Cross-coupling reactions of potassium alkyltrifluoroborates with aryl and 1-alkenyl trifluoromethanesulfonates.

Article abstract of DOI:10.1021/ol006896u

[figure: see text] The palladium-catalyzed coupling reaction of potassium alkyltrifluoroborates with aryl- or alkenyltriflates proceeds to afford the corresponding arenes or alkenes in high yield. The borates are all solids, stable in air, and thus can be stored on the shelf indefinitely. The cross coupling can be effected using PdCl2(dppf).CH2Cl2 as the catalyst in THF-H2O in the presence of Cs2CO3. A variety of functional groups can be tolerated within the borate and/or the triflate coupling partner.

Full text of DOI:10.1021/ol006896u

ORGANIC
LETTERS
2001
Vol. 3, No. 3
393-396
Cross-Coupling Reactions of Potassium
Alkyltrifluoroborates with Aryl and
1-Alkenyl Trifluoromethanesulfonates
Gary A. Molander* and Takatoshi Ito
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received November 20, 2000
ABSTRACT
The palladium-catalyzed coupling reaction of potassium alkyltrifluoroborates with aryl- or alkenyltriflates proceeds to afford the corresponding
arenes or alkenes in high yield. The borates are all solids, stable in air, and thus can be stored on the shelf indefinitely. The cross coupling
can be effected using PdCl2(dppf)‚CH Cl2 as the catalyst in THF−H O in the presence of Cs2CO . A variety of functional groups can be tolerated
2
2
3
within the borate and/or the triflate coupling partner.
The palladium-catalyzed cross-coupling reaction of electro-
philes with organometallic reagents has emerged as a
versatile method for carbon-carbon bond formation.1 Among
all possible organometallics, tin (Stille coupling)2 and boron
derivatives (Suzuki coupling)3 are most frequently used for
these cross-coupling reactions because of their tolerance for
a broad range of functional groups. The use of organoboron
compounds is especially valued for several reasons: they
are more easily accessed by a variety of routes, nontransfer-
able groups can be readily incorporated into the organome-
tallic, and the inorganic byproducts of the reaction are
nontoxic and can be readily removed by simple workup
procedures.
alkylborinate esters6 are also generally efficient coupling
partners. The scope of coupling reactions employing these
latter organoboron derivatives, however, is limited by various
selectivity characteristics exhibited by 9-BBN and related
hydroborating reagents.
Except for the recent example of cyclopropylboronic acids
or esters that possess significant sp2-carbon character,7 more
highly oxygenated derivatives such as alkylboronic acids or
esters have presented difficulties in Suzuki coupling reac-
tions. For example, an early study utilizing alkylboronic acids
(4) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 37, 3387-
3388. (b) Littke, A. F.; Chaoyang, D.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020-4028.
(5) (a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 6369-6372. (b) Miyaura, N.; Ishiyama, T.; Sasaki, H.;
Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-
321. (c) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722-9723. (d) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 9550-9561.
(6) (a) Soderquist, J. A.; Santiago, B. Tetrahedron Lett. 1990, 31, 5541-
5542. (b) Moore, W. R.; Schatzman, G. L.; Jarvi, E. T.; Gross, R. S.;
McCarthy, J. R. J. Am. Chem. Soc. 1992, 114, 360-361.
(7) (a) Chen, H.; Deng, M.-Z. Org. Lett. 2000, 2, 1649-1651. (b) Luithle,
J. E. A.; Pietruszka, J. J. Org. Chem. 1999, 64, 8287-8297. (c) Zhou, S.-
M.; Yan, Y.-L.; Deng, M.-Z. Synlett 1998, 198-200. (c) Wiberg, K. B.
Acc. Chem. Res. 1996, 29, 229-234. (d) Hildebrand, J. P.; Marsden, S. P.
Synlett 1996, 893-894.
The palladium-catalyzed reaction of various 1-alkenyl- and
arylboronic acids with electrophiles such as organic halides
and triflates proceeds readily.1,3,4 Trialkylboranes1,3,5 and
(1) (a) Tsuji, J. Palladium Reagents and Catalysis; Wiley and Sons:
Chichester, 1995. (b) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-
Coupling Reactions; VCH: Weinheim, 1998.
(2) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(b) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652.
(3) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457-2483. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (c)
Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; VCH: Weinheim, 1998; pp 49-97.
10.1021/ol006896u CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/10/2001

