N-Heterocyclic Carbene Ligand-Controlled Chemodivergent Suzuki-Miyaura Cross Coupling

Article abstract of DOI:10.1021/acs.joc.9b01692

Two N-heterocyclic carbene ligands provide orthogonal chemoselectivity during the Pd-catalyzed Suzuki-Miyaura (SM) cross-coupling of chloroaryl triflates. The use of SIPr [SIPr = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene] leads to selective cross-coupling at chloride, while the use of SIMes [SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene] provides selective coupling at triflate. With most chloroaryl triflates and arylboronic acids, ligand-controlled selectivity is high (≥10:1). The scope of this methodology is significantly more general than previously reported methods for selective SM coupling of chloroaryl triflates using phosphine ligands. Density functional theory studies suggest that palladium's ligation state during oxidative addition is different with SIMes compared to SIPr.

Full text of DOI:10.1021/acs.joc.9b01692

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Article
N-Heterocyclic Carbene Ligand-Controlled
Chemodivergent Suzuki-Miyaura Cross Coupling
Emily K. Reeves, Jenna N Humke, and Sharon R. Neufeldt
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01692 • Publication Date (Web): 02 Sep 2019
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N-Heterocyclic Carbene Ligand-Controlled
Chemodivergent Suzuki-Miyaura Cross Coupling
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Emily K. Reeves, Jenna N. Humke†, Sharon R. Neufeldt*
Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
Email: sharon.neufeldt@montana.edu
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ABSTRACT
Two N-heterocyclic carbene (NHC) ligands provide orthogonal chemoselectivity during
the Pd-catalyzed Suzuki-Miyaura (SM) cross coupling of chloroaryl triflates. The use of SIPr [SIPr
= 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene] leads to selective cross coupling
at chloride, while the use of SIMes [SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-
2-ylidene] provides selective coupling at triflate. With most chloroaryl triflates and arylboronic
acids, ligand-controlled selectivity is high (≥10:1). The scope of this methodology is significantly
more general than previously reported methods for selective SM coupling of chloroaryl triflates
using phosphine ligands. Density functional theory (DFT) studies suggest that palladium’s
ligation state during oxidative addition is different with SIMes compared to SIPr.
INTRODUCTION
Palladium-catalyzed cross couplings are among the most widely used strategies for C—C
bond formation during the preparation of diverse classes of products.1 The Suzuki-Miyaura (SM)
reaction is particularly attractive due to its mild reaction conditions, its high functional group and
moisture tolerance, and the low toxicity and good commercial availability of boronic acids and
esters.1 Sequential cross coupling reactions can be used to prepare polyfunctionalized arenes,2
which are ubiquitous in pharmaceuticals, agrochemicals, materials, and natural products.
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However, controlling the site selectivity of sequential cross coupling reactions can be challenging
when multiple (pseudo)halides are present. A particularly attractive strategy for manipulating
selectivity is through catalyst or ligand choice.3
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For example, aryl chlorides and triflates are known to react with Pd(0) under similar
conditions. The only previously known system for ligand-controlled divergent SM cross coupling
of chloroaryl triflates was initially reported by Fu (Scheme 1A and B).4,5,6 The SM coupling of 1
with 2 favors reaction at C—Cl over C—OTf with the bulky ligand PtBu3. Conversely, the less
hindered PCy3 effects reaction at triflate. However, this methodology has limited synthetic utility.
Selective cross coupling at C—OTf using PCy3 under the reported conditions is specific to the
reaction between 1 and 2; the use of other chloroaryl triflates or boronic acids leads to poor yields
and/or selectivity (Scheme 1B).7 A detailed scope of the chloride-selective cross coupling with
PtBu3 under the original conditions has not been reported.8 As such, alternative methods are
needed for selective SM cross coupling of chloroaryl triflates.
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Scheme 1. Chemodivergent Cross Coupling of Chloroaryl Triflates
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An elegant procedure for triflate-selective coupling of chloroaryl triflates with organozinc
reagents was recently described (Scheme 1C).7 However, a general method to achieve the opposite
selectivity—cross coupling of aryl chlorides in the presence of triflates—has not been detailed.
Moreover, organozinc reagents have disadvantages compared to organoboron reagents related to
functional group tolerance and commercial availability.1
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Herein we demonstrate that the use of NHC ligands enables chemodivergent SM coupling
of chloroaryl triflates. A Pd/SIPr precatalyst provides selective reaction at chloride, while a
Pd/SIMes precatalyst favors reaction at triflate. In contrast to the limited scope reported for the
prior phosphine ligand-controlled method,4,7 this NHC ligand-controlled SM coupling is general
to a variety of chloroaryl triflates and arylboronic acids.
RESULTS AND DISCUSSION
Initial Catalytic Results with NHC Ligands. Inspired by recent reports of the high
reactivity of Pd(II) precatalysts bearing NHC ligands,9,10 we investigated the selectivity of Pd/NHC
complexes 3–7 (Figure 1) in SM reactions of chloroaryl triflates.
Figure 1. Pd/NHC catalysts used in this work.
Gratifyingly, the use of Hazari’s10 air-stable Pd/SIPr precatalyst 3 or PEPPSITM-SIPr11
complex 7 provides high selectivity for coupling at C—Cl in the room-temperature SM reaction of
1 with 2 in THF (Table 1, entries 1-2). Precatalyst 4 bearing the related unsaturated ligand IPr
gives comparable selectivity to 3, albeit with reduced yield of the desired product (entry 3). In
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stark contrast, however, however, catalysts containing the moderately smaller ligands SIMes and
IMes provide the opposite selectivity under otherwise identical conditions (entries 4-5).12,13,14 For
example, the Pd/SIMes-catalyzed reaction of 1 with 2 yields 8b in high yield, resulting from
selective C—OTf activation (entry 4). Only small amounts of products from C—Cl activation (8a
and 8c) are detected with this catalyst.
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Table 1. Evaluation of NHC ligands for selective Pd-catalyzed SM coupling.a
entry cat. NHC
solvent
8a
(%)
85
55
68
3
8b
(%)
5
8c
(%)
13
9
1
3
7
SIPr
SIPr
IPr
THF
THF
THF
2
7
3
4
5
6
3
5
3
5
3
5
3
3
5
5
--
--
9
4
16
3
4
SIMes THF
90
79
5
5
IMes
SIPr
THF
2
13
2
6
PhMe
92
8
7
SIMes PhMe
SIPr DMF
SIMes DMF
13
6
2
8
1
n.d.
n.d.
8
9
n.d. 57
1,4-dioxane 93 5
10
11
12b
13c
14b
15c
16d
17d
18e
SIPr
SIMes 1,4-dioxane
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84
2
SIPr
SIPr
THF
THF
trace trace n.d.
trace trace n.d.
n.d. trace n.d.
SIMes THF
SIMes THF
trace
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n.d.
SIPr
SIMes THF
-- THF
THF
n.d. n.d. n.d.
n.d. n.d. n.d.
1
2
0
aGC yields calibrated against undecane as internal standard. Estimated error in total mass
balance ±6%. Entries 1–11 are the average of two runs. n.d. = not detected. bWithout KF.
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cWithout H2O. dNo Pd catalyst; free SIPr or SIMes was added (3 mol %). e9 = [(3-1-tBu-
indenyl)Pd(Cl)]2.
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The use of toluene instead of THF minimizes unwanted diarylation (8c) with SIPr (entry
6), but poor conversion is observed with SIMes in toluene (entry 7). Dimethylformamide (DMF)
is an effective solvent for the reaction with SIMes (entry 9) but not with SIPr (entry 8), while 1,4-
dioxane is an effective solvent with both ligands (entries 10–11). Control reactions demonstrate
that catalyst, KF, and water are each necessary for both the triflate- and the chloride-selective
cross couplings using SIMes and SIPr, respectively (entries 8–13). Furthermore, only trace cross-
coupling products are detected under ligand-free conditions using [(3-1-tBu-indenyl)Pd(Cl)]2 (9,
entry 14).
