Highly chemoselective and enantiospecific Suzuki-Miyaura cross-couplings of benzylic organoboronic esters

Article abstract of DOI:10.1055/s-0033-1338875

The use of potassium carbonate in addition to silver oxide is shown to increase the enantiospecificity of the Suzuki-Miyaura cross-coupling reaction of chiral secondary benzylic boronic esters. From mechanistic studies, it is shown that the reaction is co

Full text of DOI:10.1055/s-0033-1338875

PAPER
▌1759
pHapiegr hly Chemoselective and Enantiospecific Suzuki–Miyaura Cross-Couplings
of Benzylic Organoboronic Esters
Enantiospecific Suzuki–Miyaura Cross-Couplings
Ben W. Glasspoole, Martins S. Oderinde, Brandon D. Moore, Aurora Antoft-Finch, Cathleen M. Crudden*
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario, K7L 3N6, Canada
Fax +1(613)5336669; E-mail: cruddenc@chem.queensu.ca
Received: 10.05.2013; Accepted: 11.05.2013
This paper is dedicated to Professor Scott E. Denmark, with thanks for his mentorship, his dedication to excellence and his extensive
contributions to science.
catalysts, and typically considered to be the more reactive
Abstract: The use of potassium carbonate in addition to silver
regioisomer,12 was completely unreactive under our opti-
oxide is shown to increase the enantiospecificity of the Suzuki–
mized cross-coupling conditions (Scheme 2). Also, while
studying the mechanistic details of this reaction, we dis-
Miyaura cross-coupling reaction of chiral secondary benzylic bo-
ronic esters. From mechanistic studies, it is shown that the reaction
is compatible with Mizoroki–Heck coupling partners, even when covered that in the presence of internal or large amounts
they are present in considerable excess. This unique chemoselectiv-
ity provides the opportunity to carry out sequential reactions.
of external Heck acceptors, complete selectivity was ob-
served for the Suzuki–Miyaura product 3aa (Scheme
2).13,14 The exploration of this unique chemoselectivity
Key words: Suzuki, cross-coupling, palladium, chiral, enantiospe-
cific
and the rationale behind it is the subject of this paper.
I
PinB
Pd(PPh3)4, Ph3P
Since its discovery by Sneddon and Wilczynski1 over 30
years ago, the metal-catalyzed hydroboration of unsatu-
no reaction
+
DME, 85 °C, 24 h
R
R
Ag2O
rated carbon–carbon bonds continues to be a reaction of
considerable interest.2 The ability to transform the boronic
ester product into useful substrates is critical for the wide-
spread use of this reaction in synthesis.3 In 2009, our
group reported an important advance in this area, namely
the enantiospecific Suzuki–Miyaura cross-coupling of
aryl iodides 1 and chiral, enantiopure organoboronic es-
ters 2 (Scheme 1).4 With the exception of the very specific
class of cyclopropyl boronic esters,5 this constituted the
first example of a Suzuki–Miyaura cross-coupling reac-
tion of a secondary chiral organoboronic ester, which oc-
curred without loss of stereochemistry and with complete
regiochemical fidelity.6 Since our report,4 other examples
have appeared from the groups of Molander,7 Suginome8
and Hall,9 whilst secondary allylic boronic ester coupling
has been reported by our group,10 and propargylic cou-
plings by Aggarwal.11
1
4
I
Me
Me
Pd(PPh3)4
Ph3P
PinB
+
DME, 85 °C
24 h
Ag2O, K2CO3
Ac
Ac
1a
2a
3aa
47% yield
no Mizoroki–Heck
coupling observed
Scheme 2 Chemoselective cross-coupling of secondary boronic es-
ter in the presence of primary boronic ester or Heck acceptor
In our initial 2009 report, the Suzuki–Miyaura coupling
was shown to proceed with high levels of retention of ste-
reochemistry, although some erosion was observed.4 In-
deed, enantiospecificities in the order of 92% were
obtained, leaving room for improvement. During a subse-
quent screen of conditions, we found that the enantiospec-
ificity was improved markedly when potassium carbonate
was used in conjunction with silver oxide as the base (Ta-
ble 1).15 Interestingly, these gains in enantiospecificity
were undone when the phosphine loading was increased
above the previously optimized triphenylphosphine–
palladium ratio of 8:1 with regard to the isolated yield.
This prompted us to further examine the effect of triphe-
nylphosphine on both the yield and stereofidelity of the
coupling.
