Palladium-catalyzed α-arylation of zinc enolates of esters: Reaction conditions and substrate scope

Article abstract of DOI:10.1021/jo401476f

The intermolecular α-arylation of esters by palladium-catalyzed coupling of aryl bromides with zinc enolates of esters is reported. Reactions of three different types of zinc enolates have been developed. α-Arylation of esters occurs in high yields with i

Full text of DOI:10.1021/jo401476f

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Featured Article
Palladium-Catalyzed alpha-Arylation of Zinc Enolates
of Esters: Reaction Conditions and Substrate Scope
Takuo Hama, Shaozhong Ge, and John F. Hartwig
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 Aug 2013
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The Journal of Organic Chemistry
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Palladium-Catalyzed α-Arylation of Zinc Enolates of
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Esters: Reaction Conditions and Substrate Scope
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Takuo Hama, Shaozhong Ge, and John F. Hartwig*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107;
Department of Chemstry, University of Illinois, Urbana, 61801; and Department of Chemistry,
University of California, Berkeley, CA, 94702, United States
Email: jhartwig@berkeley.edu
ABSTRACT: The intermolecular α-arylation of esters by palladium-catalyzed coupling of aryl
bromides with zinc enolates of esters is reported. Reactions of three different types of zinc enolates have
been developed. α-Arylation of esters occurs in high yields with isolated Reformatsky reagents, with
Reformatsky reagents generated from α-bromo esters and activated zinc, and with zinc enolates
generated by quenching lithium enolates of esters with zinc chloride. The use of zinc enolates, instead of
alkali metal enolates, greatly expands the scope of the arylation of esters. The reactions occur at room
temperature or at 70 °C with bromoarenes containing cyano, nitro, ester, keto, fluoro, enolizable
hydrogen, hydroxyl or amino functionality and with bromopyridines. The scope of esters encompasses
acyclic acetates, propionates, and isobutyrates, α-alkoxyesters, and lactones. The arylation of zinc
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enolates of esters was conducted with catalysts bearing the hindered pentaphenylferrocenyl di-tert-
butylphosphine (Q-phos) or the highly reactive dimeric Pd(I) complex {[P(t-Bu) ]PdBr} .
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INTRODUCTION
The α-aryl ester unit is present in many pharmaceuticals and biologically active compounds. Best
known are the non-steroidal anti-inflammatory agents, such as Flurbiprofen, Ibuprofen, Ketoprofen, and
Naproxen. More recently, ALLEGRA (Fexofenadine hydrochloride), which contains α-arylisobutyric
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acid moiety, has been developed as an antihistamine. Besides these molecules, α-aryl esters are
valuable building blocks because they can be precursors to aryl alcohols, amines and nitriles. The ester
functionality in α-aryl esters can be used to further build the carbon skeleton containing an aryl unit.
The uncatalyzed formation of the C-C bond between an aryl electrophile and an ester enolate is a
useful transformation to prepare α-aryl esters. However, methods for this type of C-C bond formation
are limited in scope and are often incompatible with auxiliary functionalities, or require toxic reagents.
2
3
Such C-C bonds have been formed by photochemical reactions, reactions via benzyne intermediates,
4-6
7-13
and reactions with arylbismuth or aryllead reagents. The addition of aryl Grignard reagents to the
1
4
salt of α-bromopropionic acid is conducted on industrial scale, but it would be difficult to form a
quaternary center by this reaction, and the scope of this reaction has not been expanded to encompass
substrates containing reactive functional groups.
The palladium-catalyzed α-arylation of carbonyl compounds has been introduced as a mild catalytic
15,16
method to form the C-C bond between an aryl ring and the α-position of a carbonyl compound.
A
1
7-22
23-28
ester,
29-32
33,34
variety of reactions of ketone,
amide,
and aldehyde
enolates have now been reported,
but the use of strongly basic and nucleophlic alkali metal enolates limits the scope of these reactions. In
addition, the arylated product, which is more acidic than the reactant, quenches the starting enolate, and
products from undesired diarylation have formed. Furthermore, the strongly basic conditions prevent
asymmetric α-arylations that would form tertiary stereocenters. To overcome these problems, we have
begun to develop milder conditions to use zinc enolates generated from α-halo carbonyl compounds
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The Journal of Organic Chemistry
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6,31
(Reformatsky reagents).
Because Reformatsky reagents are milder bases and nucleophiles than alkali
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metal enolates, we anticipate that the coupling of Reformatsky reagents could improve the functional
group tolerance of the arylation of esters.
The zinc enolates of esters are common reagents used for Reformatsky reactions and they can be
generated from reactions of α-halo esters with zinc metal or by quenching the alkali metal enolates of
esters with zinc halides. However, only a few examples of palladium-catalyzed α-arylation of zinc ester
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5-38
enolates have been reported.
Three decades ago, the palladium-catalyzed α-arylation of zinc ester
3
5,36
enolates was reported using the isolated Reformatsky reagents of tert-butyl acetate and propionate.
These arylation reactions, in general, occurred in low yields with high palladium loading (10 mol %), in
part because of the use of triarylphosphine ligands. In 2003, we reported, in communication form, the
effective coupling of aryl bromides with the isolated Reformatsky reagents with only 1 mol %
3
1
palladium loading. This coupling process tolerates a variety of potentially reactive electrophilic and
protic functional groups, such as cyano, nitro, ester, keto, hydroxyl, and amino groups. However, these
reactions are still limited to esters that can form stable and isolable Reformatsky reagents. In 2004,
Moloney reported microwave assisted palladium-catalyzed α-arylation of the zinc enolate of tert-butyl
39
acetate in the presence of stoichiometric amount of Pd(PPh ) . Most recently, Knochel reported three
3
4
4
0
examples of palladium-catalyzed α-arylation reactions of zinc ester enolates. These zinc enolates are
formed by reaction of ethyl butyrate or isobutyrate with (TMP)ZnCl•LiCl. Because palladium-catalyzed
α-arylation of alkali metal enolates occurred in high yields in the presence of catalyst systems bearing
2
4,26-28,31
sterically hindered, electron-rich alkylphosphines,
we sought to develop general procedures for
the palladium-catalyzed α-arylation of Reformatsky reagents.
Here, we present a full account of the scope and limitation of a mild and more general palladium-
catalyzed coupling of zinc enolates of esters that are generated in situ from α-bromoesters or by
quenching the alkali metal ester enolates. The scope of these reactions now encompasses the coupling of
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acyclic acetates, propionates, and isobutyrates, α-alkoxyesters, and lactones with electronically varied
aryl bromides that contain typically reactive protic and electrophilic functional groups.
Results and Discussion
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. α-Arylation of Isolated Reformatsky Reagents.
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Our initial studies of palladium-catalyzed α-arylation of zinc enolates of esters were conducted with
the isolated Reformatsky reagents. The Reformatsky reagents were prepared by reaction of zinc
(granular 20-mesh beads) with α-bromo tert-butyl acetate and α-bromo tert-butyl propionate in THF at
0
°C. The zinc enolates of tert-butyl acetate and tert-butyl propionate were isolated as THF adducts as
white powder in 80% and 55% yields, respectively.
