Suzuki-miyaura cross-coupling of potassium dioxolanylethyltrifluoroborate and aryl/heteroaryl chlorides

Article abstract of DOI:10.1021/ol400320q

A robust and efficient protocol for the introduction of the dioxolanylethyl moiety onto various aryl and heteroaryl halides has been developed, providing cross-coupling yields up to 93%. Copper-catalyzed borylation of 2-(2-bromoethyl)-1,3-dioxolane with bis(pinacolato)diboron followed by treatment with potassium bifluoride provides the key organotrifluoroborate reagent.

Full text of DOI:10.1021/ol400320q

ORGANIC
LETTERS
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Vol. XX, No. XX
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SuzukiÀMiyaura Cross-Coupling of
Potassium Dioxolanylethyltrifluoroborate
and Aryl/Heteroaryl Chlorides
†
‡
‡
ꢀ
Nicolas Fleury-Bregeot, Daniel Oehlrich, Frederik Rombouts,
and Gary A. Molander*,†
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States, and Neuroscience
Medicinal Chemistry, Research & Development, Janssen Pharmaceutica,
Turnhoutseweg 30, 2340 Beerse, Belgium
gmolandr@sas.upenn.edu
Received February 3, 2013
ABSTRACT
A robust and efficient protocol for the introduction of the dioxolanylethyl moiety onto various aryl and heteroaryl halides has been developed,
providing cross-coupling yields up to 93%. Copper-catalyzed borylation of 2-(2-bromoethyl)-1,3-dioxolane with bis(pinacolato)diboron followed
by treatment with potassium bifluoride provides the key organotrifluoroborate reagent.
The dioxolanylethyl fragment represents a conveniently
protected synthetic equivalent for the propanal sub-
structure.1 Surprisingly, the installation of such a motif
on aryl and heteroaryl systems via cross-coupling has not
Scheme 1. Synthetic Methods Leading to Arylpropanal and the
Corresponding 1,3-Dioxolane Species
been extensively studied. Among the principle methods
encountered, the Heck reaction between aryl iodides and
allyl alcohol leads directly to the aldehyde,2 and the
Negishi cross-coupling between dioxolanylethylzinc bro-
mide and aryl iodides also provides access to the target
structures.3 Finally, the cobalt-catalyzed cross-coupling
between aryl Grignard reagents and 2-(2-bromoethyl)-
1,3-dioxolane has also been reported (Scheme 1).4
† University of Pennsylvania.
‡ Janssen Pharmaceutica.
(1) (a) Wuts, P. G. M.; Greene, T. W. In Protecting Groups in Organic
Synthesis, 3rd ed.; Greene, T. W., Wuts, P. G. M., Ed.; John Wiley & Sons,
Inc.: New York, 1999. (b) Kocienski, P. J. In Protecting Groups, 3rd ed.;
Kocienski, P. J., Ed.; Georg Thieme: Stuttgart, 2005.
(2) (a) Melpolder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41, 265.
(b) Chalk, A. J.; Magennis, S. A. J. Org. Chem. 1976, 41, 273. (c) Jeffery, T.
Tetrahedron Lett. 1991, 32, 2121. (d) Colbon, P.; Ruan, J.; Purdie, M.;
These previously reported methods suffer from several
Mulholland, K.; Xia, J. Org. Lett. 2011, 13, 5456. (e) Pan, H.; Noel, S.;
non-negligible drawbacks, such as the requisite use of aryl
iodides and high boiling solvents in the Heck reaction
(Scheme 1, eq 1), and the employment of reactive reagents
such as alkylzinc bromide or arylmagnesium bromide
Pinel, C.; Djakovitch, L. J. Organomet. Chem. 2008, 693, 2863.
ꢀ
~
(3) Phapale, V. B.; Guisan-Ceinos, M.; Bunuel, E.; Cardenas, D. J.
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Chem.;Eur. J. 2009, 15, 12681.
(4) Ohmiya, H.; Wakabayashi, K.; Yorimitsu, H.; Oshima, K. Tetra-
hedron 2006, 62, 2207.
r
10.1021/ol400320q
XXXX American Chemical Society

for the other two methods (Scheme 1, eqs 2 and 3), thus
limiting the substrate scope and versatility. Additionally,
these transformations all lack atom economy in that
they require the use of a several fold excess of reagents.
The combination of these features lowers the general
appeal and subsequent application of these methods.
A strategy based on the use of the SuzukiÀMiyaura
cross-coupling between a dioxolanylethylboron species
and aryl electrophiles has, to our knowledge, never been
reported and would provide a mild and versatile alterna-
tive pathway.5 Moreover, the use of the organotrifluoro-
borate technology would also be beneficial, allowing the
use of stable and robust reagents in near-stoichiometric
ratios. Organotrifluoroborates have been developed as
useful boron-containing reagents for various chemical
transformations, and more notably as surrogates for
boronic acids in SuzukiÀMiyaura coupling reactions.6
Scheme 2. Synthesis of Potassium Dioxolanylethyltrifluorobo-
rate 1
Table 1. SuzukiÀMiyaura Cross-Coupling of Various Aryl Halides with Dioxolanylethyltrifluoroborate 1a
a Reaction conditions: Aryl halide (1.0 equiv), organotrifluoroborate (1.1 equiv), PdCl2AtaPhos2 (5 mol %), Cs2CO3 (3.0 equiv), toluene/H2O (4:1,
C = 0.25 M), 100 °C, 14 h. b Using 2.5 mol % catalyst. c A mixture of aryl chloride and boronic acid was recovered. d Product contains up to 8% impurity.
e Reaction performed on a 3 mmol scale using a 1:1 trifluoroborate/electrophile ratio and only 1 mol % Pd.
B
Org. Lett., Vol. XX, No. XX, XXXX

