Efficient borylation of reactive aryl halides with MPBH (4,4,6-trimethyl-1,3,2-dioxaborinane)

Article abstract of DOI:10.1055/s-0030-1258059

The combination of 4,4,6-trimethyl-1,3,2-dioxaborinane, a particularly stable and inexpensive borylation reagent, and Buchwalds palladium catalyst provides a simple, fast, cost-effective borylation of electron-rich, reactive iodides, bromides, and triflates to produce stable, easily purified boronic esters. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258059

LETTER
2403
Efficient Borylation of Reactive Aryl Halides with MPBH (4,4,6-Trimethyl-
1,3,2-dioxaborinane)
Efficient
B
orylatio
a
n
of Reacti
g
ve
A
ryl
H
ali
e
w
ith
M
s
PBH waran PraveenGanesh, Emilien Demory, Christine Gamon, Véronique Blandin, Pierre Y. Chavant*
Département de Chimie Moléculaire, UMR-5250, ICMG FR-2607, CNRS, Université Joseph Fourier,
BP 53, 38041 Grenoble Cedex 09, France
Fax +33(4)76635983; E-mail: Pierre-Yves.Chavant@ujf-grenoble.fr
Received 27 April 2010
known6 to accelerate the decomplexation and solvolysis
Abstract: The combination of 4,4,6-trimethyl-1,3,2-dioxabori-
nane, a particularly stable and inexpensive borylation reagent, and
Buchwald’s palladium catalyst provides a simple, fast, cost-effec-
tive borylation of electron-rich, reactive iodides, bromides, and tri-
flates to produce stable, easily purified boronic esters.
of amine-boranes in methanol. In an analogous manner
(Scheme 1), we found that reacting N,N-diethylaniline-
borane and hexyleneglycol in the presence of Pd/C (5%
by weight of 10% Pd/C reagent) resulted in the complete
consumption of the diol in 30 min at room temperature.
Distillation of the reaction mixture in vacuo provided neat
MPBH in 75% yield.7,8
Key words: boron, palladium, catalysis, arylboronic, Suzuki
The increasing number of applications of the Suzuki–
Miyaura coupling prompts the design of efficient and
cost-effective methods for the preparation of the arylbo-
ronic precursors. Among these, the borylation of aryl ha-
lides or triflates with pinacolborane1 (PinBH) is an
excellent alternate to the more classical addition of orga-
nometallics to trialkoxyborane. Murata’s team2 and ours3
proposed the replacement of PinBH in this reaction by the
easily accessible, much less expensive, and more conve-
Cy2P
Pd2(dba)3
O
+
X
MPBH
B
Et3N
20–100 °C
R
O
R
X = I, Br, Cl, OTf
2a–j
Scheme 2 Borylation of aryl halides and triflates
niently
prepared
MPBH
[4,4,6-trimethyl-1,3,2-
dioxaborinane4 (1)]. In addition, Billingsley and
Buchwald1i completed in 2008 the original study of Bau-
doin et al.1c on the very positive role of bulky phosphine
ligands in the borylation with PinBH. We wondered if the
advantages of both implementations could be combined to
provide a convenient and cost-effective access to aryl bo-
ronic esters from aryl halides; we discuss herein the ad-
vantages and limitations of this system.
Then we studied the palladium-catalyzed borylation of
various aryl halides and triflates with MPBH and a cata-
lyst prepared from Pd2(dba)3 and CyJohnPhos9 according
to Baudoin’s procedure1c (Scheme 2, Table 1).10 In pre-
liminary experiments, we found that toluene and dioxane
were equally suitable solvents.
With PinBH, a dramatic feature of this catalyst system
compared to others1–3 is the extreme rapidity of the pro-
cess, when applied to electron-rich aryl iodides11 or bro-
mides.12 The same is true with MPBH. This high
reactivity allows complete conversion of reactive aryl io-
dides and bromides (entries 1–4, 7, 8) between 20–40 °C
within a few hours. To our knowledge, operating at 20 °C
has not been described for this reaction yet.13
H3B-NEt2Ph
Pd/C
HO
OH
75%
O
O
B
H
MPBH (1)
Scheme 1 Preparation of MPBH 1. Reagents and conditions: diox-
ane, 20 °C, 30 min.
The process remained efficient at low levels of catalyst:
the boronate ester was produced from p-bromo-N,N-dim-
ethylaniline in 90% yield in six hours at 20 °C when 0.3
mol% Pd was used (10 mmol run, entry 7).