Me
Me
I
Pd(PPh3)4, Ph3P
PinB
+
DME, 85 °C, 24 h
R
Ag2O
R
R
R
1
2
3
Scheme 1 Enantiospecific Suzuki–Miyaura cross-coupling
In addition to the high enantiospecificity observed in this
important reaction, we also found the reaction to be sur-
prisingly chemoselective.4 Notably, the linear hydrobora-
tion isomer 4, obtained by hydroboration with iridium
The results of this study showed that the stereofidelity of
the reaction decreased as the amount of triphenylphos-
phine was increased. This was juxtaposed with an in-
crease in product yield as the phosphine loading was
increased from more frugal loadings to the optimized tri-
phenylphosphine–palladium (Ph3P–Pd) ratio of 8:1.16
SYNTHESIS 2013, 45, 1759–1763
Advanced online publication: 14.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338875; Art ID: SS-2013-C0347-OP
© Georg Thieme Verlag Stuttgart · New York

1760
B. W. Glasspoole et al.
PAPER
Thus, at high loadings of triphenylphosphine, a higher In order to probe the reason for the loss in stereoretention
yield was obtained at the expense of the enantiomeric pu- with added triphenylphosphine, we first explored poten-
rity of the product.13 Although the exact values of yield tial racemization events. Thus exposure of cross-coupled
and enantioretention were found to vary slightly with the product 3ab (er = 97.5:2.5) to very harsh reaction condi-
exclusion of potassium carbonate or the inclusion of trace tions [Ph3P (12 equiv with respect to Pd), DME, H2O,
amounts of water,17 the trend was consistent over all the 85 °C, 24 h, Pd(PPh3)4, Ag2O, ArI, K2CO3] resulted in no
examined conditions.
loss of stereochemistry. The same experiment was per-
formed with enantioenriched boronic ester 2b, which,
when added to the reaction mixture (without aryl iodide)
under the same conditions, underwent less than 2% race-
mization. Therefore, scrambling of the stereochemistry of
the product or starting material through the action of phos-
phine, base or palladium can be ruled out.
Table 1 Effect of Potassium Carbonate on the Enantiospecificity of
the Suzuki–Miyaura Cross-Coupling Reactiona
Me
Me
I
Pd(PPh3)4, Ph3P
PinB
+
DME, 85 °C, 24 h
Ag2O
R
We thus turned to the events of the catalytic cycle. As
shown in Scheme 3, after oxidative addition (OA) and
transmetallation (TM), a β-hydride elimination event
would generate intermediate III. This would result in loss
of stereochemistry only if the resulting vinyl arene de-
complexes and recomplexes. Although the β-hydride
elimination should be inhibited by added ligand, once
formed, decomplexation of vinyl arene the from III is pre-
sumably a process that could be promoted by excess phos-
phine.18 This would lead to rac-III, and eventually to
racemic coupling product 3 after reductive elimination
(RE).
R
1
2b
3ab–fb
Ar–I (R)
Product
Yield (%)b
esc
esc,d
1a (4-Ac)
1b (4-Cl)
3ab
3bb
3cb
3db
3eb
3fb
65 (63)e
81 (75)
86 (60)
(71)e
92
91
92
93
93
93
98
99
99
99
96
97
1c (4-Me)
1d (4-MeO)
1e (2-Me)
1f (3,5-Me2)
(56)
86 (64)
In order to test this hypothesis, we attempted the Suzuki–
Miyaura cross-coupling under our standard conditions,
with the addition of exogenous 4-methylstyrene (5a). The
formation of cross-over product 3ac would be indicative
that an alkene decomplexation–recomplexation pathway
was operative. In the event, crossover product 3ac was not
observed, even in the presence of 15 equivalents of 4-
methylstyrene (5a). This indicated that although trace lev-
els of β-hydride elimination may have taken place,18 al-
kene decomplexation was not occurring to an appreciable
extent, even with 12 equivalents of triphenylphosphine
(Scheme 4). An added factor, however, is the ability of
potassium carbonate to deprotonate any small amounts of
palladium hydride III, which would also prevent forma-
tion of a racemic product since it would prevent rac-III
from equilibrating with II, and being converted into prod-
uct. Consistent with this, Hünig’s base, reported by Fu to
be highly effective at deprotonating palladium hydrides,19
was also effective at increasing the enantiospecificity.
a Reaction conditions: Pd(PPh3)4 (8 mol%), Ph3P (32 mol%), Ag2O
(1.5 equiv), K2CO3 (1.5 equiv, when added), DME (0.05 M), 85 °C,
24 h, N2 atm.
b NMR yield determined vs the internal standard; yield of isolated
product in parentheses.
c Enantiospecificity (es).4
d Enantiospecificity (es) in the presence of K2CO3 (1.5 equiv).
e Pd2(dba)3 was employed in place of Pd(PPh3)4.