To our knowledge, the hydroboration of 2-ethenyl-1,3-
dioxolane appears in a single report.7 In that effort, 9-BBN
was utilized to hydroborate the alkene with high regios-
electivity for terminal hydroboration, but the resulting air-
sensitive organoborane was simply oxidized to the alcohol,
and no further chemistry has ever appeared on these or
related organoboron intermediates.
Table 2. SuzukiÀMiyaura Cross-Coupling of Various Heteroaryl
Halides with Dioxolanylethyltrifluoroborate 1a
We chose another convenient route to access the requi-
site boron reagents, permitting access to shelf-stable
organotrifluoroborates. We recently reported the prepara-
tion of potassium β-alkoxyethyltrifluoroborates8 using
an adaptation of Marder and Liu’s conditions,9 wherein
a Cu(I)-catalyzed borylation of the corresponding primary
bromides was followed by treatment with KHF2 to afford
the target structures. The resulting organotrifluoroborates
were subsequently used in SuzukiÀMiyaura cross-coupling
reactions. Based on the success of this approach, we studied
an extension of this method to prepare potassium dio-
xolanylethyltrifluoroborates. Borylation of the commer-
cially available 2-(2-bromoethyl)-1,3-dioxolane with bis-
(pinacolato)diboron using CuI and polymer-bound
triphenylphosphine (PS-PPh3) as the catalytic system
afforded the desired product in 69À75% yield (Scheme 2).
Once synthesized, this new trifluoroborate was tested
in a SuzukiÀMiyaura cross-coupling. Pleasingly, the reac-
tion conditions developed for alkyloxethyltrifluoroborates
translated very well with this new substrate. Indeed,
PdCl2AtaPhos2 (5 mol %) and Cs2CO3 (3 equiv) in a
10
mixture of toluene/H2O (4:1) at 100 °C in the presence of
1.1 equiv of the trifluoroborate for 14 h allowed the forma-
tion of 89% of the desired cross-coupled product 2a when
(5) For example, it would allow the shortening of reaction pathways
where the propanal moiety is directly protected after its installation. See:
€
€
(a) Quick, M. P.; Frohlich, R.; Wunsch, B. Tetrahedron: Asymmetry
2010, 21, 524. (b) Padwa, A.; Zanka, A.; Cassidy, M. P.; Harris, J. M.
Tetrahedron 2003, 59, 4939.
(6) (a) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49.
(b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (c) Stefani,
H. A.; Cella, R.; Adriano, S. Tetrahedron 2007, 63, 3623. (d) Darses, S.;
Genet, J.-P. Chem. Rev. 2008, 108, 288. (e) Molander, G. A.; Jean-
a Reaction conditions: Heteroaryl halide (1.0 equiv), organotrifluor-
oborate (1.1 equiv), PdCl2AtaPhos2 (5 mol %), Cs2CO3 (3.0 equiv),
toluene/H2O (4:1, C = 0.25 M), 100 °C, 14 h
ꢀ
Gerard, L. In Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim,
2011; Vol. 2, pp 507À548. (f) Lennox, A. J. J.; Lloyd-Jones, G. C. Isr. J.
Chem. 2010, 50, 664.
(7) Brown, H. C.; Chen, J. C. J. Org. Chem. 1981, 46, 3978.
ꢀ
(8) Fleury-Bregeot, N.; Presset, M.; Beaumard, F.; Colombel, V.;
Oehlrich, D.; Rombouts, F.; Molander, G. A. J. Org. Chem. 2012, 77,
10399.
using 4-bromoanisole as an electrophile (Table 1, entry 1).
Halving the catalytic loading to 2.5 mol % still provided 2a
in a very acceptable 82% yield.
(9) (a) Yang, C.-T.; Zhang, Z.-Q.; Tajuddin, H.; Wu, C.-C.; Liang, J.;
Liu, J.-H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L.
Angew. Chem., Int. Ed. 2012, 51, 528. For other metal catalyzed
borylation procedures of alkyl halides see: (b) Yi, J.; Liu, J.-H.; Liang,
J.; Dai, J.-J.; Yang, C.-T.; Fu, Y.; Liu, L. Adv. Synth. Catal. 2012, 354,
1685. (c) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890. (d) Dudnik, A. S.;
Fu, G. C. J. Am. Chem. Soc. 2012, 134, 10693. (e) Joshi-Pangu, A.; Ma,
X.; Diane, M.; Iqbal, S.; Kribs, R. J.; Huang, R.; Wang, C.-Y.; Biscoe,
M. R. J. Org. Chem. 2012, 77, 6629.
(10) (a) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel,
L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli,
M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787. (b) Colacot, T. J.; Carole,
W. A.; Neide, B. A.; Harad, A. Organometallics 2008, 27, 5605.
(c) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc.
2009, 131, 15592. (d) He, A.; Falck, J. R. J. Am. Chem. Soc. 2010, 132,
2524. (e) Krasovskiy, A.; Lipshutz, B. H. Org. Lett. 2011, 13, 3822.
(f) Pudasaini, B.; Janesko, B. G. Organometallics 2012, 31, 4610. (g) Li,
H.; Seechurn, C.; Colacot, T. J. ACS Catal. 2012, 2, 1147. (h) Pu, X.; Li,
H.; Colacot, T. J. J. Org. Chem. 2013, 78, 568. (i) Colacot, T. J.
Encyclopedia of Reagents for Organic Synthesis. www.mrw.interscience.
wiley.com/eros, DOI:10.1002/047084289X.rn00968.
4-Chloroanisole was also reactive and resulted in the
formation of the desired 2-(4-methoxyphenethyl)-1,3-
dioxolane in 74% isolated yield. To examine the scope of
the reaction, aryl chlorides became the focus of the in-
vestigation, as they tend to be more challenging than their
bromide counterparts. However, when the chlorides failed
to react, the corresponding bromides were employed as
well. During the course of these studies, both electron-rich
(Table 1, entries 1À7) and electron-poor (Table 1, entries
8À14) substrates proved to be efficient partners, providing
the diversely substituted dioxolanylethylaryls with yields
ranging from 38 to 90%. Substituents at the ortho-, meta-,
and para-positions were tolerated, as all three different
Org. Lett., Vol. XX, No. XX, XXXX
C