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Scope of Arylboronic Acids. The divergent selectivities displayed by SIMes and SIPr
are general to the cross coupling of 1 with diverse arylboronic acids (Scheme 2).15,16 In most cases,
≤5% of the minor product and ≤5% of a diarylated product are observed. Pd/SIMes 5 catalyzes
coupling at triflate using electron-rich (8b, 11b–14b), -neutral (10b), and -deficient (15b–20b)
arylboronic acids. An unprotected phenol (13b), benzylic alcohol (14b), aldehyde (20b), and a
chloro substituent (17b) are tolerated on the boronic acid coupling partner. This scope is notable
because the previously reported conditions for triflate-selective SM cross coupling using Pd/PCy3
are ineffective with representative electron-rich and -deficient arylboronic acids (see Scheme 1B).7
Conversely, Pd/SIPr complex 3 catalyzes selective cross coupling of 1 at chloride using
both electron-rich and -deficient arylboronic acids. The Pd/SIPr-catalyzed cross coupling of 1
with 4-vinylphenyl boronic acid to form 22a is chemoselective for both the electrophile
(preferential reaction at C—Cl) and the nucleophile (SM coupling is favored over Heck coupling).17
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Scheme 2. Scope of arylboronic acids in the NHC ligand-controlled chemodivergent SM
coupling.a
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aIsolated yields. Unless noted, ≤5% of minor monoarylated products and ≤5% of diarylated
b
c
products were detected by crude GC. ~10% of diarylated product by crude GC. ~6% of minor
monoarylated product by crude GC. dSolvent = DMF. eSolvent = 1,4-dioxane. fSolvent = THF.
Scope of Chloroaryl Triflates.15,16 In addition to para-chlorophenyl triflate 1, the meta
and ortho analogs undergo triflate- (Table 2, entries 1-2) or chloride-selective (entries 7-8) cross
coupling with catalysts 5 and 3, respectively. Even in the presence of steric bias (entries 3, 10, 11)
or additional electron-withdrawing or -donating substituents (entries 3–6, 9–13), selectivity
remains ligand-controlled. However, conversions and selectivities are poor for some
electronically biased substrates that were evaluated (see Supporting Information).15 The expected
ligand-based selectivity is retained when chloride and triflate are connected to different aryl rings
(entry 13).
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Table 2. Scope of chloroaryl triflates in the NHC ligand-controlled chemodivergent SM
coupling.a
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aGeneral procedure: chloroaryl triflate (1 equiv), p-methoxyphenylboronic acid (1.25–1.5 equiv),
3 or 5 (3 mol %), KF (3 equiv), H2O (3.5–7.0 equiv), THF, DMF, toluene, 1,4-dioxane, or 1,4-
dioxane/toluene (1:1), 4–12 h, 25–60 ºC. PMP = p-methoxyphenyl. Isolated yields. bUnless
noted, ≤5% of minor monoarylated products and ≤5% of diarylated products were detected by
crude GC. c~28% of diarylated product by crude GC. d~6% of diarylated product by crude GC.
e~19% of minor monoarylated product by crude GC.
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DFT Studies. Having established that SIPr and SIMes ligand-controlled divergent
selectivity is general to a variety of chloroaryl triflates and arylboronic acids, we next turned to
DFT calculations to understand the origin of selectivity in this system. Calculations were
performed at the CPCM(THF) M06/BS2//M06L/BS1 level of theory (see Computational Methods
for details). Neutral transition structures were located using monoligated [Pd(SIPr)] for oxidative
addition at both C—Cl and C—OTf of 1 (Figure 2A, top). Consistent with experiment, [Pd(SIPr)]
is predicted to favor reaction at C—Cl by 4.6 kcal mol-1 (compare TS31a and TS31b). However,
the same computational method predicts that [Pd(SIMes)] should also favor reaction at C—Cl, by
9.5 kcal mol-1 (compare TS32a and TS32b). The latter result strongly contradicts the observed
experimental preference for cross coupling at C—OTf using SIMes. A variety of other DFT
methods were evaluated (see SI), and nearly all provide the same prediction that reaction at C—
OTf is disfavored with [Pd(SIMes)].
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A Neutral monoligated transition structures
ligand = SIPr
favored:
matches
‡
‡
SIPr
Pd
SIPr
Pd
experiment
O
S
CF3
O
TfO
Cl
Cl
O
TS31a
0.0
TS31b
+4.6
ligand = SIMes
favored:
‡
‡
does not match
SIMes
Pd
SIMes
experiment
Pd
O
S
O
TfO
Cl
Cl
O
CF3
TS32a
0.0
TS32b
+9.5
B Anionic heteroleptic bisligated transition structures with SIMes
‡
‡
favored:
matches
SIMes
Pd
SIMes
Pd
experiment
OH
OH
TfO
Cl
O
CF3
Cl
TS33a
TS33b
S
O
+1.5
0.0
O
∆∆G‡ values in kcal mol-1
Figure 2. Calculated transition structures for oxidative addition involving SIPr and SIMes.
This disagreement between computational and experimental results strongly suggests that
monoligated [Pd(SIMes)] is not responsible for oxidative addition of C—OTf. Instead, one
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possibility is that oxidative addition at triflate takes place through a bisligated [Pd(SIMes)2]
transition structure. This possibility is analogous to the current mechanistic understanding of Fu’s
phosphine ligand-controlled SM coupling of chloroaryl triflates.4 DFT calculations by
Schoenebeck and Houk,18 as well as studies by Sigman,6 showed that selectivity in Fu’s system
relates to palladium’s ligation state by phosphine during oxidative addition. PdL2, favored with
PCy3, reacts at the C—OTf site of 1 while PdL, favored with PtBu3, reacts at C—Cl (Scheme 1A and
1B). This relationship between ligation state and selectivity was explained by the distortion-
interaction model.18,19 PdL2 is more electron-rich than PdL and thus has a stronger interaction
with the more electrophilic C—O site compared to C—Cl. It may be possible that SIMes behaves
analogously to PCy3, and that [Pd(SIMes)2] is responsible for the selectivity observed with this
ligand. However, our attempted calculations to locate sterically congested transition structures
involving [Pd(SIMes)2] have all failed to converge.
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An alternative explanation for the triflate selectivity observed with SIMes is that oxidative
addition involves an anionic species [Pd(SIMes)X]– (X = small anionic ligand).20 Indeed, DFT
calculations predict that an anionic transition structure involving [Pd(SIMes)(OH)]– (TS33a)
favors reaction at triflate by 1.5 kcal mol-1 (Figure 2B). Formation of a palladium hydroxide species
is plausible under the catalytic conditions, which include both water and base (KF).21 The
preference for [Pd(SIMes)OH]– to react at OTf is consistent with previously reported calculations
using phosphine ligands. Anionic [Pd(PtBu3)X]– (X = F– or PhB(OH)O–) has been shown
computationally to favor oxidative addition at C—OTf over C—Cl.18,22 Interestingly however,
previous studies suggest that involvement of putative [Pd(PtBu3)X]– is only favored in certain
polar solvents like DMF and MeCN.23 In THF or other nonpolar solvents, the active catalyst is
[Pd(PtBu3)] and preferential SM cross coupling at C—Cl is observed.22 As such, if [Pd(SIMes)X]–
is the active catalyst in THF, it suggests that SIMes is better than PtBu3 at stabilizing anionic Pd.
Further studies will be needed to distinguish between mechanisms involving [Pd(SIMes)2],
[Pd(SIMes)X]–, or other active catalysts.24
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Limitations to Selective Reaction at Chloride: Heteroaryl Substrates. To test
the limits of the NHC ligand-controlled selectivity, chloropyridyl triflates were examined as
substrates for the SM reaction (Table 3). All else being equal, the reactivity of pyridine C—X bonds
toward Pd(0) generally follows the order C2 > C4 > C3/C5.25 We were interested in whether the
strong electronic biases of this substrate class would erode the NHC ligand-controlled selectivity.
Furthermore, the mechanism of oxidative addition of chloropyridines at Pd(0) may be different
from that of chloroarenes, which could affect selectivity.26 The results of the reactions of 34 and
35 with Pd/SIMes indicate that selectivity for triflate using SIMes remains ligand-controlled
(entries 1-2). Selective cross-coupling at triflate of substrate 35 occurs even though pyridine
electronics should favor reaction at the C2—Cl bond. Interestingly, however, the selectivity with
SIPr is less predictable. Selective Pd/SIPr-catalyzed cross coupling at chloride only occurs with
35, the substrate that is most heavily electronically biased for reaction at C—Cl. With this
substrate, cross coupling at C2—Cl takes place preferentially over reaction at C5—OTf to give 35a
(entry 3). However, with substrates 36, 34, and 37, Pd/SIPr-catalyzed cross coupling takes place
selectively at C—OTf (entries 4-6). The results with substrate 36 are particularly intriguing:
reaction at chloride should be expected based on both the electronic bias of the pyridine ring and
SIPr’s usual preference for reaction at chloride. However, coupling takes place selectively at C4—
OTf. Further study is needed to understand these incongruous results and their possible
relationship to differences in the mechanism of oxidative addition of chloroarenes compared to
chloropyridines.26
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Table 3. Scope and limitations of the NHC ligand-controlled chemodivergent SM coupling of
chloropyridyl triflates.a
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aGeneral procedure: chloropyridyl triflate (1 equiv), p-methoxyphenylboronic acid (1.25–1.5
equiv), 3, 5, or 7 (3 mol %), KF (3 equiv), H2O (3.5–14.0 equiv), THF (entries 1, 2, 5), toluene
(entries 3, 4), or THF/toluene (2:1, entry 6), 12 h, r.t. PMP = p-methoxyphenyl. b≤5% of the
minor monoarylated products and ≤5% of diarylated products were detected by crude GC.
cProduct not isolated; crude GC yield.