.1. Conditions and the Scope of α-Arylation of the Isolated Reformatsky Reagent from tert-Butyl
1
Acetate. Arylation reactions of the isolated Reformatsky reagent of tert-butyl acetate with phenyl
bromide catalyzed by complexes generated from Pd(dba) and a series of monodentate phosphine and
2
N-heterocyclic carbene ligands are summarized in Table 1. The reactions catalyzed by the single-
4
1-43
component catalyst precursor {[P(t-Bu) ]PdBr}
or the combination of Pd(dba) and P(t-Bu) or Q-
2 3
3
2
phos formed the coupled product quantitatively (entries 1, 2, and 7). The coupled product was formed in
lower yield with less sterically demanding trialkyl phosphine ligands (entries 3–6). In sharp contrast to
the high-yielding arylation of the lithium enolate of tert-butyl acetate catalyzed by Pd(dba) and
2
2
3,25
SIPr•HBF4,
the reaction of the isolated Reformatsky reagent with PhBr catalyzed by this Pd-SIPr
system (entries 8 and 9) afforded the coupled product in very low yields.
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The Journal of Organic Chemistry
Table 1. Effect of Ligands on the Pd-Catalyzed α-Arylation of the Isolated Zinc Enolate of tert-
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a
Butyl Acetate.
1 mol% Pd(dba)2
O
1 mol % Ligand
O
Br +
t
O Bu
THF, rt
t
O Bu
.
ZnBr THF
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entry
Ligand
GC Yield
entry
Ligand
SIPr
GC Yield
1
2
3
4
5
6
7
8
{[P(t-Bu) ]PdBr}2 100%
9
21%
45%
25%
7%
3
P(t-Bu)3
100%
0%
10
PR(t-Bu) R = Ad
PCy3
11
12
Fe
Ph
Cy P(t-Bu)
6%
Mes
2
CyP(t-Bu)2
36%
68%
100%
12%
AdP(t-Bu)2
13
14
15
R' = Ad Ar = Ph
75%
51%
64%
PR'2
Q-Phos
Cy
Cy
Ph
.
Ar
SIPr HBF4
Mes
P(t-Bu)2
i-Pr
i-Pr
N
N
Ph Fe Ph
Ph
Ph
i-Pr i-Pr
Ph
(Q-Phos)
BF4
(SIPr.HBF4)
a
b
Conditions: 1.1 equiv of enolate, 1 equiv of aryl bromide in THF (2 mL), 4 h at room temperature.
Yields were determined by GC with dodecane as an internal standard.
The combination of Pd(dba) and unsubstituted ferrocenyl dialkyl or monoalkyl phosphine ligands
2
formed less active catalysts (entries 10–12) than Pd(dba) /Q-phos (entry 7). Samples of
2
4
4,45
biphenyldialkylphosphine ligands developed by Buchwald
were also tested for this arylation
reaction, and only modest yields were obtained (entry 13–15). Thus, catalysts generated from Pd(dba)2
and either P(t-Bu) or Q-phos were chosen to study the scope of the palladium-catalyzed α-arylation of
3
zinc enolates of esters.
With an active catalyst in hand and reliable conditions for this coupling process, we investigated the
scope of the α-arylation of the isolated Reformatsky reagent of tert-butyl acetate. Our results are
summarized in Table 2. These reactions were catalyzed by the combination of Pd(dba) and Q-phos or
2
4
1-43
the single-component catalyst precursor {[P(t-Bu) ]PdBr} .
The α-arylation of this isolated zinc
3
2
enolate occurred in high isolated yields with a wide range of electronically varied bromoarenes at room
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temperature and a few cases at elevated temperature (70 ºC). In all cases, products from the diarylation
process of the enolate were not observed.
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a
Table 2. Pd-Catalyzed α-Arylation of the Isolated Zinc Enolate of tert-Butyl Acetate.
1
0
mol% Pd(dba) /Q-Phos, or
P(t-Bu)2
2
O
O
3
.5 mol% {[P(t-Bu) ]PdBr}2
Ph Fe Ph
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ArBr +
Entry
t
O Bu
.
Ar
t
THF, rt
O Bu Ph
Ph
ZnBr THF
Ph (Q-Phos)
Conda Yieldh Entry
Conda Yieldh
ArBr
ArBr
Br
Br
1
1
1
1
1
6
7
8
9
4-CO Me
A
B
A
B
A
90%
90%
86%
84%
76%
2
A
A
94%
71%
Br
2
4-CO Et
2
CO R
2
t-Bu
Cl
Br
3
20
3-CO t-Bu
Af
Bf
86%
88%
2
21
22
Br 4-CN
A
90%
90%
86%
84%
4
Br
5
3-CN
2-CN
A
Af
Bf
77%
56%
CN
Br
Ac
B
2
2
3
4
6
CF3
Br
7
Bb
Bc
67%
95%
2
2
5
6
4-NO2
A
A
96%
87%
8
NMe2
2-NO2
Br
9
NO2
Br
A
A
A
86%
84%
83%
Bd
2
7
4-OH
88%
91%
82%
83%
OMe
28
29
Be
Br
Br
Be
1
0
3-OH
2-OH
OH
3
0
Be
Bd,f
Be,g
Br 4-NH2
92%
85%
83%
11
3
3
1
2
F
Br
NH2
Be,f
33
3-NH2
3-Br
1
2
A
91%
Ab
90%
80%
79%
66%
OMe
34
35
36
37
N
Br
R = Ph Ac
Ph Bc
Bb
13
72%
67%
94%
Ab
1
1
4
5
R
O
Br
4-Br
Et
A
Bb
a
Conditions: Zinc enolate of tert-Butyl acetate (0.550 mmol), aryl bromide (0.500 mmol) in THF at
room temperature, reaction time: 4 h; (A) 1 mol % Pd(dba) , 1 mol % Q-phos; (B) 0.5 mol %
2
b
c
d
e
{[P(tBu) ]PdBr} . 70 °C. Twice catalyst loadings. 2 equiv of enolate. 1.05 equiv of KH, 1.1 equiv
3
2
f
g
h
of enolate. Reaction time: 12 h. Reaction time: 24 h. Average yield for two runs.
The scope of bromoarenes for this arylation process encompassed electron-neutral, electron-rich, and
electron-poor bromoarenes bearing relatively reactive substituents. The coupling was selective for
reaction with bromide over chloride and fluoride, and reactions of 1-bromo-4-chlorobenzene (entries 3
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The Journal of Organic Chemistry
and 4) and 1-bromo-2-fluorobenzene (entry 11) formed products resulted from replacement of bromide.
Moreover, the arylation reactions occurred smoothly with bromoarenes containing functional groups
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3
4
5
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7
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9
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2
4,25,27,28
that are incompatible with strongly basic and nucleophilic alkaline enolates of esters.
For
example, 4-bromoacetophenones (entries 13–15), methyl or ethyl 4-bromobenzoate and tert-butyl 3-
bromobenzoate (entries 16–20), 2-, 3-, and 4-bromobenzonitrile (entries 21–24), and 2- and 4-
bromonitrobenzene (entries 25–27) reacted in high isolated yields. The coupling also occurred with
ortho-substituted bromoarenes (entries 10–12, 23–24, 26, and 30). Moreover, the coupling of 3- or 4-
bromopyridine (entries 34–37) occurred in modest to good yields (66–90%) at 70 ºC.
