Nickel-catalyzed cross-coupling of potassium aryl- and heteroaryltrifluoroborates with unactivated alkyl halides

Article abstract of DOI:10.1021/ol102717x

A method for the cross-coupling of alkyl electrophiles with various potassium aryl- and heteroaryltrifluoroborates has been developed. Nearly stoichiometric amounts of organoboron species could be employed to cross-couple a large variety of challenging heteroaryl nucleophiles. Several functional groups were tolerated on both the electrophilic and the nucleophilic partners. Chemoselective reactivity of C(sp³) - Br bonds in the presence of C(sp²) - Br bonds was achieved.

Full text of DOI:10.1021/ol102717x

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5783-5785
Nickel-Catalyzed Cross-Coupling of
Potassium Aryl- and
Heteroaryltrifluoroborates with
Unactivated Alkyl Halides
Gary A. Molander,*,† O. Andreea Argintaru,† Ioana Aron,† and Spencer D. Dreher§
Roy and Diana Vagelos Laboratories and Penn/Merck Laboratory for High
Throughput Experimentation, Department of Chemistry, UniVersity of PennsylVania,
231 South 34th Street, Philadelphia, PennsylVania 19104-6323, and
Department of Process Chemistry, Merck Research Laboratories,
P.O. Box 2000, Rahway, New Jersey 07065
gmolandr@sas.upenn.edu
Received November 9, 2010
ABSTRACT
A method for the cross-coupling of alkyl electrophiles with various potassium aryl- and heteroaryltrifluoroborates has been developed. Nearly
stoichiometric amounts of organoboron species could be employed to cross-couple a large variety of challenging heteroaryl nucleophiles.
Several functional groups were tolerated on both the electrophilic and the nucleophilic partners. Chemoselective reactivity of C(sp3)-Br
bonds in the presence of C(sp2)-Br bonds was achieved.
Several recent studies have focused on the development of
cross-coupling strategies to unite alkyl electrophiles with aryl
nucleophilic partners.1 Among these, the Suzuki-Miyaura
reaction has emerged as one of the most powerful methods
because of the low toxicity, air and water stability, functional
group compatibility, and commercial availability of the orga-
noboron compounds.2,3 Nickel catalysts were reported to be
among the most successful for C(sp2)-C(sp3) bond formation
via the Suzuki-Miyaura reaction.1 Nevertheless, limitations
to the developed method remain:4-6 depending on the
nucleophile, a significant excess of boronic acid is usually
required, and ortho-substituted arylboronic acids only cross-
couple to a limited extent. Perhaps most critically, only a
few isolated examples have been reported to partner alkyl
halides with heteroarylboron nucleophiles (e.g., indole-5-
boronic acid, thiophene-3-boronic acid), and virtually all
protocols explicitly have failed for other important heterocyclic
systems.5
(2) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457–2483. (b) Little, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4177–4211.
(3) For studies and examples of palladium-catalyzed cross-coupling
reactions of alkyl electrophiles, see: (a) Ariafard, A.; Lin, Z. Organometallics
2006, 25, 4030–4033. (b) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
12527–12530. (c) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C.
J. Am. Chem. Soc. 2002, 124, 13662–13663. (d) He, A.; Falck, J. R. J. Am.
Chem. Soc. 2010, 132, 2524–2525.
† University of Pennsylvania.
§ Merck Research Laboratories.
(1) (a) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656–
2670, and references cited therein. (b) Ejiri, S.; Odo, S.; Takahashi, H.;
Nishimura, Y.; Gotoh, K.; Nishihara, Y.; Takagi, K. Org. Lett. 2010, 12,
1692–1695. (c) Hatakeyama, T.; Hashimoto, T.; Kondo, Y.; Fujiwara, Y.;
Seike, H.; Takaya, H.; Tamada, Y.; Ono, T.; Nakamura, M. J. Am. Chem.
Soc. 2010, 132, 10674–10676. (d) Owson, N. A.; Fu, G. C. J. Am. Chem.
Soc. 2010, 132, 11908–11909. (e) Lundin, P. M.; Fu, G. C. J. Am. Chem.
Soc. 2010, 132, 11027–11029. (f) Lou, S.; Fu, G. C. J. Am. Chem. Soc.
2010, 132, 1264–1266.
(4) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340–1341.
(5) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360–
5361.
(6) Duncton, M. A. J.; Estiarte, M. A.; Tan, D.; Kaub, C.; O’Mahony,
D. J. R.; Johnson, R. J.; Cox, M.; Edwards, W. T.; Wan, M.; Kincaid, J.;
Kelly, M. G. Org. Lett. 2008, 10, 3259–3262.
10.1021/ol102717x  2010 American Chemical Society
Published on Web 11/19/2010

