Iridium-catalyzed C-H activation versus directed ortho metalation: Complementary borylation of aromatics and heteroaromatics

Article abstract of DOI:10.1002/chem.201000401

Systematic studies are presented demonstrating the complementarity of directed ortho metalation (DoM) and Ir-catalyzed strategies for the provision of borylated aromatics and their subsequent Suzuki-Miyaura coupling reactions. A new concept, the use of the TMS group, readily introduced by DoM, as a latent regiodirective moiety to overcome the otherwise problematic production of isomeric borylated product mixtures is presented. Additional electrophile-induced ipso-deborylation and DoM reactions of the Bpin products are described.

Full text of DOI:10.1002/chem.201000401

FULL PAPER
DOI: 10.1002/chem.201000401
ꢀ
Iridium-Catalyzed C H Activation versus Directed ortho Metalation:
Complementary Borylation of Aromatics and Heteroaromatics
Timothy E. Hurst,[a] Todd K. Macklin,[a] Maike Becker,[a] Eduard Hartmann,[a]
Wolfgang Kꢀgel,[a] Jean-Christophe Parisienne-LaSalle,[a] Andrei S. Batsanov,[b]
Todd B. Marder,[b] and Victor Snieckus*[a]
In memory of Keith Fagnou
Abstract: Systematic studies are presented demonstrating the complementarity of
directed ortho metalation (DoM) and Ir-catalyzed strategies for the provision of
ꢀ
borylated aromatics and their subsequent Suzuki–Miyaura coupling reactions. A
new concept, the use of the TMS group, readily introduced by DoM, as a latent re-
giodirective moiety to overcome the otherwise problematic production of isomeric
borylated product mixtures is presented. Additional electrophile-induced ipso-de-
borylation and DoM reactions of the Bpin products are described.
Keywords: boron · C H activation ·
deborylation · metalation · Suzuki–
Miyaura coupling
Introduction
source.[9] The recurring suggestion that the regioselectivity
of this aromatic ring borylation is controlled predominantly
by steric rather than electronic substituent effects and the
evident impending value of this reaction in aromatic and
heteroaromatic synthetic chemistry provided the impetus for
The resurgence of organoboron chemistry,[1] initiated, argua-
bly, almost 30 years ago by the discovery of the Suzuki–
Miyaura reaction,[2] has made not only a vast and well ap-
preciated impact on organic synthesis but also contributed
to the current productive activity in unrelated areas of mo-
lecular recognition, sensors, linear and nonlinear optical ma-
terials,[3] neutron capture therapy,[4] and medicinal chemistry
and drug discovery.[5] The continuum in this rebirth is due to
the salient disclosures of Smith,[6] Hartwig, Ishiyama and
Miyaura,[7] and Marder,[8] who demonstrated a direct, IrI-cat-
ꢀ
consideration of the juxtaposition of the C H borylation,
2!3 and the directed ortho metalation (DoM),[10] 2!1 pro-
cesses to accentuate complementary beneficial synthetic
methodologies (Scheme 1).[11]
ꢀ
alyzed C H borylation of aromatic substrates, under mild
conditions, to yield aryl boronates using bis(pinacolato)di-
boron (B2pin2) or pinacolborane (HBpin) as the boron
[a] Dr. T. E. Hurst, Dr. T. K. Macklin, M. Becker, E. Hartmann,
W. Kꢀgel, J.-C. Parisienne-LaSalle, Prof. Dr. V. Snieckus
Department of Chemistry
Scheme 1. Complementary borylation/Suzuki–Miyaura cross-coupling re-
actions of DMG bearing arenes.
Queenꢁs University
Kingston, Ontario, K7L 3N6 (Canada)
Fax : (+1)613-533-6089
E-mail: snieckus@chem.queensu.ca
We describe results of systematic studies which a) high-
ꢀ
light the C H activation-DoM complementarity for the pro-
[b] Dr. A. S. Batsanov, Prof. Dr. T. B. Marder
Department of Chemistry
vision of valuable borylated benzene and pyridine deriva-
tives and their subsequent Suzuki–Miyaura reactions,[12]
b) highlight the interesting regiodirective borylation effects
of latent TMS ring substituents, c) provide useful products
of subsequent electrophile-induced ipso-deborylation[6h, 7l]
Durham University
South Road, Durham, DH1 3LE (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000401.
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and d) demonstrate, for the first time, in situ Bpin protec-
tion to allow further DoM reactions. Considered together,
these results provide new methodology with potential to
enrich the area of polysubstituted aromatic molecule synthe-
sis.
introduction of the TMS substituent as a latent directing
group in 6g led to increased yield and regioselectivity of the
borylated product (entry 7). Nicotinamide 6h, which may be
considered, by virtue of the presence of the N-lone pair, a
meta-substituted aromatic, also afforded the 5-borylated
product 7h in modest yield (entry 8).