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Bromoarenes containing protic functionality also reacted to form α-aryl esters. In addition to reaction
with enolizable 4-bromoacetophenone (entry 15), the coupling of the zinc enolate with 2-, 3- and 4-
bromophenol and 3- and 4-bromoaniline occurred and afforded the corresponding α-aryl ester (entries
2
7–33). Use of 2 equiv of zinc enolate (entries 27 and 31) or use of 1.05 equiv of KH to deprotonate the
hydroxyl or amino group prior to addition of the zinc enolate (entries 28–30 and 32–33) allowed these
coupling reactions to occur. High yields were achieved when single-component catalyst precursor {[P(t-
Bu) ]PdBr} was used.
3
2
Although the scope of these coupling was broad, the coupling of the isolated Reformatsky reagent of
tert-butyl acetate does have some limitations. For example, reactions of this isolated Reformastky
reagent with 2-bromopyridine did not occur either at room temperature or at 70 ºC with both catalysts,
even though the coupling reactions with 3- or 4-bromopyridine occurred in high yields. Although the
coupling of this Reformatsky reagent showed high tolerance towards cyano, nitro, ester, ketone,
hydroxyl, and amino functionalities, bromoarenes containing strong electrophiles, e.g. 4-
bromobenzaldehyde and 4-bromobenzyl bromide, did not react to give the coupling products.
1.2. Conditions and the Scope of α-Arylation of the Isolated Reformatsky Reagent of tert-Butyl
Propionate. Table 3 summarizes selected experiments to identify conditions for the coupling of the
isolated Reformatsky reagent of tert-butyl propionate with bromobenzene. The combination of Pd(dba)2
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and P(t-Bu) was a highly active catalyst for coupling of the isolated Reformatsky reagent of tert-butyl
3
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acetate, and was also employed for the arylation of the isolated Reformatsky reagent of tert-butyl
propionate (entries 1–3). When 1.1 equiv of the zinc enolate was used, only modest GC yields were
obtained either at room temperature or at 70 ºC; however, quantitative yield was achieved at 70 ºC when
a large excess (e.g. 5 equiv) of the zinc enolate was used (entry 3). When the combination of Pd(dba)2
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and Q-phos or the single-component catalyst precursor {[P(t-Bu) ]PdBr} was used, this coupling
3
2
occurred in quantitative yield at room temperature with only 1.1 equiv of the enolate (entries 4–5).
Table 3. Identification of Conditions for Pd-catalyzed α-Arylation of the Isolated Zinc Enolate of
a
tert-Butyl Propionate.
P(t-Bu)2
O
O
Catalyst
THF, 4 h
Ph Fe Ph
PhBr +
t
Ph
O Bu
t
O Bu Ph
Ph
(Q-Phos)
ZnBr.THF
Ph
Entry
Catalyst
Enolate
Temperature
rt
Yiledb
1
2
3
4
5
1 mol% Pd(dba) /P(t-Bu)3
1.1 euqiv
1.1 equiv
5 equiv
60%
45%
2
o
1 mol% Pd(dba) /P(t-Bu)3
70 C
2
o
1 mol% Pd(dba) /P(t-Bu)3
70 C
100%
100%
100%
2
1 mol% Pd(dba) /Q-phos
1.1 equiv
1.1 equiv
rt
rt
2
0.5 mol% {[P(t-Bu) ]PdBr}2
3
a
Conditions: Aryl bromide (0.500 mmol), Pd(dba) (5.00 μmol) and P(t-Bu) or Q-Phos (5.00 μmol),
2
b
3
{
[P(t-Bu) ]PdBr} (0.250 µmol), THF (2 mL), 4 h. Yields were determined by GC with dodecane as
3 2
internal standard.
The coupling of the isolated Reformatsky reagent of tert-butyl propionate with aryl bromides is
summarized in Table 4. These reactions were catalyzed by the combination of Pd(dba) and Q-phos or
2
{
[P(t-Bu) ]PdBr} . This arylation occurred with a scope that was similar to that of the isolated
3 2
Reformatsky reagent of tert-butyl acetate. Most of these couplings with aryl bromides occurred at room
temperature; only a few cases required heating at 70 ºC to assure full conversion of aryl bromides.
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a
Table 4. Pd-Catalyzed α-Arylation of the Isolated Reformatsky Reagent of tert-Butyl Acetate.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
0
mol% Pd(dba) /Q-Phos, or
P(t-Bu)2
2
O
O
3
.5 mol% {[P(t-Bu) ]PdBr}2
Ph Fe Ph
Ar
ArBr +
Entry
t
t
O Bu
.
O Bu
THF, rt
Ph
Ph
ZnBr THF
Ph (Q-Phos)
Conda Yieldh
ArBr
Conda Yieldh Entry
ArBr
Br
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
A
B
88%
83%
Br
1
1
2
3
R' = Me
R' = Et
A
B
A
B
87%
81%
88%
84%
t-Bu
Cl
Br
Br
Af
Bf
14
15
3
4
86%
79%
CO R'
2
5
6
Af
Bf
69%
61%
1
6
Br 4-CN
A
83%
80%
85%
CF3
17
3-CN
2-CN
A
Br
CN
Ac
1
8
7
8
9
Bb
A
91%
91%
81%
Br
NMe2
19
4-NO2
A
A
88%
81%
Br
2
0
2-NO2
NO2
Bd
2
2
1
2
Br 4-OH
92%
95%
87%
70%
Br
Be
A
F
23
OH
3-OH
Be
Br
Bd,f
2
2
2
4
5
6
Br 4-NH2
10
11
A
90%
67%
Be,g 66%
OMe
NH2
Br
Be,f
Br
3-NH2
74%
27
28
Ab
Bb
90%
80%
Ph Bc
Ph
O
N
a
Conditions: Zinc enolate of tert-butyl acetate (0.550 mmol), aryl bromide (0.500 mmol) in THF at
room temperature, reaction time: 4 h; (A) 1 mol % Pd(dba) , 1 mol % Q-phos; (B) 0.5 mol % {[P(t-
Bu) ]PdBr} . 70 °C. Twice catalyst loadings. 2 equiv of enolate. 1.05 equiv of KH, 1.1 equiv of
2
b
c
d
e
3
2
f
g
h
enolate. Reaction time: 12 h. Reaction time: 24 h. Average yield for two runs..
In general, the coupling of this isolated zinc enolate of tert-butyl propionate occurred with electron-
neutral, electron-rich, and electron-poor aryl bromides in high yields. This enolate underwent the
coupling in high yields with aryl bromides containing electron-donating (entries 8 and 10) and electron-
withdrawing substituent at the ortho-position (entries 9, 18, and 20). This arylation reaction also occurs
selectively at an aryl bromide over an aryl chloride (entry 3) or aryl fluoride (entry 9). The reactions
catalyzed by the combination of Pd(dba) and Q-phos formed the coupled products in higher yields
2
(
entries 1, 3, 5, 12, 14, 27) than those catalyzed by {[P(t-Bu) ]PdBr} (entries 2, 4, 6, 13, 15, 28).