CONCLUSIONS
This work provides an improved method for chemodivergent Suzuki-Miyaura cross
coupling of chloroaryl triflates. Although phosphine ligands (PtBu3 and PCy3) have been
previously shown to control selectivity in the cross coupling of 1 with 2, the Pd/phosphine-
catalyzed method is narrow in scope.4,7 In contrast, the use of Pd/NHC catalysts enables selective
coupling with diverse chloroaryl triflates and arylboronic acids. Pd/SIPr favors cross coupling at
chloride, while Pd/SIMes favors reaction at triflate.
DFT studies suggest that, with SIPr, oxidative addition takes place preferentially at
chloride through a neutral monoligated transition state. However, monoligated [Pd(SIMes)] is
not responsible for oxidative addition of C—OTf. Instead, triflate selectivity with SIMes may be
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attributed to oxidative addition at bisligated [Pd(SIMes)2] or [Pd(SIMes)X]–. Further study is
needed to distinguish between these and other mechanistic possibilities for oxidative addition
with Pd/SIMes.
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The Pd/SIMes system remains selective for reaction of triflate even with electronically
biased chloropyridyl triflate substrates. However, the Pd/SIPr-catalyzed cross coupling of
chloropyridyl triflates does not clearly fit a pattern dictated by pyridine electronics or SIPr’s
typical preference for chloride. The incongruous results with chloropyridyl triflates and SIPr may
relate to differences in the mechanism for oxidative addition of chloropyridines versus
chloroarenes.26 This possibility is the subject of ongoing study in our laboratory.
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EXPERIMENTAL AND COMPUTATIONAL DETAILS
Computational Methods. Calculations were performed with Gaussian 09.27 An
ultrafine integration grid and the keyword 5d were used for all calculations. Unless otherwise
specified in Section II-D of the Supporting Information, geometry optimizations of stationary
points were carried out in the gas phase with the M06L28 functional with BS1 (BS1 = the SDD29
pseudopotential for Pd, the 6-31+G(d) basis set for O and Cl, and the the 6-31G(d) basis set for all
other atoms). Frequency analyses were carried out at the same level to evaluate the zero-point
vibrational energy and thermal corrections at 298 K. Gibbs free energy values are reported after
applying Cramer and Truhlar’s anharmonic correction to frequencies that are less than 100 cm-1.30
The nature of the stationary points was determined in each case according to the appropriate
number of negative eigenvalues of the Hessian matrix. Forward and reverse intrinsic reaction
coordinate (IRC) calculations were carried out on the optimized transition structures to ensure
that the TSs indeed connect the appropriate reactants and products.31 Multiple conformations
were considered for all structures, and the lowest energy conformations are reported. Unless
otherwise specified in Section 1D of the Supporting Information, single point energy calculations
were performed on the gas-phase optimized geometries using the M06 functional with BS2 (BS2
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= the SDD pseudopotential for Pd and the 6-311++G(2d,p) basis set for all other atoms). Bulk
solvent effects in tetrahydrofuran were considered implicitly in the single point energy
calculations through the CPCM continuum solvation model.32 Images of optimized structures
were generated with CYLview.33
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General Materials and Methods. PEPPSITM-SIPr (7) and Pd(OAc)2 were obtained
from Sigma-Aldrich and used as received. (3-1-tBu-indenyl)2(-Cl)2Pd2, (3-1-tBu-
indenyl)Pd(IMes)(Cl), and (3-1-tBu-indenyl)Pd(IPr)(Cl) were synthesized from a literature
procedure.10 NMR spectra were recorded at 298 K on a Bruker DRX 500 MHz (500.233 MHz for
1H, 125.795 MHz for 13C, 470.639 MHz for 19F) or a Bruker DPX 300 MHz (300.172 MHz for 1H)
spectrometer. 1H and 13C NMR chemical shifts are reported in parts per million (ppm) relative to
TMS, with the residual solvent peak used as an internal reference [1H NMR: CHCl3 (7.26 ppm) or
C6D5H (7.16 ppm); 13C NMR: CDCl3 (77.16 ppm) or C6D6 (128.06 ppm)]. 19F chemical shifts are
reported in ppm relative to hexafluorobenzene (–164.9 ppm). Multiplicities are reported as
follows: singlet (s), doublet (d), doublet of doublets (dd), doublet of doublets of doublets (ddd),
triplet (t), triplet of doublets (td), triplet of triplets (tt), quartet (q), and multiplet (m). GC data
were collected using a Shimadzu GC-2010 Plus with a flame ionization detector equipped with a
SH-Rxi-5ms capillary column (15 m x 0.25 mm ID x 0.25 m df). HRMS data were collected on
an Agilent 6538 UHD-QTOF or a Bruker MicroTOF. LRMS (GC-MS) data were collected on an
Agilent 7890A/5975C GC/MSD system equipped with an Agilent J&W VF-5ms column (30 m x
0.25 mm x 0.25 m). Melting points were measured using a Thomas-Hoover “Uni-Melt” capillary
melting point apparatus. Flash column chromatography was performed on SiliCycle silica gel 60
(40-63 μm particle size) and thin layer chromatography was performed on SiliCycle TLC plates
pre-coated with extra hard silica gel 60 F254
.
General Procedure for Synthesis of Chloroaryl Triflates. Chloroaryl triflates were
prepared according to a modified literature procedure.34 To an oven-dried 250 mL round-bottom
flask equipped with a stir bar was added the chlorophenol (1 equiv). The flask was then sealed
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with a septum and subjected to 3 evacuation-refill cycles using N2. Degassed pyridine (2 equiv)
and CH2Cl2 were added by syringe. The solution was cooled to 0 ºC and trifluoromethanesulfonate
anhydride (1.2 equiv) was added dropwise over 15 minutes. The solution was allowed to warm to
room temperature and stir for 16 hours under N2. The reaction was quenched with 5% aqueous
HCl (2/3 of the volume of CH2Cl2 used) and diluted with Et2O (2/3 of the volume of CH2Cl2 used).
The layers were separated, and the aqueous layer was extracted with Et2O (3 x 2/3 of the volume
of CH2Cl2 used). The combined organic layers were washed with 10% aqueous NaHCO3 (1 x the
volume of CH2Cl2 used) and brine (1 x 2/3 of the volume of CH2Cl2 used), dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude residue was purified by flash
column chromatography on silica gel or by taking up the residue in a nonpolar solvent and
filtering through a silica plug.