Of greater significance due to the position of OCONR2 as
one of the most powerful DMGs[10] are the results of studies
of the Ir-catalyzed borylation of aryl O-carbamates (en-
tries 9–20). For the selected 1,2,3-trisubstitued aryl O-carba-
mates 8a–d, all derived by efficient DoM reactions,[14] bory-
lated products 9a–d were obtained in synthetically useful
yields (entries 9–12). Analogously to para-anisamide 6c, the
corresponding O-carbamate 8e afforded a poor yield of the
3-Bpin product 9e (entry 13).
The simple meta-substituted aryl O-carbamates 8 f–i un-
derwent borylation to afford the corresponding products
9 f–i in good yields; in support of the hypothesis that regio-
selectivity of borylation is driven by steric rather than elec-
tronic effects, meta-fluoro O-carbamate 8 f was found to
give an inseparable 2:1 mixture of borylated derivatives 9 f
in quantitative yield. Notable is the lack of complication
from halogen substituents (9b, 9 f–g, 9l), although similar
observations have been reported previously.[9] The 3,4-meth-
ylenedioxy derivative 8j underwent highly meta-selective
borylation to give product 9j, a contra-electrophilic substitu-
tion result. Possibly heralding future synthetic opportunity,
the 1-naphthyl O-carbamate 8k led to the 3-Bpin product
9k in high yield. Pyridine O-carbamate 8l also participated
efficiently in the reaction to give 9l. As noted above, boryla-
tion may be driven either para (9a–c) or meta (9d–l) to the
DMG depending on the substitution pattern or, uniquely, by
the use of TMS as a latent regiodirective group (7g, 9a–
c).[15,16]
Results and Discussion
Ir-catalyzed borylation of directed metalation group
(DMG)-bearing arenes: We initiated our studies with mind-
ful consideration of previous results which indicate that
monosubstituted aromatics usually undergo Ir-catalyzed bor-
ylation to furnish synthetically compromised mixtures of re-
gioisomeric products while 1,3-disubstituted systems gener-
ally lead to common meta-borylation with high regioselectiv-
ity and good efficiency.[9] Thus, the prototype meta-methoxy
aromatics 4a–d, bearing four widely used DMGs, were sub-
jected to the most commonly used Ir-catalyzed conditions
and were found to afford the respective 5-boropinacolato
products 5a–d, respectively, in good to excellent yields
(Scheme 2).[13]
Scheme 2. Conditions: Arene (1 equiv), [IrACHTNUGRTNENUG(cod)ACHUTNGTREN(NUGN OMe)]2 (2 mol%),
dtbpy (4 mol%), B2pin2 (0.6 equiv), hexanes, 808C, 18 h. Yields refer to
isolated pure materials. cod=1,5-cyclooctadiene. dtbpy=4,4’-di-tert-
butyl-2,2’-dipyridyl.
Complementary DoM and Ir-catalyzed borylation-Suzuki–
Miyaura cross-coupling reactions: With the above borylation
results in hand, we pursued the main goal of this work: to
establish complementary DoM and catalytic Ir-derived ap-
proaches for the synthesis of isomeric biaryls and hetero-
biaryls by the Suzuki–Miyaura crossACTHNUTRGNEUNG-coupling reaction. The
comparative results are shown in Table 2.
The DoM-derived products 10a–h involve metalation
under standard conditions based on the specific DMG fol-
lowed by quenching with BACTHNUTRGNE(UNG OMe)3 to give the crude boronic
acids after aqueous workup. These were then subjected to
previously established Suzuki–Miyaura cross-coupling condi-
tions[17] with either electron-rich or electron-deficient aryl
bromides to afford the biaryl products. For the Ir-catalyzed
borylation counterpart results, initially the isolated Bpin de-
rivatives were subjected to standard cross-coupling condi-
tions (Pd2dba3/S-Phos) developed by Buchwald and co-
workers with aryl bromides to give the isomeric biaryl deriv-
atives 11a–h. Subsequently, application of an in situ proce-
dure recently reported by Marder, Steel et al.,[8c,d] which in-
volves carrying out both the Ir-catalyzed borylation and
Suzuki–Miyaura reactions in one pot and in the same sol-
With these encouraging results in hand, studies of ben-
zene and pyridine substrates bearing the extensively used
amide and O-carbamate DMGs[10] were undertaken and the
results, summarized in Table 1, warrant brief comment.
Whilst diethyl 2-methoxybenzamide gave an inseparable
mixture of 4- and 5-borylated products, TMS derivative 6a,
obtained by efficient DoM reaction,[14] led to a single regio-
isomer 7a in excellent yield (entry 1). Trisubstituted benza-
mide 6b also participated efficiently in the reaction
(entry 2). para-Anisamide 6c, however, while still showing a
steric effect from the amide function, led to a low yield of
product 7c (entry 3). Bis-borylated naphthalene derivative
7e was also formed in good yield on increasing the amount
of B2pin2 used in the reaction.
