Use of in situ isopropoxide protection in the metal-halogen exchange of arylboronates

Article abstract of DOI:10.1021/jo0710329

(Chemical Equation Presented) Isopropoxide protection of arylboronates allowed their use in metal-halogen exchange reactions. The isopropoxide- protected borate species were obtained from a boronate or in situ from dibromoarenes. meta- and para-dibromoare

Full text of DOI:10.1021/jo0710329

Use of in Situ Isopropoxide Protection in the
Metal-Halogen Exchange of Arylboronates
SCHEME 1. Protection of Boronates with Lithium
Isopropoxide
Qin Jiang, Meagan Ryan, and Paul Zhichkin*
AMRI, 26 Corporate Circle, P.O. Box 15098,
Albany, New York, 12212
paul.zhichkin@amriglobal.com
ReceiVed May 16, 2007
SCHEME 2. Synthesis of Functionalized
(Hetero)arylboronates
Isopropoxide protection of arylboronates allowed their use
in metal-halogen exchange reactions. The isopropoxide-
protected borate species were obtained from a boronate or
in situ from dibromoarenes. meta- and para-dibromoarenes
were converted via these intermediates into functionalized
arylboronates in a one-pot manner.
In this Note we disclose a method for effecting a metal-
halogen exchange in halogenated arylboronates, which is free
from the disadvantages of the above two methods. Inexpensive
dibromoarenes or commercially available and easily prepared
bromoarylpinacolatoboronates are employed in our method as
the starting materials. The reaction affords pinacolatoboronates
5
which can be purified by flash chromatography.
Metal-halogen exchange is an important and widely used
method of selective functionalization of organic compounds. It
has been clear since the first unsuccessful attempt by Gilman
in 1958 that a “halogen-metal interconversion in bromosub-
stituted benzeneboronic acids [...] would have provided many
The key to preventing side reactions with the metalating agent
is the reversible protection of the boron atom as an aryltri-
alkoxyborate anion. To the best of our knowledge, this paper
is the first reported case of such protection. The choice of
protecting pinacolatoisopropoxyborate group is important. Pi-
nacolatoboronates are more stable than isopropoxyboronates;
therefore, isopropoxide can be cleaved selectively, avoiding the
1
possibilities for new syntheses.” However, until very recently
there have been no precedents of a successful metal-halogen
exchange employing molecules containing a boronate or boronic
acid moiety. This can be explained by the fact that boronates,
being Lewis acids, actively react with most organometallic
6
scrambling of the ester. For example, p-bromophenylpinaco-
latoboronate (1a) was protected by a reaction with commercially
available lithium isopropoxide to provide anionic species 2a.
The subsequent metal-halogen exchange and quench with
benzaldehyde followed by a standard aqueous workup afforded
the desired product 3a (Scheme 1). This reaction is also
applicable to meta-substituted aryl boronates as illustrated by
conversion of 1b into 3b (Scheme 1). Boronates 1a,b are
2
reagents used in metal-halogen exchange. In 2005, Knochel
established that iodo-substituted aryl boronates could be meta-
3
lated with i-PrMgCl‚LiCl. Although Knochel’s method has a
wide applicability, the substrates are not commercially available
and are prepared from expensive diiodoarenes. In 2006, Molan-
der proposed metalation of readily available potassium bro-
moaryltrifluoroborates with n-BuLi-TMEDA as an alternative
7
commercially available and can also be easily prepared from
the corresponding boronic acids (see the Supporting Informa-
tion). The yield of 3a (78%) and 3b (70%) was similar to the
yield reported by Knochel (83% of 3a and 71% of 3b) starting
with iodophenylboronates. Lower yield (62%) of the trifluo-
4
approach. However, as trifluoroborates are purified by crystal-
lization, his method is applicable only to 1,4-substituted
benzenes. When the products are less crystalline, as in the case
of 1,3-disubstituted benzenes, the purification becomes prob-
lematic.4
(5) (a) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992, 57,
3
482. (b) Pereira, S.; Srebnik, M. Tetrahedron Lett. 1996, 37, 3283.
(6) Pinacolatoboronates have been prepared via hydrolysis of pinacola-
(1) Santucci, L.; Gilman, H. J. Am. Chem. Soc. 1958, 80, 193.
(
2) For example, see: (a) Letsinger, R. L.; Remes, N. J. Am. Chem.
toisopropoxyborate intermediate, for example, see: (a) Hoffmann, R. W.;
Metternich, R.; Lanz, J. W. Liebigs Ann. Chem. 1987, 881. (b) Krueger, J.;
Hoffmann, R. W. J. Am. Chem. Soc. 1997, 119, 7499. (c) Mohacrishnan,
A. K.; Hucke, A.; Lyon, M. A.; Lakshmikantham, M. V.; Cava, M. P.
Tetrahedron 1999, 55, 11745. (d) Karsten, M.; Dimichele, L.; Mills, P.;
Frantz, D. E.; Nelson, T. D.; Kress, M. H. Synlett 2006, 1948.
Soc. 1955, 77, 2489. (b) Letsinger, R. L.; Skoog, I. J. Am. Chem. Soc.
1
1
1
955, 77, 2491. (c) Brown, H. C.; Cole, T. E.; Srebnik, M. Organometallics
985, 4, 1788. (d) Brown, H. C.; Srebnik, M.; Cole, T. E. Organometallics
986, 5, 2300.
(
(
3) Baron, O.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 3133.
4) Molander, G. A.; Ellis, N. M. J. Org. Chem. 2006, 71, 7491.
(7) Combi-Blocks: 1a (cat. no. PN-2629) and 1b (cat. no. PN-2655).
10.1021/jo0710329 CCC: $37.00 © 2007 American Chemical Society
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618
J. Org. Chem. 2007, 72, 6618-6620
Published on Web 07/26/2007