Ar2
Me
PdLn
Ar1
Ar1–I
1
3
RE
OA
Ar1
Pd
Ar1
Pd
Ar2
Me
TM
L
L
I
L
L
I
Ar2
2
II
"PinB–I"
PinB
+ L – L
Me
Ar1
Ar1
Ar2
Ar2
decomplex–
Remarkably, less than 0.5% of the corresponding Mizoroki–
Heck product 6ac was observed, even when a tenfold ex-
cess of the styrene derivative was added to the reaction.
Thus this mechanistic probe illustrated another significant
aspect of the chemoselectivity of the conditions devel-
L
Pd
H
L
Pd
H
rac-3
recomplexation
III
rac-III
Scheme 3 Potential mechanism for the coupling of 1 and 2 with con-
sideration of β-hydride elimination pathways
Me
Me
Tol
Pd(PPh3)4 (8 mol%)
1a
(1 equiv)
2b
+
+
Ph
Tol
Tol
(1.5 equiv)
Ph3P (64 mol%)
Ag2O (1.5 equiv)
K2CO3 (1.5 equiv)
5a
(15 equiv)
Ac
Ac
Ac
3ab
47% yield
3ac
6ac
not observed
not observed
Scheme 4 Crossover experiment with vinyl arene demonstrating selectivity for Suzuki–Miyaura coupling rather than Mizoroki–Heck coupling
Synthesis 2013, 45, 1759–1763 © Georg Thieme Verlag Stuttgart · New York

PAPER
Enantiospecific Suzuki–Miyaura Cross-Couplings
1761
oped to cross-couple secondary benzylic boronic esters, boronic esters 2 simultaneously disfavor the Mizoroki–
namely the lack of reaction via competitive Mizoroki– Heck reaction, which provides the opportunity for consid-
Heck pathways, even in the presence of large excesses of erable cross reactivity in coupling reactions of benzylic
styrenes. To explore this further, we examined the boronic esters. This is currently being explored in our
Suzuki–Miyaura cross-coupling in the presence of a vari- group for the synthesis of π-extended aromatic systems
ety of Heck acceptors and aryl iodides (Table 2).
using sequential hydroboration–coupling–hydroboration/
diboration–coupling strategies. These results will be re-
ported in due course.
As shown in Table 2, neither styrene derivatives nor meth-
yl acrylate were competent Heck acceptors under the con-
ditions where the Suzuki–Miyaura coupling of 2b took
place. This provides the interesting possibility that vinyl-
ated aromatic boronic esters such as 3aa will be able to
undergo sequential Suzuki–Miyaura coupling and then re-
action at the styrene unit.
Unless otherwise noted, all reactions were performed under an inert
atmosphere using dried glassware. Solvents were dried by standard
methods before being degassed by a minimum of three freeze-
pump–thaw cycles and were stored over 4 Å molecular sieves. Aryl
halides were purified before use following accepted protocols.20
Ag2O was purified by continuous hot water extraction in a Soxhlet
condenser over three days, and dried under vacuum in the presence
of P2O5. Pd(PPh3)4 was used as purchased from Strem. Ph3P was pu-
rified by recrystallization from absolute ethanol. Cross-coupling re-
actions were assembled in a glovebox in 4 dram vials, sealed with
air-tight Teflon caps and placed in an 85 °C oil bath for 24 h.4 Once
cooled, the reactions were filtered through Celite, washed with co-
pious amounts of Et2O and hexanes and concentrated in vacuo.
Crude yields were determined by gas chromatography (GC) em-
ploying an internal standard (octadecane) with calibration curve, or
by NMR with hexamethylbenzene (HMB) or dimethoxybenzene
(DMB) serving as internal standards. Thin-layer chromatography
was performed on EMD Chemicals Inc. TLC silica gel 60 alumi-
num-backed plates with F254 indicator. Visualization was accom-
plished with a UV source (254, 365 nm) and by treatment with
phosphomolybdic acid. Column chromatography was performed
with flash grade silica (Silicycle, 50 μm particle size, 60 Å porosity)
and reagent grade solvents. NMR spectra were recorded at 400
MHz (1H), and 100 MHz (13C) in CDCl3 using a Bruker Avance-400
spectrometer. High-resolution mass spectrometry (HRMS) was per-
formed using a Micromass GCT (GC-Time of Flight Mass Spec-
trometer). GC analyses were performed on an HP 6850 network
FID-GC fitted with an automatic injector. The column used was an
HP-5 of 30 m in length with an internal diameter of 0.32 mm. The
inlet conditions were 250 °C, 25 psi and a flow rate of 28.9 mL/min
using a splitless injector with helium as the carrier gas. The method
used had an initial temperature of 70 °C with an immediate increase
to 240 °C using a 6°/min ramp. Determination of stereochemistry
was performed by analysis on a Supercritical Fluid Chromatograph
(SFC). Analytical SFC was performed on a Berger SFC HPLC us-
ing the specified chiracel Berger Silica column and appropriate co-
eluent, flow rate and pressure conditions.