Marder has shown that the presence of a 2-substituent is
preferred for efficient borylation of pyridines by enforcing
steric shielding of the detrimental N-coordination effect,
leading to products in higher yields.[8b] In accordance with
this hypothesis, borylation of picolinamide 6 f furnished a
mixture of products in modest yield (entry 6). Once again,
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Borylation of Aromatics and Heteroaromatics
FULL PAPER
Table 1. Ir-catalyzed borylation of benzamides 6a–e, pyridine amides 6 f–h, and aryl O-carbamates 8a–l.[a]
Entry
1
7
Yield[b] [%]
Entry
8
7/9
Yield[b] [%]
Entry
15
9
Yield[b] [%]
86
63[c]
72
2
3
72
9
70
93
16
17
18
82
58
76
32[c]
10
4
5
95
11
12
59
86
72[c,d]
19
20
88
84
6
7
47[e]
13
14
16
71
quant.[f]
[a] Conditions: Arene (1 equiv), [IrACHTUNTRGENNUG(cod)CAHTUNGTREN(NGUN OMe)]2 (2 mol%), dtbpy (4 mol%), B2pin2 (0.6 equiv), hexanes, 808C, 18 h. [b] Yields refer to isolated pure
materials. [c] MTBE used as solvent (see reference [8c,d]). [d] 2 equiv of B2pin2 used. [e] GC-MS of the crude reaction mixture indicated the presence of
a second isomer (presumably the 4-borylated product), which was not observed after purification by silica gel chromatography. [f] 2:1 ratio of regioisom-
ers obtained.
vent (MTBE) led to cleaner reactions and isolation of the
biaryls in improved yields. Thus, for the prototype meta-me-
thoxyaryl systems 4a–d, DoM-derived Suzuki–Miyaura cou-
pling provided the biaryls 10a–d while the Ir-catalyzed bory-
lation followed by Suzuki–Miyaura coupling furnished the
isomeric biaryl products 11a–d (entries 1-4) in excellent
yield. The directed metalation of sulfonamide 4d deserves
further comment, as trapping of the resulting anion with B-
phile gave the corresponding aryl boropinacolate in good
yield (72%), which participated in Suzuki–Miyaura coupling
with 4-bromoanisole to give 10d with moderate efficiency.[18]
Comparative results for other aryl and heteroaryl amides
(entries 5–6) and aryl carbamates (entries 7–8) further dem-
onstrate the utility of these divergent processes.
Sequential DoM-Suzuki–Miyaura cross-couplings of aryl
boropinacolates: Motivated by the recent results of Zhich-
kin and co-workers who showed that reversible protection
ACHTUNGTRENNUNG
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V. Snieckus et al.
Table 2. Complementary DoM[a] and Ir-catalyzed[b] borylation-Suzuki–
Miyaura cross-couplings (Scheme 1).
aryl boronates 12a–c, which were immediately subjected to
Suzuki–Miyaura coupling to give biaryls 13a–c in modest
yields over the two steps (Table 3). Application of in situ
metalation/quench conditions (LDA/TMSCl) led to the for-
mation of silylated derivative 13d in 43% yield after cou-
pling without the need for Bpin protection. Studies to
expand the scope of this first DoM-Suzuki–Miyaura proto-
col for aromatic Bpin derivatives are underway in our labo-
ratories and will be disclosed in due course.
Entry 10[c]
Yield[d]
[%]
11[c]
Yield[d]
[%]
1
89
83
2
3
4
49
86
85
85
Table 3. Sequential DoM-Suzuki–Miyaura cross-couplings of aryl boropi-
nacolates 5a,b.
78
45[e,g]
Entry
13
DMG
E
R
Yield[c] [%]
1
2
3
4
13a
13b
13c
13d
CONEt2
CONEt2
OCONEt2
OCONEt2
Me
TMS
Me
CHO
CHO
NO2
38[a]
50[a]
68[a]
43[b]
5
73
95
TMS
CHO
[a] Conditions: 1) ArBpin (1 equiv), LiOiPr (1 equiv), THF, RT, 2 h; 2)
sBuLi (2.4 equiv), TMEDA (2.4 equiv), THF, ꢀ788C, 2 h; 3) E+, THF,
ꢀ88C to RT, 1 h; 4) NH4Cl (aq) workup; 5) ArBr (1.2–1.5 equiv), [Pd-
6
7
71[h]
90
98
AHCTUNTGERN(GNUN dppf)Cl2]·CH2Cl2 (3 mol%), KOH (5 equiv), MTBE/H2O (3:1), 808C,
16 h. [b] Conditions: 1) ArBpin (1 equiv), LDA (2.5 equiv), TMSCl
(3.3 equiv), THF, ꢀ788C, 1 h then ꢀ408C, 2 h; 2) NH4Cl (aq) workup; 3)
ArBr (1.2 equiv), [PdACTHNUTRGNENUG(dppf)Cl2]·CH2Cl2 (3 mol%), KOH (5 equiv),
MTBE/H2O 3:1, 808C, 17 h. [c] Yields refer to isolated pure materials.
