Ligand effects on the stereochemical outcome of suzuki-miyaura couplings

Article abstract of DOI:10.1021/jo300437t

The ligands associated with various Pd catalysts play a crucial role in determining the stereochemistry of cross-couplings between boronic acids and Z-alkenyl halides. A ligand on palladium has been found that leads to the desired products under mild conditions and in high yields that, in most cases, retain their Z-olefin geometry.

Full text of DOI:10.1021/jo300437t

Brief Communication
pubs.acs.org/joc
Ligand Effects on the Stereochemical Outcome of Suzuki−Miyaura
Couplings
Guo-Ping Lu,†,‡ Karl R. Voigtritter,† Chun Cai,‡ and Bruce H. Lipshutz*,†
†Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
‡Chemical Engineering College, Nanjing University of Science & Technology, Nanjing, Jiangsu 210094, P. R. China
S
* Supporting Information
ABSTRACT: The ligands associated with various Pd catalysts
play a crucial role in determining the stereochemistry of cross-
couplings between boronic acids and Z-alkenyl halides. A
ligand on palladium has been found that leads to the desired
products under mild conditions and in high yields that, in most
cases, retain their Z-olefin geometry.
a
Table 1. Ligand Effects on Suzuki−Miyaura Couplings
uzuki−Miyaura cross-couplings have emerged as among
the most valued methods for C−C bond constructions.1
S
Historically, such reactions focused on elaboration of sp2-based
carbon arrays, typically involving various boronic acids along
with aryl or alkenyl partners.2 Part of the textbook discussion
associated with such traditional and, now, Nobel Prize winning
chemistry, is the stereochemical outcome when olefin geometry
in the substrate is at issue.3 In general, it is accepted that the
coupling of a stereochemically defined alkenyl halide with a
boronic acid will proceed with retention, regardless of its
original E- or Z-state.4 In a recent disclosure concerning
analogous Negishi couplings, it was revealed that the nature of
the catalyst, specifically the ligand coordinating to palladium,
has a profound effect on the stereochemical outcome.5
Although there are a few scattered reports mentioning slight
erosions of stereoselectivity in the case of Pd-catalyzed, boron-
mediated couplings,6 none attempt to address this potentially
crucial observation, nor do they provide a general solution to
remedy the isomerization that may be occurring. We now
describe a study on the effect of ligands on Suzuki−Miyaura
couplings as manifested by reactions involving Z-olefinic
substrates (Scheme 1) and offer a catalyst system that appears
to minimize any Z-to-E isomerization.
a
Alkenyl halide (0.25 mmol), phenylboronic acid (0.30 mmol),
Scheme 1. Suzuki−Miyaura Couplings with Z-Alkenyl
Halides
K2CO3 (0.50 mmol), catalyst (0.005 mmol), THF (0.50 mL), H2O
b
(0.10 mL), rt, 5 h (24 h for entries 11−15). The conversion, Z/E, 1/
2 and 3/4 ratio determined by GC/MS and 1H NMR on crude
c
d
products. The reaction was performed at 40 °C for 18 h. Isolated
yield of Z-product.
reactions. However, more significant differences were found
when the identical conditions were applied to the reaction
between (Z)-1-iodooctene and phenylboronic acid, where loss
of Z-olefin geometry was significant, including those reactions
As a representative example, the cross-coupling of (Z)-β-
bromostyrene with phenylboronic acid was selected to examine
the impact of different ligands (Table 1, entries 1−10).
Although most led to retention of Z-olefin geometry, ligand-
complexed Pd2(dba)3 and PdCl2(dppf) resulted in noticeable
losses of stereochemistry (entries 4−6). Variable but modest
levels of homocoupling (to product 2) took place in these
Received: March 2, 2012
Published: April 5, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Brief Communication
a
using the same catalysts which led to maintenance of Z-
stereochemistry in the model reaction above (entries 11−13).
Although isomerization was not observed using catalysts
Pd(PPh3)2Cl2 and Pd(P(o-Tol)3)2, low conversions and
undesired homocoupling products 4 were noted (entries 14
and 15).