TABLE 1. Synthesis of Functionalized (Hetero)arylboronates
roborate derivative corresponding to 3a was obtained by
Molander from potassium p-bromophenyltrifluoroborate.
quenched with various electrophiles to afford functionalized
arylboronates 3 and 7 (Table 1).
The use of triisopropylborate in place of 5 gave the corre-
sponding boronic acids. However, they were difficult to purify,
and that approach was abandoned. An attempt to substitute
n-BuLi for t-BuLi in this reaction was unsuccessful, causing
decomposition of the “ate” intermediate.
The yield of 3a (entry 1) and 3b (entry 5) was similar to the
yield obtained in the stepwise procedure in Scheme 1. Starting
with p-dibromobenzene (4a), the corresponding formyl (entry
As a more economical alternative, the protected “ate”
intermediate can be generated in situ in a one-pot procedure
8
starting with dibromoarene (4, Scheme 2). Due to its simplicity,
this procedure was preferred. To minimize side reactions, t-BuLi
(
2 equiv) was added to a mixture of 4 and 5 at -78 °C (“in situ
9
quench” protocol). After 30 min, formation of intermediate 6
was complete, and the metal-halogen exchange was effected
by a further addition of t-BuLi. The resulting anion was
2
), methoxycarbonyl (entry 3), and phenylsulfanyl (entry 4)
substituted boronates were prepared in good yield. To further
probe the scope of the synthesis, benzaldehyde was used as a
(
8) For the metalation of dibromobenzenes, see: (a) Gilman, H.;
Langham, W.; Moore, F. W. J. Am. Chem. Soc. 1940, 62, 2327. (b) Caron,
S.; Nga, M. D. Synlett 2004, 1440 and references cited therein.
(
9) For the use of triisoporopylborate with the following bases, see: (a)
1998, 63, 5438. (b) n-BuLi: Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner,
R. S.; Cai, D.; Larsen, R. D.; Reider, P. J. J. Org. Chem. 2002, 67, 5394.
(c) LTMP: Kristensen, J.; Lys e´ n, M.; Vedso, P.; Begtrup, M. Org. Lett.
2001, 3, 1435. (d) LDA: Caron, S.; Hawkins, J. M.; J. Org. Chem. 1998,
63, 2054.
n-BuLi: Yasuda, N.; Huffman, M. A.; Ho, G.-J.; Xavier, L. C.; Yang, C.;
Emerson, K. M.; Tsay, F.-R.; Li, Y.; Kress, M. H.; Rieger, D. L.; Karady,
S.; Sohar, P.; Abramson, N. L.; DeCamp, A. E.; Mathre, D. J.; Douglas,
A. W.; Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem.
J. Org. Chem, Vol. 72, No. 17, 2007 6619