3
2
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Like the coupling of tert-butyl acetate, the coupling of tert-butyl propionate occurred in high yields
with aryl bromides containing reactive functional groups such as ketones (entry 11), esters (entries 12–
15), cyano groups (entries 16–18), and nitro groups (entries 19–20). Remarkably, these couplings also
tolerated the hydroxyl and amino groups, provided that these groups were deprotonated by additional
equivalent of the Reformatsky reagent (entries 21 and 24) or 1.1 equiv of KH (entries 22–23 and 25–
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
6); however, higher yields were achieved with the single-component catalyst precursor {[P(t-
Bu) ]PdBr} than with the combination of Pd(dba) and Q-phos for these reactions. The arylation with
3
2
2
3-bromopyridine occurred at 70 ºC in high yield in the presence of both catalysts (entries 34–35);
however, no coupling occurred with 2- or 4-bromopyridine under these conditions.
2
. Arylation of Reformatsky Reagents Generated in situ from α-Bromoesters and Rieke's
Activated Zinc.
Even though α-arylation reactions of the isolated Reformatsky reagents of tert-butyl acetate and
propionate catalyzed by Pd(0)/Q-phos or {[P(t-Bu) ]PdBr} occur with high tolerance toward functional
3
2
groups under mild conditions, this methodology does have some drawbacks. For example, excess zinc
was employed during the generation of the isolated Reformatsky reagents, and this excess zinc would
46
likely interfere with the Pd(II) intermediates during catalysis by oxidation-reduction processes.
Furthermore, the substrate scope was limited to esters that form stable and isolable Reformatsky
reagents, e.g. methyl isobutyarte does not form an isolable Reformatsky reagent, precluding α-arylation
reactions of methyl isobutyate with an isolated reagent. To overcome these drawbacks, we developed
conditions for the α-arylation of Reformatsky reagents generated in situ by conducting reactions of α-
bromo esters with stoichiometric highly active zinc powder. This highly active zinc powder was
prepared by reduction of zinc chloride with lithium metal according to the procedure described by
47
Rieke.
2
.1. Scope of the α-Arylatoin of the Reformatsky Reagent Generated in situ from tert-Butyl
Bromoacetate. The selected examples of α-arylation of this in situ generated Reformatsky reagent are
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summarized in Table 5. These reactions were conducted with 1 mol % Pd(dba) and 1 mol % Q-phos.
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Like the α-arylation of the isolated Reformatsky reagent of tert-butyl acetate, the arylation of this
Reformtsky reagent generated in situ occurred with electron-neutral, electron-rich, and electron-poor
bromoarenes in high yields. Aryl bromides containing an ortho substituent reacted in high isolated
yields (entries 1–4). Entries 4–6 illustrate that this α-arylation occurs with aryl bromides bearing the
potentially reactive cyano group at the ortho-, meta-, or para-position. This coupling also occurs in high
yields with aryl bromides containing ketone functionality (entries 7–9), even with enolizable hydrogens
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(entries 7 and 8).
Table 5. Pd-Catalyzed α-Arylation of the Reformatsky Reagent Generated in situ from tert-Butyl
a
Bromoacetate.
1
mol% Pd(dba) /Q-Phos
2
O
O
Zn*
ArBr
Br
Ar
t
t
O Bu
O Bu
THF, rt, 10 min
THF, rt, 4 h
Yieldb
Yieldb
Entry
1
ArBr
Entry
ArBr
Br
Br
CN
88%
5
95%
Br
6
7
97%
83%
Br
Br
CN
2
3
98%
92%
O
F
Br
Me
O
OMe
Br
8
9
Br
Br
90%
93%
Et
O
4
98%
CN
Ph
a
Conditions: tert-butyl bromoacetate (0.550 mmol), activated Znic (0.750 mmol), aryl bromide (0.500
b
mmol), Pd(dba) (5.00 μmol), Q-Phos (5.00 μmol), THF (2 mL), room temperature, 4 h. Average yield
2
for two runs.
2
.2. Scope of the α-Arylation of the Reformatsky Reagent Generated in situ from tert-Butyl 2-
Bromopropionate. Table 6 summarizes selected examples of Pd-catalyzed α-arylations of the
Reformatsky reagent generated in situ from tert-butyl 2-bromopropionate and the Rieke activated zinc.
These reactions were performed with catalysts generated from 1 mol % Pd(dba) and 1 mol % Q-phos.
2
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Because the scope of the α-arylation of the Reformatsky reagent of tert-butyl acetate generated in situ
was similar to that of the reactions of the isolated Reformatsky reagent, we investigated a selection of
the reactions of tert-butyl propionate to determine if this trend also applied to the reactions of the in situ
generated Reformatsky reagent of tert-butyl propionate. Indeed, these reactions occurred with similar
scope of aryl bromides. High yields were again obtained for reactions of ortho-substituted aryl bromides
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(entries 1–3). Entries 4 and 5 illustrate that reactions occurred in high yields with the bromoarenes
containing cyano functionality at the meta- or para-position. However, the reaction of 2-
bromobenzonitrile with the enolate generated in situ was different from the reaction with the isolated
enolate. In contrast to the reaction of 2-bromobenzonitrile with the isolated enolate, which afforded the
coupled product in 85% isolated yield, the corresponding reaction with the enolate generated in situ
afforded only trace amount of the coupled product (<5% by GC analysis).
Table 6. Pd-Catalyzed α-Arylation of the Reformatsky Reagent Generated in situ from tert-Butyl
a
2
-Bromopropionate.
1
mol% Pd(dba) /Q-Phos
O
2
O
Zn*
ArBr
Br
Ar
t
O Bu
t
O Bu
THF, rt, 10 min
THF, rt, 4 h
Yieldb
88%
Yieldb
Entry
1
ArBr
Entry
4
ArBr
Br
Br
Br
CN
86%
85%
Br
5
CN
2
3
98%
92%
F
Br
OMe
a
Conditions: tert-Butyl 2-Bromopropionate (0.550 mmol), activated Zinc (0.750 mmol), aryl bromide
b
(
0.500 mmol), Pd(dba) (5.00 μmol), Q-Phos (5.00 μmol), THF (2 mL), room temperature, 4 h.
2
Average yield for two runs.
2.3. Scope of the α-Arylation of the Reformatsky Reagent Generated in situ from Methyl α-
Bromoisobutyrate. At first, we attempted α-arylation reactions of methyl isobutyrate generated in situ
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from the Rieke activated zinc and methyl α-bromoisobutyrate under the conditions described for the
arylation of the Reformatsky reagents of tert-butyl acetate and propionate. However, reactions of the
Reformatsky reagent of methyl isobutyrate generated in situ occurred in low yields under these
conditions. For example, the coupling of this zinc enolate with 1-bromo-4-tert-butylbenzene afforded
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the desired product in only 32% yield in the presence of 5% of Pd(dba) and Q-phos. However, the same
2
reaction conducted with 2.5% of {[P(t-Bu) ]PdBr} occurred in 88% isolated yield. Such enhanced
3
2
reactivity can be rationalized by the slightly more open structure of the arylpalladium halide
intermediate containing P(t-Bu) , relative to the structure of the arylpalladium halide containing Q-
3
48
phos. The Pd(I) dimer, {[P(t-Bu) ]PdBr} was chosen as catalyst precursor to study the scope of
3
2
arylation of the in situ generated zinc enolate of methyl isobutyrate.