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4-Chlorophenyl trifluoromethanesulfonate (1): Chloroaryl triflate 1 was prepared
according to the general procedure using 4-chlorophenol (2.57 g, 20 mmol, 1.0 equiv), pyridine
(3.2 mL, 40 mmol, 2.0 equiv), CH2Cl2 (30 mL), and Tf2O (4 mL, 24 mmol, 1.2 equiv). The crude
residue was purified by flash column chromatography on silica gel (Rf = 0.45 in 100% hexanes) to
yield 1 as a pale yellow oil (3.40 g, 65% yield). 1H NMR (500 MHz, CDCl3, δ): 7.43 (d, J = 9.1 Hz,
2H), 7.23 (d, J = 9.1 Hz, 2H); 13C{1H} NMR (126 MHz, CDCl3, δ): 148.0, 134.5, 130.5, 122.9, 118.9
(q, 1JCF = 320.7 Hz); 19F NMR (470 MHz, CDCl3, δ): –72.7. Spectral data are consistent with those
previously reported.35
3-Chlorophenyl trifluoromethanesulfonate (23): Chloroaryl triflate 23 was prepared
according to the general procedure using 3-chlorophenol (1.93 g, 15 mmol, 1 equiv), pyridine (2.4
mL, 30 mmol, 2.0 equiv), CH2Cl2 (20 mL), and Tf2O (3 mL, 18 mmol, 1.2 equiv). The crude residue
was purified by flash column chromatography on silica gel (Rf = 0.45 in 100% hexanes) to yield
23 as a colorless oil (3.15 g, 81% yield). 1H NMR (500 MHz, CDCl3, δ): 7.38-7.42 (multiple peaks,
2H), 7.30-7.32 (m, 1H), 7.18-7.23 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3, δ): 149.7, 135.9, 131.1,
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129.0, 122.2, 119.9, 119.0 (q, 1JCF = 320.2 Hz); 19F NMR (470 MHz, CDCl3, δ): –72.7. Spectral data
are consistent with those previously reported.35
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2-Chlorophenyl trifluoromethanesulfonate (24): Chloroaryl triflate 24 was prepared
according to the general procedure using 2-chlorophenol (1.29 g, 10 mmol, 1 equiv), pyridine (1.6
mL, 20 mmol, 2.0 equiv), CH2Cl2 (15 mL), and Tf2O (2 mL, 12 mmol, 1.2 equiv). The crude residue
was purified by flash column chromatography on silica gel (Rf = 0.32 in 100% hexanes) to yield
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24 as a colorless oil (1.75 g, 67% yield). H NMR (500 MHz, CDCl3, δ): 7.56-7.51 (m, 1H), 7.38-
7.31 (multiple peaks, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 145.9, 131.5, 129.4, 128.5, 127.4,
1
123.2, 118.7 (q, JC-F = 320.7 Hz); 19F NMR (470 MHz, CDCl3, δ): –73.5. Spectral data are
consistent with those previously reported.35
4-Chloro-2-methylphenyl trifluoromethanesulfonate (25): Chloroaryl triflate 25 was
prepared according to the general procedure using 4-chloro-2-methylphenol (0.5 g, 3.5 mmol, 1
equiv), pyridine (0.56 mL, 7 mmol, 2.0 equiv), CH2Cl2 (5 mL), and Tf2O (0.71 mL, 4.2 mmol, 1.2
equiv). The crude residue was purified by flash column chromatography on silica gel (Rf = 0.43 in
1
100% hexanes) to yield 25 as a colorless oil (1.21 g, 41% yield). H NMR (300 MHz, CDCl3, δ):
7.31 (d, J = 2.1 Hz, 1H), 7.24 (m, 1H, overlaps with solvent), 7.18 (d, J = 7.2 Hz, 1H), 2.37 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3, δ): 147.0, 134.0, 133.0, 132.2, 127.9, 122.7, 118.8 (q, 1JCF = 319.8
Hz), 16.5; 19F NMR (470 MHz, CDCl3, δ): –73.7. HRMS (ESI/Q-TOF) m/z: [M - H]– Calcd for
C8H5ClF3O3S— 272.9606; Found 272.9612.
4-Chloro-3-(trifluoromethyl)phenyl trifluoromethanesulfonate (26): Chloroaryl triflate
26 was prepared according to the general procedure using 4-chloro-3-(trifluoromethyl)phenol
(487.4 mg, 2.5 mmol, 1 equiv), pyridine (0.4 mL, 5 mmol, 2 equiv), CH2Cl2 (5 mL), and Tf2O (0.5
mL, 3 mmol, 1.2 equiv). The crude residue was purified by dissolving in pentane and filtering
through a silica plug to remove solid impurities before drying in vacuo to yield 26 as a colorless
oil (676.4 mg, 83% yield). 1H NMR (500 MHz, CDCl3, δ): 7.62 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 3.1
Hz, 1H), 7.43 (dd, J = 8.8, 3.1 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3, δ): 147.5, 133.6, 132.8,
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130.7 (q, 2JCF = 32.9 Hz), 126.0, 121.6 (q, 1JCF = 274.5 Hz), 121.3 (q, 3JCF = 5.6 Hz), 118.9 (q, 1JCF
=
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322.2 Hz); 19F NMR (470 MHz, CDCl3, δ): –73.5, –63.4. Anal. Calcd for C8H3ClF6O3S: C, 29.24;
H, 0.92. Found: C, 29.21; H, 0.92.
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2-Chloro-4-formylphenyl trifluoromethanesulfonate (27): Chloroaryl triflate 27 was
prepared according to the general procedure using 3-chloro-4-hydroxybenzaldehyde (187.9 mg,
1.2 mmol, 1 equiv), pyridine (0.3 mL, 3.6 mmol, 2 equiv), CH2Cl2 (2.9 mL), and Tf2O (0.29 mL,
3.6 mmol, 1.2 equiv). The crude residue was purified by flash column chromatography on silica
gel (Rf = 0.36 in 95% hexanes, 5% acetone) to yield 27 as a colorless oil (131.6 mg, 38% yield). 1H
NMR (500 MHz, CDCl3, δ): 10.01 (s, 1H), 8.06 (d, J = 2.0 Hz, 2H), 7.88 (d, J = 8.5, 2.0 Hz, 2H),
7.56 (d, J = 8.5 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3, δ): 188.9, 149.3, 136.5, 132.1, 129.4,
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128.8, 123.9, 118.6 (q, JCF = 320 Hz); 19F NMR (470 MHz, CDCl3, δ): –73.2. Spectral data are
consistent with those previously reported.36
3-Chloro-4-methylphenyl trifluoromethanesulfonate (28): Chloroaryl triflate 28 was
prepared according to the general procedure using 3-chloro-4-methylphenol (171.1 mg, 1.2 mmol,
1 equiv), pyridine (0.29 mL, 1.8 mmol, 2 equiv), CH2Cl2 (3 mL), and Tf2O (0.3 mL, 1.8 mmol, 1.2
equiv). The crude residue was purified by dissolving in hexanes and filtering through a silica plug
to remove solid impurities before drying in vacuo to yield 28 as a colorless oil (198 mg, 60% yield).
1H NMR (500 MHz, CDCl3, δ): 7.30 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H, overlaps with solvent), 7.18
(d, J = 8.6 Hz, 1H), 2.37 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 146.9, 134.0, 133.0, 132.1,
127.8, 122.7, 118.8 (q, 1JCF = 320.2 Hz), 16.4. 19F NMR (470 MHz, CDCl3, δ): –73.7. Anal. Calcd for
C8H6ClF3O3S: C, 34.99; H, 2.20; Found: C, 35.19; H, 2.22.
2-Chloro-5-formylphenyl trifluoromethanesulfonate (29): Chloroaryl triflate 29 was
prepared according to the general procedure using 4-chloro-3-hydroxybenzaldehyde (388.3 mg,
2.5 mmol, 1 equiv), pyridine (0.4 mL, 5 mmol, 2 equiv), CH2Cl2 (5 mL), and Tf2O (0.5 mL, 3 mmol,
1.2 equiv). The crude residue was purified by dissolving in hexanes and Et2O and filtering through
a silica plug to remove solid impurities before drying in vacuo to yield 29 as a yellow oil (243.4
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mg, 34% yield). 1H NMR (500 MHz, CDCl3, δ): 10.09 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H),
7.73 (d, J = 8.4 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3, δ): 188.9, 146.5, 136.6, 134.0, 132.4, 130.1,
123.3, 118.7 (q, 1JCF = 322.7 Hz); 19F NMR (470 MHz, CDCl3, δ): –73.2. HRMS (EI/Q-TOF) m/z:
[M]+ Calcd for C8H4ClF3O4S+ 287.9471; Found 287.9475. The product gradually decomposes in
ambient conditions.
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4-(4-Chlorobenzoyl)phenyl trifluoromethanesulfonate (30): Chloroaryl triflate 30 was
prepared according to the general procedure using 4-chloro-4'-hydroxybenzophenone (500 mg,
2.15 mmol, 1 equiv), pyridine (0.34 mL, 4.3 mmol, 2 equiv), CH2Cl2 (3 mL), and Tf2O (0.43 mL,
2.58 mmol, 1.2 equiv). The crude residue was purified by flash column chromatography on silica
gel (Rf = 0.48 in 90% hexanes, 10% acetone) to yield 30 as a colorless oil (203.9 mg, 26% yield).
1H NMR (500 MHz, CDCl3, δ): 7.88 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.6
Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3, δ): 193.6, 152.2, 139.8, 137.4,
1
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135.1, 132.1, 131.5, 129.1, 121.7, 118.9 (q, JCF = 321.4 Hz); F NMR (470 MHz, CDCl3, δ): –72.7.
Spectral data are consistent with those previously reported.37 The product gradually decomposes
in ambient conditions.