Table 3. Ligand Effects on Couplings of Z-Alkenyl Halides
On the basis of these results, further investigation was
needed both to improve the extent of conversion and to
minimize homocoupling. Various solvents and bases were
screened in the coupling of (Z)-1-iodooctene and phenyl-
boronic acid catalyzed by PdCl2(PPh3)2 (Table 2). The results
a
Table 2. Effects of Solvents and Bases
b
b
b
entry solvents (5/1)
base
conv (%)
Z/E
3/4
1
2
3
4
5
6
7
8
9
THF/H2O
THF/H2O
EtOH/H2O
PhMe/H2O
THF/H2O
THF/H2O
THF/H2O
EtOH/H2O
EtOH/H2O
KF
32
50
85
85
15
72
76
100
98/2
98/2
98/2
95/5
98/2
98/2
98/2
97/3
99/1
54/46
55/45
90/10
69/31
64/36
74/26
78/22
87/13
94/6
K2CO3
K2CO3
K2CO3
K3FO4
NaOH
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
c
96
a
Reaction conditions: (Z)-1-iodooctene (0.25 mmol), phenylboronic
acid (0.30 mmol), base (0.50 mmol), Pd(PPh3)2Cl2 (0.005 mmol; 2
b
mol %), solvents (0.6 mL), rt, 24 h. The conversion, Z/E, and 3/4
c
1
ratio determined by GC/MS and H NMR on crude products. The
catalyst is Pd(P(o-Tol)3)2 (2 mol %).
indicated that the combination of strong base (NaO-t-Bu) in
EtOH enhances conversion and discourages homocoupling
while maintaining high levels of stereoretention (entry 8).7
Catalyst Pd(P(o-Tol)3)2, rather than PdCl2(PPh3)2, afforded
fewer side products (entry 9).
Several Z-alkenyl halides were coupled with aryl- and β-
styrylboronic acids to assess the generality of ligand effects on
the stereochemical outcome (Table 3). Not surprisingly, based
on the variations illustrated in Tables 1 and 2 above, the
stereoselectivity varied with both the ligand on palladium as
well as the educt. Pd(P(o-Tol)3)2 (C) consistently afforded
high yields and complete retention of Z-olefin geometry. In
most cases, Pd(P(t-Bu)3)2 and PdCl2(Amphos)2 (A and B) led
to highly variable levels of isomerization and are not good
choices for these couplings under these conditions. Oddly,
Pd(P(t-Bu)3)2 (A) led to almost complete isomerization to
produce E-5 (entry 4). With (Z)-ethyl 3-iodobut-2-enoate,
isomerization was not observed with any of the three ligands
examined (entries 13−15). In changing the boronic acid
partner from phenyl to β-styryl, however, a 3−11% erosion in
Z-stereochemistry was noted (entries 19−22). In this case,
PdCl2(PPh3)2 (D) (rather than Pd(P(o-Tol)3)2) proved to be
the better choice to yield product Z-10 (entry 22).
A brief study was also made as to ligand effects with a
representative heteroaromatic boronic acid (3-thiophenebor-
onic acid) using β-bromostyrene as the reaction partner.
Although high stereoselectivity (Z/E = 96/4) could be
maintained, the extent of conversion was poor (18%) using
Pd(P(o-Tol)3)2 in EtOH/H2O, even at 50 °C for 40 h. A
solvent switch to toluene along with an increase in reaction
temperature to 80 °C were found to enhance the yield (entry
25). While both catalysts Pd(P(o-Tol)3)2 and Pd(P(t-Bu)3)2
led to retention of Z-olefin geometry, a better yield (80%) was
a
Alkenyl halide (0.25 mmol), aryl- or β-styryl-boronic acid (0.30
mmol), NaO-t-Bu (0.50 mmol), catalyst (0.005 mmol), EtOH (0.50
b
mL), H2O (0.10 mL), rt, 24 h. Key: (A) Pd(P(t-Bu)3)2, (B)
Pd(Amphos)2Cl2, (C) Pd(P(o-Tol)3)2, (D) Pd(PPh3)2Cl2. The yield
c
1
of Z-product and Z/E ratio determined by GC/MS and H NMR.
