Use of potassium β-trifluoroborato amides in suzuki-miyaura cross-coupling reactions

Article abstract of DOI:10.1021/jo900968h

(Chemical Equation Presented) Potassium β-trifluoroborato amides were prepared and used as successful partners in Suzuki-Miyaura reactions with various aryl chlorides, including electron-rich and electron-poor derivatives, as well as several heteroaryl ch

Full text of DOI:10.1021/jo900968h

pubs.acs.org/joc
Use of Potassium β-Trifluoroborato Amides in Suzuki-Miyaura
Cross-Coupling Reactions
ꢀ
Gary A. Molander* and Ludivine Jean-Gerard
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323
gmolandr@sas.upenn.edu
Received May 8, 2009
Potassium β-trifluoroborato amides were prepared and used as successful partners in Suzuki-
Miyaura reactions with various aryl chlorides, including electron-rich and electron-poor derivatives,
as well as several heteroaryl chloride partners.
Introduction
certainly the transition-metal-catalyzed addition of diboron
reagents to R,β-unsaturated carbonyl compounds. This pro-
cedure employs platinum,4 rhodium,5 nickel,6 or copper
catalysts7 and permits the boration of a variety of R,β-
unsaturated esters, nitriles, ketones, and amides. However,
the engagement of the organoboron reagents thus formed
has not been studied as extensively as their zinc8 or titanium9
counterparts.
Even though the metal-catalyzed cross-coupling reaction
is by far the most important and widely used application of
organoborons,1,10 surprisingly, the first use of β-borato
esters in Suzuki-Miyaura reactions was reported only in
2006 by Snieckus et al.11 Our group recently described the
preparation of β-trifluoroborato esters and ketones and their
Organoborons are valuable synthetic intermediates for the
preparation of a wide variety of organic molecules owing to
their functional group tolerance and low toxicity.1 β-Boryl
carbonyl compounds,2 which possess an anion equivalent β
to a carbonyl group, constitute an important subclass of
organoboron reagents. These synthons exhibit a charge-
inverted reactivity compared to more traditional synthons,
thus allowing potentially valuable, strategic C-C bond
connections (Scheme 1). This is illustrated in Scheme 1,
wherein the well-known Michael addition of nucleophiles
to R,β-unsaturated carbonyl compounds3 takes advantage of
the electrophilic character of the β carbon in R,β-unsaturated
carbonyl substrates. In contrast, the corresponding carbon
in β-boryl carbonyl derivatives bears a partial negative
charge, acting as a nucleophile during the C-C bond-form-
ing event.
(5) Kabalka, G. W.; Das, B. C.; Das, S. Tetrahedron Lett. 2002, 43, 2323.
(6) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 5031.
(7) (a) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett.
2000, 41, 6821. (b) Takayashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet.
Chem. 2001, 625, 47. (c) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8, 4887.
(d) Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145.
Many studies have been devoted to the preparation of
β-boryl carbonyl substrates, and the most important route is
(8) (a) Tamaru, Y.; Ochia, H.; Nakamura, T.; Yoshida, Z. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1157. (b) Nakamura, E.; Kuwajima, I. J. Am. Chem.
Soc. 1984, 106, 3368. (c) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Tsubaki, K.;
Yoshida, Z. Tetrahedron Lett. 1985, 26, 5559. (d) Nakamura, E.; Aoki, S.;
Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am. Chem. Soc. 1987, 109, 8056. (e)
Ochiai, H.; Nishihara, T.; Tamaru, Y.; Yoshida, Z. J. Org. Chem. 1988, 53,
1343. (f) McWilliams, J. C.; Armstrong, J. D. III; Zheng, N.; Bhupathy, M.;
Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1996, 118, 11970. (g) Rilatt, I.;
Caggiano, L.; Jackson, R. F. W. Synlett 2005, 18, 2701.
(1) (a) Zaidlewicz, M.; Brown, H. C. Organic Syntheses via Boranes;
Aldrich Chemical Co.: Milwaukee, 2002. (b) Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 95, 2457. (c) Kaufmann, D. E.; Matteson, D. S. Science of Synthesis:
Boron Compounds; Thieme: Stuttgart, 2004; Vol. 6.