MPBH is a particularly stable dioxaborinane,4 readily ac-
cessible from hexyleneglycol and borane. We described
earlier2,3 convenient preparations using BH3–DMS or
B2H6 generated from NaBH4 and MeSO3H. We consid-
ered the use of N,N-diethylaniline-borane, a safe5 source
of borane for large-scale applications, but the reaction of
hexylene glycol with this reagent was sluggish. Pd/C is
When less reactive iodides were used, some hydrodehalo-
genation was observed. This side reaction is always met in
analogous borylation with PinBH and is favored by elec-
tron-withdrawing substituents on the aryl ring. In the
present work as well as in the literature,1 it is the only side
reaction: the homocoupling product was never observed.
We indicate whenever available the ArB(OR)2/ArH ratio,
but low-boiling arenes were seldom accurately measur-
able. Note that all reactions of Table 1 were run to com-
plete conversion of the starting material. Thus, lower
SYNLETT 2010, No. 16, pp 2403–2406
x
x
.x
x
.2
0
1
0
Advanced online publication: 19.08.2010
DOI: 10.1055/s-0030-1258059; Art ID: D10810ST
© Georg Thieme Verlag Stuttgart · New York

2404
N. PraveenGanesh et al.
LETTER
Table 1 Borylation of Various Aryl Halides and Triflates with MPBH Catalyzed by Pd/CyJohnPhosa,10
Entry
1
Substrate
Conditions
ArB(OR)2/ArHb
>99:1
Product yield (%)c
Me2N
2a
90
Pd (3 mol%), 20 °C, <0.5 h
I
MeO
H2N
2b
91
2
3
4
5
6
7
8
Pd (1 mol%), 20 °C, 1 h
Pd (0.5 mol%), 20 °C, 0.5 h
Pd (1 mol%), 20 °C, 3 h
Pd (1 mol%), 80 °C, 3 h
Pd (1 mol%), 40 °C, 16 h
Pd (0.3 mol%), 20 °C, 6 h
Pd (0.5 mol%), 40 °C, 6 h
>95:5
>97:3
>97:3
70:30
n.d.d
I
2c
79
I
NH2
2d
88
I
MeOOC
2e
69
I
2f
60
O2N
I
Me2N
2a
>99:1
>95:5
90e
Br
MeO
2b
81
Br
Br
2g
–
3g
–
9
10
MPBH (3 equiv), Pd (1 mol%), 100 °C, toluene,f 30 h
PinBH (3 equiv), Pd (1 mol%), 100 °C, toluene,f 15 h
30:70
92:8
2h
–
O
11
12
MPBH, Pd (1 mol%), 150 °C, toluene,f 15 ming
PinBH, Pd (1 mol%), 150 °C, toluene,f 15 ming
29:71
70:30
Ph
3h
701i
Br
2i
82
13
14
Pd (1 mol%), 80 °C, 6 h
Pd (1 mol%), 80 °C, 16 h
n.d.
n.d.
OTf
O
2j
73
OTf
Cl
MeO
2b
90
15
Pd (1 mol%), 100 °C, 16 h
>95:5
OMe
Cl
2k
45
16
17
Pd (2 mol%), 80 °C, 16 h
Pd (1 mol%), 80 °C, 24 h
51:49
n.d.
2i
62
Cl
a Unless otherwise stated: MPBH (1.5 equiv), Et3N (3 equiv), Pd [as Pd2(dba)3], CyJohnPhos (2 equiv per Pd), in dioxane.
b Measured by GC, except entries 3 and 4: 1H NMR.
c Isolated yields after chromatography.
d n.d.: not determined.
e 10 mmol bromide.
f Run in toluene.
g Sealed vessel, microwaves heating.
Synlett 2010, No. 16, 2403–2406 © Thieme Stuttgart · New York

LETTER
Efficient Borylation of Reactive Aryl Halides with MPBH
2405
isolated yields reflect a higher level of hydrodehalogena- vored hydrodehalogenation and best results were obtained
tion. With the reactive substrates of entries 1–4, 7, and 8, with only 1.5 equivalents dialkoxyborane.
the reduced product was below detection. In all cases, it
Our hypothesis is that MPBH is more prone than PinBH
was found to be less present than with the PdCl2(TPP)2
to some disproportionation19 under the reaction condi-
catalyst in our former work.3 It can be concluded that in
tions, releasing small amounts of BH3 that would favor
the case of reactive, electron-rich aryl iodides and bro-
Pd-catalyzed reduction of the substrate. Indeed, replacing
mides, MPBH is a cost-effective substitute to pinacolbo-
MPBH by BH3–Et3N caused extensive hydrodehalogena-
rane in a fast and efficient palladium-catalyzed borylation.
tion.