d
e
f
Isolated yield. The yield of E-product. The Z/E ratio of 1-(2-
g
iodovinyl)cyclohex-1-ene is 97/3. The Z/E ratio of ethyl 3-
h
iodoacrylate is 95/5. The solvent is toluene/H2O (v/v = 5/1).
i
The Z/E ratio of β-bromostyrene is 96/4, and the reaction is
j
k
−
performed at 80 °C. PhBF3 K+ is employed. 4 mol % of catalyst was
used.
obtained with Pd(P(t-Bu)3)2 (entry 23 vs 25). Using Molander
Ate potassium phenyltrifluoroborate8 as an alternative to
phenylboronic acid under our general conditions (2 mol %
catalyst), low conversion to Z-stilbene was seen.9 However,
increasing the catalyst loading to 4 mol % and temperature to
80 °C raised the conversion (91%) and resulting yield to 69%
(entry 28). Only Pd(P(o-Tol)3)2 as catalyst was effective at
preventing a significant loss of Z-stereochemistry.
In conclusion, contrary to the prevailing thought that Pd-
catalyzed Suzuki−Miyaura couplings involving both E- and Z-
alkenyl halides are expected to maintain their stereochemical
integrity, the results herein document that Z-disposed, 1,2-
disubstituted educts can easily undergo Z-to-E isomerization,
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The Journal of Organic Chemistry
Brief Communication
Hz, 1H), 6.31 (d, J = 12.5 Hz, 1H), 7.17−7.20 (m, 1H), 7.25−7.31
(m, 4H); 13C NMR (125 MHz, CDCl3) δ 22.1, 22.8, 25.7, 28.1, 126.4,
127.2, 127.7, 128.9, 129.1, 133.7, 135.6, 138.6; HRMS (FI) calcd for
C14H16 184.1252, found 184.1223.
the extent of which is dictated mainly by the ligand on
palladium.10 New conditions have been found that point to
Pd(P(o-Tol)3)2 as the ligand of choice. When used in couplings
of Z-alkenyl halides, along with changes in the base and solvent
system, stereoretention is observed. Moreover, high chemical
yields are to be expected, and in most cases, reactions occur at
room temperature. Given the now established sensitivity of
both Negishi and Suzuki−Miyaura couplings to the ligands on
palladium in their reactions with Z-alkenyl halides, it may well
be that other related Pd-catalyzed processes, such as Stille
couplings, follow the same trend. Results from this ongoing
study will soon be reported.
(2Z,4E)-Ethyl 5-phenylpenta-2,4-dienoate14 (Z-10): 42 mg, 84%
1
yield; H NMR (500 MHz, CDCl3) δ 1.32−1.35 (t, J = 7.3 Hz, 3H),
4.21−4.25 (q, J = 7.2 Hz, 2H), 5.73 (d, J = 11.0 Hz, 1H), 6.72−6.77
(td, J = 11.0, 0.7 Hz, 1H) 6.82 (d, J = 16.0 Hz, 1H), 7.26−7.37 (m,
3H), 7.52−7.53 (m, 2H), 8.13−8.18 (ddd, J = 16.0, 11.5, 1.0 Hz, 1H).
(Z)-3-Styrylthiophene15 (Z-11): 37 mg, 80% yield; H NMR (500
1
MHz, CDCl3) δ 6.55 (d, J = 12.0 Hz, 1H), 6.58 (d, J = 12.0 Hz, 1H),
6.86−6.87 (dd, J = 5.0, 1.0 Hz, 1H), 7.11−7.14 (m, 2H), 7.23−7.30
(m, 5H).
ASSOCIATED CONTENT
* Supporting Information
Additional experimental details and copies of NMR spectra of
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
EXPERIMENTAL SECTION
■
S
General Procedure for Suzuki−Miyaura Couplings. Catalyst
(0.005 mmol), boronic acid (0.30 mmol), and base (0.50 mmol) were
weighed into a round-bottom flask or microwave vial at room
temperature. The alkenyl halide (0.25 mmol), H2O (0.1 mL) and
distilled organic solvent (0.5 mL) were then added by syringe. The
resulting solution was allowed to stir at rt or 80 °C for 5 to 24 h. The
homogeneous reaction mixture was then diluted with EtOAc (4 mL)
and filtered through a bed of silica gel layered over Celite, and the
volatiles were removed in vacuo to afford the crude product. Analyses
AUTHOR INFORMATION
Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu.