Our experiments on the scope of arylation of the zinc enolate of methyl isobutyrate focused on
reactions of bromoarenes that do not couple with alkali metal enolates of methyl isobutyrate. Although a
2
5,27,28
variety of electronically varied aryl bromides reacted with the alkali metal enolates in good yields,
the coupling of alkali metal enolates of methyl isobutyrate with ortho-substituted aryl bromides do not
occur. Furthermore, the high nucleophilicity of alkali metal enolates of methyl isobutyrate limits
reactions of aryl bromides containing electrophilic functionality. The scope of the coupling of this in
situ generated Reformatsky reagent was briefly screened and summarized in Table 7. Like the alkali
2
5,27,28
metal enolates of methyl isobutyrate,
this zinc enolate coupled with relatively electron-neutral 4-
bromo-1-tert-butylbenzene at room temperature in 88% isolated yield (entry 1). The coupling of this
zinc enolate with ortho-substituted aryl bromides occurred in high yields as well (entries 2 and 4). 4-
Bromobenzonitrile reacted in 95% isolated yield without any apparent interference with the cyano group
(entry 3). The extended scope of arylation of this zinc enolate will be further studied in the next section
on the arylation of zinc enolates generated in situ by quenching alkali metal enolates with zinc chloride.
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Table 7. Pd-Catalyzed α-Arylation of the Zinc Enolate Generated in situ from Methyl α-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Bromoisobutyrate.
2
.5 mol% {[P(t-Bu) ]PdBr}2
O
3
O
Zn*
ArBr
Br
Ar
OMe
ArBr
OMe
Yieldb
THF, rt, 30 min
THF, rt, 4 h
Yieldb
Entry
1
Entry
3
ArBr
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Br
t-Bu
88%
98%
Br
CN
95%
97%
Br
Br
OMe
2
4
a
Conditions: Methyl α-Bromoisobutyrate (0.550 mmol),activated Zinc (0.750 mmol), aryl bromide
b
(
0.500 mmol), {[P(t-Bu) ]PdBr} (12.5 μmol), THF (2 mL), room temperature, 4 h. Average yield for
3 2
two runs.
3
. α-Arylation of Zinc Enolates Generated by Quenching Alkali Metal Enolates with ZnCl2.
A procedure to couple a zinc ester enolate that is generated directly from the ester, rather than from
the α-bromoester, would combine the functional group tolerance of the Reformatsky reagents and the
convenience of the coupling of the alkali metal enolates of esters. In addition, a procedure that generates
zinc enolates from ZnCl is simpler to conduct than a procedure that generates the zinc enolates from
2
activated zinc metal. Thus, we sought to develop the conditions for the α-arylation of the zinc ester
enolate by quenching the alkali metal enolate of an ester with ZnCl . The reactivity of zinc ester
2
enolates generated by quenching alkali metal enolates of esters with ZnCl and the reactivity of
2
Reformatsky reagents generated from α-bromoesters are different. The use of certain bases to generate
the alkali metal ester enolate precursor to the zinc ester enolate led to the development of a general
coupling of esters with aryl bromides. Thus, the palladium-catalyzed α-arylation of these zinc enolates
required careful choice of reaction stoichiometry, temperature, and base.
3
.1. Evaluation of Conditions for α-Arylation of the Zinc Enolate of tert-Butyl Acetate by
Quenching the Alkali Metal Enolate with ZnCl . To study the arylation of the zinc enolate of tert-
2
butyl acetate generated in situ by quenching the alkali metal enolate with ZnCl , we first attempted to
2
add zinc chloride to the enolate of tert-butyl acetate generated under the conditions we have developed
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5,27,28
for the arylation of alkali metal enolates.
These alkali metal enolates were generated by reaction of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the ester with LiHMDS or LiNCy in toluene at room temperature. Because ZnCl is soluble in THF and
2
2
the palladium-catalyzed α-arylation of zinc enolates occurs in THF, the alkali metal enolate was first
generated in THF instead of toluene and then quenched with ZnCl (Scheme 1). Methyl 4-
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
bromobenzoate was chosen as electrophile because this aryl bromide does not couple with lithium
25,27,28
enolate of tert-butyl acetate.
However, the arylation of this zinc enolate generated in situ in THF
with methyl 4-bromobenzoate did not occur. Alternative conditions needed to be developed for the
arylation of the zinc enolate generated in situ.
Scheme 1
1.1 equiv 1.1 equiv 1% Pd(dba) and 1% P(t-Bu)3
2
O
LiNCy2
ZnCl2 methyl 4-bromobenzoate
no arylation
coupling
t
THF
THF
THF
rt, 4 h
O Bu
rt, 10 min rt, 10 min
1
.1 equiv
The formation of zinc enolates was reported by reactions of carbonyl compounds with alkylzinc
4
9
reagents. Thus, we attempted to generate the zinc enolate of tert-butyl acetate by reaction of tert-butyl
acetate with diethylzinc or butylzinc bromide (Scheme 2). When diethylzinc was used as base to
generate the zinc enolate, the reaction of the resulting mixture with methyl 4-bromobenzoate in the
presence of Pd(dba) and P(t-Bu) did not yield the desired α-aryl ester; In contrast, the product from the
2
3
Negishi coupling, methyl 4-ethylbenzoate, was detected by GC-MS analysis. These results indicated
either diethylzinc was not basic enough to generate the zinc enolate of tert-butyl acetate or the ethyl
group transferred faster to the palladium center than the enolate in the mixed ethylzinc enolate of tert-
butyl acetate. The corresponding reaction with butylzinc bromide as base yielded methyl 4-
butylbenzoate, the product from the Negishi coupling. This reaction suggested that butylzinc bromide
was not a sufficiently strong base to generate the zinc enolate of tert-butyl acetate.
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Scheme 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
% Pd(dba) and 1% P(t-Bu)3
O
R Zn or RZnX methyl 4-bromobenzoate
2
MeO C
R
2
t
THF
rt, 4 h
O Bu
.1 equiv
1
We also attempted to generate the zinc enolate of tert-butyl acetate by allowing tert-butyl acetate to
react with a zinc amide generated in situ by combining one or two equivalents of LiHMDS with ZnCl2.
However, this mixture of ester and zinc amide did not react with 4-bromo ehtylbenzoate to form the α-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aryl ester in the presence of the palladium catalyst containing Q-phos or P(t-Bu) ligand.
3
Ultimately, we found that quenching of the lithium enolate generated from tert-butyl acetate and
LiHMDS at room temperature after only one minute or at -78 °C after 1 h in a mixed solvent of toluene
and THF (volume ratio of 4:1) enable the coupling of ethyl 4-bromobenzoate with the zinc enolate of
tert-butyl acetate in high yield. A series of experiments was conducted to evaluate the conditions for the
coupling of ethyl 4-bromobenzoate with the zinc enolate generated in situ from tert-butyl acetate,
lithium bases, and ZnCl . When LDA or LiNCy were used as bases, the coupling did not occur.
2
2
However, the α-aryl ester was detected by GC-MS analysis when LiHMDS was used as base to
generate the lithium enolate in THF, provided that the lithium enolate was quenched with ZnCl after a
2
short time (1 min) at room temperate. This reaction was studied in different solvents, such as dioxane,
ether, and the mixture of toluene and THF with varied volume ratios; the coupling reaction performed in
the mixture of toluene and THF with 4:1 volume ratio yielded the desired α-aryl ester in nearly
quantitative yield.