(2) (a) Matteson, D. S.; Cheng, T.-C. J. Org. Chem. 1968, 33, 3055. (b)
Matteson, D. S.; Beedle, D. S. Tetrahedron Lett. 1987, 28, 4499. (c) Whiting,
A. Tetrahedron Lett. 1991, 32, 1503. (d) Curtis, A. D. M.; Whiting, A.
Tetrahedron Lett. 1993, 49, 187.
(3) Zou, G.; Guo, J.; Wang, Z.; Huang, W.; Tang, J. Dalton Trans. 2007,
3055.
(9) (a) Goswami, R. J. Org. Chem. 1985, 50, 5907. (b) Nakamura, E.;
Kuwajima, I. J. Am. Chem. Soc. 1983, 105, 652. (c) Martins, E.; Gleason, J.
Org. Lett. 1999, 1, 1643. (d) Ochiai, H.; Nishihara, T.; Tamaru, Y.; Yoshida,
Z. J. Org. Chem. 1988, 53, 1343.
(10) Miyaura, N. Top. Curr. Chem. 2002, 219, 11.
(11) Scherer, S.; Meudt, A.; Nerdinger, S.; Lehnemann, B.; Jagusch, T.;
Snieckus, V. WO 2006/097221, 2006.
(4) (a) Lawson, Y. G.; Lesley, M. J. G.; Marder, T. B.; Norman, N. C.;
Rice, C. R. Chem. Commun. 1997, 2051. (b) Ali, H. A.; Goldberg, I.; Srebnik,
M. Organometallics 2001, 20, 3962. (c) Bell, N. J.; Cox, A. J.; Cameron, N. R.;
Evans, J. S. O.; Marder, T. B.; Duin, M. A.; Elsevier, C. J.; Baucherel, X.;
Tulloch, A. A. D.; Tooze, R. P. Chem. Commun. 2004, 1854.
5446 J. Org. Chem. 2009, 74, 5446–5450
Published on Web 07/02/2009
DOI: 10.1021/jo900968h
r
2009 American Chemical Society

ꢀ
Molander and Jean-Gerard
JOCArticle
SCHEME 1
FIGURE 1. DPEPhos ligand.
successful use in Suzuki-Miyaura reactions.12 The develop-
ment of these methods permitted the cross-coupling of a wide
variety of β-trifluoroborato ketones with aryl chlorides in
good to excellent yields.13 Of special note, in contrast to the
use of other β-metallo-substituted carbonyl reagents,14 no
β-hydride elimination was observed during the reaction.
The preparation of β-borato amides has also been studied
recently,6 but their use as coupling partners is even more
scarce and challenging than the ester or ketone counterparts.
To the best of our knowledge, our group published the only
example of their application in the Suzuki-Miyaura reac-
tion, which involved the use of a potassium β-trifluoroborato
amide.12 The desired cross-coupled product was isolated in
only a moderate yield (eq 1).
TABLE 1. Preparation of Potassium β-Trifluoroborato Amides
Potassium organotrifluoroborates are counterparts of
boronic acids/boronate esters that possess valuable physical
and chemical properties,15 including indefinite stability to
moisture and air and a low tendency to protodeboronate.16
Owing to these interesting characteristics, they have been
subjected to extensive study over the past 10 years.15
Because of the usefulness of amide groups in organic
synthesis, we envisioned that an extension of our previous
work on potassium β-trifluoroborato ketones12,13 to the
amide counterparts would be potentially useful. In addition
to their significance in peptide chemistry, amide groups are
also present in a number of chiral auxiliairies17 and are
therefore important in asymmetric synthesis.
aSee ref 18 for the preparation of the R,β-unsaturated Weinreb amide
(entry 5).
Herein, we report the preparation of various β-trifluorobor-
ato amides and the first efficient Suzuki-Miyaura cross-cou-
pling of these agents with various aryl and heteroaryl chlorides.
ers.7c The starting commercially available R,β-unsaturated
amides18 were treated with bis(pinacolato)diboron using a
combination of a copper catalyst and a phosphine ligand
(Figure 1).
Results and Discussion
Initially, several potassium β-trifluoroborato amides were
prepared using the strategy developed by Yun and co-work-
The organoborons thus formed were converted to the
corresponding trifluoroborate salts, in moderate to excellent
yields, by quenching with a saturated aqueous solution of
KHF2 (Table 1).
(12) Molander, G. A.; Petrillo, D. E. Org. Lett. 2008, 10, 1795.
