Palladium-catalyzed borylation of phenyl bromides and application in one-pot Suzuki-Miyaura biphenyl synthesis

Article abstract of DOI:10.1021/ol048303b

(Chemical equation presented) The coupling reaction of pinacolborane with various aryl bromides in the presence of a catalytic amount of Pd(OAc) ₂ together with DPEphos as ligand and Et₃N as base provided arylboronates. High yields were obtained in the case of electron-donor substituted aryl bromides. The direct preparation of arylboronates allowed the one-pot, two-step synthesis of unsymmetrical biaryls in high yields.

Full text of DOI:10.1021/ol048303b

ORGANIC
LETTERS
2
004
Vol. 6, No. 24
419-4422
Palladium-Catalyzed Borylation of
Phenyl Bromides and Application in
4
One-Pot Suzuki
Synthesis
−
Miyaura Biphenyl
Pierre-Emmanuel Broutin, Igor C
ˇ
er nˇ a, Maria Campaniello, Fr e´ d e´ ric Leroux, and
Francoise Colobert*
¸
Laboratoire de St e´ r e´ ochimie associ e´ au CNRS (UMR 7008), UniVersit e´ Louis Pasteur
ECPM), 25 rue Becquerel, F-67087 Strasbourg Cedex 2, France
(
fcolober@chimie.u-strasbg.fr
Received August 25, 2004
ABSTRACT
The coupling reaction of pinacolborane with various aryl bromides in the presence of a catalytic amount of Pd(OAc)
as ligand and Et N as base provided arylboronates. High yields were obtained in the case of electron-donor substituted aryl bromides. The
direct preparation of arylboronates allowed the one-pot, two-step synthesis of unsymmetrical biaryls in high yields.
2
together with DPEphos
3
Substituted biphenyls are central components of fine chemi-
cals for a diverse range of applications. In particular, pharma-
ceuticals and herbicides with biaryl substructures are of gen-
improvements are still necessary, especially when electroni-
cally deactivated coupling partners are involved.
The arylboronic acids or arylboronates needed for the
Suzuki-Miyaura coupling can be synthesized by two
principal methods: (1) the transmetalation between aryl-
magnesium or -lithium intermediates and boron compounds
1
eral interest. In addition, biaryls are applied as chiral ligands
2
in catalysis, as liquid crystals, or organic conductors. The
most common method used for linking the central aryl-aryl
bond is the palladium-catalyzed coupling of aryl halides or
pseudo halides with arylboronic acids (Suzuki-Miyaura
that have good leaving groups such as halogen or alkoxy
4
groups, (2) the more recently developed PdCl
2
(dppf)-
3
reaction). This method has the advantage over other
catalyzed borylation of aryl halides with tetra(alkoxy)-
alternatives in that stoichiometric amounts of heavy metals
are not required. Although this method is well-established,
Scheme 1. Arylboronate Synthesis Using Pinacolborane
(
1) Patchett, A. A.; Nargund, R. P. In Topics in Drug Design and
DiscoVery; Trainor, G. L., Ed.; Annu. Rep. Med. Chem. (Section IV) 2000,
5, 289.
2) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525 and
references therein.
3) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
3
(
(
P. J., Eds; Wiley-VCH: New York, 1998. (b) Farina, V. In ComprehensiVe
Organometallic Chemistry II; Hegedus, L. S., Ed.; Pergamon: Oxford, 1995;
Vol. 12, p 161. (c) Tsuji, J. In Palladium Rreagents and Catalyst; John
Wiley and Sons: Chichester, U.K., 1995. (d) Trost, B. M.; Verhoeven, T.
R. In ComprehensiVe Organometallic Chemistry; Wilkinson, G., Stone, F.
G. A., Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol. 8, p 799. (e) Mi-
yaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (f) Stanforth, S. P. Tetra-
hedron 1998, 54, 263. (f) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
1
0.1021/ol048303b CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/30/2004