Finally, to ensure greater reproducibility on larger scales, the lithium enolate of tert-butyl acetate was
generated with LiHMDS at -78 °C and subsequently quenched with ZnCl at -78 °C. The conversion of
2
methyl 4-bromobenzoate was highly dependent on the amount of ZnCl used to quench the lithium
2
enolate. When 1.1 equiv of ZnCl , relative to methyl 4-bromobenzoate, was used to quench the lithium
2
enolate, only 50% conversion of methyl 4-bromobenzoate was achieved. When 2.2 equiv of ZnCl was
2
used, methyl 4-bromobenzoate was fully converted to the desired α-aryl ester.
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3
.2. Scope of the Coupling of the Zinc Enolate of tert-Butyl Acetate Generated by Quenching the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Lithium Enolate with ZnCl . With reliable reaction conditions in hand, we studied the scope of the α-
2
arylation of the zinc enolate of tert-butyl acetate generated in situ by quenching of the lithium enolate
with ZnCl , and the results are summarized in Table 8. These reactions were conducted with the catalyst
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
generated from 1 mol % Pd(dba) and 1 mol % Q-phos. The zinc enolate was generated after reaction of
2
tert-butyl acetate with LiHMDS at -78 °C for 1 h, followed by quenching the resulting lithium enolate
with ZnCl at -78 °C for 0.5 h. The scope of the α-arylation of this zinc enolate was similar to that of the
2
α-arylation of the corresponding isolated Reformatsky reagent. The arylation reactions of this zinc
enolate occurred in high isolated yields (89–96%) with electron-neutral (Entry 1), electron-poor (Entries
2
–7), and electron-rich (Entry 8) bromoarenes. This coupling tolerated electrophilic functionalities, such
as ester (Entry 3), cyano (Entry 4), nitro (Entry 5), and ketone moiety with or without enolizable
hydrogen atoms (Entries 6–7). Sterically hindered 2,6-substituted bromoarene reacted in high yield
(Entry 9). In addition, this zinc enolate of tert-butyl acetate also reacted with 3-bromopyridine at 70 °C
in 90% yield (Entry 10).
Table 8. Pd-Catalyzed α-Arylation of the Zinc Enolate Generated in situ by Quenching Lithium
a
Enolate of tert-Butyl Acetate with ZnCl2.
1
mol% Pd(dba) /Q-Phos
2
O
O
LiHMDS
ZnCl2
THF
ArBr
Ar
t
t
O Bu
toluene
o
toluene / THF
rt, 4 h
O Bu
o
-
78 C, 1 h -78 C, 0.5 h
Yieldc
Yieldc
Entry
ArBr
Entry
ArBr
O
R
6
7
R = Me 91%
R = Ph 92%
1
2
Br
Br
t-Bu
95%
Br
Br
CF3
96%
8
89%
MeO
3
4
Br
Br
CO Me 95%
2
9
Br
Br
94%
CN
92%
92%
5
Br
NO2
10
90%b
N
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a
Standard conditions: tert-Butyl acetate (0.550 mmol), LiHMDS (0.550 mmol), ZnCl (1.10 mmol),
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
aryl bromide (0.500 mmol), Pd(dba) (5.00 μmol), Q-Phos (5.00 μmol), in mixed solvent of THF (30%)
and toluene (70%), Room temperature, 4 h. at 70 °C. Average yield for two runs.
2
b
c
3.3. Conditions for the Coupling of the Zinc Enolate of tert-Butyl Propionate Generated from the
Alkali Metal Enolate. The coupling of the zinc enolate of tert-butyl propionate generated in situ by
quenching of the alkali metal enolate requires somewhat different conditions than the coupling of the
analogous enolate of tert-butyl acetate. A series of arylation reactions of this enolate with 4-
bromobenzonitrile showed that high yields were obtained when the enolate was generated from an
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
excess (2 equiv) of LiHMDS and quenched with 2 equiv of ZnCl . Therefore, we tested reactions with
2
stronger lithium bases. However, no coupled product was observed when either LiNCy (effective for
2
25,28
arylation of esters with base-stable bromoarenes in the absence of zinc ) or sec-BuLi (effective for
2
6
arylation of propionamides ) was used as base instead of LiHMDS. Also, no coupled product was
observed with the enolate generated from these bases in THF or a 3:1 mixture of toluene and THF at
either room temperature or -78 °C. However, the simple substitution of NaHMDS for LiHMDS in the
protocol, deprotonation at 0 °C, quenching of this enolate at 0 °C, and the use of a 3:1 mixture of
toluene and THF as solvent led to the coupling of the zinc enolate of tert-butyl propionate with 4-
bromobenzonitrile in almost quantitative yield.
3
.4. Scope of Coupling of the Zinc Enolate of tert-Butyl Propionate Generated in situ from
NaHMDS and ZnCl . Table 9 summarizes examples of palladium-catalyzed α-arylations of the zinc
2
enolate of tert-butyl propionate formed in situ by quenching the sodium enolate generated from
NaHMDS in toluene at 0 °C with ZnCl . The catalyst used for these reaction was the combination of
2
Pd(dba) and Q-phos. A range of electronically varied para-substituted (Entries 1–4) and ortho-
2
substituted (Entries 5–9) aryl bromides underwent the coupling with this enolate in high yields (74–
9
4%). These reactions are compatible with bromoarenes bearing reactive functional groups, such as
carboalkoxy (Entry 2), cyano (Entries 3 and 9) and nitro (Entries 4 and 8) groups on either the para- or
ortho-position. The sterically hindered 2,6-substituted 2-bromomesitylene reacted with this enolate in
8
2% yield (entry 10). The coupling with 3-bromopyridine also occurred in high yield (Entry 11),
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although a higher temperature of 70 °C was required. Coupling reactions of bromoarenes containing
enolizable keto functionality did not occur.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 9. Pd-Catalyzed α-Arylation of the Zinc Enolate Generated in situ by Quenching Sodium
a
Enolate of tert-Butyl Propionate with ZnCl2.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1 mol% Pd(dba) /Q-Phos
2
O
O
NaHMDS
ZnCl2
THF
ArBr
Ar
t
t
O Bu
toluene
0 oC, 0.5 h
toluene / THF
rt, 4 h
O Bu
o
0 C, 0.5 h
Yieldb
Yieldb
87%
Entry
ArBr
Entry
7
ArBr
Br
1
2
Br
Br
t-Bu
94%
F
Br
CO Me 84%
2
74%d,e
8
9
NO2
Br
3
Br
Br
CN
86%
92%c
4
5
NO2
Br
88%
89%
CN
10
Br
Br
82%
Br
6
89%
90%f
11
OMe
N
a
Standard conditions: 1.1 equiv of ester, 1.3 equiv of base, 2.6 equiv of zinc chloride, 1 equiv of aryl
bromide (0.5 mmol), 1 mol % Pd(dba) , 1 mol % Q-phos in mixed solvent of toluene and THF at room
2
b
c
d
temperature. Average yield for two runs. 2 mol % Pd(dba) and 2 mol % Q-phos. 4 mol % Pd(dba)
and 4 mol % Q-phos. Isolated by distillation (one isolation). 70 °C.