Disappointingly, with less reactive aryl halides, a clear-
In conclusion, the combination of MPBH, a particularly
cut difference in reactivity between PinBH and MPBH ap-
stable and inexpensive reagent, and Buchwald’s palladi-
peared, with MPBH favoring the unwanted hydrodehalo-
um catalyst provides a simple, very fast, cost-effective bo-
genation. The difference remained limited with electron-
rylation of reactive, electron-rich aryl iodides, bromides,
depleted iodides (entries 5 and 6). Entry 5 (69% yield)
and triflates, to produce stable, easily purified boronic
should be compared with Masuda’s1b result: borylation of
esters, that can be readily used as such in Suzuki cou-
ethyl 4-iodobenzoate with PinBH in the presence of
plings.1,2
PdCl2dppf yielded 79% ArPin (hydrodehalogenated prod-
uct 17%). More dramatic differences appeared with elec-
tron-depleted bromides, for which hydrodehalogenation
became deleterious (entries 9–12). In the same conditions,
PinBH was much more efficient (compare entries 9 and
10, 11 and 12).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The borylation of chlorides was practically limited to the
most reactive, electron-rich ones (entries 15–17).14 Re-
markably, aryl triflates1b,15 were borylated efficiently (en-
tries 13 and 14). The extent of the hydrodetriflation
seemed less dependent of the electron-donating (entry 13)
or electron-withdrawing nature of the substituents (entry
14, compare also with entry 11).
We gratefully thank the Université J. Fourier and the CNRS for
financial support.
References and Notes
(1) (a) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem.
1997, 62, 6458. (b) Murata, M.; Oyama, T.; Watanabe, S.;
Masuda, Y. J. Org. Chem. 2000, 65, 164. (c) Baudoin, O.;
Guenard, D.; Gueritte, F. J. Org. Chem. 2000, 65, 9268.
(d) Melaimi, M.; Mathey, F.; Le Floch, P. J. Organomet.
Chem. 2001, 640, 197. (e) Doux, M.; Mezailles, N.;
Melaimi, M.; Ricard, L.; Le Floch, P. Chem. Commun. 2002,
1566. (f) Broutin, P. E.; Cerna, I.; Campaniello, M.; Leroux,
F.; Colobert, F. Org. Lett. 2004, 6, 4419. (g) Murata, M.;
Sambommatsu, T.; Watanabe, S.; Masuda, Y. Synlett 2006,
1867. (h) Miller, W. D.; Fray, A. H.; Quatroche, J. T.;
Sturgill, C. D. Org. Process Res. Dev. 2007, 11, 359.
(i) Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008,
73, 5589. Mechanism: (j) Lam, K. C.; Marder, T. B.; Lin, Z.
Organometallics 2010, 29, 1849. (k) Dang, L.; Lin, Z.;
Marder, T. B. Chem. Commun. 2009, 3987. For borylation
with aminoborane reagent, see: (l) Euzenat, L.; Horhant, D.;
Ribourdouille, Y.; Duriez, C.; Alcaraz, G.; Vaultier, M.
Chem. Commun. 2003, 2280. For a related Cu-catalyzed
borylation, see: (m) Zhu, W.; Ma, D. Org. Lett. 2006, 8,
261. For a related Ni-catalyzed borylation with in situ
prepared 5,5-dimethyl-1,3,2-dioxaborinane, see: (n) Rosen,
B. M.; Huang, C.; Percec, V. Org. Lett. 2008, 10, 2597.
(o) Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Corcoran,
P.; Rosen, B. M.; Percec, V. Org. Lett. 2009, 11, 4974.
(p) Wilson, D. A.; Wilson, C. J.; Moldoveanu, C.;
Resmerita, A.-M.; Corcoran, P.; Hoang, L. M.; Rosen, B.
M.; Percec, V. J. Am. Chem. Soc. 2010, 1800. (q) Morgan,
A. B.; Jurs, J. L.; Tour, J. M. J. Appl. Polym. Sci. 2000, 76,
1257. Arene C–H borylation has been recently reviewed:
(r) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy,
J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890.