Table 2 Chemoselectivity in the Suzuki–Miyaura Cross-Coupling
of Boronic Ester 2b in the Presence of Mizoroki–Heck Acceptors 5a
I
Me
Me
Y
+
Ph
Ph
PinB
Y
R
1
2b
R
R
3
6
5
Entry Ar–I (R)
Styrene 5 (Y)
Product
Yield (%)b
1
2
3
4
5
6
7
1a (4-Ac)
1g (H)
4-C6H4Mec
Phd
3ab
3gb
3hb
3cb
3db
3ab
3ab
47
(66)
(70)
(40)
(56)
60 (52)
60
1h (Naphth)e
1c (4-Me)
1d (4-MeO)
1a (4-Ac)
Phd
Phd
Phd
CO2Med
CO2Mef
1a (4-Ac)
a Reaction conditions: Pd(PPh3)4 (8%), Ph3P (32%), Ag2O (1.5 equiv),
K2CO3 (1.5 equiv, when added), DME (0.05 M), H2O (350 ppm) add-
ed to entries 2–5, 85 °C, 24 h, N2 atm.
b Isolated yields in parentheses; GC yield for entry 1; NMR yields for
entries 6 and 7. No Mizoroki–Heck product 6 was observed.
c Heck acceptor (15 equiv).
d Heck acceptor (2 equiv).
e 1-Iodonaphthalene was employed.
f Heck acceptor (10 equiv).
rac-1-(Styren-4-yl)-1-(4-acetylphenyl)ethane (3aa)
In an N2-filled glovebox, 1-(4-iodophenyl)ethanone (1a) (6.91 mg,
245.9 g/mol, 0.0281 mmol), 4,4,5,5-tetramethyl-2-[1-(4-vinylphe-
nyl)ethyl]-1,3,2-dioxaborolane (2a) (11.0 mg, 0.043 mmol, 1.53
equiv), Ag2O (10.20 mg, 234 g/mol, 0.0436 mmol), Pd(PPh3)4 (2.85
mg, 1155.6 g/mol, 0.0025 mmol, 8.8 mol% Pd) and Ph3P (2.31 mg,
262 g/mol, 0.009 mmol, 7.5:1 P/Pd) were taken up in DME (0.7
mL). The reaction vessel was sealed and the contents stirred at
85 °C for 24 h. Once cooled, the mixture was filtered through Celite
and washed with copious amounts of Et2O. The solvents were evap-
orated in vacuo and an internal NMR standard was added [hexa-
methylbenzene (HMB), 7.8 mg]. Product 3aa was obtained in 54%
NMR yield. The diaryl product was purified by column chromatog-
raphy (hexanes–EtOAc, 20:1) to give 7.03 mg of a clear oil, repre-
senting a 48% isolated yield of product. The Mizoroki–Heck
stilbene product was not detected in significant amounts by GC–MS
or NMR.
In order to determine which conditions prevent the
Mizoroki–Heck reaction, we adjusted several of the reac-
tion parameters and determined that under our conditions,
the temperature and phosphine loading were responsible
for the observed chemoselectivity. Thus, by omitting ad-
ditional phosphine, above what is present with tetrakis(tri-
phenylphosphine)palladium(0) [Pd(PPh3)4], increasing
the temperature, changing the solvent to N,N-dimethyl-
formamide, and omitting silver oxide (Ag2O), we were
able to observe Mizoroki–Heck coupling of aryl iodide 1a
with methyl acrylate in 50% isolated yield; methyl cinna-
mate was also an effective partner.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.0 Hz, 2 H), 7.27 (d,
J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.4 Hz, 2 H),
6.61 (dd, J = 17.6 Hz, 10.8 Hz, 1 H), 5.63 (dd, J = 17.6 Hz, 0.8 Hz,
In conclusion, it would appear that the conditions opti-
mized to favor the Suzuki–Miyaura coupling of benzylic
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1759–1763

1762
B. W. Glasspoole et al.
PAPER
1 H), 5.13 (dd, J = 10.8 Hz, 0.8 Hz, 1 H), 4.12 (q, J = 7.2 Hz, 1 H),
2.50 (s, 3 H), 1.58 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.8, 145.0, 136.4, 135.8, 135.3,
128.6, 127.79, 127.73, 126.4, 113.5, 44.6, 26.6, 21.5, 15.3 (C=O
signal not observed).