We envisioned that these limitations could be overcome
through the use of the more robust potassium aryl- and
heteroaryltrifluoroborates as nucleophilic coupling partners
in the Ni-catalyzed cross-coupling with various alkyl elec-
trophiles.7 Using the reaction between 1-bromo-3-phenyl-
propane and a stoichiometric amount of potassium (4-
methoxyphenyl)-trifluoroborate (Scheme 1) as a template, a
Table 1. Cross-Coupling of 2-(Bromomethyl)tetrahydro-
2H-pyran with Potassium Aryltrifluoroborates
Scheme 1. Optimization of the Cross-Coupling Conditions
wide variety of catalyst/ligand combinations, solvents, bases,
and temperatures were screened.8 The best coupling condi-
tions were determined to be 10 mol % of NiBr2•glyme, 10
mol % of 4,7-diphenyl-1,10-phenanthroline (bathophenan-
throline), and 3 equiv of LiHMDS in sec-butanol.8
a Reactions run at 80 °C. b Reaction performed on 5 mmol scale using
1 mol % catalyst loading.
With these results in hand, we investigated the cross-
coupling of 2-(bromomethyl)tetrahydro-2H-pyran with dif-
ferent potassium aryltrifluoroborates (Table 1).
Table 2. Cross-Coupling of 2-(Bromomethyl)tetrahydro-
2H-pyran with Potassium Heteroaryltrifluoroborates
Both electron-rich and electron-poor substituted trifluo-
roborates successfully underwent cross-coupling using nearly
stoichiometric amounts of the nucleophile (1.02 equiv).
Sterically hindered ortho-substituted trifluoroborates also
underwent the reaction in good yields (Table 1, entries 2
and 9). Additionally, substrates containing a secondary
alcohol (entry 7), a ketone (entries 8 and 9), and an alkene
(entry 5) were tolerated. Importantly, the reactions could be
performed on gram scale using only a 1 mol % catalyst
loading with little effect on the yield (entry 2).
To expand the scope of this method, we examined the
cross-coupling of the same alkyl bromide with a large variety
of heteroaryltrifluoroborates including furans, benzo- and
dibenzofuran, pyridines, pyrimidines, thiophenes, quinolines,
indole, and imidazole, again using virtually stoichiometric
organotrifluoroborates (Table 2).
The corresponding cross-coupled products were obtained
in moderate to good yields. Given the extraordinarily high
propensity for heteroarylboron reagents to undergo protode-
boronation,9 these transformations represent a significant
advance in the formation of core substructures of greatest
a Reaction performed on 5 mmol scale using 1 mol % catalyst loading.
(7) For reviews on potassium organotrifluoroborates in cross-coupling
reactions, see: (a) Molander, G. A.; Ellis, N. M. Acc. Chem. Res. 2007, 40,
275–286. (b) Darses, S.; Genet, J. P. Chem. ReV. 2008, 108, 288–325. (c)
Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240–
9286. (d) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63,
3623–3658.
interest in the pharmaceutical, agrochemical, and materials
science sectors. As in the case of the aryltrifluoroborates, a
heteroaryl cross-coupling could be carried out on gram scale
using only 1 mol % of the nickel catalyst (entry 4). Of
additional interest, the C(sp2)-Br bond in 5-bromo-3-
pyridyltrifluoroborate remained intact during the cross-
coupling reactions, maintaining the potential for further
functionalization of the pyridine (entry 13).
(8) The screening was performed through microscale High Throughput
Experimentation (HTE). Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.;
Molander, G. A. J. Am. Chem. Soc. 2008, 130, 9257–9259. See Supporting
Information.
(9) (a) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem.
2009, 74, 973–980, and references therein. (b) Knapp, D. M.; Gillis, E. P.;
Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961–6963.
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Org. Lett., Vol. 12, No. 24, 2010