ꢀ
(13) Molander, G. A.; Jean-Gerard, L. J. Org. Chem. 2009, 74, 1297.
With these trifluoroborates in hand, we then explored
their application in Suzuki-Miyaura cross-coupling reac-
tions using the inexpensive and easily available aryl chlor-
ides. As mentioned above, our group reported the cross-
coupling of potassium β-trifluoroborato amide 1a with
(14) Ryu, I.; Matsumoto, K.; Ando, M.; Murai, S.; Sonoda, N. Tetra-
hedron Lett. 1980, 21, 4283.
(15) For reviews on organotrifluoroborate salts, see: (a) Darses, S.;
^
Genet, J.-P. Chem. Rev. 2008, 108, 288. (b) Molander, G. A.; Figueroa, R.
Aldrichim. Acta 2005, 38, 49. (c) Darses, S.; Genet, J.-P. Eur. J. Org. Chem.
^
2003, 4313. (d) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (e)
Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623.
(16) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(17) (a) Evans, D. A. Aldrichim. Acta 1982, 15, 23. (b) Myers, A. G.;
Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Cleason, J. L. J. Am.
Chem. Soc. 1997, 119, 6496.
(18) The unsaturated Weinreb amide is not commercially available and
was thus prepared according to the literature: Corminboeuf, O.; Renaud, P.
Org. Lett. 2002, 4, 1735.
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TABLE 2. Cross-Coupling of Potassium β-Trifluoroborato Amide 1a
with Various Electron-Poor Aryl Chloridesa
FIGURE 2. RuPhos ligand.
4-bromoanisole in an unoptimized 50% yield (eq 1). When
these conditions were used for the cross-coupling of β-borato
amide 1a with 2-chloroanisole as the electrophile, the desired
product was obtained in a yield lower than 50%. We
determined that simply increasing the catalyst/ligand load-
ing to 5 mol % of Pd(OAc)2 and 10 mol % of RuPhos
(Figure 2), respectively, was suitable to carry out this reac-
tion. Under these conditions, a 79% yield of the cross-
coupled product 2b was obtained (eq 2).
Encouraged by this result, we thus investigated the
cross-coupling of β-trifluoroborato amide 1a with various
electron-poor aryl chlorides (Table 2). Pleasingly, all the
electrophiles gave the desired cross-coupled products in very
good yields. As expected, the reaction conditions were
tolerant of many functional groups including nitriles,
aldehydes, ketones, and esters. In particular, the con-
ditions of the reaction were amenable to nitro groups, which
are often reduced in the palladium-catalyzed Suzuki-
Miyaura cross-coupling reaction using alkylborane
nucleophiles.19 In addition, ortho-, meta-, and para-substi-
tuted derivatives were all effective coupling partners. Of
special note, all the reactions were run using only a small
excess (1-2%) of the trifluoroborate. This is made possible
by the resistance of these reagents to protodeboronation
under conditions of the cross-coupling, making the organo-
trifluoroborates unique among organoboron coupling
partners.
The study was then expanded to electron-rich aryl chlor-
ides (Table 3), which are known to be more challenging
electrophilic coupling partners than the electron-deficient
counterparts.20 The conditions developed worked equally
well for these systems. The ortho-, meta-, and para-substi-
tuted derivatives, along with the more hindered substrate,
2-chloro-1,3-dimethylbenzene (Table 3, entry 3), were toler-
ant of the reaction conditions.
aAll reactions were carried out using 0.25 mmol of aryl chloride and
0.253 mmol of potassium organotrifluoroborate 1a.
previous studies,12 a mixture of the desired compound
with varying amounts (3-10%) of the corresponding un-
saturated product was obtained. The use of the sterically
hindered, electron-rich RuPhos as the ligand, which
provides monoligated organopalladium intermediates,
permits the exclusive formation of the desired cross-
coupled product, presumably by increasing the relative
rate of reductive elimination as compared to β-hydride
elimination.21
It is noteworthy that, as expected from our previous
reported results,12,13 we did not observe the formation of
the Heck product resulting from the β-hydride elimination of
the palladium intermediate using this catalytic system
To investigate the method further, attention was turned to
heteroaryl chlorides (Table 4). Nitrogen-, oxygen-, and
sulfur-containing heteroaryl chlorides of various ring sizes
were studied. Under the developed conditions using RuPhos,
(eq 3). When PdCl2(dppf) CH2Cl2 was used in one of our
3
(19) Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221.
