Allylic Ethers as educts for Suzuki-Miyaura couplings in water at room temperature

Article abstract of DOI:10.1021/ja905082c

(Chemical Equation Presented) The first examples of Suzuki-Miyaura couplings of allylic ethers are reported. These can be done not only under very mild room-temperature conditions but also in water as the only medium. The process is made possible by micel

Full text of DOI:10.1021/ja905082c

Published on Web 08/11/2009
Allylic Ethers as Educts for Suzuki-Miyaura Couplings in Water at Room
Temperature
Takashi Nishikata and Bruce H. Lipshutz*
Department of Chemistry & Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received June 20, 2009; E-mail: lipshutz@chem.ucsb.edu
The Pd-catalyzed Suzuki-Miyaura coupling reaction, which
employs air- and moisture-stable organoboronic acids,1 is among
the most valued of methods for C-C bond formation in organic
synthesis. A broad range of electrophiles undergo cross-couplings
with organoboronic acids, including alkyl, aryl, alkenyl, and alkynyl
groups. However, reports on allylic partners, such as acetates,
carbonates, halides and pseudohalides, are rare.2,3 Generally, a
monodentate phosphine is required to obtain a π-allylpalladium
intermediate, which subsequently undergoes smooth transmetalation
with arylboronic acids. Coordinatively saturated π-allylpalladium
intermediates having bidentate phosphine ligands tend to slow
transmetalation, since a π-allylpalladium species must rearrange
to a σ-allylpalladium complex prior to transmetalation (Scheme 1).
However, σ-allylpalladium species are stable only in the presence
of bulky ligands (e.g., pincer ligands).4 Thus, while phosphines
typically promote oxidative addition, they may inhibit transmeta-
lation.5 This subtle phenomenon is still somewhat controversial but
could be one explanation for the limited development of Suzuki-
Miyaura couplings with allylic fragments. Recent related progress
in this area includes the use of allylic trifluoroborates as nucleo-
philes; these have been applied to asymmetric cross-coupling
reactions by Yamamoto and Miyaura.6 Sawamura has described
γ-selective couplings between allylic acetates and arylboronic acids
in heated chlorinated media.7 A number of issues remain to be
addressed, including (1) development of reactions with function-
alized allylic fragments, (2) couplings that involve allylic electro-
philes other than carbonyl-containing esters and carbonates, (3)
solutions to regiochemical issues, and (4) the discovery of “greener”
processes that can be conducted under environmentally benign
conditions.
attack. Only recently have Kakiuchi and Chatani found nickel or
ruthenium to be an efficient catalyst for couplings of arylboronic
acids with aryl ethers.12 Herein we disclose the first Suzuki-Miyaura
couplings with functionalized allylic ethers at ambient temperatures.
This new methodology, which is conducted in water as the only
medium, is made possible by micellar catalysis using the nonionic
amphiphile PTS (Scheme 2).13
Scheme 2. Cross-Couplings with Allylic Ethers in Water at rt
Optimization studies employed the combination of cinnamyl
phenyl ether (1a, 0.25 mmol) and 4-methoxyphenylboronic acid
(2a, 0.38 mmol) in the presence of a Pd catalyst in 2 wt % PTS/
water at room temperature (Table 1). The effect of the base was
examined initially. Although K2CO3 is effective in many Suzuki-
Miyaura coupling protocols, only a trace amount of product 3a was
obtained (run 1). Use of a strong base, which could assist in
transmetalation, is detrimental not only to the goal of mild reaction
conditions but also to PTS diester stability. Therefore, several
amines were screened (run 2), with triethylamine emerging as the
best choice (runs 3-7). The preformed catalyst complex PdCl2(Dt-
BPF) gave good conversions; its generation in situ from Pd(OAc)2
and Dt-BPF was notably less effective (run 5). Ultimately,
preformed catalyst PdCl2(DPEphos) was identified as the most
effective at mediating the coupling in excellent yield (run 7).14
As illustrated in Table 2, several boronic acids can be coupled
with allylic ether 1a to give linearly coupled products akin to 3a.
Generally, ortho-substituted boronic acids, such as 2b, 2c, and 2d,
are more reluctant to participate in transmetalation, although on
the other hand, once the aryl residue is metal-bound, reductive
elimination is expected to occur readily. Under micellar catalysis
conditions, the overall sequence led to excellent yields at room
temperature within 5 h (runs 1-3). Although PdCl2(DPEphos) was
generally useful in this reaction, 4-chlorophenylboronic acid (2e)
and 2-thiopheneboronic acid (2f) coupled more readily with 1a in
the presence of PdCl2(Dt-BPF) (runs 4 and 5). Arylboronic acid
2g required 6 mol % catalyst to obtain a high yield of the
corresponding E-linear allylic arene, although the catalyst loading
could be reduced to only 0.5 mol % when the reaction was carried
Scheme 1. Transmetalation between π- or σ-Allylpalladium and
Arylboronic Acid
Although oxidative addition of Pd(0) to electron-deficient bonds
[e.g., C-X or C-OC(O)R] is facile, insertion into electron-rich
functionality such as C-OH (or C-OR)3,8 or into C-H bonds9 is
