Tetrabutylammonium 2-pyridyltriolborate salts for Suzuki-Miyaura cross-coupling reactions with aryl chlorides

Article abstract of DOI:10.1021/ol402268g

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of tetrabutylammonium 2-pyridyltriolborate salts with various aryl (heteroaryl) chlorides can produce the corresponding desired coupling products with good to excellent yields. These tetrabutylammonium salts are more reactive than the corresponding lithium salts. The coupling reactions with aryl chlorides progressed in the presence of PdCl₂dcpp (3 mol %) and CuI/MeNHCH ₂CH₂OH (20 mol %) in anhydrous DMF without bases.

Full text of DOI:10.1021/ol402268g

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4308–4311
Tetrabutylammonium 2‑Pyridyltriolborate
Salts for SuzukiꢀMiyaura Cross-Coupling
Reactions with Aryl Chlorides
Shohei Sakashita, Miho Takizawa, Juugaku Sugai, Hajime Ito, and
Yasunori Yamamoto*
Division of Chemical Process Engineering and Frontier Chemistry Center,
Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
yasuyama@eng.hokudai.ac.jp
Received June 12, 2013
ABSTRACT
Palladium-catalyzed SuzukiꢀMiyaura cross-coupling reactions of tetrabutylammonium 2-pyridyltriolborate salts with various aryl (heteroaryl)
chlorides can produce the corresponding desired coupling products with good to excellent yields. These tetrabutylammonium salts are more
reactive than the corresponding lithium salts. The coupling reactions with aryl chlorides progressed in the presence of PdCl2dcpp (3 mol %) and
CuI/MeNHCH2CH2OH (20 mol %) in anhydrous DMF without bases.
SuzukiꢀMiyaura cross-coupling (SMC) reactions pro-
vide a powerful and general method for the synthesis of
pharmaceuticals and materials.1 However, SMC reactions
under basic aqueous conditions often give undesirable
results due to competitive hydrolytic BꢀC bond cleavage.2,3
Such cleavage is significantly accelerated by adjacent
heteroatoms in boronic acids.2,4 2-Pyridylboronic acid
derivatives are typical boron compounds that undergo
very rapid cleavage with water during coupling reactions.
Several approaches for cross-coupling of these conver-
sions to boronic acid derivatives have been reported,5
including esters such as pinacol organoboronates,6
(1) For reviews: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (b) Miyaura, N. In Advances in Meta-Organic Chemistry; Liebeskind,
L. S., Ed.; JAI Press: London, 1998; Vol. 6, pp 187ꢀ243. (c) Miyaura, N.
Top. Curr. Chem. 2002, 219, 11. (d) Miyaura, N. J. Organomet. Chem.
2002, 653, 54. (e) Suzuki, A.; Brown, H. C. Organic Syntheses via
Boranes; Aldrich Chemical Co.: Milwaukee, 2003; Vol. 3. (f) Miyaura,
N. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, pp 41ꢀ124. (g)
Hall, D. G. Boronic Acids, 2nd ed.; Wiley-VCH: Weinheim, 2011. (h)
Suzuki, A.; Yamamoto, Y. Chem. Lett. 2011, 40, 894.
ꢁ
(5) (a) Matondo, H.; Souirti, S.; Baboulene, M. Synth. Commun.
2003, 33, 795. (b) Bouillon, A.; Lancelot, J.-C.; Sopkova de Oliveira
Santos, J.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2003, 59, 10043.
(c) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132,
14073. (d) Ge, S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 12837.
(e) Thakur, A.; Zhang, K.; Louie, J. Chem. Commun. 2012, 48, 203.
(6) (a) Mkhalid, I. A. I.; Coventry, D. N.; Albesa-Jove, D.; Batsanov,
A. S.; Howard, J. A. K.; Perutz, R. N.; Marder, T. B. Angew. Chem., Int.
Ed. 2006, 45, 489. (b) Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.;
Kurihara, H.; Dreher, S. D.; Weissman, S. A.; Stauffer, S. R.; Burgey,
C. S. Org. Lett. 2009, 11, 345. (c) Yang, D. X.; Colletti, S. L.; Wu, K.;
Song, M.; Li, G. Y.; Shen, H. C. Org. Lett. 2009, 11, 381. (e) Crowley,
B. M.; Potteiger, C. M.; Deng, J. Z.; Prier, C. K.; Paone, D. V.; Burgey,
C. S. Tetrahedron Lett. 2011, 52, 5055. (f) Robbins, D. W.; Hartwig, J. F.
Org. Lett. 2012, 14, 4266.