provided yields in the 20-30% range,8 while coupling of
methyl boronic acid required the addition of 40 mol % of
triphenylarsine.9 More recent studies show promise of
improving this situation, although the scope of this particular
protocol has not been fully investigated.4b A similar situation
exists for various alkylboronic esters, wherein very low yields
in the cross-coupling reaction were achieved5b unless highly
toxic10 thallium compounds such as TlOH or Tl2CO3 were
utilized as bases for the reaction.11 It has been assumed that
this is because of the difficulty in transmetalation between
the boronic ester and the intermediate Pd species.11 Thus,
although Suzuki coupling reactions incorporating aryl- and
alkenylboron reagents are reasonably well in hand, new and
effective methods for the successful coupling of simple
primary alkylboron species are still subject to significant
improvement.
Perhaps quite naturally, much of the recent development
effort on the Suzuki coupling reaction has focused on metal
ligand systems that facilitate the cross coupling and expand
its scope.4,5c,d Much less effort has been concentrated on
expanding the range of the organoboron coupling partner,
which should be an equally rewarding endeavor.
With regard to the use of alternative organoboron deriva-
tives, it has been revealed that several potassium aryl- and
1-alkenyltrifluoroborates, easily prepared from organoboronic
acids or esters, undergo the palladium-catalyzed coupling
reaction with arenediazonium tetrafluoroborates12 or diaryl-
iodonium salts13 as the coupling partners. In addition to their
air stability, the greater nucleophilicity14 of the potassium
trifluoroborates over the corresponding organoboranes and
organoboronic acid derivatives makes the fluoroborates
potentially valuable starting materials for palladium-catalyzed
cross coupling with sp2-hybridized carbon centers. One
caveat is that potassium aryltrifluoroborates appear reluctant
to couple to aryl halides.4b
aryltrifluoroborates. Several groups have utilized a slight
modification of this original procedure for the synthesis of
various potassium organotrifluoroborates.14,16 By adapting
these methods, the formation of potassium alkyltrifluorobo-
rates was achieved via the corresponding boronic acids and
esters. The requisite alkylboronic acids and esters were
readily synthesized using established literature protocols
involving the addition of Grignard reagent to trimethyl-
borate,17 the hydroboration of alkenes with dibromoborane-
dimethyl sulfide complex followed by hydrolysis,18 and the
catalytic hydroboration19 of alkenes with catecholborane or
pinacolborane. Treatment of the alkylated boronic acids or
esters with KHF2 afforded the corresponding potassium
alkyltrifluoroborates as powders or crystalline solids in good
yields. The products were indefinitely stable in the air.
The conditions for carrying out the coupling reaction were
optimized by using phenyltriflate and potassium benzyltri-
fluoroborate in the presence of PdCl2(dppf) (9 mol %).
Briefly, utilizing a variety of different solvents (THF, DME,
DMA, toluene, dioxane, EtOH) under both anhydrous and
aqueous conditions, with an ensemble of diverse bases (e.g.,
Cs2CO3, K2CO3, K3PO4, CsOH, NaOAc, and KOH), we
determined that the use of 9-10 mol % of PdCl2(dppf) with
3 equiv of Cs2CO3 as a base in THF-H2O heated at reflux
were optimal, and these conditions were applied to the
remainder of the substrates in the study.20
As outlined in the Table, the cross-coupling reaction of
potassium alkyltrifluoroborates with various triflates pro-
ceeded readily with satisfactory yields in most cases. The
reaction was tolerant of a variety of functional groups
including ketones, esters, nitriles, and nitro groups despite
the aqueous basic conditions. Of significance was the
observation that although the reaction of nitrophenyltriflate
(13) Xia, M.; Chen, Z.-C. Synth. Commun. 1999, 29, 2457-2465.
(14) (a) Batey, R. A.; Thadani, A. N.; Smil, D. V.; Lough, A. J. Synthesis
2000, 990-998. (b) Batey R. A.; Thadani, A. N.; Smil, D. V. Org. Lett.
1999, 1, 1683-1686. (c) Batey, R. A.; Thadani, A. N.; Smil, D. V.
Tetrahedron Lett. 1999, 40, 4289-4292. (d) Batey, R. A.; MacKay, D. B.;
Santhakumar, V. J. Am. Chem. Soc. 1999, 121, 5075-5076.
(15) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020-3027. (b) Vedejs, E.; Fields, S. C.;
Hayashi, R.; Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem.
Soc. 1999, 121, 2460-2470.
We believed that the enhanced nucleophilicity of alkyl-
trifluoroborates relative to their boronic acid and boronic ester
analogues might be brought to bear on this problem. Herein,
we outline the scope of the coupling reaction of potassium
alkyltrifluoroborates with organic triflates as the coupling
partner (eq 1).
(16) Petasis, N. A.; Yudin, A. K.; Zavialov, I. A.; Prakash, G. K. S.;
Olah, G. A. Synlett 1997, 606-608.
(17) Matteson, D. S. Tetrahedron 1989, 45, 1859-1885.
(18) Brown, H. C.; Bhat, N. G.; Somayaji, V. Organometallics 1983, 2,
1311-1316.
(19) (a) Burgess, K.; Ohlmeyer, M. J. Chem. ReV. 1991, 91, 1179-1191.
(b) Pereira, S.; Srebnik, M. J. Am. Chem. Soc. 1996, 118, 909-910. (c)
Kabalka, G. W.; Narayana, C.; Reddy, N. K. Synth. Commun. 1994, 24,
1019-1023. (d) Ma¨nnig, D.; No¨th, H. Angew. Chem., Int. Ed. Engl. 1985,
24, 878-879. (e) Evans, D. A.; Muci, A. R.; Stu¨rmer, R. J. Org. Chem.
1993, 58, 5307-5309. (f) Garrett, C. E.; Fu, G. C. J. Org. Chem. 1996, 61,
3224-3225.
(20) Representative Procedure for the Cross-Coupling Reaction of
Triflates with Potassium Alkyltrifluoroborates. 1-(4-Acetylphenyl)-1-
phenylmethane (3b). To a suspension of potassium benzyltrifluoroborate
(1a) (106 mg, 0.5 mmol), Cs2CO3 (489 mg, 1.5 mmol), PdCl2(dppf)‚CH2-
Cl2 (36 mg, 0.045 mmol), and 4-acetylphenyltriflate (134 mg, 0.5 mmol)
in THF (5 mL) was added water (0.5 mL) under an argon atmosphere,
followed by heating at reflux. The reaction mixture was stirred at reflux
temperature for 18 h, then cooled to room temperature, and diluted with
water (10 mL) followed by extraction with ether (50 mL × 3). The ethereal
solution was washed with 1 N HCl (10 mL) and brine (20 mL) and dried
over magnesium sulfate. The solvent was removed in vacuo and the crude
product was purified by silica gel column chromatography (eluting with
hexane/ether 20:1) to yield 3b (108 mg, 0.48 mmol, 96%).
Vedejs et al.15 reported the reaction of arylboronic acids
with potassium hydrogen fluoride, leading to potassium
(8) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994,
59, 6095-6097.
(9) Mu, Y.; Gibbs, R. A. Tetrahedron Lett. 1995, 36, 5669-5672.
(10) Douglas, K. T.; Bunni, M. A.; Baindur, S. R. Int. J. Biochem. 1990,
22, 429; Chem. Abstr. 1990, 113, 2120q.
(11) Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405-1408.
(12) (a) Darses, S.; Michaud, G.; Geneˆt, J.-P. Eur. J. Org. Chem. 1999,
1875-1883. (b) Darses, S.; Michaud, G.; Geneˆt, J.-P. Tetrahedron Lett.
1998, 39, 5045-5048. (c) Darses, S.; Geneˆt, J.-P.; Brayer, J.-L.; Demoute,
J.-P. Tetrahedron Lett. 1997, 38, 4393-4396.
394
Org. Lett., Vol. 3, No. 3, 2001