So far, all reported optimizations of this reaction were car-
ried out with electron-rich substrates.1–3 We decided to
check the influence of reaction parameters on the boryla-
tion/hydrodehalogenation ratio when the substrate was
electron withdrawn; 2-bromonaphthalene was our model
of such an ‘unreactive’ substrate.16 Reactions were moni-
tored by GC with an internal standard. Although we could
not increase the yield in boronic ester 2g above 50%,
some interesting trends became apparent. Higher temper-
atures favored borylation over hydrodehalogenation (37%
yield in 2g at 80 °C, 50% at 150 °C), making this reaction
a good candidate for closed-vessel, microwaves-heated
conditions. Nevertheless, at identical temperatures, mi-
crowave heating did not lead to significantly faster reac-
tion than conventional heating. With 2-bromonaphthalene
and MPBH, other ligand systems (dppf,1a,b dpePhos,1f
excess
TPP,3
N-(dicyclohexylphosphino)-2-(2¢-
tolyl)indole17 or di-tert-butylbipyridyl) led to slower reac-
tions and increased hydrodehalogenation.
Monitoring the course of the reaction showed that the bo-
rylation/hydrodehalogenation ratio is lower at early stages
of the reaction. Examples have been reported with
PinBH18 where prolonged heating of the reaction mixtures
caused an increase of the hydrodehalogenation. In the
present conditions, both reactions are concurrent. Pro-
longed heating after the end of the conversion of the bro-
mide never caused any significant loss of borylated
product. A larger excess of MPBH (3 equiv) slightly fa-
(2) Murata, M.; Oda, T.; Watanabe, S.; Masuda, Y. Synthesis
2007, 351.
(3) PraveenGanesh, N.; Chavant, P. Y. Eur. J. Org. Chem. 2008,
4690.
Synlett 2010, No. 16, 2403–2406 © Thieme Stuttgart · New York

2406
N. PraveenGanesh et al.
LETTER
2 H), 7.82–7.76 (m, 2 H), 7.48–7.40 (m, 2 H), 4.38 (dqd,
(4) (a) Chavant, P. Y.; PraveenGanesh, N. In Electronic
Encyclopaedia of Reagents for Organic Synthesis (e-EROS);
Paquette, L. A., Ed.; John Wiley and Sons: New York,
2008. (b) Woods, W. G.; Strong, P. L. J. Am. Chem. Soc.
1966, 88, 4667. (c) Fish, R. H.; Newsom, H. C. FR 1536699,
1968. (d) Fish, R. H.; Newsom, H. C. US 19670427, 1968.
(e) Kono, H.; Ito, K.; Nagai, Y. Chem. Lett. 1975, 1095.
(f) Männig, D.; Nöth, H. Angew. Chem., Int. Ed. Engl. 1985,
24, 878. (g) PraveenGanesh, N.; d’Hondt, S.; Chavant, P. Y.
J. Org. Chem. 2007, 72, 4510.
J = 11.8, 6.2, 2.9 Hz, 1 H), 1.87 (dd, J = 13.7, 2.9 Hz, 1 H),
1.62 (dd, J = 13.7, 11.8 Hz, 1 H), 1.41 (s, 3 H), 1.39 (s, 3 H),
1.38 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3):
d = 134.8 (2×), 132.99, 130.14, 128.68, 127.67, 129.5 (v br,
CB), 126.62, 126.39, 125.44, 71.16, 65.14, 46.15, 31.38,
28.27, 23.30 ppm. 11B NMR (128 MHz, CDCl3): d = 27.10.
IR (neat): 3053, 2972, 2932, 2911, 1630, 1598, 1503, 861,
823, 765, 746, 685 cm–1. MS (EI, 70 eV): m/z (%) = 255 (26),
254 (100), 253 (28).
(5) Wilkinson, H. S.; Tanoury, G. J.; Wald, S. A.; Senanayake,
(11) (a) Baudoin, O.; Decor, A.; Cesario, M.; Gueritte, F. Synlett
2003, 2009. (b) Joncour, A.; Decor, A.; Thoret, S.; Chiaroni,
A.; Baudoin, O. Angew. Chem. Int. Ed. 2006, 45, 4149.
(c) Poriel, C.; Lachia, M.; Wilson, C.; Davies, J. R.; Moody,
C. J. J. Org. Chem. 2007, 72, 2978.
(12) (a) Combs, A.; Zhu, W.; Crawley, M.; Glass, B.; Polam, P.;
Sparks, R. B.; Modi, D.; Takvorian, A.; McLaughlin, E.;
Yue, E.; Wasserman, Z.; Bower, M.; Wei, M.; Rupar, M.;
Ala, P. J.; Reid, B. M.; Ellis, D.; Gonneville, L.; Emm, T.;
Taylor, N.; Yeleswaram, S.; Li, Y.; Wynn, R.; Burn, T. C.;
Hollis, G.; Liu, P. C. C.; Metcalf, B. J. Med. Chem. 2006, 49,
3774. (b) Mentzel, U. V.; Tanner, D.; Tonder, J. E. J. Org.