manner, tolerating various functional groups, being insensi-
tive to air, moisture, temperature and mostly chromatography
7
stable.
However, there are few examples of the Pd-catalyzed
borylation of ortho-substituted aryl bromides. Baudoin et al.
reported on the improved borylation of sterically hindered
aryl halides using the biphenyl ligand 4 (Figure 1) in the
8
2 2
presence of Pd(OAc) instead of PdCl (dppf).
In the course of our investigations on the Suzuki-Miyaura
coupling reaction leading potentially to the biphenyl part of
Vancomycin as well as Steganacin, we turned our attention
9
toward the use of DPEphos (Figure 1) as ligand in the
borylation of phenyl bromides. The advantage of DPEphos
toward dppf is its cheaper availability (DPEphos: 7 kEuros/
mol vs dppf: 15 kEuros/mol) and its higher air stability
compared to ligand 4.
Figure 1. Ligands used for the palladium-catalyzed borylation of
aryl halides.
5
diboron or with dialkoxyboranes such as pinacolborane
(
To investigate the scope and limitations of this ligand, we
subjected various phenyl bromides bearing different electron-
donating and electron-withdrawing substituents in the ortho-,
6
Scheme 1). The latter method possesses several advantages.
The borylation using pinacolborane is an atom economical
Table 1. Synthesis of Arylboronates 3 from Phenyl Bromides 1a
a
Conditions: Et3N (4.0 equiv), 2 (3.0 equiv), dioxane, 100 °C. b A ) 5 mol % Pd(OAc)2/10 mol % DPEphos (this work), B ) 5mol % Pd(OAc)2/20 mol
%
4, C ) 5 mol % PdCl2(dppf). c Isolated yields after flash chromatography.
4420
Org. Lett., Vol. 6, No. 24, 2004