HRMS–TOF (EI): m/z [M]+ calcd for C18H18O: 250.1358; found:
250.1351.
(R)-1-Phenyl-1-(4-methoxyphenyl)ethane (3db)4
In an N2-filled glovebox, 4-iodoanisole (1d) (35.08 mg, 0.150
mmol), (R)-2b (52.67 mg, 0.227 mmol, er = 94:6), Ag2O (52.34 mg,
0.226 mmol), K2CO3 (32.12 mg, 0.232 mmol), Pd(PPh3)4 (13.55
mg, 0.0117 mmol) and Ph3P (12.33 mg, 0.0470 mmol) were
weighed into a dried vial and taken up in DME (3 mL). The reaction
vessel was sealed and the contents stirred at 85 °C for 24 h. The
mixture was cooled and filtered through Celite. The desired product
was isolated as a clear oil in 71% yield after column chromatogra-
phy (pentane–Et2O, 50:1). The enantiomeric ratio was determined
by SFC [OD, 1% MeOH (2 mL), 200 bar] to be 93.1:6.9 (99% re-
tention of er).
(R)-1-Phenyl-1-(4-acetylphenyl)ethane (3ab)4
Under an inert atm, 1-(4-iodophenyl)ethanone (1a) (12.45 mg,
0.051 mmol), (R)-4,4,5,5-tetramethyl-2-(1-phenylethyl)-1,3,2-di-
oxaborolane [(R)-2b] (17.41 mg, 0.075 mmol, er = 93.3:6.7), Ag2O
(17.68 mg, 0.076 mmol), K2CO3 (10.5 mg, 0.076 mmol), Pd2(dba)3
(1.186 mg, 0.0020 mmol, 8.1 mol% Pd) and Ph3P (8.54 mg, 0.033
mmol) were taken up in DME (1.0 mL). The reaction vessel was
sealed, and the contents stirred at 85 °C for 24 h. The desired prod-
uct was isolated as a clear oil in 63% yield after column chromatog-
raphy (hexanes–EtOAc, 20:1 to 10:1). The enantiomeric ratio was
determined by SFC analysis [AD-H column, 5% MeOH (2 mL),
200 bar] to be 91.5:8.5 (98% retention of er).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.17 (m, 7 H), 6.89–6.85 (m,
2 H), 4.15 (q, J = 7.2 Hz, 1 H), 3.82 (s, 3 H), 1.66 (d, J = 7.2 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 157.9, 146.9, 138.7, 128.6, 128.5,
127.7, 126.1, 113.8, 55.4, 44.1, 22.2.
HRMS–TOF (EI): m/z [M]+ calcd for C15H16O: 212.1201; found:
212.1211.
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 7.2 Hz, 2 H), 7.35–
7.22 (m, 7 H), 4.23 (q, J = 7.2 Hz, 1 H), 2.59 (s, 3 H), 1.68 (d,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 197.8, 152.4, 146.0, 135.7, 128.9,
128.8, 128.1, 127.9, 126.7, 45.2, 26.8, 21.6.
HRMS–TOF (EI): m/z [M]+ calcd for C16H16O: 224.1201; found:
224.1197.
(R)-1-Phenyl-1-(2-methylphenyl)ethane (3eb)4
In an N2-filled glovebox, 1-iodo-2-methylbenzene (1e) (31.20 mg,
0.143 mmol), (R)-2b (50.15 mg, 0.216 mmol, er = 94:6), Ag2O
(51.21 mg, 0.221 mmol), K2CO3 (30.40 mg, 0.220 mmol),
Pd(PPh3)4 (13.05 mg, 0.0113 mmol) and Ph3P (12.11 mg, 0.0462
mmol) were weighed into a dried vial and taken up in DME (3 mL).
The reaction vessel was sealed and the contents stirred at 85 °C for
24 h. The mixture was cooled and filtered through Celite. The de-
sired product was isolated as a clear oil in 64% yield (containing ca.
8% of the homo-coupled product) after column chromatography
(pentane–Et2O, 50:1). The enantiomeric ratio was determined by
SFC [OJ, 1.5% i-PrOH (2 mL), 200 bar] to be 89.9:10.1 (96% reten-
tion of er).