model electrophile. The reaction proceeded smoothly with
hindered dibromoarene (entry 6) and also afforded good to
moderate yields of m-phenylcarbinol substituted thiophene (entry
2 4
mL). The combined extracts were dried (Na SO ), filtered, and
concentrated. The residue was purified by flash column chroma-
tography (silica gel, 85:15 hexanes/ethyl acetate) to provide 3a (1.13
g, 78%) as a colorless oil: 1H NMR (500 MHz, DMSO-d
6
) δ 7.61
7
) and pyridine (entry 8) boronates. Unfortunately, unlike
(
2
d, J ) 8.0 Hz, 2H), 7.39 (d, J ) 8.0 Hz, 2H), 7.35 (d, J ) 7.3 Hz,
Knochel’s approach, application of our method to the preparation
of ortho-substituted arylboronates was unsuccessful, with the
second step leading instead to decomposion products.
In conclusion, a new method for metal-halogen exchange
on bromoarylboronate molecules via an in situ isopropoxide
protection has been developed. The desired protected intermedi-
ates can also be generated from dibromoarenes, making this
procedure a convenient alternative for the preparation of
functionalized (hetero)arylboronates.
H), 7.31-7.27 (m, 2H), 7.19 (t, J ) 7.3 Hz, 1H), 5.93 (d, J ) 4.0
Hz, 1H), 5.71 (d, J ) 4.0 Hz, 1H), 1.27 (s, 12H).
Typical Experimental Procedure B: Preparation of Phenyl-
(
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)metha-
nol (3a) from 4a. To a solution of 4a (1.17 g, 5.00 mmol) and 5
0.948 g, 5.10 mmol) in anhydrous THF (20 mL) was added t-BuLi
(5.90 mL, 1.7 M in pentane, 10.0 mmol) dropwise over 3 min at
-78 °C under N . After 30 min at -78 °C, additional t-BuLi (5.90
(
2
mL, 1.7 M in pentane, 10.0 mmol) was added dropwise over 3
min, and the reaction was stirred for a further 20 min. After this
time benzaldehyde (0.588 g, 5.54 mmol) was added, and the
reaction was stirred for 20 min and quenched with saturated aq
Experimental Section
Typical Experimental Procedure A: Preparation of Phenyl-
4
NH Cl (20 mL). The workup was carried out as described above,
affording 3a in 71% yield (1.10 g).
(
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)metha-
3
nol (3a) from 1a. To a solution of 1a (1.32 g, 4.66 mmol) in
anhydrous THF (20 mL) was added LiOi-Pr (2.33 mL, 2 M in THF,
Acknowledgment. The authors would like to thank Dr. R.
Jason Herr for helpful suggestions to this manuscript.
4
.66 mmol) at room temperature under N
mixture was cooled to -78 °C; t-BuLi (5.50 mL, 1.7 M in pentane,
.35 mmol) was added dropwise over 3 min, and the reaction was
2
. After 2 h the reaction
9
Supporting Information Available: Full experimental details
and characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
stirred for an additional 20 min at -78 °C. After this time
benzaldehyde (0.588 g, 5.54 mmol) was added; the reaction was
stirred for 20 min and quenched with saturated aq NH
4
Cl (20 mL).
The resulting mixture was extracted with ethyl acetate (3 × 50
JO0710329
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