(2) (a) Tyrrell, E.; Brookes, P. Synthesis 2003, 469. (b) Campeau,
L. C.; Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058. (c) Hapke, M.;
€
Brandt, L.; Lutzen, A. Chem. Soc. Rev. 2008, 37, 2782.
(3) (a) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57,
9813. (b) Fuller, A. A.; Hester, H. R.; Salo, E. V.; Stevens, E. P.
Tetrahedron Lett. 2003, 44, 2935.
(4) (a) Kuiliva, H. G.; Nahabedian, K. V. Chem. Ind. 1959, 1120. (b)
Kuivila, H. G.; Nahabedian, K. V. J. Am. Chem. Soc. 1961, 83, 2164. (c)
Nahabedian, K. V.; Kuivila, H. G. J. Am. Chem. Soc. 1961, 83, 2167. (d)
Kuivila, H. G.; Reuwer, J. F., Jr.; Mangravite, J. A. Can. J. Chem. 1963,
41, 3081. (e) Kuivila, H. G.; Reuwer, J. F., Jr.; Mangravite, J. A. J. Am.
Chem. Soc. 1964, 86, 2666. (f) Brown, R. D.; Buchanan, A. S.; Humffray,
A. A. Aust. J. Chem. 1965, 18, 1521. (g) Fischer, F. C.; Havinga, E.
Recueil 1974, 93, 21. (h) Roques, B. P.; Florentin, D.; Callanquin, M.
(7) (a) Hodgson, P. B.; Salingu, F. H. Tetrahedron Lett. 2004, 45, 685.
(b) Gros, P.; Doudouh, A.; Fort, Y. Tetrahedron Lett. 2004, 45, 6239. (c)
€
€
Gutz, C.; Lutzen, A. Synthesis 2010, 85.
ꢀ
J. Heterocycl. Chem. 1975, 12, 195. (i) Florentin, D.; Fournie-Zaluski,
(8) (a) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (b)
Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288. (c) Molander, G. A.;
Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240.
M. C.; Callanquin, M.; Roques, B. P. J. Heterocycl. Chem. 1976, 13,
1265.
r
10.1021/ol402268g
Published on Web 08/16/2013
2013 American Chemical Society

diethanolamine adducts,7 trifluoroborate salts,8,9 lithium
triisopropoxyborates,10 and N-methyliminodiacetic acid
(MIDA) boronates.11,12 We have developed heteroaryl-
triolborate salts that are stable for metal-catalyzed reac-
tions.13ꢀ15 Triolborate salts possessing 2-pyridyl, 3-pyridyl,
and other heteroarenes afforded biaryls by SMC reac-
tions in high yields at 50ꢀ120 °C in anhydrous DMF
without bases. There was a strong accelerating effect of
copper salts for reactions of 2-pyridyltriolborate deriva-
tives (1).13 However, the coupling of 1 with aryl chlorides
(3) remains an important and challenging issue. We here-
in report the cross-coupling of 2-pyridyltriolborates with
a wide range of 3 involving electronically deactivated aryl
chlorides (Scheme 1). We have already reported that 1
couples in high yield with several aryl bromides and
iodides in the presence of a PdCl2dppp and CuI catalyst
without bases.13b,c,g The yield of SMC reactions of reac-
tive aryl chloride catalyzed by PdCl2dppp and CuI in
slowly than their activated ones. To overcome the pro-
blem of deactivated aryl chlorides, we considered chan-
ging the countercation of pyridyltriolborate.16 The reac-
tion of phenyltriolborate salt with 2-bromo-m-xylene at
room temperature shows the following order of reactiv-
n
ity: Bu4Nþ > Csþ > Kþ > Naþ > Liþ (eq 1). The
tetrabutylammonium salt exhibits a greater accelerating
effect. Similarly, in the SMC reaction of phenyltriolbo-
rate salt with p-anisyl chloride as an electronically deac-
tivated aryl chloride, the tetrabutylammonium salt was
more reactive than the rubidium salt (eq 2). p-Methoxy-
biphenyl was obteined finally in 78% yield at 100 °C.
Scheme 1. Cross-Coupling of 2-Pyridyltriolborates
To confirm the influence of countercations on transme-
talation, (Ph3P)2Pd(Ph)Br (6) was reacted with phenyl-
triolborate salts at room temperature. A difference in
reaction rate was observed with the order of efficiency
being nBu4Nþ > Csþ > Kþ > Liþ (Figure 1). Although
the lithium salt has been synthetically useful, this has the
limitation of being insoluble in an organic solvent such as
THF or AcOEt. The tetrabutylammonium salt has the
advantage of being readily soluble in THF or AcOEt.