(20) Littke, A.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(21) (a) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
(b) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
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Molander and Jean-Gerard
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TABLE 3. Cross-Coupling of Potassium β-Trifluoroborato Amide 1a
TABLE 4. Cross-Coupling of Potassium β-Trifluoroborato Amide 1a
with Various Electron-Neutral and Electron-Rich Aryl Chloridesa
with Various Heteroaryl Chloridesa
aAll reactions were carried out using 0.25 mmol of aryl chloride and
0.253 mmol of potassium organotrifluoroborate 1a.
the desired cross-coupled compounds were isolated in low
yields (entry 6, Table 4). These results prompted us to
investigate another catalytic system, and we determined
that 2.5 mol
% of Pd(OAc)2 in conjunction with
aAll reactions were carried out using 0.25 mmol of heteroaryl chloride
and 0.253 mmol of potassium organotrifluoroborate 1a. bYield with
Pd(OAc)2 (5 mol %) and RuPhos (10 mol %).
5 mol % of 2-dicyclohexylphosphino-20,60-dimethoxybiphe-
nyl (SPhos, Figure 3) was more suitable for these cross-
coupling reactions. These conditions permitted the forma-
tion of the desired cross-coupled products in moderate to
very good yields, except for 2-chloropyridine, which proved
to be an unsuitable coupling partner because only a trace
amount of the expected cross-coupled product was obtained.
Previous studies had shown that 2-bromopyridine was also a
problematic substrate for these reactions, providing virtually
none of the desired cross-coupling product but rather com-
plex reaction mixtures.13
To demonstrate the scope of the method further, different
potassium β-trifluoroboratoamides were cross-coupled with
the unactivated 2-chloroanisole (Table 5). All the reactions
were performed using the catalytic system composed of
5 mol % of Pd(OAc)2 and 10 mol % of RuPhos, and the
desired products were obtained in good to very good
yields. Among the organotrifluoroborates studied, two
proved to be particularly challenging substrates to
cross-couple. The Weinreb amide derivative 1e failed to
FIGURE 3. SPhos ligand.
provide the desired cross-coupled product in useful and
reproducible yields, and the acrylamide derivative 1f did
not afford any trace of the expected product. Disappoint-
ingly, preliminary screening of various ligands that had
previously been shown to be useful (e.g., SPhos, XPhos,
and CataCXium A) did not provide any improvement in
these cases.
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Molander and Jean-Gerard
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was stirred for 30 min at room temperature. A solution of
bis(pinacolato)diboron (8.45 g, 33.0 mmol) in THF (28 mL)
was added dropwise. Additional THF (28 mL) was used to rinse
the flask containing the bis(pinacolato)diboron. The mixture
was stirred for 30 min before cooling to 0 °C. At this point, N,N-
dimethylacrylamide (3.0 g, 30.0 mmol) and methanol (2.4 mL,
60.0 mmol) were successively added, and the mixture was stirred
for 30 min at 0 °C followed by 5 h at room temperature. The
resulting suspension was filtered through Celite, rinsing with
EtOAc (3 ꢀ 15 mL). The filtrate was concentrated under
reduced pressure, and the resulting oil was dissolved in MeCN
(90 mL) and cooled to 0 °C. Saturated aq KHF2 (4.5 M, 20 mL,
90.0 mmol) was added dropwise. The resulting suspension was
stirred for 3 h, concentrated under reduced pressure, and then
placed under high vacuum overnight. The crude product was
then extracted with hot acetone (3 ꢀ 40 mL). The insoluble salts
were filtered off, and the filtrate was concentrated in vacuo. To
the crude solid obtained after drying overnight under vacuum
was added Et2O (50 mL), and the suspension was sonicated for
30 min and then filtered to provide the desired potassium
β-trifluoroborato amide 1a as a white solid in 60% yield (3.7
g, 18 mmol): mp = 125-128 °C; 1H NMR (500 MHz, DMSO-
d6) δ 2.92 (s, 3H), 2.75 (s, 3H), 2.05-2.00 (m, 2H), 0.17 (br s,
2H); 13C NMR (125.8 MHz, DMSO-d6) δ 176.2, 40.0, 34.7, 30.2;
19F NMR (471 MHz, DMSO-d6) δ -138.7 (m); 11B NMR (128
TABLE 5. Cross-Coupling of Various Potassium β-Trifluoroborato-
amides with 2-Chloroanisolea
MHz, DMSO-d6) δ 4.53 (br s); IR (KBr) 2922, 1631 cm-1
;
HRMS (ES-) m/z calcd. for C5H10BF3NO (M - Kþ) 168.0813,
found 168.0802.