To test the general applicability of our method to other
electrophiles, potassium 2-benzofuranyl- and 4-pyridinyltri-
fluoroborate were reacted with various functionalized alkyl
halides (Table 3).
Table 4. Cross-Coupling of Various Alkyl Chlorides with
Potassium Aryl- and Heteroaryltrifluoroborates
Table 3. Cross-Coupling of Diverse Alkyl Halides with
Potassium 2-Benzofuranyl- and 4-Pyridinyltrifluoroborates
a Reaction using KHMDS (3 equiv).
cross-coupling of alkyl bromides and iodides with aryl and
heteroaryl nucleophiles, while L-prolinol was required for the
cross-coupling of alkyl chlorides. Several major advances have
derived from these studies: (1) Only 1 equiv of the organoboron
reagent is necessary, as opposed to 1.2 to 2 equiv reported in
previous studies; (2) both heteroaryl- and sterically hindered
ortho-substituted organoborons, previously reported to be
problematic substrates, can be coupled in good yields; and (3)
on a larger scale, low (1 mol %) catalyst loadings can be used
to effect efficient cross-coupling. The use of organotrifluorobo-
rates thus represents a significant advance in cross-coupling with
alkyl halide electrophiles.
a Isolated as the s-Bu ester.
Electrophiles containing an acetal, a benzyl ether, and a
distal olefin were tolerated (Table 3). p-Bromo-(3-bromopro-
pyl)-benzene smoothly underwent chemoselective cross-
coupling at the C(sp3)-Br bond, leaving the C(sp2)-Br bond
available for further functionalization (entry 2). Another
bidirectional functionalization opportunity arises from the
selective reactivity of alkyl bromides and iodides over alkyl
chlorides (entries 7 and 8). The same set of conditions could
be applied to the successful cross-coupling of secondary
bromides and iodides (entries 9-12). Although stereochem-
ical studies have not been conducted, on the basis of
previously reported investigations5 we would anticipate that
these processes would transpire via radical intermediates, and
thereby the stereochemical fidelity of enantioenriched starting
materials would not be transferred to the products.
The conditions employed for the cross-coupling of alkyl
iodides and bromides were not successful when applied to the
more challenging alkyl chlorides. As previously reported in the
literature,5 the use of L-prolinol as a ligand was required for
the reaction of alkyl chlorides (Table 4). Although the ortho-
substituted boronic acids have been problematic in the Ni-
catalyzed cross-coupling with alkyl chlorides,5 use of the more
stable potassium trifluoroborates led to the formation of the
desired product in 60% yield (entry 5).10
Acknowledgment. We thank Frontier Scientific for bo-
ronic acids. Deidre L. Sandrock (University of Pennsylvania)
is acknowledged for performing HTE experiments. Financial
support has been provided by the NIH General Medical
Sciences (R01 GM035249) and the NSF GOALI program
(CHE-0848460). I.A. thanks CURF (University of Pennsyl-
vania) for a fellowship. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL102717X
(10) Under these conditions, reactions of other heteroaryltrifluoroborates
(furans, thiophenes, pyrazoles) proceeded in relatively low yield (<40%,
data not shown). The cross-coupling of alkyl chlorides with aryl- and
heteroaryltrifluoroborates is currently under study.
In conclusion, we have developed an efficient method for
the Ni-catalyzed cross-coupling of unactivated halides. Batho-
phenanthroline was used as a ligand for the Suzuki-Miyaura
Org. Lett., Vol. 12, No. 24, 2010
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