Counterion exchangefrom lithium toammonium can be
achieved by treating with tetrabutylammonium hydroxide
in THF. Next, we tried reactions of lithium and tetrabu-
tylammonium 2-pyridyltriolborate salts with (Ph3P)2Pd-
(Ph)Br (6) and dpppPd(Ph)Br (7) at room temperature in
anhydrous DMF (eqs 3 and 4).
DMF at 80 °C was low. Moreover, electronically and
sterically deactivated aryl chlorides tended to react more
(9) (a) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302. (b)
Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009, 74,
973. (c) Ren, W.; Li, J.; Zou, D.; Wu, Y.; Wu, Y. Tetrahedron 2012, 68,
1351.
(10) (a) O’Neill, B. T.; Yohannes, D.; Bundesmann, M. W.; Arnold,
E. P. Org. Lett. 2000, 2, 4201. (b) Billingsley, K. L.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 4695. (c) Ackermann, L.; Potukuchi,
€
H. K. Synlett 2009, 2852. (d) Haag, B. A.; Samann, C.; Jana, A.;
Knochel, P. Angew. Chem., Int. Ed. 2011, 50, 7290. (e) Oberli, M. A.;
Buchwald, S. L. Org. Lett. 2012, 14, 4606. (f) Chen, K.; Peterson, R.;
Math, S. K.; Lamunyon, J. B.; Testa, C. A.; Cefalo, D. R. Tetrahedron
Lett. 2012, 53, 4873.
(11) Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 42, 17.
(12) (a) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2009, 131, 6961. (b) Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Burke,
M. D. Org. Lett. 2010, 12, 2314. (c) Dick, G. R.; Woerly, E. M.; Burke,
M. D. Angew. Chem., Int. Ed. 2012, 51, 2667.
(13) (a) Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N.
Angew. Chem., Int. Ed. 2008, 47, 928. (b) Yamamoto, Y.; Takizawa,
M.; Yu, X.-Q.; Miyaura, N. Heterocycles 2010, 80, 359. (c) Yamamoto,
Y.; Sugai, J.; Takizawa, M.; Miyaura, N. Org. Synth. 2011, 88, 79. (d) Li,
G.-Q.; Kiyomura, S.; Yamamoto, Y.; Miyaura, N. Chem. Lett. 2011, 40,
702. (e) Li, G.-Q.; Yamamoto, Y.; Miyaura, N. Synlett 2011, 1769. (f) Li,
G.-Q.; Yamamoto, Y.; Miyaura, N. Tetrahedron 2011, 67, 6804. (g)
Yamamoto, Y. Heterocycles 2012, 85, 799.
(14) Yu, X.-Q.; Yamamoto, Y.; Miyaura, N. Chem.;Asian. J. 2008,
3, 1517.
(15) (a) Yu, X.-Q.; Yamamoto, Y.; Miyaura, N. Synlett 2009, 994. (b)
Yu, X.-Q.; Shirai, T.; Yamamoto, Y.; Miyaura, N. Chem.;Asian. J.
2011, 6, 932. (c) Yamamoto, Y.; Takahashi, Y.; Kurihara, K.; Miyaura,
N. Aust. J. Chem. 2011, 64, 1447.
The tetrabutylammonium salt also gave a better yield
than that of the lithium salt. As a result, we examined the
SMC reaction of tetrabutylammonium 2-pyridyltriolbo-
rate salt with aryl chlorides. Unlike the stoichiometric
Org. Lett., Vol. 15, No. 17, 2013
4309

salt (57 and 83%, entries 2 and 5). Unfortunately, when
the tetrabutylammonium salt was used for reaction with
chlorobenzene, the desired products were obtained in
only 5% yield (entry 7). Next, we investigated the effects
of catalysts. PdCl2dcpp (dcpp = 1,3-bis(dicyclohexylphos-
phino)propane) gave a 55% yield (entry 10). By further
investigations of reaction conditions, 2-phenylpyridine
was finally obtained in 78% yield at 100 °C (entry 11).
The role of copper salts seems to be to facilitate the
transmetalation of 2a to arylpalladium chloride by gen-
eration of a 2-pyridylcopper species.6b,12c,17,18 Therefore,
we investigated a wide range of ligands for copper iodide
(Table 2). As expected, the addition of TMEDA or etha-
nolamine led to an increase in coupling yield (entries 2ꢀ6).