4-Chloropyridin-2-yl trifluoromethanesulfonate (34): Chloropyridyl triflate 34 was
prepared according to the general procedure using 4-chloro-2-hydroxypyridine (321.3 mg,
2.5mmol, 1 equiv), pyridine (0.40 mL, 5 mmol, 2 equiv), CH2Cl2 (5 mL), and Tf2O (0.50 mL, 3
mmol, 1.2 equiv). The crude residue was purified by dissolving in hexanes and filtering through a
silica plug to remove solid impurities before drying in vacuo to yield 34 as a yellow oil (418.6 mg,
64% yield). 1H NMR (500 MHz, CDCl3, δ): 8.32 (d, J = 5.4 Hz, 1H), 7.40 (dd, J = 5.4, 1.6 Hz, 1H),
7.21 (d, J = 1.6 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3, δ): 156.3, 149.2, 148.1, 124.9, 118.7 (q, 1JCF
= 320.7 Hz), 115.9; 19F NMR (470 MHz, CDCl3, δ): –73.0. HRMS (EI/Q-TOF) m/z: [M]+ Calcd for
C6H3ClF3NO3S+ 260.9474; Found 260.9484.
6-Chloropyridin-3-yl trifluoromethanesulfonate (35): Chloroaryl triflate 35 was
prepared according to the general procedure using 2-chloro-5-hydroxypyridine (155.4 mg, 1.2
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mmol, 1 equiv), pyridine (0.29 mL, 3.6 mmol, 2 equiv), CH2Cl2 (3 mL), and Tf2O (0.3 mL, 1.8
mmol, 1.2 equiv). The crude residue was purified by dissolving in hexanes and filtering through a
silica plug to remove solid impurities before drying in vacuo to yield 35 as a white solid (235.4
mg, 75% yield). 1H NMR (500 MHz, CDCl3, δ): 8.39 (d, J = 2.9 Hz, 1H), 7.61 (d, J = 8.8, 2.9 Hz,
1H), 7.45 (d, J = 8.8 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3, δ): 151.1, 145.8, 142.8, 132.0, 125.8,
118.8 (q, 1JCF = 321.9 Hz); 19F NMR (470 MHz, CDCl3, δ): –72.3. Spectral data are consistent with
those previously reported.7
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2-Chloropyridin-4-yl trifluoromethanesulfonate (36): Chloroaryl triflate 36 was
prepared according to the general procedure using 2-chloro-4-hydroxypyridine (453.4 mg, 3.5
mmol, 1 equiv), pyridine (0.56 mL, 7 mmol, 2 equiv), CH2Cl2 (3 mL), and Tf2O (0.7 mL, 4.2 mmol,
1.2 equiv). The crude residue was purified by dissolving in hexanes and filtering through a silica
plug to remove solid impurities before drying in vacuo to yield 36 as a colorless oil (677.5 mg,
74% yield). 1H NMR (500 MHz, CDCl3, δ): 8.52 (d, J = 5.6 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.21
13
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(dd, J = 5.6, 1.9 Hz, 1H); C{1H} NMR (125 MHz, CDCl3, δ): 157.1, 153.6, 152.0, 118.6 (q, JCF
=
322.4 Hz), 117.2, 115.3. 19F NMR (470 MHz, CDCl3, δ): –72.6. Anal. Calcd for C6H3ClF3NO3S: C,
27.55; H, 1.16; N, 5.35. Found: C, 27.27; H, 1.13; N, 5.26.
5-Chloropyridin-2-yl trifluoromethanesulfonate (37): Chloroaryl triflate 37 was
prepared according to the general procedure using 5-chloro-2-hydroxypyridine (453.4 mg, 3.5
mmol, 1 equiv), pyridine (0.56 mL, 7 mmol, 2 equiv), CH2Cl2 (3 mL), and Tf2O (0.7 mL, 4.2 mmol,
1.2 equiv). The crude residue was purified by dissolving in hexanes and filtering through a silica
plug to remove solid impurities before drying in vacuo to yield 37 as a colorless oil (460.7 mg,
68% yield). 1H NMR (500 MHz, CDCl3, δ): 8.35 (d, J = 2.5 Hz, 1H), 7.86 (dd, J = 8.7, 2.5 Hz, 1H),
13
7.16 (d, J = 8.7 Hz, 1H); C{1H} NMR (125 MHz, CDCl3, δ): 154.0, 147.6, 140.7, 132.6, 118.7 (q,
19
1JCF = 320.6 Hz), 116.4. F NMR (470 MHz, CDCl3, δ): –73.0. Spectral data are consistent with
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Synthesis of (3-1-tBu-indenyl)Pd(SIPr)Cl (3): In a nitrogen-atmosphere glovebox,
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and a 1:1 mixture of THF/Et2O (5 mL) were combined in a 20 mL vial equipped with a magnetic
stir bar. The vial was sealed with a PTFE-lined cap and the reaction was allowed to stir for 2 h at
room temperature. The vial was removed from the glovebox, opened to air, and the contents
filtered through celite to afford a deep red filtrate. The filtrate was concentrated under vacuum,
triturated with hexanes, and the residue was purified by recrystallization from DCM/hexanes to
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yield 3 as orange-red needles (225 mg, 80% yield). H NMR (500 MHz, C6D6, δ): 7.23 (dd, J =
15.3, 7.6 Hz, 2H), 7.15 (d, 3H, overlaps with solvent), 7.07 (dd, J = 7.7, 1.4 Hz, 2H), 6.80 (td, J =
7.6, 1.0 Hz, 1H), 6.39 (t, J = 7.4 Hz, 1H), 6.06 (d, J = 3.0 Hz, 1H), 5.83 (d, J = 7.4 Hz, 1H), 5.20 (d,
J = 3.0 Hz, 1H), 3.72-3.38 (multiple peaks, 8H), 1.57 (d, J = 6.6 Hz, 6H), 1.42 (s, 9H), 1.18 (d, J =
6.6 Hz, 6H), 1.13 (d, J = 6.8 Hz, 6H), 1.06 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (125 MHz, C6D6, δ):
204.6, 147.8, 147.5, 139.3, 139.0, 137.2, 129.2, 124.7, 124.5, 124.2, 119.4, 117.0, 116.0, 107.4, 64.0,
53.7, 35.0, 34.9, 34.2, 32.0, 30.0, 29.4, 28.9, 28.6, 26.7, 26.5, 25.7, 24.4, 23.5, 23.1, 20.9, 18.0,
14.3, 11.7; HRMS (ESI/Q-TOF) m/z: [M – Cl]+ Calcd for [C40H53N2Pd]+ 667.3238; Found
667.3253.
Synthesis of (3-1-tBu-indenyl)Pd(SIMes)Cl (5): In a nitrogen-atmosphere
glovebox, (3-1-tBu-indenyl)2(-Cl)2Pd2 (100 mg, 0.16 mmol, 1 equiv), SIMes (98 mg, 0.32 mmol,
2 equiv), and a 1:1 mixture of THF/Et2O (5 mL) were combined in a 20 mL vial equipped with a
magnetic stir bar. The vial was sealed with a PTFE-lined cap and the reaction was allowed to stir
for 2 h at room temperature. The vial was removed from the glovebox, opened to air, and the
contents filtered through celite to afford a deep red filtrate. The filtrate was concentrated under
vacuum, triturated with hexanes, and the residue was purified by recrystallization from
DCM/hexanes to yield 5 as red crystals (198 mg, 87% yield). 1H NMR (500 MHz, C6D6, δ): 7.09
(d, J = 7.8 Hz, 1H), 6.80 (s, 2H), 6.76 (td, J = 8.0, 1.1 Hz, 1H), 6.68 (s, 2H), 6.57 (td, J = 7.8, 0.8
Hz, 1H), 6.48 (d, J = 7.4 Hz, 1H), 5.88 (d, J = 2.8 Hz, 1H), 5.05 (d, J = 2.6 Hz, 1H), 3.13 (m, 4H),
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2.39 (s, 6H), 2.27 (s, 6H), 2.15 (s, 6H), 1.42 (s, 9H); 13C{1H} NMR (125 MHz, C6D6, δ): 203.8,
139.2, 139.0, 137.8, 136.6, 129.6, 129.5, 125.2, 122.9, 119.6, 117.7, 115.5, 108.3, 64.2, 50.7, 34.2,
29.7, 21.0, 19.1, 18.7; HRMS (ESI/Q-TOF) m/z: [M – Cl]+ Calcd for [C34H41N2Pd]+ 583.2299;
Found 583.2287.
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General Procedure for Chemoselective SM Coupling. Pd catalyst 3, 5, or 7 (3 mol
%), KF (3 equiv), and boronic acid (1-1.5 equiv) were combined in a 4 mL vial. The vial was
transferred into a nitrogen-atmosphere glovebox, and solvent and chloroaryl triflate substrate (1
equiv) were added. The vial was sealed with a cap equipped with a PTFE-lined septum and
removed from the glovebox. Within 60 seconds, degassed water was added through the septum
cap, and the puncture hole in the septum was sealed with grease. The reactions were stirred at
room temperature for 12 h unless otherwise indicated. The reaction mixture was diluted with Et2O
and filtered through celite. The product was purified according to procedures A, B, or C as follows.