particularly challenging. There are no general methods that rely
on allylic ethers,2j,3b,10,11 in spite of their advantageous stability
under acidic or basic aqueous conditions and toward nucleophilic
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out at 40 °C (run 6). Nanomicelle reactor generation from surfactant
PTS is also very important. The corresponding reaction with educt
2c “on water” was very sluggish (run 2).13b,d
partners. Nonetheless, under our conditions, allylic ethers having
various functional groups can be coupled with ortho-substituted
arylboronic acids (e.g., 2b; Table 3). Cinnamic ethers bearing
electron-withdrawing or -donating groups react uneventfully to
afford the corresponding E-linear allylic arenes in excellent yields
at room temperature in water in the presence of 2 mol % catalyst
(runs 1-4). Representative examples of dibenzylamine-, amino
acid-, and malonate ester-substituted allylic ethers underwent
efficient cross-couplings to produce highly functionalized allylic
arenes in excellent yields (runs 5-8). That bulky allylic ether 1i
Table 1. Optimization of Suzuki-Miyaura Couplings with Ethersa
Table 3. Reactions of o-Tolylboronic Acid (2b) with Functionalized
Allylic Phenyl Ethersa
run
catalyst (3 mol %)
base (equiv)
% yield (lin:br)
1
2
3
4
PdCl2(Dt-BPF)
PdCl2(Dt-BPF)
PdCl2(Dt-BPF)
PdCl2(Dt-BPF)
Pd(OAc)2/Dt-BPF
PdCl2(Dt-BPF)
PdCl2(DPEphos)
K2CO3(3)
amineb (3)
Et3N (1.5)
Et3N (3)
Et3N (3)
Et3N (6)
Et3N (3)
trace
trace
20 (>25:1)
72 (88)c (>25:1)
33 (>25:1)
78 (99)c (>25:1)
99 (>25:1)
5
6
7d
a Conducted at rt for 6 h in 2% PTS/water with catalyst (3 mol %),
base (3 equiv), 2a (1.5 equiv), and 1a. b Bu3N, i-Pr2EtN, N(CH2CH2-
OCH2CH2OMe)3, (Me2NCH2)2CH2, or N,N′-dimethylpiperazine. c Run
for 18 h. d Run for 5 h using 2 mol % Pd.
Table 2. Reactions of 1a with Arylboronic Acids (2)a
a Conducted at rt for 5 h in 2% PTS/water with 2 mol % PdCl2(DPEphos),
Et3N (3 equiv), arylboronic acid (1.5 equiv), and 1a. The linear:branched
ratios of the products were >25:1. b Run for 20 h using 6 mol %
PdCl2(Dt-BPF) as the catalyst. c Run for 22 h using 0.15 mol % catalyst.
d Using 0.5 mol % catalyst. e Using 1 mol % catalyst.
a Conducted at rt for 6 h in 2% PTS/water with 6 mol % PdCl2(DPEphos),
Et3N (3 equiv), allylic ether, and 2b (1.5 equiv). b Run for 10 h using 2
mol % catalyst. c Using 8 mol % catalyst. d Using 2 equiv of 2b. e Run
at 40 °C using 1 mol % catalyst. f Using 6 mol % PdCl2(Dt-BPF); E:Z
of linear minor product was >25:1.
Functionalized allylic fragments in Suzuki-Miyaura couplings
have previously been shown to be especially challenging reaction
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C O M M U N I C A T I O N S
led to an almost quantitative yield of the desired product is
especially noteworthy (run 8). Doubly allylated ether 1j underwent
successive couplings in one pot in the presence of 2 equiv of 2b in
good overall isolated yield (run 9). While most reactions of
functionalized allylic ethers occurred at room temperature in the
presence of ∼2 mol % catalyst, catalyst loadings down to 1 mol %
were effective with gentle heating to 40 °C (run 7). Although
conjugated networks such as 1a predominantly gave the linear
coupling product, aliphatic ethers (e.g., 1k, 1l) selectively afforded
branched products, reflecting the favored rate of reductive elimina-
tion from a more hindered Pd(II) intermediate (runs 10 and 11).6
For an allylic substrate containing both acetate and ether moieties
(e.g., 4 in Scheme 3), reaction occurs first at the acetate and
subsequently at the less reactive ether residue. Xantphos15 was
found to be the preferred ligand, leading to an initial chemoselective
coupling product 1f. Second-stage allylic alkylation completes a
one-pot amination/Suzuki-Miyaura sequence to give the corre-
sponding aminated methallylbenzene derivative 3l in 76% isolated
yield (Scheme 3).
typically inert allylic ethers as reaction partners are currently under
investigation.
Acknowledgment. We thank Zymes, LLC for financial support
and Johnson Matthey for providing the catalysts PdCl2(DPEphos)
(Pd-117) and PdCl2(Dt-BPF) (Pd-118) used in this study.
Supporting Information Available: Experimental procedures and
characterization of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Although the mechanism of this reaction is still under investiga-
tion, one plausible pathway is shown in Scheme 4. The reaction
starts with oxidative addition of palladium(0) to allylic ether 1 to
produce an allylpalladium intermediate (5, 5′, or 5′′) with the
bidentate ligand. After generation of a σ-allylpalladium species (5
or 5′), transmetalation with arylboronic acid 2 takes place to give
the σ-allylarylpalladium intermediate (6 or 6′). Linear product 3
or branched product 7 is then produced by reductive elimination
from 6′ or 6, respectively.
In conclusion, the first general Suzuki-Miyaura coupling of
boronic acids with allylic ethers has been described. Conditions
have been developed that are especially mild and do not rely on an
organic solvent as the reaction medium. Further applications of
transition-metal-catalyzed cross-coupling chemistry using such
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