pharmaceuticals for their therapeutic potential in inflammation,
cancer, and asthma.13d The one-pot Suzuki-Miyaura cross-
coupling/elimination process described herein could be used as
an efficient synthetic approach toward the preparation of
pharmaceutical targets (Figure 3).13d,16
In summary, a series of 4,5-disubstituted potassium
oxazolinetrifluoroborates were prepared via the condensation
of the corresponding aldehydes with TosMIC under basic
conditions. The Suzuki-Miyaura cross-coupling of the
oxazolines was successfully achieved in good yields under
the optimized conditions. The method presented here allows
the facile preparation of oxazole-containing biaryl products
in two steps from simple potassium formyl-substituted aryl-
or heteroaryltrifluoroborates.
´
Acknowledgment. We thank Dr. Angel I. Morales-Ramos
(Vitae Pharmaceuticals, Fort Washington, PA) for valuable
scientific discussions. Dr. Ruth Figueroa, Jason E. Melvin, and
Dr. David Cooper (University of Pennsylvania) are acknowl-
edged for the preparation of some starting materials. Frontier
Scientific is acknowledged for their kind donation of boronic
acids. Dr. Rakesh Kohli (University of Pennsylvania) is
acknowledged for obtaining HRMS data. This work was
supported by the NIH (GM086209, GM035249), to whom we
are grateful.
Supporting Information Available: Experimental proce-
dures, compound characterization data, and NMR spectra for
all compounds prepared by the method described. This material
is available free of charge via the Internet at http://pubs.acs.org.
a All reactions, unless specified, were carried out using 0.25 mmol of
ArBr and 0.28 mmol of RBF3K. b Reaction performed on a 1.0 mmol scale.
OL901395C
(15) The variables optimized included: catalyst/ligands [Pd(OAc)2,
Pd(OAc)2/SPhos, Pd(OAc)2/XPhos, Pd(OAc)2/RuPhos, Pd(OAc)2/DavePhos,
Pd(OAc)2/(S)-BINAP/PEPPSI, Pd(OAc)2/XantPhos, Pd(PPh3)4, PdCl2(PPh3)2,
Pd(dppf)Cl2], catalyst/ligand mol % [0.5/1, 1/2, 2/4, 3/6, 5/10], solvents
[MeOH, dioxane/H2O, EtOH, toluene/H2O, DMF/H2O, 2-MeTHF/H2O], and
and triethylamine as the base in refluxing methanol. Aromatic-
containing trifluoroborates cross-coupled in satisfactory yields
with electron-poor and electron-rich aryl bromides, and a
heteroaryl bromide could be utilized in the process as well
(Table 3). Difficulties were encountered with the cross-coupling
bases [K2CO3, Cs2CO3, NEt3, DIPEA, DABCO, Na2CO3]
(16) Rudi, A.; Stein, Z.; Green, S.; Goldberg, I.; Kashman, Y.; Benayahu,
Y.; Schleyer, M. Tetrahedron Lett. 1994, 35, 2589–2592
.
.
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