N-Methyl ethanolamine gave the best yield (95%, entry 6).
In examination of the amount of N-methyl ethanolamine
(entries 6ꢀ9), we found that the product was obtained
quantitatively by adding 20 mol % (an equivalent amount
Figure 1. Effect of counterions on transmetalation.
Table 2. Screen of Additives for the Cross-Coupling
of 2-Pyridyltriolborate with Chlorobenzenea
Table 1. Optimization of Cross-Coupling Reactions
of 2-Pyridyltriolborate with Aryl Chloridesa
entry
additive (equiv)
none
yield (%)
1
78
84
64
82
89
95
95
99
99
13
77
2
TMEDA (3)
3
H2NCH2CH2OH (3)
H2NCH2CH(CH3)OH (3)
BnHNCH2CH2OH (3)
MeHNCH2CH2OH (3)
MeHNCH2CH2OH (1)
MeHNCH2CH2OH (0.4)
MeHNCH2CH2OH (0.2)
HN(CH2CH3)2 (3)
4
5
additive
yield
(%)
6
entry
M =
Li
R =
catalyst
(mol %)
7
8
1
NO2 PdCl2dppp
NO2 PdCl2dppp
NO2 PdCl2dppp
NO2 PdCl2dppp
none
0
9
2
Li
Li
Li
CuI (20)
CuBr (20)
CuCl (20)
CuI (20)
CuI (20)
CuI (20)
57
45
47
83
0
10
11
3
HN(CH2CH2OH)2 (3)
4
nBu4N NO2 PdCl2dppp
a Reaction conditions: tetrabutylammonium 2-pyridyltriolborate salt
(2a, 1.25 mmol), chlorobenzene (3, 0.5 mmol), PdCl2dcpp (3 mol %),
CuI (20 mol %), DMF (3 mL), 100 °C, 22 h.
5
6
Li
H
H
H
H
H
H
PdCl2dppp
PdCl2dppp
7
nBu4N
nBu4N
nBu4N
nBu4N
nBu4N
5
8
Pd(OAc)2/2JohnPhos CuI (20)
23
31
55
78b
9
Pd(OAc)2/2XPhos
PdCl2dcpp
CuI (20)
CuI (20)
CuI (20)
of copper iodide, entry 9). However, diethylamine pro-
videdonly13%yield (entry10). Theyield withthe addition
of diethanolamine was the same yield as that without
diethanolamine (entry 11).
On the basis of these results, cross-coupling reactions of
tetrabutylammonium 2-pyridyltriolborate salts (2) with aryl
chlorides (3) were performed in the presence of PdCl2dcpp
(3 mol %) and CuI/MeHNCH2CH2OH (20 mol %) in
anhydrous DMF at 100 °C. As shown in Table 3, the cross-
coupling reactions of 2a with a series of electron-
10
11
PdCl2dcpp
a Reaction conditions: 2-pyridyltriolborate salt (1a or 2a, 1.25 mmol),
aryl chloride (3, 0.5 mmol), Pd catalyst (3 mol %), CuI (20 mol %), DMF
(3 mL), 80 °C, 22 h. b The reaction was carried out at 100 °C.
reactions with palladium bromides, in the catalytic reac-
tions with aryl chlorides, no reaction of the lithium
2-pyridyltriolborate (1a) with p-nitrochlorobenzene was
observed in the absence of CuI (entry 1, Table 1). The
addition of catalytic amounts of copper salts such as CuI,
CuBr, and CuCl increased the coupling yields to 57%,
45%, and 47%, respectively (entries 2ꢀ4). Tetrabutylam-
monium salt 2a gave a better yield than that of the lithium
(17) (a) Miyaura, N.; Itoh, M.; Suzuki, A. Tetrahedron Lett. 1976, 17,
255. (b) Miyaura, N.; Sasaki, N.; Itoh, M.; Suzuki, A. Tetrahedron Lett.
1977, 18, 173. (c) Miyaura, N.; Sasaki, N.; Itoh, M.; Suzuki, A.
Tetrahedron Lett. 1977, 18, 3369. (d) Ichikawa, J.; Minami, T.; Sonoda,
T.; Kobayashi, H. Tetrahedron Lett. 1992, 33, 3779.
(18) (a) Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697. (b) Mee,
S. P. H.; Lee, V.; Baldwin, J. E. Chem.;Eur. J. 2005, 11, 3294.
(16) Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2001, 42, 9099.