anisole isomers reacted to give the desired products 2aÀc
with good to excellent yields (Table 1, entries 1À3).
Although the sterically hindered 2,6-dimethyl-4-meth-
oxychlorobenzene did not react, the bromo derivative
afforded the cross-coupled product 2d in a promising
48% yield (Table 1, entry 4). A wide array of functional
groups proved to be compatible in the process, including
free or protected anilines (Table 1, entries 6, 7), nitriles
(Table 1, entries 8, 9), aldehydes and ketones (Table 1,
entries 11, 12), and fluoro and trifluoromethyl groups
(Table 1, entries 13, 14).
Importantly, nitro groups are tolerated as well, provid-
ing access to products that were not accessible with the
Negishi protocol reported by Cardenas et al.2 Overall,
meta-substituted electrophiles (Table 1, entries 3, 5, and 9)
provide better yields. Protected amine substrates (entry 7)
would appear to be preferred over the free amine counter-
parts (entry 6). The reaction was also tested on a larger scale
(Table 1, entry 14), by using a 1:1 trifluoroborate/electrophile
ratio and lowering the catalyst loading to 1 mol %. This
protocol provided access to the (4-fluorophenethyl)-1,3-
dioxolane 2m in a modest 38% yield.
and the hydrolyzed trifluoroborate, the bromo analog
afforded the expected dioxolanylethylpyrimidine 3g in
74% yield (Table 2, entry 7).
In conclusion, a new trifluoroborate has been synthe-
sized and successfully cross-coupled with a wide array
of aryl and heteroaryl chlorides or bromides, providing
easy and straightforward access to a large variety of
dioxolanylethylaryl compounds. The method comple-
ments previously reported methods leading to the same
substructures. This new sp3Àsp2 cross-coupling protocol,
based on the reliability and versatility of organotrifluor-
oborates, allows the facile introduction of dioxolanylethyl
moieties onto aryl and heteroaryl halides. After hydrolysis
of the dioxolanyl moiety to the aldehyde group, further
functionalization is possible, including intramolecular
transformations, allowing access to interesting polycyclic
structures.11
Acknowledgment. This research was supported by the
National Science Foundation (GOALI) and the NIGMS
(R01 GM-081376). AllyChem is acknowledged for the
generous donation of bis(pinacolato)diboron. Dr. Rakesh
Kohli (University of Pennsylvania) is acknowledged for
obtaining HRMS data.
To explore the scope of the method further, a variety
of diverse heteroaryl halides were tested using the same set
of conditions. Pyridine, quinoline, furan, thiophene, and
indole systems reacted well, providing the desired products
3aÀf with modest to excellent yields ranging from 44 to
93% (Table 2, entries 1À6). Although 2-chloropyrimidine
did not react, yielding a mixture of the starting electrophile
Supporting Information Available. Experimental pro-
cedures, spectral characterization, and copies of 1H, 13C,
19F, and 11B NMR spectra for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Bunce, R. A.; Herron, D. M.; Johnson, L. B.; Kotturi, S. V.
J. Org. Chem. 2001, 66, 2822.
The authors declare no competing financial interest.
D
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