2
f
2
e
3
.5. Conditions for Coupling of the Zinc Enolate of Methyl Isobutyrate Generated in situ by
Quenching of the Alkali Metal Enolate with ZnCl . Our studies to develop conditions for the α-
2
arylation of the zinc enolate of methyl isobutyrate generated in situ by quenching the alkali metal
enolate with ZnCl were conducted primarily with the dimeric Pd(I) catalyst {[P(t-Bu) ]PdBr} , instead
2
3
2
of a combination of Pd(dba) and Q-phos. This Pd(I) catalyst was selected because arylation reactions of
2
the zinc enolate generated from methyl α-bromoisobutyrate and Rieke activated zinc occurred in higher
yield when catalyzed by the Pd(I) dimer {[P(t-Bu) ]PdBr} than when catalyzed by a combination of
3
2
Pd(dba) and Q-phos. Like the reactions of tert-butyl propionate, the reactions of methyl isobutyrate
2
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occurred in high yields when the zinc enolate was generated by deprotonation with NaHMDS, followed
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
by quenching the resulting sodium enolate with an excess of ZnCl . Consistent with the reaction of 1-
2
bromo-4-tert-butylbenzene with the zinc enolate generated from methyl α-bromoisobutyrate and
Rieke’s activated zinc, the reaction of the zinc enolate generated by quenching of the sodium enolate
with ZnCl occurred in only 37% yield when a combination of Pd(dba) and Q-phos was used as
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
catalyst.
Table 10. Pd-Catalyzed α-Arylation of the Zinc Enolate Generated in situ by Quenching the
a
Sodium Enolate of Methyl Isobutyrate with ZnCl2.
2
.5 mol% {[P(t-Bu) ]PdBr}2
3
O
O
NaHMDS
toluene
ZnCl2
ArBr
Ar
OMe
THF
rt, 1 h
toluene / THF
rt, 4 h
OMe
o
0 C–rt, 1 h
Yieldb
93%
Yieldb
92%
Entry
1
ArBr
Entry
ArBr
Br
Br
Br
t-Bu
5
6
Br
CO Me
2
O
Br
87%
2
3
NMe2 84%
Et
Br
7
8
90%c
CN
90%
89%
Br
91%c
4
Br
NO2
OMe
a
Standard conditions: 1.5 equiv of ester, 1.7 equiv of base, 3.4 equiv of zinc chloride, 1 equiv of aryl
bromide (0.5 mmol), 2.5 mol % {[P(t-Bu) ]PdBr} in mixed solvent of toluene and THF at room
3
2
b
c
temperature. Average yield for two runs. 70 °C.
3
.6. Scope of the Coupling of the Zinc Enolate of Methyl Isobutyrate Generated in situ by
Quenching of the Alkali Metal Enolate with ZnCl . Table 10 summarizes the scope of the palladium-
2
catalyzed arylation of the zinc enolate of methyl isobutyrate generated in situ by quenching the sodium
enolate with ZnCl . Reactions occurred in high yields with electron-neutral (Entry 1), electron-rich
2
(Entry 2), and electron-poor (Entries 3–6) para-substituted bromoarenes at room temperature. However,
reactions with both electron-neutral (Entry 7) and electron-rich (Entry 8) ortho-substituted bromoarenes
required high temperature (70 °C) to go to completion. These coupling reactions were compatible with
reactive functionalities, such as nitrile (Entry 3), nitro (Entry 4), ester (Entry 5), and ketone (Entry 6)
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groups. Different from arylation reactions of the zinc enolates of tert-butyl acetate and propionate,
reactions of this hindered enolate with 2,6-disubstituted arenes did not form the coupled product, and
reactions with arenes containing reactive functional groups, such as cyano and nitro groups, at the
ortho-position did not occur.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
.7. Scope of the Coupling of the Zinc Enolate of Methyl Propionate Generated in situ by
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Quenching of the Alkali Metal Enolate with ZnCl . Methyl esters are readily accessible esters, and
2
they easily undergo hydrolysis to generate the corresponding acids. Thus, the sequential reaction of the
arylation of methyl esters followed by hydrolysis will provide a valuable route to prepare α-aryl acids.
α-Aryl methyl esters can be prepared by nickel-catalyzed Suzuki coupling of α-haloesters with
arylboronic acids or nickel-catalyzed reductive coupling of aryl halides with α-haloesters in the
5
0,51
presence of manganese.
However, the direct arylation of methyl esters with aryl halides has been
2
5,27
limited to sterically hindered esters such as methyl isobutyrate catalyzed by palladium complexes.
It
is challenging to conduct the arylation of less hindered methyl esters, such as methyl acetate and
propionate because the enolates of these esters are thermodynamically unstable and readily undergo the
Claisen condensation reaction.
To address this limitation, we sought to develop conditions for the arylation of zinc enolate of methyl
propionate. First, we attempted to generate the zinc enolate of methyl propionate under the conditions
that we developed to generate the zinc enolate of tert-butyl propionate involving deprotonation of the
ester with NaHMDS at 0 °C in toluene, followed by quenching of the sodium enolate with ZnCl in
2
THF. The coupling of this zinc enolate with 1-bromo-4-tert-butylbenzene catalyzed by 2.5 mol%
Pd(dba) and 2.5 mol% Q-phos did not afforded any arylation product. Generation of the zinc enolate at
2
-78 °C or between -40 °C and -15 °C in toluene, followed by quenching with ZnCl in THF at the same
2
temperature, gave coupled product, but in less than 50% yield. However, when the sodium enolate was
generated by reaction of methyl propionate with NaHMDS in toluene at -60 °C and quenched with
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ZnCl at -35 °C, the coupling of the resulting enolate with 1-bromo-4-tert-butylbenzene afforded the
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
desired product in 86% isolated yield.
Under these conditions, we studied the scope of the arylation of the zinc enolate of methyl propionate,
and the selected examples are listed in Table 11. The coupling occurred with a range of electronically
varied aryl bromides in high isolated yields. It also occurred with ortho-substituted (entries 3–5) and di-
ortho-substituted (entry 9) aryl bromides in high isolated yields and with aryl bromides containing ester
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(entry 6), cyano (entry 7), and nitro (entry 8) groups. This zinc enolate coupled with 3-bromopyridine at
7
0 °C to afforded the product in 84% isolated yield. For all of these reactions, the Claisen condensation
products between the α-aryl ester products and the remaining zinc enolate were not observed.
Table 11. Pd-Catalyzed α-Arylation of the Zinc Enolate Generated in situ by Quenching the
a
Sodium Enolate of Methyl Propionate with ZnCl2.
a
Standard conditions: 1.5 equiv of ester, 1.7 equiv of NaHMDS, 3.4 equiv of zinc chloride, 1 equiv of
aryl bromide (0.5 mmol), 2.5 mol % Pd(dba) , 2.5 mol % Q-phos, in mixed solvent of toluene and THF,
2
b
c
o
4 h at room temperature. Average yield for two runs. Performed at 70 C.
3.8. Coupling of the Zinc Enolate of Methyl 2-Benzyloxyacetate Generated in situ by Quenching
of the Alkali Metal Enolate with ZnCl . α-Hydroxy or alkoxy acids are biologically important
2
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2
53-59
compounds, and they can be used as auxiliaries or synthons for the synthesis of chiral ligands.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
However, the methods for preparation of these compounds are limited. Derivatives of mandelic acid or
atrolactic acid are generally prepared by oxidation of the α-carbon of α-arylcarbonyl compounds or by
reduction of α-dicarbonyl compounds. Fu and coworkers reported an enantioselective O-H insertion to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
60
generate various sets of α-alkoxy esters, but this route requires α-aryl esters as the reactant. A reaction
sequence comprising the arylation of α-alkoxyesters and hydrolysis of the coupled product would
provide an alternative route to prepare α-aryl-α-alkoxy acids. This route would expand the number of
derivatives of mandelic acid or atrolactic acids to derivatives containing diverse functionalities on the
aryl group.