(R)-1-Phenyl-1-(4-chlorophenyl)ethane (3bb)4
In an N2-filled glovebox, 1-chloro-4-iodobenzene (1b) (35.96 mg,
0.151 mmol), (R)-2b (51.20 mg, 0.221 mmol, er = 94:6), Ag2O
(52.81 mg, 0.228 mmol), K2CO3 (32.20 mg, 0.233 mmol),
Pd(PPh3)4 (13.82 mg, 0.012 mmol) and Ph3P (12.58 mg, 0.0480
mmol) were weighed into a dried vial and taken up in DME (3 mL).
The reaction vessel was sealed and the contents stirred at 85 °C for
24 h. The mixture was cooled and filtered through Celite. The de-
sired product was isolated as a clear oil in 75% yield after column
chromatography (pentane). The enantiomeric ratio was determined
by SFC [OD, 1% MeOH (2 mL), 200 bar] to be 92.8:7.2 (a 98.7%
retention of er).
1H NMR (400 MHz, CDCl3): δ = 7.31–7.15 (m, 9 H), 4.34 (q,
J = 7.2 Hz, 1 H), 2.26 (s, 3 H), 1.63 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 146.4, 144.0, 136.2, 130.5, 128.4,
127.8, 126.8, 126.21, 126.15, 125.9, 41.1, 22.3, 19.9.
(R)-1-Phenyl-1-(3,5-dimethylphenyl)ethane (3fb)4
In an N2-filled glovebox, 1-iodo-3,5-dimethylbenzene (1f) (32.58
mg, 0.140 mmol), (R)-2b (53.47 mg, 0.230 mmol, er = 94:6), Ag2O
(52.01 mg, 0.224 mmol), K2CO3 (31.11 mg, 0.225 mmol),
Pd(PPh3)4 (13.15 mg, 0.0114 mmol) and Ph3P (12.80 mg, 0.0488
mmol) were weighed into a dried vial and taken up in DME (3 mL).
The reaction vessel was sealed and the contents stirred at 85 °C for
24 h. The mixture was cooled and filtered through Celite. The de-
sired product was isolated as a clear oil in 77% yield (containing ca.
10% of the homo-coupled product) after column chromatography
(pentane–Et2O, 50:1). The isolated yield without K2CO3 was 64%
(1H NMR yield = 86%). The enantiomeric ratio was determined by
SFC [OD, 1% i-PrOH (2 mL), 100 bar] to be 91.3:8.7 (97% reten-
tion of er).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.16 (m, 9 H), 4.15 (q,
J = 7.2 Hz, 1 H), 1.64 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.9, 145.0, 131.9, 129.1,
128.60, 128.59, 127.7, 126.4, 44.3, 21.9.
HRMS–TOF (EI): m/z [M]+ calcd for C14H13Cl: 216.0706; found:
216.0702.
(R)-1-Phenyl-1-(4-methylphenyl)ethane (3cb)4
In an N2-filled glovebox, 1-iodo-4-methylbenzene (1c) (33.09 mg,
0.152 mmol), (R)-2b (53.26 mg, 0.229 mmol, er = 94:6), Ag2O
(52.66 mg, 0.227 mmol), K2CO3 (32.68 mg, 0.237 mmol),
Pd(PPh3)4 (14.82 mg, 0.0128 mmol) and Ph3P (12.56 mg, 0.0479
mmol) were weighed into a dried vial and taken up in DME (3 mL).
The reaction vessel was sealed and the contents stirred at 85 °C for
24 h. The mixture was cooled and filtered through Celite. The de-
sired product was isolated as a clear oil in 60% yield after column
chromatography (pentane). The enantiomeric ratio was determined
by SFC [OD, 1% MeOH (2 mL), 200 bar] to be 93:7 (99% retention
of er).
1H NMR (400 MHz, CDCl3): δ = 7.32–7.15 (m, 5 H), 6.83 (m, 3 H),
4.07 (q, J = 7.2 Hz, 1 H), 2.27 (s, 6 H), 1.61 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 146.7, 146.4, 137.9, 128.5,
127.91, 127.86, 127.8, 127.7, 126.0, 125.6, 44.8, 22.1, 21.5.
HRMS–TOF (EI): m/z [M]+ calcd for C16H18: 210.1409; found:
210.1402.