Table 1. Cross-Coupling of Organic Halides and Triflates with Potassium Alkyltrifluoroboratesa
a The reactions were conducted using potassium alkyltrifluoroborates (0.5 mmol) and triflates (0.5-0.55 mmol) in the presence of PdCl2(dppf)‚CH2Cl2
(9 mol %) and Cs2CO3 (3 equiv) in THF-H2O heated at reflux for 18 h. b Isolated yields. GC yields based on n-undecane or bibenzyl as an internal standard
are in parentheses. c Borates were prepared via the Grignard method. d Borates were prepared via the catalytic hydroboration method. e As a 1:1 mixture of
diastereomers.
with B-alkyl-9-BBN provided a mixture of reduced aniline
products,21 good yields of coupled product were obtained
under our conditions without difficulty (entries 3 and 7). A
good yield of geometrically pure alkene22 was obtained by
the reaction with (Z)-alkene 2g (entry 12), whereas the use
of (E)-alkene 2h afforded a mixture of diastereomeric
products (entry 13). Highly selective coupling with the C-X
bond in 4-bromo- and 4-iodophenyltriflate was observed.
Unfortunately, the use of 4-iodophenyltriflate provided 4,4′-
bis(trifluoromethylsulfonyloxy)biphenyl arising from homo-
coupling of the iodides in addition to the desired coupled
product (entries 14 and 15). Thus, the reactivity of the
electrophile in our reaction systems with the alkyltrifluo-
roborates decreases in the order Br > OTf . Cl as reported
for organotin23 and B-alkyl-9-BBN21 reagents. Finally, the
yield of the reaction with secondary alkylborates such as
potassium 1-phenethyltrifluoroborate was not satisfactory
(entry 17). In this case, the generation of styrene by
â-elimination and ethylbenzene by dehydroboronation were
the predominant reaction pathways.
have been performed. For example, when potassium 3-phe-
nylpropyltrifluoroborate was exposed to water for 4 days at
room temperature, the 11B NMR revealed that a new signal
was observed at δ 33.5 ppm in addition to the resonance at
δ 5.6 ppm for the original compound. This observation
indicated that alkylboronic acids (for which the 11B NMR
signal typically appears at δ 31.9 ppm24) could be generated
in situ. To explore further the nature of the reactive species
under our conditions, we examined the coupling reaction
using 3-phenylpropylboronic acid24 and the corresponding
pinacol ester using 4-acetylphenyltriflate as the coupling
partner. Somewhat surprisingly, under our optimized reaction
conditions these compounds afforded 77% (eq 2) and 60%
(eq 3) isolated yields of cross-coupled products, which is
The mechanism of the reaction has not been studied in
detail, but the question arises as to whether the alkyltrifluo-
roborates are hydrolyzed in situ to provide the corresponding
alkylboronic acids, which subsequently undergo cross cou-
pling. To address this issue, some preliminary experiments
(21) Oh-e, T.; Miyaura, N.; Suzuki, A. Chem. Lett. 1990, 221-223.
(22) The Z geometry of compound 3l was confirmed by NOE.
(23) (a) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-
3040. (b) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109,
5478-5488.
nearly the same yields obtained in the reaction of the
potassium 3-phenylpropyltrifluoroborate (entry 6). This
observation is not only of possible mechanistic importance
Org. Lett., Vol. 3, No. 3, 2001
395