Representative Procedure for the Suzuki-Miyaura Cross-
Coupling Reaction of Potassium β-Trifluoroboratoamides and
Aryl Electrophiles: Preparation of 3-(2-Methoxyphenyl)-N,N-
dimethylpropanamide (2b). Method A. To a mixture of potas-
sium β-trifluoroborato-N,N-dimethylpropanamide (1a) (418.2
mg, 2.02 mmol), 2-chloroanisole (285.2 mg, 2.0 mmol), K2CO3
(829.3 mg, 6.0 mmol), Pd(OAc)2 (22.5 mg, 0.1 mmol), and
RuPhos (93.3 mg, 0.2 mmol) under nitrogen was added to-
luene/H2O (5:1, 10.0 mL). The reaction was heated at 85 °C with
stirring under a nitrogen atmosphere for 14 h and then cooled to
rt. A solution of pH 7 buffer (10.0 mL) was added, and the
resulting mixture was extracted with EtOAc (3 ꢀ 6 mL). The
organic layer was dried (MgSO4) and then filtered. The solvent
was removed in vacuo, and the crude product was purified by
silica gel chromatography to afford the product as a colorless oil
in 79% yield (331.3 mg, 1.6 mmol): 1H NMR (500 MHz, CDCl3)
δ 7.22-7.16 (m, 2H), 6.91-6.82 (m, 2H), 3.82 (s, 3H), 2.96-2.93
(m, 2H), 2.95 (s, 3H), 2.94 (s, 3H), 2.59 (m, 2H); 13C NMR (125.8
MHz, CDCl3) δ 172.9, 157.6, 130.3, 129.8, 127.5, 120.6, 110.3,
aAll reactions were carried out using 0.25 mmol of 2-chloroanisole
and 0.253 mmol of potassium organotrifluoroborates. bThe reaction of
the Weinreb amide 1e with 2-chloroanisole under the shown conditions
did not permit the isolation of the desired cross-coupled product in a
reproducible and useful yield. cNo trace of the desired cross-coupled
product was obtained.
Conclusion
55.3, 37.2, 35.4, 33.8, 26.7; IR (neat) 2935, 1633, 1243 cm-1
;
HRMS (CIþ) m/z calcd for C12H18NO2 (M þ Hþ) 208.1338,
In conclusion, an efficient procedure for both the prepara-
tion of β-trifluoroborato amides and their engagement in
Suzuki-Miyaura cross-coupling reactions using inexpensive
aryl chlorides has been reported. These unprecedented re-
sults will allow the use of this chemistry for the synthesis of
more complex molecules. R-Amino-β-borato amides could,
for example, be prepared by this strategy and subsequently
used as coupling partners to prepare functionalized dipep-
tides. We are currently investigating the use of chiral amides
to access chiral β-borato amides.
found 208.1336.
Acknowledgment. This work was generously supported
by the National Institutes of Health (General Medical
Sciences) and Merck Research Laboratories. BASF is
thanked for their donation of bis(pinacolato)diboron.
We also acknowledge Frontier Scientific and Johnson
Matthey for a donation of palladium catalysts and Professor
Stephen L. Buchwald (MIT) for a sample of phosphine
ligands.
Experimental Section
Supporting Information Available: Experimental proce-
dures, spectral characterization, and copies of 1H, 13C, 11B,
and 19F spectra for all compounds prepared by the method
described. This material is available free of charge via the
Internet at http://pubs.acs.org.
Preparation of Potassium β-Trifluoroborato-N,N-dimethyl-
propanamide (1a).12 CuCl (90.0 mg, 0.9 mmol), sodium tert-
butoxide (259.5 mg, 2.7 mmol), and DPEPhos (484.7 mg,
0.9 mmol) were combined in a flask that was evacuated and
filled with nitrogen. THF (28 mL) was added, and the mixture
5450 J. Org. Chem. Vol. 74, No. 15, 2009