(rac)-1-(1-Phenylethyl)naphthalene (3hb)4
1H NMR (400 MHz, CDCl3): δ = 7.29–7.07 (m, 9 H), 4.11 (q,
J = 7.2 Hz, 1 H), 2.30 (s, 3 H), 1.62 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.6, 143.4, 135.5, 129.0, 128.3,
127.54, 127.46, 125.9, 44.4, 21.9, 20.9.
HRMS–TOF (EI): m/z [M]+ calcd for C15H16: 196.1252; found:
In an N2-filled glovebox, 1-iodonaphthalene (1h) (12.7 mg, 0.05
mmol, 1.0 equiv), rac-2b (17.4 mg, 0.075 mmol), Pd(PPh3)4 (4.62
mg, 0.004 mmol), Ph3P (4.19 mg), Ag2O (17.4 mg, 0.075 mmol),
K2CO3 (10.4 mg, 0.075 mmol), styrene (10.4 mg, 0.1 mmol) and
DME (1 g), were weighed into a 5 mL vial containing a Teflon-coat-
ed stir bar. The reaction vessel was sealed inside the glovebox with
a Teflon cap possessing a rubber septum, and then removed. Out-
196.1256.
Synthesis 2013, 45, 1759–1763
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantiospecific Suzuki–Miyaura Cross-Couplings
1763
side the glovebox, a mixture of H2O–DME (7.40 mg, 7.33 mg of de-
ionized, degassed H2O in 145.3 mg of anhyd DME) was added via
a microsyringe through the rubber septum. The vial was placed in
an 85 °C oil bath for 24 h. After cooling to r.t., the crude mixture
was filtered through a silica plug, washed with copious amounts of
EtOAc, and then concentrated in vacuo. The crude residue was pu-
rified by column chromatography (hexanes–EtOAc, 50:1 to 20:1) to
provide the product in 70% yield (8.13 mg, 0.035 mmol) as a color-
less oil.
(3) (a) Fernandez, E.; Maeda, K.; Hooper, M. W.; Brown, J. M.
Chem. Eur. J. 2000, 6, 1840. (b) Fernandez, E.; Hooper, M.
W.; Knight, F. I.; Brown, J. M. Chem. Commun. 1997, 173.
(4) Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M.
J. Am. Chem. Soc. 2009, 131, 5024.
(5) (a) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc.
2003, 125, 7198. (b) Luithle, J. E. A.; Pietruszka, J. J. Org.
Chem. 1999, 64, 8287. (c) Wang, X.-Z.; Deng, M.-Z.
J. Chem. Soc., Perkin Trans. 1 1996, 2663.
1H NMR (400 MHz, CDCl3): δ = 7.86–7.78 (m, 1 H), 7.64–7.59 (m,
1 H), 7.54–7.50 (m, 1 H), 7.28–7.16 (m, 4 H), 7.06–6.90 (m, 4 H),
6.96–6.90 (m, 1 H), 4.70 (q, J = 7.1 Hz, 1 H), 1.54 (d, J = 7.2 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 146.8, 141.7, 134.1, 131.8, 128.9,
128.6, 127.8, 127.1, 126.1, 125.9, 125.6, 125.5, 124.5, 124.1, 40.7,
22.7.
(6) (a) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander,
G. A. J. Am. Chem. Soc. 2008, 130, 9257. (b) van den
Hoogenband, A.; Lange, J. H. M.; Terpstra, J. W.; Koch, M.;
Visser, G. M.; Visser, M.; Korstanje, T. J.; Jastrzebski, J. T.
B. H. Tetrahedron Lett. 2008, 49, 4122.
(7) Molander, G. A.; Wisniewski, S. R. J. Am. Chem. Soc. 2012,
134, 16856.
(8) (a) Awano, T.; Ohmura, T.; Suginome, M. J. Am. Chem.
Soc. 2011, 133, 20738. (b) Ohmura, T.; Awano, T.;
Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191.
(9) Lee, J. C. H.; MacDonald, R.; Hall, D. G. Nat. Chem. 2011,
3, 894.
(10) Glasspoole, B. W.; Ghozati, K.; Moir, J.; Crudden, C. M.
Chem. Commun. 2012, 48, 1230.
(11) Partridge, B. M.; Chausset-Boissarie, L.; Burns, M.; Pulis,
A. P.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2012, 51,
11795.
(12) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393.
(13) Glasspoole, B. W. PhD Dissertation; Queen’s University:
Canada, 2011.
(14) For an example of a system where a Mizoroki–Heck reaction
occurs to the exclusion of Suzuki–Miyaura coupling, see:
(a) Itami, K.; Tonogaki, K.; Ohashi, Y.; Yoshida, J.-I. Org.