Chem. 2006, 71, 5807.
(13) For related room-temperature Suzuki couplings, see:
(a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158.
(b) Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2007, 46, 5359.
(14) Very recently, Murata et al. borylated aryl chlorides with
both PinBH and MPBH in the presence of excess Bu4NI:
Murata, M.; Sambommatsu, T.; Oda, T.; Watanabe, S.;
Masuda, Y. Heterocycles 2010, 80, 213.
C. H. Org. Process Res. Dev. 2002, 6, 146.
(6) (a) Couturier, M.; Tucker, J. L.; Andresen, B. M.; Dube, P.;
Negri, J. T. Org. Lett. 2001, 3, 465. (b) Couturier, M.;
Tucker, J. L.; Andresen, B. M.; Dube, P.; Brenek, S. J.;
Negri, J. T. Tetrahedron Lett. 2001, 42, 2285.
(7) Preparation of MPBH
Under a well-ventilated fume hood (H2 evolution), a 100 mL
flask equipped with a Claisen distillation head was charged
with 10% Pd/C (320 mg) and anhyd dioxane (10 mL). The
flask was flushed with nitrogen and freshly distilled 2-
methyl-2,4-pentanediol (50 mmol, 6.4 g) in dioxane (10 mL)
was added. A solution of N,N-diethylaniline-borane (60
mmol, 9.78 g) in dioxane (10 mL) was added at 20 °C over
30 min. The reaction mixture was stirred for an additional 30
min at 20 °C. Low pressure distillation gave neat MPBH (4.8
g, 75%, bp 45 °C/0.05 bar).
(8) Our attempts to use N,N-diethylaniline as the base in
subsequent borylations failed.
(9) [1,1¢-Biphenyl]-2-yl-dicyclohexylphosphine: Wolfe, J. P.;
Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9550.
(10) Typical Procedure for the Borylation
(15) (a) Wakim, S.; Bouchard, J.; Simard, M.; Drolet, N.; Tao,
Y.; Leclerc, M. Chem. Mater. 2004, 16, 4386. (b) Ahmed,
V.; Liu, Y.; Silvestro, C.; Taylor, S. D. Bioorg. Med. Chem.
2006, 14, 8564. (c) Tam, V. K.; Liu, Q.; Tor, Y. Chem.
Commun. 2006, 2684.
(16) See Supporting Information for a detailed table of these
experiments.
(17) So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2007, 9, 2795.
(18) (a) Altemoeller, M.; Podlech, J.; Fenske, D. Eur. J. Org.
Chem. 2006, 1678. (b) Suzuki, A. Proc. Jpn. Acad. 2004,
80, 359.
An oven-dried Schlenk vessel (or a 10 mL microwaves vial)
was charged with Pd2(dba)3 (2.3 mg, 2.5 mmol, described as
0.5% in Table 1) and CyJohnPhos (3.5 mg, 10 mmol, always
2 equiv/Pd) and placed under an atmosphere of Argon.
Anhydrous dioxane (0.6 mL), the aryl halide (0.5 mmol),
Et3N (152 mg, 1.5 mmol) and MPBH (96 mg, 0.75 mmol)
were introduced (solid aryl halides were added along with
the other solid reagents). The reaction mixture was then
heated at the indicated temperature until the aryl halide has
been completely consumed as determined by gas chroma-
tography. The reaction was allowed to cool to r.t., and
filtered through a short pad of Celite (eluent Et2O). The
eluate was concentrated and the crude material purified by
flash chromatography on silica gel. Products 2a-j2,3, 3g1b and
3h1i have been previously described.
(19) The disproportionation of dialkoxyboranes yields
trialkoxyboranes and BH3. See: (a) Rose, S. H.; Shore, S. G.
Inorg. Chem. 1962, 1, 744. (b) Pasto, D. J.;
Balasubramaniyan, V.; Wojtkowski, P. W. Inorg. Chem.
1969, 8, 594. The reaction is influenced by phosphines and/
or metal species: (c) Hadebe, S. W.; Robinson, R. S. Eur. J.
Org. Chem. 2006, 4898; and references cited therein.
4,4,6-Trimethyl-2-naphthalen-2-yl[1,3,2]dioxaborinane
(2g)
1H NMR (400 MHz, CDCl3): d = 8.34 (s, 1 H), 7.89–7.85 (m,
Synlett 2010, No. 16, 2403–2406 © Thieme Stuttgart · New York