Silyl-directed, iridium-catalyzed ortho-borylation of arenes. A one-pot ortho-borylation of phenols, arylamines, and alkylarenes

Article abstract of DOI:10.1021/ja8015878

The regioselectivity of the borylation of arenes catalyzed by the combination of 4,4′-di-tert-butylbipyridine (dtbpy) and [Ir(cod)Cl]₂ has typically been governed by steric effects. We describe a strategy that makes use of a new substituent for ortho-functionalization to overcome this bias. We show that arenes containing hydrosilyl substituents on an atom attached to the arene ring undergo borylation at the position ortho to the hydrosilyl group. Using iridium-catalyzed formation of silyl ethers and silylamines from silanes and either phenols or arylamines, we have developed the ortho-borylation into a one-pot conversion of free phenols and monoprotected anilines into hydroxy- and amino-substituted organoboron derivatives. Copyright

Full text of DOI:10.1021/ja8015878

Published on Web 05/22/2008
Silyl-Directed, Iridium-Catalyzed ortho-Borylation of Arenes. A One-Pot
ortho-Borylation of Phenols, Arylamines, and Alkylarenes
Timothy A. Boebel and John. F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue, Urbana, Illinois 61801
Received March 6, 2008; E-mail: jhartwig@scs.uiuc.edu
Arylboron reagents are versatile synthetic intermediates in chemical
synthesis.1 The traditional route to these reagents involves the addition
of organolithium or magnesium species to borates. More recently, a
direct route to arylboronic esters from arenes has been developed using
metal-catalyzed functionalization of aromatic C-H bonds with bis(pina-
colato)diboron (B2pin2) (eq 1).2 The most efficient catalyst for this
transformation is generated from 4,4′-di-tert-butylbipyridine (dtbpy),
[Ir(cod)X]2 (X ) Cl, OMe), and the boron reagents.3–5
Chart 1. Regioselective Borylation of Benzylic Hydrosilanes
The regioselectivity of this catalytic C-H borylation of arenes has
typically been governed by steric factors; functionalization occurs at
the least hindered aryl C-H bond, not at the most electron-rich or
electron-poor C-H bond. Thus, the functionalization of 1,3-disubsti-
tuted arenes leads to 1,3,5-trisubstituted products (eq 2, left), and ortho-
substituted boronic esters are usually formed only from 1,4-
disubstituted arenes.6 The ortho-substituted boronic esters can be
produced using directed ortho-metalation with organolithium reagents,7
but a direct, ortho-borylation of C-H bonds could be a milder synthetic
(3) in a combined 71% isolated yield. No accompanying products
method. Such a process would require strategies to override the
underlying steric control of regioselectivity (eq 2, right).
resulting from C-H borylation at the meta- or para-positions of 3
were detected by 1H NMR spectroscopy.
Chart 1 summarizes the reactions of several hydrodimethylbenzyl-
silanes. Reactions of 2-, 3-, and 4-substituted arenes (4) provided ortho-
functionalized products (5). Reactions of the methoxy-substituted
arenes show the dominance of the silylmethyl group over the methoxy
group as an ortho-director for this catalytic process. This directing effect
We describe a method to conduct ortho-C-H borylation that makes
use of a new directing group for ortho-functionalization, a dimethyl-
hydrosilyl group. By this method, arenes undergo iridium-catalyzed
borylation at the C-H bond ortho to a hydrosilylmethyl, siloxide, or
silylamine substituent. Using the formation of siloxides and silylamines
from phenols and amines, we have developed this reaction into a one-
pot directed borylation of free phenols and N-alkylanilines.
These studies began with consideration of reaction sequences in
which a hydrosilyl group would direct ortho-functionalization. In one
sequence, a hydrosilyl group could undergo borylation to form a
silylborane, and this event could trigger an intramolecular borylation
of the arene. In a second sequence, a silyl group could serve as a
temporary attachment to the metal that would trigger cleavage of the
ortho-C-H bond8 and subsequent functionalization.
Initial studies to use a hydrosilyl moiety to direct arene borylation
are summarized in eqs 3 and 4. The reaction of phenyldimethylsilane
(1) with B2pin2 and pinacolborane (HBpin)9 in the presence of the
combination of [Ir(cod)Cl]2 and dtbpy as ligand at 80 °C in THF
solvent (eq 3) formed a series of products, some resulting from
redistribution of the arylsilane.10 However, reactions of aromatic
hydrosilanes lacking a direct aryl-Si bond occurred in higher yields
(eq 4). Benzyldimethylsilane (2) reacted with B2pin2 in the presence
of 0.25 mol % of [Ir(COD)Cl]2 and 0.5 mol % of dtbpy to form a
2.3:1 mixture of mono- and di-ortho-functionalized arylboronic esters
of the silylmethyl group contrasts with the strong directing effect of
an alkoxo group toward ortho-lithiations.11 In addition, an R-silyl-
ethylarene formed the ortho-borylated product in good yield, and this
reaction was more selective for monoborylation than the reaction of
the benzyl dimethylhydrosilane.
Although benzylsilanes can be cleaved with fluoride to form
methylarenes,12 or oxidized to form aryl alcohols,13 methods to use
more readily cleavable silicon linkers would be valuable. Thus, we
studied reactions of aryl hydrosilyl ethers derived from phenols.
Treatment of an aryl alcohol (10) with 1.5 equiv of diethylsilane