Notes
■
1
by H NMR and GC/MS gave both the conversion and Z/E ratio.
Further column chromatography on silica gel afforded the pure desired
The authors declare no competing financial interest.
Z-product.
(Z)-1,2-Diphenylethene11 (Z-1): 40 mg, 88% yield; H NMR (500
1
REFERENCES
■
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1
(Z)-Oct-1-enylbenzene (Z-3): 38 mg, 80% yield; H NMR (500
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(m, 2H), 2.31−2.36 (m, 2H), 5.65−5.71 (m, 1H), 6.41 (d, J = 11.5
Hz, 1H), 7.21−7.36 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 14.1,
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1
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1.37−1.43 (m, 2H), 2.13−2.18 (m, 2H), 2.26 (s, 3H), 5.70−5.75 (m,
1H), 6.42−6.45 (d, J = 11.5 Hz, 1H), 7.15−7.27 (m, 4H); 13C NMR
(125 MHz, CDCl3) δ 14.1, 19.9, 22.6, 28.4, 28.9, 29.8, 31.7, 125.2,
126.7, 127.8, 129.7, 133.0, 136.2, 137.0; HRMS (EI) calcd for C15H22
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̀
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1
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1
(Z)-(6-(Benzyloxy)hex-1-enyl)benzene (Z-6): 57 mg, 86% yield; H
NMR (500 MHz, CDCl3) δ 1.54−1.60 (m, 2H), 1.65−1.71 (m, 2H),
2.35−2.40 (m, 2H), 3.47−3.50 (t, 2H), 4.51 (s, 2H), 5.65−5.71 (m,
1H), 6.44 (d, J = 11.5 Hz, 1H), 7.22−7.37 (m, 10H); 13C NMR (125
MHz, CDCl3) δ 26.6, 28.3, 29.4, 70.2, 72.9, 126.5, 127.5, 127.6, 128.1,
128.4, 128.7, 129.0, 132.8, 137.7, 138.6; HRMS (EI) calcd for
C19H22O 266.1671, found 266.1677.
((1E,3Z)-5-(Benzyloxy)penta-1,3-dienyl)benzene (Z-7): 55 mg,
1
88% yield; H NMR (500 MHz, CDCl3) δ = 4.30−4.32 (dd, J =
7.0, 1.5 Hz, 2H), 4.59 (s, 2H), 5.68−5.73 (m, 1H), 6.33−6.38 (td, J =
11.2, 0.7 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.97−7.03 (ddd, J = 15.5,
11.0, 1.0 Hz, 1H), 7.24−7.41 (m, 10H); 13C NMR (125 MHz, CDCl3)
δ 66.0, 72.3, 123.9, 126.8, 127.9, 127.9, 128.6, 128.8, 132.1, 134.4,
137.3, 138.4; HRMS (EI) calcd for C18H18O 250.1358, found
250.1338.
(Z)-Ethyl 3-phenylbut-2-enoate13 (Z-8): 45 mg, 94% yield; 1H
NMR (500 MHz, CDCl3) δ 1.08−1.11 (t, 3H), 2.19 (d, J = 1.5 Hz,
3H), 3.99−4.03 (m, 2H), 5.92 (q, J = 1.5 Hz, 1H), 7.21−7.23 (m,
2H), 7.30−7.38 (m, 3H).
(Z)-(2-Cyclohexenylvinyl)benzene (Z-9): 32 mg, 69% yield; 1H
NMR (500 MHz, CDCl3) δ 1.51−1.58 (m, 4H), 1.89−1.91 (m, 2H),
2.07−2.08 (m, 2H), 5.75−5.77 (m, 1H), 6.07−6.10 (dd, J = 12.5, 1.0
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