4310
Org. Lett., Vol. 15, No. 17, 2013

withdrawing (entries 1ꢀ6) or electron-donating (entries
8ꢀ10, 13, 14) para-substituted chloroarenes proceeded
in good to excellent yields. In addition, meta- and ortho-
substituted aryl chlorides reacted with 2a in good yield
(entries 11, 12, 15, 16).
Table 4. Scope of Cross-Coupling of Tetrabutylammonium
2-Pyridyltriolborate Salt with Aryl Chloridesa
Table 3. Scope of Cross-Coupling of Tetrabutylammonium
2-Pyridyltriolborate Salt with Aryl Chloridesa
entry
Ar = (3)
4
yield (%)
1
4-O2NC6H4 (3a)
4-NCC6H4 (3b)
4-MeCOC6H4 (3c)
4-MeO2CC6H4 (3d)
4-HOCC6H4 (3e)
4-FC6H4 (3f)
4aa
4ab
4ac
4ad
4ae
4af
93
60
66
67
56
91
99
62
94
95
90
79
92
88
99
74
2
3
4
5
6
7
C6H5 (3g)
4ag
4ah
4ai
8
4-AcNHC6H4 (3h)
4-PhOC6H4 (3i)
4-MeC6H4 (3j)
3-MeC6H4 (3k)
2-MeC6H4 (3l)
4-tBuC6H4 (3m)
4-MeOC6H4 (3n)
3-MeOC6H4 (3o)
2-MeOC6H4 (3p)
9
10
11
12
13
14
15
16
4aj
4ak
4al
4am
4an
4ao
4ap
a Reaction conditions: tetrabutylammonium 2-pyridyltriolborate
salt (2a, 1.25 mmol), aryl chloride (3, 0.5 mmol), PdCl2dcpp (3 mol %),
CuI/MeHNCH2CH2OH (20 mol %), DMF (3 mL), 100 °C, 16 h.
b 2-Chloro-5-nitropyridine (0.5 mmol), lithium 2-pyridyltriolborate salt
(1.0 mmol), PdCl2dppp (3 mol %), CuI (20 mol %), NaI (1.0 mmol) in
DMF at 80 °C for 22 h. c CuI/MeHNCH2CH2OH (40 mol %) were used.
d NMR yield.
a Reaction conditions: tetrabutylammonium 2-pyridyltriolborate
salt (2a, 1.25 mmol), chlorobenzene (3, 0.5 mmol), PdCl2dcpp (3 mol %),
CuI (20 mol %), DMF (3 mL), 100 °C, 22 h.
Cross-coupling between two nitrogen-containing het-
erobiaryl compounds is challenging, presumably because
of the coordinating property of pyridines or bipyridines.
As shown in Table 4, we initially studied the coupling of 2a
with 2-chloropyridine derivatives (3q, 3r, and 3s) or
2-chloroquinoline derivatives (3t and 3u). These reactions
generated products with good yields. We presumed that
the catalyst is stable because of the chelating property of
the dcpp ligand. In coupling with 5-chloro-2-methylbenzo-
[d]oxazole (3v), this catalytic system showed good reactiv-
ity (81%). Utilizing this catalytic system, chloronaphtha-
lenes were also suitable coupling partners as seen in the
reactions of 2a with 1-chloronaphthalene and 2-chloro-
naphthalene, which resulted in 93% (4aw) and 94% (4ax)
yields, respectively.
chloride. This reaction proceeded well to provide the
desired products (4co) with quantitative yields.
In conclusion, we have newly prepared tetrabutylam-
monium 2-pyridyltriolborate salts for challenging cross-
coupling with aryl (heteroaryl) chlorides. We have devel-
oped conditions catalyzed by PdCl2dcpp and CuI/
MeNHCH2CH2OH in anhydrous DMF without bases,
which provided various 2-arylpyridine derivatives in good
to excellent yields.
Acknowledgment. This research was supported in part
by Strategic Molecular and Materials Chemistry through
Innovative Coupling Reactions from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan.
Substrates 2, possessing functional groups, successfully
coupled with 3-anisyl chloride (4boꢀeo).Theuseof40mol%
CuI/MeNHCH2CH2OH led to an increase in the coupling
yield with 3-methyl- (2b) and 6-fluoro-2-pyridyltriolborate
(2d). We further investigated the coupling reaction be-
tween 4-methyl-2-pyridyltriolborate (2c) and 3-anisyl
Supporting Information Available. Experimental pro-
cedures, preparation of triolborates, spectral data, and
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
4311