for the present study but of potential synthetic value in its
own right because satisfactory cross-coupling reactions of
alkylboronic acids have been achieved previously only with
difficulty,8,25 even when thallium bases have been used.
Thus although boronic acids generated in situ could very
well be the reactive species under our reaction conditions,
well as by hydroboration of alkenes employing several
different hydroborating protocols. The alkyltrifluoroborates
are solids that are easily handled (i.e., indefinitely stable in
the air). As a consequence, this could be prove to be a
watershed discovery for combinatorial synthesis, because a
variety of highly functionalized, structurally diverse alkyl-
trifluoroborates can be synthesized and stored in bulk,
awaiting coupling. Additionally, we have discovered that
alkylboronic acids and esters can be coupled under the same
conditions, and this development awaits further investigation.
The present method thus provides a new and effective
approach to alkylated aromatic and alkenyl compounds.
Further study on the scope and detailed mechanism of the
reaction is in progress.
-
fluorinated boron species such as RBF3 , RBF2(OH)-, and/
-
or RBF(OH)2 might also be involved. Wright et al.8 have
argued that such intermediates could be the key species in
the reaction of fluoride-mediated coupling of boronic acids,
and these derivatives undoubtedly exist during the hydrolysis
process of potassium alkyltrifluoroborates. It is also possible
that the reaction is somehow accelerated by fluoride ions.
Conclusions concerning these issues await further, more
detailed kinetic and mechanistic investigations.
Acknowledgment. We thank Mr. Jason Burke for the
preparation of potassium 6-bromohexyltrifluoroborate. We
acknowledge the National Institutes of Health (GM-48580)
and Merck & Co., Inc., for their generous support of our
program.
In summary, the first palladium-catalyzed cross-coupling
reactions of potassium alkyltrifluoroborates with aryl- and
alkenyltriflates have been achieved. The inclusion of water
was found to be essential, and Cs2CO3 was determined to
be the most effective base. Functionalized alkyltrifluorobo-
rates are readily available utilizing a Grignard approach as
Supporting Information Available: Full experimental
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Green, M. L. H.; Wagner, M. J. Chem. Soc., Dalton Trans. 1996,
2467-2473.
(25) Kabalka, G. W.; Pagni, R. M.; Hair, C. M. Org. Lett. 1999, 1, 1423-
1425.
OL006896U
396
Org. Lett., Vol. 3, No. 3, 2001