Purification Procedure A: The crude filtrate was concentrated onto silica under vacuum and dry-
loaded onto a silica column for purification by flash column chromatography. Purification
Procedure B: The crude filtrate was concentrated under vacuum and purified by flash column
chromatography or preparatory thin layer chromatography. Following isolation, the product was
stored under nitrogen or in a desiccator to avoid hydrolysis. Purification Procedure C: The crude
filtrate was concentrated under vacuum. The residue was dissolved in a minimal amount of
acetonitrile or DMSO/acetone and purified by reverse-phase preparatory HPLC using H2O/MeCN
(note: no acidic additives were added to the mobile phase in order to avoid hydrolysis of the
product). The aqueous fractions were extracted with pentane, dried over MgSO4, filtered,
concentrated to a small volume, and passed over a plug of silica pretreated with 1%
triethylamine/99% hexanes. The silica plug was rinsed with pentane and the collected solution
was concentrated under vacuum. Following isolation, the product was stored under nitrogen or
in a desiccator to avoid hydrolysis.
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General Procedure for Larger Scale Chemoselective SM Coupling. Pd catalyst 3
or 5 (1.5 mol %), KF (3 equiv), and boronic acid (1.1 equiv) were combined in a 20 mL vial. The
vial was transferred into a nitrogen-atmosphere glovebox, and solvent and chloroaryl triflate
substrate (1 equiv) were added. The vial was sealed with a rubber septum and removed from the
glovebox. Within 60 seconds, degassed water was added through the septum, and the puncture
hole in the septum was sealed with grease. The reactions were stirred vigorously at room
temperature for 12 h. The reaction mixture was diluted with Et2O and filtered through celite. The
crude filtrate was dissolved in MeCN, then filtered to remove solid precipitates. The crude
material was then purified by flash column chromatography.
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4'-Chloro-2-methyl-1,1'-biphenyl (8b): Product 8b was prepared according to the general
procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1 equiv), 2-
tolylboronic acid (68.0 mg, 0.5 mmol, 1.25 equiv), KF (69.7 mg, 1.2 mmol, 3 equiv), 5 (7.5 mg,
0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and THF (0.8 mL) followed
by purification procedure A. Purification by flash column chromatography (Rf = 0.62 in 100%
hexanes) provided 8b as a colorless oil (76.2 mg, 94% yield). 1H NMR (500 MHz, CDCl3, δ): 7.38
(d, J = 8.4 Hz, 2H), 7.28-7.21 (multiple peaks, 5H, overlaps with solvent), 7.19 (d, J = 6.9 Hz, 1H),
2.25 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 140.8, 140.5, 135.4, 133.0, 130.7, 130.6, 129.8,
128.4, 127.7, 126.0, 20.5. Spectral data are consistent with those previously reported.4 Larger
scale reaction: Product 8b was prepared according to the general procedure using 4-
chlorophenyl trifluoromethanesulfonate (1, 437.5 L, 2.5 mmol, 1 equiv), 2-tolylboronic acid
(373.9 mg, 2.75 mmol, 1.1 equiv) KF (435.6 mg, 7.5 mmol, 3 equiv), 5 (18.6 mg, 0.03 mmol, 1.5
mol %), degassed H2O (312.5 L, 17.25 mmol, 7 equiv), and THF (5 mL). Purification by flash
column chromatography (Rf = 0.62 in 100% hexanes) provided 8b as a colorless oil (366.9 mg,
72% yield). Spectral data are identical to those reported above.
4-Chloro-1,1'-biphenyl (10b): Product 10b was prepared according to the general
procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1 equiv),
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phenylboronic acid (61.0 mg, 0.5 mmol, 1.25 equiv), KF (69.7 mg, 1.2 mmol, 3 equiv), 5 (7.5 mg,
0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and THF (1.6 mL) followed
by purification procedure A. Purification by flash column chromatography (Rf = 0.69 in 100%
hexanes) provided 10b as a white solid (66.2 mg, 88% yield). 1H NMR (500 MHz, CDCl3, δ): 7.58-
7.51 (multiple peaks, 4H), 7.48-7.40 (multiple peaks, 4H), 7.37 (tt, J = 7.5, 1.3 Hz, 1H); 13C{1H}
NMR (125 MHz, CDCl3, δ): 140.1, 139.8, 133.5, 129.05, 129.02, 128.5, 127.7, 127.1. Spectral data
are consistent with those previously reported.4
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4'-Chloro-3-methyl-1,1'-biphenyl (11b): Product 11b was prepared according to the
general procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1 equiv),
3-tolylboronic acid (68.0 mg, 0.5 mmol, 1.25 equiv), KF (69.7 mg, 1.2 mmol, 3 equiv), 5 (7.5 mg,
0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and THF (0.8 mL) followed
by purification procedure A. Purification by flash column chromatography (Rf = 0.69 in 100%
hexanes) provided 11b as a white solid (75.7 mg, 93% yield). 1H NMR (500 MHz, CDCl3, δ): 7.52
(d, J = 8.6 Hz, 2H). 7.40 (d, J = 8.6 Hz, 2H), 7.38-7.31 (multiple peaks, 3H), 7.18 (d, J = 6.9 Hz,
1H), 2.43 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 140.1, 139.9, 138.7, 133.4, 129.0, 128.9,
128.54, 128.48, 127.9, 124.2, 21.7. Spectral data are consistent with those previously reported.39
4-Chloro-4'-methoxy-1,1'-biphenyl (12b): Product 12b was prepared according to the
general procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1 equiv),
4-methoxyphenylboronic acid (91.2 mg, 0.6 mmol, 1.5 equiv), KF (69.7 mg, 1.2 mmol, 3 equiv), 5
(7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and THF (0.8 mL)
followed by purification procedure A. Purification by flash column chromatography (Rf = 0.41 in
3% EtOAc, 97% hexanes) provided 12b as a white solid (78.7 mg, 90% yield). 1H NMR (500 MHz,
CDCl3, δ): 7.49 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.98 (d, J =
13
8.8 Hz, 2H), 3.85 (s, 3H); C{1H} NMR (125 MHz, CDCl3, δ): 159.5, 139.4, 132.8, 132.7, 129.0,
128.2, 128.1, 114.5, 55.5. Spectral data are consistent with those previously reported.22
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4'-Chloro-[1,1'-biphenyl]-4-ol (13b): Product 13b was prepared according to the general
procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1 equiv), 4-
hydroxyphenylboronic acid (82.8 mg, 0.6 mmol, 1.5 equiv), KF (69.7 mg, 1.2 mmol, 3 equiv), 5
(7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and THF (0.8 mL)
followed by purification procedure A. Purification by flash column chromatography (Rf = 0.48 in
20% EtOAc, 10% benzene, 70% hexanes) provided 13b as an off-white solid (46.4 mg, 57% yield).