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
50[f,g]
Electrophile-induced ipso-deborylation: To provide addi-
tional synthetic scope to the above methodology, exemplary
oxidative conversions of Bpin substrates were effected
(Table 4).[6h] Thus, treatment of benzamides 5a/7e and O-
carbamates 9g/9j with Oxone resulted in the formation of
the corresponding phenols 14a–d in generally good yields
(52–96%). Following recently established mild conditions
for the reduction of tertiary amides and carbamates to their
corresponding aldehydes and phenols using in situ generated
Schwartz reagent,[21] 14a–b and 14c–d were converted into
aldehydes 15a–b and phenols 15c–d, respectively, by
TBDMS protection followed by Schwartz reduction.[22] This
process represents an efficient method for the preparation
of orthogonally protected hydroxylated benzaldehydes and
phenols that may be difficult to access by traditional electro-
philic aromatic chemisty.
8
52
63
[a] Conditions: 1) Arene (1 equiv), sBuLi (1.1 equiv), TMEDA
(1.1 equiv), THF, ꢀ788C, 1 h then B(OMe)3 (4 equiv), THF, ꢀ408C, 3 h;
2) NH4Cl (aq) workup; 3) ArBr (0.8 equiv), [Pd(PPh3)4] (4 mol%), 2m
Na2CO3 (aq), DME, 1008C, 16 h. [b] Conditions: 1) Arene (1 equiv), [Ir-
(cod)(OMe)]2 (2 mol%), dtbpy (4 mol%), B2pin2 (1 equiv), MTBE,
808C, 16 h; 2) ArBr (1.2 equiv), [Pd(dppf)Cl2]·CH2Cl2 (3 mol%), KOH
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
T
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(5 equiv), MTBE/H2O 3:1, 808C, 4 h. [c] Ar1 =p-NCC6H4, Ar2 =p-
MeOC6H4, Ar3 m-MeC6H4. [d] Yields refer to isolated pure materials.
[e] Conditions: 1) Arene (1 equiv), nBuLi (1.5 equiv), THF, ꢀ788C, 1 h
then MeOBpin (4 equiv), ꢀ788C to RT, 16 h; 2) ArBr (0.8 equiv), [Pd-
ACHTUNGTRENNUNG(dtbpf)Cl2]·CH2Cl2 (4 mol%), 2m Na2CO3 (aq), DME, 1008C, 21 h.
[f] Conditions: 1) Arene (1 equiv), sBuLi (1.2 equiv), TMEDA
(1.2 equiv), THF, ꢀ788C, 2 h then MeOBpin (4 equiv), ꢀ788C to RT,
16 h; 2) ArBr (1.4 equiv), [PdACHTUNGTRENUNG(dtbpf)Cl2] (4 mol%), 2m Na2CO3 (aq),
DME, 808C, 21 h. [g] Combined yield over 2 steps. [h] see ref. [20].
dppf=1,1’-bis(diphenylphosphino)ferrocene. dtbpf=1,1’-bis(di-tert-butyl-
phosphino)ferrocene.
Conclusion
of aryl and heteroaryl Bpin derivatives to metal–halogen ex-
change could be achieved by using lithium isopropoxide,[19]
treatment of 5a–b under modified Zhichkin conditions fol-
lowed by E+ (MeI or TMSCl) quench and workup gave the
In conclusion, Ir-catalyzed borylation reactions have been
achieved on a variety of aryl and pyridyl amide and O-car-
bamate substrates (Table 1) which afford the corresponding
boropinacolates with regioselectivity which complements
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Borylation of Aromatics and Heteroaromatics
FULL PAPER
Table 4. ipso-Hydroxydeborylation of aryl boropinacolates 5a, 7e, 9g, 9j
or flame-dried glassware. Anhydrous hexane, MTBE, and DME were
purchased from Sigma–Aldrich and degassed by purging with a stream of
argon for 20–30 min prior to use. Anhydrous THF and toluene were ob-
tained using an Innovative Technologies “Pure-Solve” SPS-400-4 system.
n-Butyllithium (2.5m solution in hexanes) and sec-butyllithium (1.6m in
hexanes) were purchased from Sigma–Aldrich and titrated biweekly ac-
cording to the method of Chong and co-workers.[23] Internal temperatures
for low temperature reactions were measured using a Barnant thermo-
couple thermometer. Chlorotrimethylsilane was freshly distilled prior to
use. Flash chromatography was carried out using Silicycle Silicaflash P60
silica gel.
and DMG reduction using the Schwartz reagent.[a,b]
Entry 14
Yield[c] 15
Yield[c]
[%]
[%]
ꢀ
H
General procedure 1—C
activation/borylation: [IrACTHNGURTENNU(G cod)ACHTUNGTRENNUNG(OMe)]2
(0.013 g, 0.02 mmol, 2 mol%), 4,4’-di-tert-butyl-2,2’-dipyridyl (0.011 g,
0.040 mmol, 4 mol%) and bis(pinacolato)diboron (0.152 g, 0.600 mmol)
were added to the (hetero)arene (1.00 mmol) in a Schlenk tube under
argon. Hexanes (6 mL) were added and the tube sealed. The reaction
mixture was heated to 808C for 16–24 h and cooled to room temperature.