Lett. 2004, 6, 4093. (b) Itami, K.; Tonogaki, K.; Nokami, T.;
Ohashi, Y.; Yoshida, J.-I. Angew. Chem. Int. Ed. 2006, 45,
2404.
(15) Note that Falck reported the use of both silver oxide and
potassium carbonate in the coupling of linear alkyl boronic
acids, see: Zou, G.; Krishna Reddy, Y.; Falck, J. R.
Tetrahedron Lett. 2001, 42, 7213.
(16) Note that this is not the case for the coupling of allylic
boronic esters where only a 2:1 phosphine/Pd ratio is
sufficient, see: Chausset-Boissarie, L.; Ghozati, K.; LaBine,
E.; Chen, J. L.-Y.; Aggarwal, V. K.; Crudden, C. M.
manuscript submitted for publication.
HRMS–TOF (EI): m/z [M]+ calcd for C18H16: 232.1252; found:
232.1258.
Acknowledgment
C.M.C. acknowledges the Natural Sciences and Engineering Re-
search Council (NSERC) for support of this work in terms of a dis-
covery grant, an accelerator grant and a research tools grant. The
Canada Foundation for Innovation (CFI) is acknowledged for infra-
structure support in terms of a Leaders Opportunity Fund (LOF) ap-
plication. B.W.G. is grateful to NSERC for support in the form of a
graduate fellowship, and B.W.G., M.S.O. and B.D.M. acknowledge
Queen’s University for graduate fellowship support. The authors
thank GNR for assistance with the preparation of this manuscript.
References
(1) Wilczynski, R.; Sneddon, L. G. J. Am. Chem. Soc. 1980,
103, 2857.
(2) (a) Crudden, C. M.; Edwards, D. Eur. J. Org. Chem. 2003,
4695. (b) Lata, C. J.; Crudden, C. M. J. Am. Chem. Soc.
2010, 132, 131. (c) Gonzalez, A. Z.; Roman, J. G.;
Gonzalez, E.; Martinez, J.; Medina, J. R.; Matos, K.;
Soderquist, J. A. J. Am. Chem. Soc. 2008, 130, 9218.
(d) Smith, S. M.; Thacker, N. C.; Takacs, J. M. J. Am. Chem.
Soc. 2008, 130, 3734. (e) Vogels, C. M.; Westcott, S. A.
Curr. Org. Chem. 2005, 9, 687. (f) Carroll, A. M.;
O’Sullivan, T. P.; Guiry, P. J. Adv. Synth. Catal. 2005, 347,
609. (g) Blume, F.; Zemolka, S.; Fey, T.; Kranich, R.;
Schmalz, H. G. Adv. Synth. Catal. 2002, 344, 868.
(h) Vogels, C. M.; Hayes, P. G.; Shaver, M. P.; Westcott, S.
A. Chem. Commun. 2000, 51. (i) Ramachandran, P. V.;
Jennings, M. P.; Brown, H. C. Org. Lett. 1999, 1, 1399.
(j) Beletskaya, I.; Pelter, A. Tetrahedron 1997, 53, 4957.
(k) Brown, J. M.; Lloyd-Jones, G. C. J. Am. Chem. Soc.
1994, 116, 866. (l) Burgess, K.; Vanderdonk, W. A.;
Westcott, S. A.; Marder, T. B.; Baker, R. T.; Calabrese, J. C.
J. Am. Chem. Soc. 1992, 114, 9350. (m) Evans, D. A.; Fu, G.
C.; Anderson, B. A. J. Am. Chem. Soc. 1992, 114, 6679.
(n) Burgess, K.; Ohlmeyer, M. J. Chem. Rev. 1991, 91, 1179.
(o) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc.
1989, 111, 3426. (p) Mannig, D.; Noth, H. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 878.
(17) The addition of trace amounts of water has been found to
increase the yield at the expense of enantiospecificity, even
in the presence of potassium carbonate. The use of
approximately 300 ppm of degassed water is typically
employed in cases where yield is an issue.13 If the yield of
the reaction is good, water can be omitted.16 These results
will be described in more detail in a future publication.
(18) Note that in couplings of 1-iodonaphthalene (1h), the
presence of trace amounts of naphthalene were observed,
consistent with the possible intermediacy of III, from which
reductive elimination produces naphthalene.
(19) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem. Int.
Ed. 2003, 42, 5749.
(20) Armarego, W. L. F.; Perrin, D. D. Purification of
Laboratory Chemicals, 4th ed.; Pergamon: New York, 1997.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1759–1763