1H NMR (500 MHz, CDCl3, δ): 7.46 (d, J = 9.3 Hz, 2H), 7.44 (d, J = 9.3 Hz, 2H), 7.37 (d, J = 8.6
Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 4.71 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3, δ): 155.4, 139.3,
133.0, 132.9, 129.0, 128.4, 128.1, 115.9. Spectral data are consistent with those previously
reported.40
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(4'-Chloro-[1,1'-biphenyl]-4-yl)methanol (14b): Product 14b was prepared according to
the general procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1
equiv), 4-(hydroxymethyl)phenylboronic acid (76.0 mg, 0.5 mmol, 1.25 equiv), KF (69.7 mg, 1.2
mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv),
and THF (0.8 mL) followed by purification procedure A. Purification by flash column
chromatography (Rf = 0.3 in 20% EtOAc, 10% benzene, 70% hexanes) provided 14b as a white
solid (52.9 mg, 60% yield). 1H NMR (500 MHz, CDCl3, δ): 7.56 (d, J = 8.3, 2H). 7.52 (d, J = 8.6,
2H), 7.45 (d, J = 8.3, 2H), 7.41 (d, J = 8.6, 2H), 4.75 (d, J= 4.0 Hz, 2H), 1.66 (s, 1H); 13C{1H} NMR
(125 MHz, CDCl3, δ): 140.3, 139.4, 139.3, 133.5, 129.0, 128.3, 127.5, 127.2, 65.1. Spectral data are
consistent with those previously reported.41
4-Chloro-4'-fluoro-1,1'-biphenyl (15b): Product 15b was prepared according to the
general procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1 equiv),
4-fluorophenylboronic acid (78.4 mg, 0.56 mmol, 1.4 equiv), KF (69.7 mg, 1.2 mmol, 3 equiv), 5
(7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and THF (1.6 mL)
followed by purification procedure A. Purification by flash column chromatography (Rf = 0.59 in
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100% hexanes) provided 15b as a white solid (49.6 mg, 60% yield). H NMR (500 MHz, CDCl3,
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δ): 7.51 (dd, J = 8.5, 5.8 Hz, 2H), 7.47 (d, 2H, J = 8.5 Hz), 7.40 (d, J = 8.5 Hz, 2H), 7.13 (t, J =
7
8
8.5 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3, δ): 162.8 (d, 1JCF = 247.0 Hz), 138.9, 136.3 (d, 4JCF
=
9
3.2 Hz), 133.6, 129.1, 128.7 (d, JCF = 8.2 Hz), 128.4, 115.92 (d, JCF = 21.76 Hz); 19F NMR (470
MHz, CDCl3, δ): –115.17. Spectral data are consistent with those previously reported.42
Methyl 4'-chloro-[1,1'-biphenyl]-4-carboxylate (16b): Product 16b was prepared
according to the general procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4
mmol, 1 equiv), (4-(methoxycarbonyl)phenyl)boronic acid (108.0 mg, 0.6 mmol, 1.5 equiv), KF
(69.7 mg, 1.2 mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol,
6.9 equiv), and THF (0.8 mL) followed by purification procedure A. Purification by flash column
chromatography (Rf = 0.41 in 5% EtOAc, 95% hexanes) provided 16b as a white solid (87.7 mg,
89% yield). 1H NMR (500 MHz, CDCl3, δ): 8.11 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.56
(d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 3.95 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ):
144.6, 138.6, 134.6, 130.4, 129.4, 129.3, 128.7, 127.1, 52.4. Spectral data are consistent with those
previously reported.43
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4,4'-Dichloro-1,1'-biphenyl (17b): Product 17b was prepared according to the general
procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1 equiv), 4-
chlorophenylboronic acid (68.8 mg, 0.44 mmol, 1.1 equiv), KF (69.7 mg, 1.2 mmol, 3 equiv), 5
(7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and DMF (0.8 mL),
with a reaction time of 7 h at 60 ºC, followed by purification procedure A. Purification by flash
column chromatography (Rf = 0.62 in 100% hexanes) provided 17b as a white solid (81.7 mg, 92%
yield). 1H NMR (500 MHz, CDCl3, δ): 7.48 (d, J = 8.4 Hz, 4H), 7.40 (d, J = 8.4 Hz, 4H); 13C{1H}
NMR (125 MHz, CDCl3, δ): 138.6, 133.9, 129.2, 128.4. Spectral data are consistent with those
previously reported.44
4-Chloro-4'-(trifluoromethyl)-1,1'-biphenyl (18b): Product 18b was prepared according
to the general procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1
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equiv), (4-(trifluoromethyl)phenyl)boronic acid (87.5 mg, 0.44 mmol, 1.1 equiv), KF (69.7 mg, 1.2
mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv),
and THF (0.8 mL) followed by purification procedure A. Purification by flash column
chromatography (Rf = 0.67 in 100% hexanes) provided 18b as a white solid (82.2 mg, 80% yield).
1H NMR (500 MHz, CDCl3, δ): 7.70 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.5
Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3, δ): 143.5, 138.2, 134.5, 129.7
(q, 2JCF = 32.4 Hz), 129.2, 128.5, 127.3, 125.9 (q, 3JCF = 3.7 Hz), 124.2 (q, 1JCF = 272.5 Hz); 19F NMR
(470 MHz, CDCl3, δ): –62.5. Spectral data are consistent with those previously reported.45
4'-Chloro-[1,1'-biphenyl]-4-carbonitrile (19b): Product 19b was prepared according to
the general procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1
equiv), (4-cyanophenyl)boronic acid (70.7 mg, 0.48 mmol, 1.2 equiv), KF (69.7 mg, 1.2 mmol, 3
equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and DMF
(0.8 mL), with a reaction temperature of 60 ºC, followed by purification procedure A. Purification
by flash column chromatography (Rf = 0.33 in 5% EtOAc, 95% hexanes) provided 19b as a white
solid (52.9 mg, 62% yield). 1H NMR (500 MHz, CDCl3, δ): 7.73 (d, J = 8.6 Hz, 2H), 7.65 (d, J =
8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H); 13C{1H} NMR (125 MHz CDCl3, δ):
144.6, 137.8, 135.2, 132.9, 129.5, 128.7, 127.8, 118.9, 111.5. Spectral data are consistent with those
previously reported.46
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4'-Chloro-[1,1'-biphenyl]-4-carbaldehyde (20b): Product 20b was prepared according to
the general procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 L, 0.4 mmol, 1
equiv), (4-formylphenyl)boronic acid (75.0 mg, 0.5 mmol, 1.25 equiv), KF (69.7 mg, 1.2 mmol, 3
equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and THF
(0.8 mL) followed by purification procedure A. Purification by flash column chromatography (Rf
= 0.26 in 5% EtOAc, 95% hexanes) provided 20b as a white solid (68.2 mg, 79% yield). 1H NMR
(500 MHz, CDCl3, δ): 10.06 (s, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.57 (d, J =
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8.6 Hz, 2H) 7.46 (d, J = 8.6 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3, δ): 191.9, 146.1, 138.3, 135.6,
134.9, 130.5, 129.4, 128.8, 127.7. Spectral data are consistent with those previously reported.47
3-Chloro-4'-methoxy-1,1'-biphenyl (23b): Product 23b was prepared according to the
general procedure using 3-chlorophenyl trifluoromethanesulfonate (23, 70.5 L, 0.4 mmol, 1
equiv), 4-methoxyphenylboronic acid (91.2 mg, 0.6 mmol, 1.5 equiv), KF (69.7 mg, 1.2 mmol, 3
equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and THF
(1.6 mL) followed by purification procedure A. Purification by flash column chromatography (Rf
= 0.52 in 5% EtOAc, 95% hexanes) provided 23b as a white solid (64.8 mg, 74% yield). 1H NMR
(500 MHz, CDCl3, δ): 7.53 (dd, J = 1.9, 1.9 Hz 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.42 (ddd, J = 7.9,
1.9, 1.9 Hz, 1H), 7.34 (dd, J = 7.9, 7.9 Hz, 1H), 7.27 (ddd, J = 7.9, 1.9, 1.9 Hz, 1H, overlaps with
solvent), 6.98 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 159.6, 142.7,
134.6, 132.3, 129.9, 128.2, 126.8, 126.6, 124.8, 114.3, 55.4. Spectral data are consistent with those
previously reported.48
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2-Chloro-4'-methoxy-1,1'-biphenyl (24b): Product 24b was prepared according to the
general procedure using 2-chlorophenyltrifluoromethanesulfonate (24, 69.5 L, 0.4 mmol, 1
equiv), 4-methoxyphenylboronic acid (91.2 mg, 0.6 mmol, 1.5 equiv), KF (69.7 mg, 1.2 mmol, 3
equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv), and DMF
(0.8 mL) with a reaction time of 4 h at 60 ºC followed by purification procedure A. Purification
by flash column chromatography (Rf = 0.51 in 5% EtOAc, 95% hexanes) provided 24b as a pale
1
yellow oil (67.8 mg, 77% yield). H NMR (300 MHz, CDCl3, δ): 7.48-7.18 (multiple peaks, 6H,
overlaps with solvent), 6.96 (d, J = 8.3 Hz, 2H), 3.84 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ):
159.3, 140.3, 132.8, 132.0, 131.6, 130.8, 130.1, 128.4, 127.0, 113.67, 55.5. Spectral data are
consistent with those previously reported.7
4-Chloro-4'-methoxy-2-methyl-1,1'-biphenyl (25b): Product 25b was prepared according
to the general procedure using 4-chloro-2-methylphenyl trifluoromethanesulfonate (25, 74.5 L,
0.4 mmol, 1 equiv), 4-methoxyphenylboronic acid (76.0 mg, 0.5 mmol, 1.25 equiv), KF (69.7 mg,
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1.2 mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76 mmol, 6.9 equiv),
and DMF (0.8 mL) with a reaction time of 4 h at 60 ºC followed by purification procedure A.