The crude product was purified by flash chromatography on silica gel to
afford the title compound.
1
93
52
63
41
2
ꢀ
General procedure 2—C H activation/borylation/Suzuki–Miyaura cross-
coupling: [Ir
A
G
butyl-2,2’-dipyridyl (0.011 g, 0.040 mmol, 4 mol%) and bis(pinacolato)di-
boron (0.254 g, 1.00 mmol) were added to the (hetero)arene (1.00 mmol)
in a Schlenk tube under argon. MTBE (3 mL) was added and the tube
sealed. The reaction mixture was heated to 808C for 16 h and then
cooled to room temperature. Degassed H2O (1 mL) was added, followed
3
4
64
96
48
62
by [PdACHTUNGRTNE(GNU dppf)Cl2]·CH2Cl2 (0.025 g, 0.030 mmol, 3 mol%), potassium hy-
droxide (0.280 g, 5.00 mmol) and the aryl halide (1.20 mmol). The tube
was resealed and the reaction mixture heated at 808C for 4 h. The result-
ing mixture was filtered through Celite and partitioned between H2O
(15 mL) and CH2Cl2 (3ꢃ15 mL). The combined organics were dried over
Na2SO4, filtered, and concentrated in vacuo. The crude product was puri-
fied by flash chromatography on silica gel to afford the title compound.
[a] Conditions: ArBpin (1 equiv), Oxone (1.1 equiv), acetone/H2O 1:1,
RT, 30 min to 1 h. [b] 1) ArOH (1 equiv), TBDMSCl (1.5 equiv), imida-
zole (1.5 equiv), CH2Cl2, RT, 1 h; 2) [Cp2ZrCl2] (1.5–3.0 equiv), LiAlH-
General procedure 3—Directed ortho metalation/borylation/Suzuki–
Miyaura cross-coupling: To a solution of TMEDA (0.165 mL, 1.10 mmol)
in dry THF (3 mL) at ꢀ788C was added sec-butyllithium (1.23m in hex-
anes, 0.90 mL, 1.10 mmol) dropwise over 5 min. The (hetero)arene
(1.00 mmol) in THF (2 mL) was added dropwise over 15 min so that the
internal temperature did not rise above ꢀ708C, and the reaction mixture
was stirred at ꢀ788C for 1 h. Trimethylborate (0.446 mL, 4.00 mmol) was
then added over 10 min. The reaction was allowed to warm to ꢀ408C,
stirred for 3 h, and then quenched carefully at this temperature by the
addition of saturated aqueous NH4Cl (5 mL), H2O (5 mL) and CH2Cl2
(10 mL). The aqueous layer was separated and further extracted with
CH2Cl2 (2ꢃ10 mL). The combined organics were dried over Na2SO4, fil-
tered, and concentrated in vacuo to afford the crude boronic acid, which
was dried under high vacuum for 30 min and used without further purifi-
cation.
ACHTUNGTRENNUNG(OtBu)3 (1.5–3.0 equiv), THF, RT, 3-16 h. [c] Yields refer to isolated pure
materials. TBDMS=tert-butyldimethylsilyl.
products obtained by the DoM-borylation reaction se-
quence. Significantly, a new concept, the use of a TMS
group, readily introduced by DoM, as a latent regiodirective
moiety to overcome the otherwise problematic production
of isomeric borylated product mixtures has been presented.
The complementarity of the DoM and Ir-catalyzed strategies
for the construction of biaryls and heterobiaryls has been
demonstrated by the establishment of respective Suzuki–
Miyaura cross-coupling procedures (Table 2). The polysub-
stituted biaryls obtained are expected to be amenable to fur-
ther DoM-borylation/cross-coupling as well as directed
remote metalation (DreM) reactions.[10d] Aside from ipso-
hydroxydeborylation (Table 4), in situ Bpin protection for
subsequent DoM reactions (Table 3) broadens the scope of
the reported chemistry. Taken in sum, the results allow con-
ceptual contemplation of metalation- and cross-coupling-
based transformations of potential value for the construction
of polysubstituted aromatics and heteroaromatics.