(Et2SiH2) in the presence of 0.5 mol % of [Ir(cod)Cl]2 as catalyst in
hydrocarbon solvent formed the silyl ether 11 and H2 (Chart 2).14 After
evaporation of the volatile materials and dissolution of the residue in
THF in the same pot, addition of the boron reagents and the
combination of [Ir(cod)Cl]2 and dtbpy as catalyst led to the product
of ortho-borylation (12).15,16
Purification of the initial products was complicated by facile
protodeborylation, but treatment of the crude product with excess
aqueous potassium hydrogen fluoride (KHF2) formed the more stable,
isolable trifluoroborate salt 13.17,18 Using this procedure, borylation
of both electron-rich and electron-poor phenols formed the ortho-
trifluoroborylated aryl alcohols in Chart 2.
This strategy was also followed to effect a similar one-pot,
regioselective functionalization of anilines. Dehydrogenative coupling
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10.1021/ja8015878 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Chart 2. One-Pot ortho-Borylation of Phenolsa
in the presence of [Ir(cod)Cl]2 and dtbpy and heated in a sealed vessel
at 80 °C for 20 min in THF. Subsequent 1H and 2H NMR spectroscopic
analysis of the recovered hydrosilane 2-dn indicated the absence of
deuterium at the meta- or para-position during the time in which 14%
deuterium incorporation had occurred at the ortho-C-H bonds and
28% deuterium incorporation had occurred into the Si-H bond.19
Thus, we conclude that the ortho-substituted product results from
selective C-H activation at the ortho-position directed by the hydrosilyl
group, rather than selective functionalization of product of ortho-C-H
bond cleavage by a silylborane moiety.
Scheme 1 shows a proposed mechanism for the ortho-borylation
that is based on our previous demonstration of the intermediacy of
the trisboryl complex 22 in arene borylation. We suggest that the ortho-
borylation occurs by generation of the bisboryl monosilyl complex
24, followed by selective ortho-C-H bond activation8 and function-
alization to give hydride complex 25 (Scheme 1).20 Subsequent
addition of B2pin2 would then extrude the arylboronic ester (3) and
regenerate the iridium fragment 23.
In conclusion, we have demonstrated a method to conduct iridium-
catalyzed ortho-borylation of arenes using a conceptually novel
approach based on hydrosilanes as directing groups. This concept has
been applied to the development of regioselective functionalization
of benzylic silanes, phenols, and anilines. Future studies will exploit
this strategy to effect additional regioselective hydrocarbon borylations
and related functionalizations.
Acknowledgment. We thank the NSF (CHE-0653335) for fund-
ing. We thank Frontier Scientific and AllyChem for the gift of
bis(pinacolato)diboron. We thank members of the Denmark research
group for many helpful discussions.
a Yields corrected for the presence of small quantities of KBF4 and
K[HOBF3] contaminants in isolated products. b Isolated with 2-5%
contaminants. c Isolated with 12% contaminants.
of diethylsilane with N-methyl-2-chloroaniline (21, eq 5) catalyzed by
[Ir(cod)Cl]2, followed by reaction of the silylamine with B2pin2
catalyzed by [Ir(cod)Cl]2, and dtbpy formed the ortho-borylated aniline
22a in high yield. A small amount of diborylated product (22b) was
also formed.
Supporting Information Available: Reaction procedures and spec-
troscopic details for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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Two sets of experiments imply that the ortho-functionalization
results from temporary formation of an Ir-Si bond, rather than
formation of a silylborane. First, the silylborane BnMe2SiBpin was
not kinetically competent to be an intermediate in the ortho-borylation.
BnMe2SiBpin reacted in the presence of [Ir(cod)Cl]2/dtbpy and B2pin2
to form an ortho-borylarene more slowly than the reaction of 2 under
the same conditions.
Second, H/D exchange indicated selective cleavage of the ortho-
C-H bonds. Benzyldimethylsilane (2, eq 6) was treated with DBpin
(14) Field, L. D.; Messerle, B. A.; Rehr, M.; Soler, L. P.; Hambley, T. W.
Organometallics 2003, 22, 2387.
(15) Attempted borylation of crude silyl ethers (11) without the addition of
additional [Ir(cod)Cl]2 resulted in no reaction.
Scheme 1
(16) Substrates containing a single atom between silicon and the arene proved
to be more reactive than those with longer linkers. The silyl ether formed
from benzyl alcohol did not undergo a similar ortho-borylation.
(17) Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. 2007, 9, 757.
(18) Despite the enhanced stability of these salts, purification was frequently
complicated by the presence of small quantities of KBF4 and K[HOBF3].
(19) In contrast, the iridium-catalyzed reaction of toluene-d8 with HBpin results
in non-selective H/D exchange. See Supporting Information.
(20) (a) This C-H bond activation and C-B bond formation could occur by
oxidative addition and reduction or by σ bond metathesis. For calculations
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H.; Sakaki, S. J. Am. Chem. Soc. 2003, 125, 16114. For evidence of σ
bond metathesis in related C-H borylations, see: (b) Webster, C. E.; Fan,
Y.; Hall, M. B.; Kunz, D.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
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