meta-, and para-position of the phenyl ring to the same
reaction conditions (Table 1).
(Table 1, entries 9-12), little or no pinacolboronate was
obtained, in accordance with literature observations.6
We observed a high difference in the yields among phenyl
bromides having electron-donating or -withdrawing groups.
In previous studies such a strong reactivity difference was
It should be noted that the yields using DPEphos are
significantly higher in the case of phenyl bromides with
electron-donating substituents compared to previous re-
sults using the more expensive dppf ligand or the biphenyl
ligand 4 (see Table 1, entries 1, 3, and 15). Contrarily, dppf
gave higher yields in the case of the unsubstituted bro-
mobenzene (Table 1, entry 7). The borylation of a sterically
hindered phenyl bromide, mesityl bromide, afforded with
DPEphos the corresponding mesityl pinacolboronate in a
yield of 25% (Table 1, entry 8). In contrast, Baudoin showed
that the analogous 2,6-dimethylbromobenzene could be
6
b
never observed. Although it is known that the presence of
powerful electron-withdrawing substituents such as NO
2
10
induces the reductive dehalogenation of the aryl halide, the
yields among aryl halides having electron-donating or
-withdrawing groups were not substantially affected by their
substituents. In contrast, in our studies we observed very low
yields for aryl halides having electron-withdrawing substit-
uents and high yields in the case of electron-donor-substituted
ones.
Thus, 2-bromoanisol, 3-bromoanisol, and 4-bromoanisol
gave the corresponding boronates in yields of 78%, 27%,
and 99%, respectively (Table 1, entries 1-3). The same holds
converted into the corresponding boronate using the ligand
8
4
in a yield of 51%. The same borylation using dppf as
8
ligand gave only very poor yields (<5%) of boronate. Thus,
the borylation of sterically hindered bromides works par-
ticularly well with higher yields and under milder conditions
with the ligand 4, as shown by Baudoin.
2
for the NMe -substituted phenyl bromides. N,N-(Dimeth-
ylamino)-3-bromoaniline and N,N-(dimethylamino)-4-bro-
moaniline afforded the m- and p-phenyl boronates in 63%
and 96% yield, respectively (Table 1, entries 14 and 15). In
both cases the strong electron-donor capacity (+M-effect)
With these results in hand, we thought that this methodol-
ogy could be extended to the synthesis of unsymmetrically
substituted biphenyls via a one-pot, two-step Suzuki-
Miyaura cross-coupling reaction. This was indeed achieved
by adding after completion of the borylation step the needed
ingredients in the same reaction flask (Table 2).
2
of the substituent (OMe and NMe ), being only effective in
the ortho- and para-position, leads to the high yields with
these derivatives. In contrast, only low yields were obtained
for the unactivated meta-substituted phenyl bromides. As a
result of the strong steric hindrance in the case of N,N-
(
dimethylamino)-2-bromoaniline, no borylation can be ob-
Table 2. One-Pot, Two-Step Synthesis of Biphenyls 5a
served in this case (Table 1, entry 13).
Next we studied the borylation of Me-substituted phenyl
bromides. As expected, the Me-group as an inductive
electron-donor substituent (+I-effect) activates strongly the
ortho- and to a small extent the meta-substituted phenyl
bromide. Both 2- and 3-bromotoluene afforded the corre-
sponding boronates in 84% and 70% yield, respectively
(Table 1, entries 16 and 17). The para-substituted derivative,
4-bromotoluene, being not activated, is formed in a poor yield
of 36% (Table 1, entry 18). This result can be compared to
the borylation of the unsubstituted bromobenzene (Table 1,
entry 7, 33%).
entry
product
yield (%)
With phenyl bromides bearing electron-withdrawing sub-
stituents such as bromonitrobenzene or bromobenzonitrile
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
62
72
51
73
58
90
80
(4) (a) Matteson, D. S. In The Chemistry of the Metal-Carbon Bond;
Hartley, F. R., Patai, S., Eds.; Wiley: New York, 1987; Vol. 4, p 307. (b)
Vaultier, M.; Carboni, B. In ComprehensiVe Organometallic Chemistry II;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995;
Vol. 11, p 191. (c) Miyaura, N.; Maruoka, K. In Synthesis of Organometallic
Compounds; Komiya, S., Ed.; Wiley: New York, 1997; p 345.
5g
a
Conditions: (1) Et3N (3.0 equiv), 2 (2.0 equiv), Pd(OAc)2 (5 mol %),
dioxane, 100 °C, 3 h; (2) bromide (1.0 equiv), Pd(OAc)2 (5 mol %), CsF
8 equiv), dioxane, 100 °C, 20 h.
(
5) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
(
7
1
508. (b) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
997, 38, 3447.
(
6) (a) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62,
6
458. (b) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem.
2
000, 65, 164.
Thus, the borylation of 4-bromo-N,N-dimethylaniline in
(7) (a) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992, 57,
the above conditions (100 °C, 3 h) was followed by addition
of excess CsF (8 equiv), Pd(OAc) (5 mol %), and the second
3
482. (b) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127. (c)
Pereira, S.; Srebnik, M. J. Am. Chem. Soc. 1996, 118, 909. (d) Pereira, S.;
Srebnik, M. Tetrahedron Lett. 1996, 37, 3283. (e) Murata, M.; Watanabe,
S.; Masuda, Y. Tetrahedron Lett. 1999, 40, 2585.
2
aryl bromide (2-bromotoluene, 4-bromotoluene, 2-bromoben-
zonitrile, 4-bromobenzonitrile, 2-bromonitrobenzene, and
4-bromonitrobenzene, respectively). The corresponding bi-
phenyls were obtained in high yields (Table 2). Similarly,
4-bromoanisole was cross-coupled with 4-bromobenzonitrile.
(
8) Baudoin, O.; Gu e´ nard, D.; Gu e´ ritte, F. J. Org. Chem. 2000, 65, 9268.
(9) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwn, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
081.
10) Echavarrene, A. M.; Stille, J. K. J. Am. Chem. Soc. 1988, 110, 1557.
3
(
Org. Lett., Vol. 6, No. 24, 2004
4421

In conclusion, we reported the borylation of various
unactivated and sterically hindered phenyl bromides, using
the cheap and oxidatively stable phosphine ligand DPEphos.
These findings were extended to the one-pot, two-step
Suzuki-Miyaura reaction with different phenyl bromides,
yielding dissymmetrically substituted biphenyls in a simple,
rapid, and efficient manner.
SOKRATES/ERASMUS fellowship, and P.E.B. is very
grateful to “la r e´ gion Alsace” for a grant.
Supporting Information Available: Experimental pro-
cedures and details of compound characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We are grateful to the CNRS and
Minist e` re de la Recherche. I.C. and M.C. are thankful for a
OL048303B
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Org. Lett., Vol. 6, No. 24, 2004