To the boronic acid was added [PdACHTUGNTERN(UNNG PPh3)4] (0.046 g, 0.040 mmol, 4
mol%) and the aryl halide (0.800 mmol), followed by degassed DME
(4 mL) and degassed 2m aqueous Na2CO3 solution (2 mL). The reaction
mixture was heated under reflux for 16 h, cooled to room temperature
and partitioned between H2O (15 mL) and EtOAc (3ꢃ15 mL). The com-
bined organics were washed with H2O (15 mL) and saturated brine
(15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography on silica gel to
afford the title compound.
General procedure 4—Directed ortho metalation/Suzuki–Miyaura cross-
coupling: To a solution of the aryl boropinacolate (1.00 mmol) in THF
(10 mL) was added lithium isopropoxide (1m in hexanes, 1.00 mL,
1.00 mmol). The reaction mixture stirred at room temperature for 2 h,
then cooled to ꢀ788C. TMEDA (0.36 mL, 2.40 mmol) was added, fol-
lowed by sec-butyllithium (1.29m in hexanes, 1.86 mL, 2.40 mmol) drop-
wise over 10 min so that the internal temperature did not rise above
ꢀ708C, and the reaction mixture was stirred at ꢀ788C for 1 h. The elec-
trophile (3.00 mmol) was added and the reaction mixture was stirred at
ꢀ788C for 30 min before warming to room temperature. After a further
1 h at room temperature saturated aqueous NH4Cl (25 mL) was added,
Experimental Section
General methods: Commercially available reagents were used through-
out without further purification unless otherwise stated. Reactions were
routinely carried out under a nitrogen or argon atmosphere using oven
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V. Snieckus et al.
and the aqueous layer was extracted with CH2Cl2 (3ꢃ25 mL). The com-
bined organics were dried over Na2SO4, filtered, and concentrated in
vacuo. The crude aryl boropinacolate was used directly in the next step
without further purification.
Dowlut, D. G. Hall, J. Am. Chem. Soc. 2006, 128, 4226–4227; Vel-
cade (bortezomib): J. Adams, M. Behnke, S. Chen, A. A. Cruick-
shank, L. R. Dick, L. Grenier, J. M. Klunder, Y.-T. Ma, L. Plamon-
don, R. L. Stein, Bioorg. Med. Chem. Lett. 1998, 8, 333–338.
[6] a) C. N. Iverson, M. R. Smith III, J. Am. Chem. Soc. 1999, 121,
7696–7697; b) J.-Y. Cho, C. N. Iverson, M. R. Smith, III, J. Am.
Chem. Soc. 2000, 122, 12868–12869; c) M. K. Tse, J.-Y. Cho, M. R.
Smith, III, Org. Lett. 2001, 3, 2831–2833; d) J.-Y. Cho, M. K. Tse,
D. Holmes, R. E. Maleczka, Jr., M. R. Smith, III, Science 2002, 295,
305–308; e) R. E. Maleczka, Jr., F. Shi, D. Holmes, M. R. Smith,
III, J. Am. Chem. Soc. 2003, 125, 7792–7793; f) G. A. Chotana,
M. A. Rak, M. R. Smith, III, J. Am. Chem. Soc. 2005, 127, 10539–
10544; g) D. Holmes, G. A. Chotana, R. E. Maleczka, Jr., M. R.
Smith, III, Org. Lett. 2006, 8, 1407–1410; h) F. Shi, M. R. SmithIII,
R. E. Maleczka, Jr., Org. Lett. 2006, 8, 1411–1414; i) S. Paul, G. A.
Chotana, D. Holmes, R. C. Reichle, R. E. Maleczka, Jr., M. R.
Smith, III, J. Am. Chem. Soc. 2006, 128, 15552–15553; j) V. A. Kal-
lepalli, F. Shi, S. Paul, E. N. Onyeozilli, R. E. Maleczka, Jr., M. R.
Smith, III, J. Org. Chem. 2009, 74, 9199–9201.
[7] a) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi, J. F.
Hartwig, J. Am. Chem. Soc. 2002, 124, 390–391; b) J. Takagi, K.
Sato, J. F. Hartwig, T. Ishiyama, N. Miyaura, Tetrahedron Lett. 2002,
43, 5649–5651; c) T. Ishiyama, J. Takagi, J. F. Hartwig, N. Miyaura,
Angew. Chem. 2002, 114, 3182–3184; Angew. Chem. Int. Ed. 2002,
41, 3056–3058; d) T. Ishiyama, Y. Nobuta, J. F. Hartwig, N. Miyaura,
Chem. Commun. 2003, 2924–2925; e) T. Ishiyama, N. Miyaura, J.
Organomet. Chem. 2003, 680, 3–11; f) T. Ishiyama, N. Miyaura,
Chem. Rec. 2004, 3, 271–280; g) T. M. Boller, J. M. Murphy, M.
Hapke, T. Ishiyama, N. Miyaura, J. F. Hartwig, J. Am. Chem. Soc.