Purification by flash column chromatography (Rf = 0.64 in 10% CH2Cl2, 20% toluene, 70%
hexanes) provided 25b as a pale yellow oil (84.9 mg, 91% yield). 1H NMR (300 MHz, CDCl3, δ):
7.25-7.15 (multiple peaks, 4H), 7.11 (d, J = 8.1 Hz, 1H), 6.93 (dd, J = 9.0, 4.9 Hz, 2H), 3.84 (s, 3H),
2.23 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 158.9, 140.2, 137.6, 133.3, 132.7, 131.3, 130.4,
130.2, 126.0, 113.8, 55.5, 20.6. HRMS (ESI/Q-TOF) m/z: [M + H]+ Calcd for C14H14ClO 233.0728;
Found 233.0728.
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4-Chloro-4'-methoxy-3-(trifluoromethyl)-1,1'-biphenyl (26b): Product 26b was
prepared according to the general procedure using 4-chloro-3-(trifluoromethyl)phenyl
trifluoromethanesulfonate (26, 131.4 mg, 0.4 mmol, 1 equiv), 4-methoxyphenylboronic acid
(76.0 mg, 0.5 mmol, 1.25 equiv), KF (69.7 mg, 1.2 mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol
%), degassed H2O (50 L, 2.8 mmol, 6.9 equiv), and THF (0.8 mL) followed by purification
procedure A. The crude residue was purified by flash column chromatography (Rf = 0.48 in 5%
EtOAc, 95% hexanes) to yield 26b as a white solid (70.0 mg, 61% yield); m.p. 47-48 ºC
[uncorrected, measured against benzoic acid (109–112 ºC)]. 1H NMR (500 MHz, CDCl3, δ): 7.85
(d, J = 2.0 Hz, 1H), 7.63 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.7 Hz,
2H), 7.00 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 160.1, 139.9, 131.9,
131.2, 130.9, 130.5, 128.8 (q, 2JCF = 31.9 Hz), 128.3, 125.8 (q, 3JCF = 5.5 Hz), 123.1 (q, 1JCF = 272.6
Hz), 114.7, 55.6; 19F NMR (470 MHz, CDCl3, δ): –62.6. HRMS (EI/Q-TOF) m/z: [M]+ Calcd for
C14H10ClF3O 286.0372; Found 286.0373.
2-Chloro-4'-methoxy-[1,1'‐biphenyl]-4-carbaldehyde (27b): Product 27b was prepared
according to the general procedure using 2-chloro-4-formylphenyl trifluoromethanesulfonate
(27, 115.4 mg, 0.4 mmol, 1 equiv), 4-methoxyphenylboronic acid (76.0, 0.5 mmol, 1.25 equiv), KF
(69.7 mg, 1.2 mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.8 mmol,
6.9 equiv), and THF (0.8 mL) followed by purification procedure A. The crude residue was
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purified by flash column chromatography (Rf = 0.3 in 5% EtOAc, 95% hexanes) to yield 27b as a
off-white solid (68.5 mg, 69% yield). 1H NMR (500 MHz, CDCl3, δ): 10.00 (s, 1H), 7.97 (d, J = 1.6
Hz, 1H), 7.80 (dd, J = 7.9, 1.6 Hz, 1H), 7.51 (d, J =7.9 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.00 (d, J
= 8.7 Hz, 2H), 3.87 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 190.7, 160.0, 146.2, 136.3, 133.8,
132.2, 131.3, 130.7, 130.6, 128.0, 113.9, 55.5. Spectral data are consistent with those previously
reported.49
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3-Chloro-4'-methoxy-4-methyl-1,1'-biphenyl (28b): Product 28b was prepared
according to the general procedure using 3-chloro-4-methylphenyl trifluoromethanesulfonate
(28, 109.9 mg, 0.4 mmol, 1 equiv), 4-methoxyphenylboronic acid (76.0 mg, 0.5 mmol, 1.25 equiv),
KF (69.7 mg, 1.2 mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.76
mmol, 6.9 equiv), and THF (0.8 mL, 0.5 M) followed by purification procedure A. Purification by
flash column chromatography (Rf = 0.63 in 15% EtOAc, 85% hexanes) provided 28b as a white
solid (73.4 mg, 79% yield). 1H NMR (500 MHz, CDCl3), δ (ppm): 7.54 (d, J = 1.8 Hz, 1H), 7.49 (d,
J = 8.7 Hz, 2H), 7.34 (dd, J = 7.8, 1.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H, overlaps with solvent), 6.97
(d, J = 8.7 Hz, 2H), 3.85 (s, 3H), 2.40 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3), δ (ppm): 159.5,
140.2, 134.8, 134.3, 132.5, 131.3, 128.1, 127.3, 125.0, 114.4, 55.5, 19.8. Spectral data are consistent
with those previously reported.50
4-Chloro-2-(4-methoxyphenyl)pyridine (34b): With SIMes: Product 34b was prepared
according to the general procedure using 4-chloropyridin-2-yl trifluoromethanesulfonate (34,
104.6 mg, 0.4 mmol, 1 equiv), 4-methoxyphenylboronic acid (91.2 mg, 0.6 mmol, 1.5 equiv), KF
(69.7 mg, 1.2 mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (50 L, 2.8 mmol,
6.9 equiv), and THF (0.8 mL, 0.5 M) followed by purification procedure A. The crude residue was
purified by flash column chromatography (Rf = 0.32 in 8% EtOAc, 92% hexanes) to yield 34b as
a white solid (81.7 mg, 93% yield). 1H NMR (500 MHz, CDCl3, δ): 8.54 (d, J = 5.3 Hz, 1H); 7.94
(d, J = 8.8 Hz, 2H), 7.67 (d, J = 1.7 Hz, 1H), 7.18 (dd, J = 5.3, 1.7 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H),
3.87 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 161.1, 158.1, 150.5, 144.8, 130.9, 128.5, 121.7,
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120.1, 114.4, 55.5. Spectral data are consistent with those previously reported.51 With SIPr:
Product 34b was prepared according to the general procedure using using 4-chloropyridin-2-yl
trifluoromethanesulfonate (34, 20.9 mg, 0.08 mmol, 1 equiv), 4-methoxyphenylboronic acid
(15.2 mg, 0.1 mmol, 1.25 equiv), KF (13.9 mg, .24 mmol, 3 equiv), 3 (1.7 mg, 0.0024 mmol, 3 mol
%), degassed H2O (10 L, 0.56 mmol, 7 equiv), and THF (0.32 mL). Undecane was added as an
internal GC standard, and the reaction mixture was diluted with Et2O, filtered through celite, and
analyzed by GC, indicating 27% crude GC yield of 34b. The retention time of the product prepared
by this method matches that of the analogous reaction with SIMes.
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2-Chloro-5-(4-methoxyphenyl)pyridine (35b): Product 35b was prepared according to
the general procedure using 2-chloropyridin-5-yl trifluoromethanesulfonate (35, 104.6 mg, 0.4
mmol, 1 equiv), 4-methoxyphenylboronic acid (76.0 mg, 0.5 mmol, 1.25 equiv), KF (69.7 mg, 1.2
mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H2O (100 L, 5.6 mmol, 13.9 equiv),
and THF (0.8 mL) followed by purification procedure A. The crude residue was purified by flash
column chromatography (Rf = 0.35 in 10% EtOAc, 90% hexanes) to yield 35b as a white solid
(47.0 mg, 53% yield). 1H NMR (500 MHz, CDCl3, δ): 8.56 (d, J = 2.6 Hz, 1H), 7.79 (dd, J = 8.4,
2.6 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.7 Hz, 2H), 3.86 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3, δ): 160.2, 149.8, 147.7, 136.8, 135.4, 129.0, 128.3, 124.3,
114.8, 55.6. Spectral data are consistent with those previously reported.52
2-Chloro-4-(4-methoxyphenyl)pyridine (36b): Product 36b was prepared according to a
modified procedure using 2-chloropyridin-4-yl trifluoromethanesulfonate (36, 104.6 mg, 0.4
mmol, 1 equiv), 4-methoxyphenylboronic acid (76.0, 0.5 mmol, 1.25 equiv), KF (69.7 mg, 1.2
mmol, 3 equiv), 7 (8.2 mg, 0.012 mmol, 3 mol %), degassed H2O (25 L, 1.4 mmol, 3.5 equiv), and
toluene (0.8 mL). The reaction was run at 60 ºC, followed by purification procedure A. The crude
residue was purified by flash column chromatography (Rf = 0.42 in 20% EtOAc, 80% hexanes) to
yield 36b as a white solid (105.5 mg, 79% yield); 1H NMR (500 MHz, CDCl3, δ): 8.38 (d, J = 5.2
Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 1.2 Hz, 1H), 7.39 (dd, J = 5.2, 1.2 Hz, 1H), 7.01 (d, J
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