2005, 127, 14263–14278; h) T. Ishiyama, J. Takagi, Y. Nobuta, N.
Miyaura, Org. Synth. 2005, 82, 126–133; i) T. Ishiyama, N. Miyaura,
Pure Appl. Chem. 2006, 78, 1369–1375; j) J. M. Murphy, C. C.
Tzschucke, J. F. Hartwig, Org. Lett. 2007, 9, 757–760; k) C. C.
Tzschucke, J. M. Murphy, J. F. Hartwig, Org. Lett. 2007, 9, 761–764;
l) J. M. Murphy, X. Liao, J. F. Hartwig, J. Am. Chem. Soc. 2007, 129,
15434–15435.
To the aryl boropinacolate in degassed MTBE (3 mL) and degassed
water (1 mL) in a Schlenk tube was added [PdACTHUNRGTENUNG(dppf)Cl2]·CH2Cl2 (0.025 g,
0.030 mmol, 3 mol%), potassium hydroxide (0.281 g, 5.00 mmol) and the
aryl bromide (1.2–1.5 mmol). The tube was sealed and the reaction was
heated at 808C for 16 h, then partitioned between H2O (25 mL) and
EtOAc (3ꢃ25 mL). The combined organics were dried over Na2SO4, fil-
tered, and concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel to afford the title compound.
General procedure 5—Arylboropinacolate oxidation: To a solution of
the aryl boropinacolate (1.00 mmol) in acetone (5 mL) was added a solu-
tion of Oxone (0.369 g, 1.2 mmol) in water (5 mL). The reaction mixture
was stirred at room temperature for 1 h, diluted with H2O (10 mL) and
the aqueous layer extracted with EtOAc (3ꢃ10 mL). The combined or-
ganics were washed with saturated brine (10 mL), dried over Na2SO4, fil-
tered, and concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel to afford the title compound.
General Procedure 6—Phenol protection/Schwartz reduction: To a solu-
tion of the phenol (0.500 mmol) in CH2Cl2 (5 mL) was added tert-butyldi-
methylsilyl chloride (0.113 g, 0.750 mmol) and imidazole (0.051 g,
0.750 mmol). The reaction mixture was stirred at room temperature for
2–4 h, then passed through a short plug of silica gel to afford the
TBDMS-protected phenol, which was used directly in the next step with-
out further purification.
To the protected phenol (0.350 mmol) in THF (3.5 mL) was added bis(cy-
clopentadienyl)zirconium(IV) dichloride (0.153 g, 0.525 mmol for amide
reduction or 0.307 g, 1.05 mmol for carbamate reduction) and lithium
tri(tert-butoxy)aluminium hydride (1.0m in THF, 0.53 mL, 0.525 mmol for
amide reduction or 1.10 mL, 1.05 mmol for carbamate reduction) drop-
wise over 2 min. The reaction mixture was stirred at room temperature
for 3–16 h and quenched with 0.5m HCl (10 mL). The aqueous layer was
extracted with EtOAc (3ꢃ10 mL) and the combined organics were
washed with saturated brine (10 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by flash chroma-
tography on silica gel to afford the title compound.
[8] a) D. N. Coventry, A. S. Batsanov, A. E. Goeta, J. A. K. Howard,
T. B. Marder, R. N. Perutz, Chem. Commun. 2005, 2172–2174;
b) I. A. I. Mkhalid, D. N. Coventry, D. Albesa-Jove, A. S. Batsanov,
J. A. K. Howard, R. N. Perutz, T. B. Marder, Angew. Chem. 2006,
118, 503–505; Angew. Chem. Int. Ed. 2006, 45, 489–491; c) P. Har-
risson, J. Morris, P. G. Steel, T. B. Marder, Synlett 2009, 147–150;
d) P. Harrisson, J. Morris, T. B. Marder, P. G. Steel, Org. Lett. 2009,
11, 3586–3589.
Acknowledgements
We thank NSERC for financial support of this work and Johnson-Mat-
they and AllyChem Co. Ltd. for generous donations of palladium cata-
lysts and B2pin2, respectively.
[9] For
a recent review, see: I. A. I. Mkhalid, J. H. Barnard, T. B.
Marder, J. M. Murphy, J. F. Hartwig, Chem. Rev. 2010, 110, 890–931.
ꢀ
[10] a) T. Macklin, V. Snieckus in Handbook of C H Transformations
(Ed.: G. Dyker), Wiley-VCH, Weinheim, 2005, pp. 106–119; b) J.
Clayden in The Chemistry of Organolithium Compounds (Eds.: Z.
Rappoport, I. Marek), Wiley, New York, 2004, pp. 497–648; c) E. J.-
G. Anctil, V. Snieckus in Metal-Catalyzed Cross-Coupling Reactions
(Eds.: A. de Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004,
pp. 761–814; d) M. C. Whisler, S. MacNeil, V. Snieckus, P. Beak,
Angew. Chem. 2004, 116, 2256–2276; Angew. Chem. Int. Ed. 2004,
43, 2206–2225; e) C. G. Hartung, V. Snieckus in Modern Arene
Chemistry (Ed.: D. Astruc), Wiley-VCH, Weinheim, 2002, pp. 330–
367; f) V. Snieckus, Chem. Rev. 1990, 90, 879–933.
[1] a) A. Pelter, K. Smith, H. C. Brown, Borane Reagents, Academic
Press, London, 1988; b) D. S. Matteson, Stereodirected Synthesis with
Organoboranes, Springer, Berlin, 1995; c) Science of Synthesis Vol. 6
(Eds.: D. E. Kaufmann, D. S. Matteson), Thieme, Stuttgart, 2004,
pp. 1–1408.
[2] a) N. Miyaura, A. Suzuki, Chem. Commun. 1979, 866–867; b) N.
Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483.
[3] a) C. D. Entwistle, T. B. Marder, Angew. Chem. 2002, 114, 3051–
3056; Angew. Chem. Int. Ed. 2002, 41, 2927–2931; b) C. D. Entwis-
tle, T. B. Marder, Chem. Mater. 2004, 16, 4574–4585.
[4] a) A. H. Soloway, W. Tjarks, B. A. Barnum, F.-G. Rong, R. F. Barth,
I. M. Codogni, J. G. Wilson, Chem. Rev. 1998, 98, 1515–1562;
b) M. F. Hawthorne, A. Maderna, Chem. Rev. 1999, 99, 3421–3434;
c) W. Tjarks, J. Organomet. Chem. 2000, 614–615, 37–47.
[5] a) Boronic Acids—Preparation and Applications in Organic Synthe-
sis and Medicine (Ed.: D. G. Hall), Wiley-VCH, Weinheim, 2005;
b) for recent work, see, among others, multicomponent reactions: X.
Gao, D. G. Hall, J. Am. Chem. Soc. 2005, 127, 1628–1629; solid-
phase synthesis: S. Mothana, N. Chahal, S. Vanneste, D. G. Hall, J.
Comb. Chem. 2007, 9, 193–196; carbohydrate recognition: M.
[11] For some recent Ir-catalyzed ortho-borylations which may have fur-
ther impact on the complementary nature of the two synthetic strat-
egies, see: a) T. A. Boebel, J. F. Hartwig, J. Am. Chem. Soc. 2008,
130, 7534–7535; b) N. Miyaura, Bull. Chem. Soc. Jpn. 2008, 81,
1535–1553; c) S. Kawamorita, H. Ohmiya, K. Hara, A. Fukuoka, M.
Sawamura, J. Am. Chem. Soc. 2009, 131, 5058–5059; d) T. Ishiyama,
H. Isou, T. Kikuchi, N. Miyaura, Chem. Commun. 2010, 159–161.
[12] N. Miyaura in Metal-Catalyzed Cross-Coupling Reactions (Eds.: A.
de Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004, pp. 41–124.
[13] For reasons currently unappreciated, N-tert-butoxycarbonyl 3-me-
thoxyaniline led to mixtures of unidentified products.
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Chem. Eur. J. 2010, 16, 8155 – 8161

Borylation of Aromatics and Heteroaromatics
FULL PAPER
[14] See the Supporting Information for the synthesis of these com-
pounds.
[15] The TMS group may be readily cleaved on treatment with CsF in
DMF, see the Supporting Information.
[16] The structure of one example (9b) was confirmed by X-ray crystal-
lographic analysis, see the Supporting Information.
[21] Y. Zhao, V. Snieckus, unpublished results.
[22] The reduction of amides to aldehydes using the Schwartz reagent
was first reported by Georg and co-workers: a) J. T. Spletstoser,
J. M. White, A. Rao Tunoori, G. I. Georg, J. Am. Chem. Soc. 2007,
129, 3408–3419; b) J. M. White, A. Rao Tunoori, G. I. Georg, J. Am.
Chem. Soc. 2000, 122, 11995–11996.
[17] J.-M. Fu, V. Snieckus, Can. J. Chem. 2000, 78, 905–919.
[18] C. Schneider, E. Broda, V. Snieckus, unpublished results.
[19] Q. Jiang, M. Ryan, P. Zhichkin, J. Org. Chem. 2007, 72, 6618–6620.
[20] M. Alessi, A. L. Larkin, K. A. Ogilvie, L. A. Green, S. Lai, S. Lopez
V. Snieckus, J. Org. Chem. 2007, 72, 1588–1594.
[23] A. F. Burchat, J. M. Chong, N. Nielsen, J. Organomet. Chem. 1997,
542, 281–283.
Received: February 15, 2010
Published online: June 8, 2010
Chem. Eur. J. 2010, 16, 8155 – 8161
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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