6
1
The palladium-catalyzed arylation of alkali-metal enolates of α-alkoxy esters has been studied, and
these reactions occurred in poor yields. The use of the silyl enolates of α-alkoxy esters greatly increased
6
1
the yields of these reactions. However, isolated silyl enolates are needed for these reactions to occur in
high yields. To further simplify the reaction procedure by avoiding the isolation step of the silyl enolate,
we attempted to develop the conditions for the coupling of aryl halides with the zinc enolates of α-
alkoxy esters. We first studied the arylation of the dianionic zinc enolate of ethyl α-hydroxyacetate
(Scheme 3), but no successful coupling was achieved. Subsequently, we attempted the arylation of α-
alkoxy esters that can be readily converted to α-hydroxyesters, and we chose methyl 2-benzyloxyacetate
as the target substrate.
Scheme 3
a
Solvent: THF or 25% THF in toluene; Reagents (equiv): 2.2 equiv LiHMDS / 4.4 equiv ZnCl , or 4.4
2
equiv LiHMDS / 4.4 equiv ZnCl ; Catalysts: 1% Pd(dba) / 1% Q-phos, or 0.5% {[P(t-Bu) ]PdBr} .
2
2
3
2
We developed two sets of conditions for the arylation of zinc enolates of α-alkoxy esters. The zinc
enolate of methyl 2-benzyloxyacetate generated in situ by quenching its lithium enolate with ZnCl in
2
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o
THF at -20 C coupled with a series of aryl bromides in the presence of 3 mol% Pd and 4.5 mol% Q-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
phos at room temperature or 1 mol% Pd and 1.5 mol% Q-phos at 40 C. Selected examples of the
reaction scope are summarized in Table 12. A range of electron-poor (entries 1–4, 7, and 8) and
electron-rich (entries 5, 6, and 9) aryl bromides reacted in high yields. The arylation of this zinc enolate
tolerates the ester (entries 1 and 2) and cyano (entries 3, 4, and 8) groups. Under both conditions, the
coupling with ortho-substituted aryl bromides and heteroaryl bromides did not occur.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 12. Pd-Catalyzed α-Arylation of the Zinc Enolate Generated in situ by Quenching the
a
Lithium Enolate of Methyl 2-Benzyloxyacetate with ZnCl2.
Pd(dba) / Q-phos
2
O
O
LiHMDS
THF
ZnCl2
ArBr
BnO
BnO
OMe
ArBr
THF
THF
OMe
o
o
-20 C, 1 h
-20 C, 1 h
temp, 4 h
Ar
Entry
Conditions
Yieldb Entry
ArBr
Conditions
Yieldb
78%
1
2
A
B
77%
91%
Br
Br
Br
Br
CO Me
2
7
8
9
B
F
3
4
A
B
81%
84%
Br
Br
CN
B
B
84%
87%
CN
5
6
A
B
86%
92%
OMe
OMe
a
Standard conditions: (A) 1.3 equiv of ester, 1.5 equiv of LiHMDS, 3 equiv of zinc chloride, 1 equiv
of aryl bromide (0.5 mmol), 3 mol% Pd(dba) , 4.5 mol% Q-phos, in THF, 4 h at room temperature; (B)
2
1
.5 equiv of ester, 1.7 equiv of LiHMDS, 3.4 equiv of zinc chloride, 1 equiv of aryl bromide (0.5
o
b
mmol), 1 mol% Pd(dba) , 1.5 mol% Q-phos, in THF, 4 h at 40 C. Average yield for two runs.
2
3.9. Coupling of the Zinc Enolate of Valerolactone Generated in situ by Quenching of the Alkali
Metal Enolate with ZnCl . α-Aryl lactones are intermediates of biologically or pharmaceutically
2
6
2
important molecules. However, methods to prepare such cyclic esters are limited, and the synthesis of
these molecules generally takes several steps. Pour reported the multiple-step syntheses of various α-
6
3,64
aryl-α-valerolactones as intermediates of Incrustoporine derivatives starting from α-arylacetic acids.
Lei reported the synthesis of α-aryl-γ-butyrolactones by nickel-catalyzed Suzuki coupling of PhB(OH)2
5
1
and α-bromo-γ-butyrolactone, but a metal-catalyzed coupling of aryl halides with lactones would be
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an alternative, more direct, approach to α-aryl lactones. Buchwald reported palladium- and nickel-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
5
catalyzed enantioselective α-arylation of α-substituted γ-butyrolactones. These nickel-catalyzed
reactions occurred in good yields and in high ee’s in the presence of 5–30 mol% ZnBr . However, these
2
reactions were inhibited when stoichiometric Zn(II) salts were used, due to the formation of less reactive
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
zinc enolates. We studied the palladium-catalyzed arylation of the zinc enolate of γ-valerolactone to
6
6
generate tertiary α-aryl lactones.
Table 13. Pd-Catalyzed α-Arylation of the Zinc Enolate Generated in situ by Quenching the
a
Lithium Enolate of Valerolactone with ZnCl2.
O
O
Pd(dba) / Q-phos
2
LiHMDS
THF
ZnCl2
THF
ArBr
Ar
O
O
THF
o
o
-
50 C, 1 h
-50 C, 1 h
RT, 4 h
Entry
1
ArBr
Yield cis/trans Entry
ArBr
Yield cis/trans
Br
Br
Br
t-Bu 90% 57/43
4
5
Br
Br
CO2Me 92%
68/32
63/37
2
3
OMe 81% 57/43
84% 28/72
CN
84%
77%
6
Br
NO2
67/33
a
Standard conditions: 1.5 equiv of ester, 1.7 equiv of LiHMDS, 3.4 equiv of zinc chloride, 1 equiv of
aryl bromide (0.5 mmol), 1 mol% Pd(dba) , 1.5 mol% Q-phos, in mixed solvent of toluene and THF, 4 h
2
1
at room temperature. Ratio of isomers was determined from H NMR integrated ratio.
The zinc enolate of γ-valerolactone was generated by reaction of 1.5 equivalents of γ-valerolactone
(relative to the aryl bromide added after the generation of the enolate) and 1.7 equiv of LiHMDS
o
followed by quenching with 3.4 equivalents of ZnCl at -50 C. The catalyst was generated from 1 mol
2
%
Pd(dba) and 1.5 mol% Q-phos. Selected examples of this coupling reaction are summarized in Table
2
13. Starting from racemic γ-valerolactone, the products were obtained as mixtures of cis- and trans-
isomers. Aryl bromides having a range of electronic properties reacted in high yields with modest
cis/trans selectivities, and this arylation tolerates the ester (entry 4), cyano (entry 5), and nitro (entry 6)
groups. Reactions of electron-poor para-substituted aryl bromides (entries 4–6) occurred in slightly
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higher cis/trans selectivity than reactions of electron-rich, para-substituted aryl bromides (entries 1 and
). The electron-rich, ortho-substituted 4-bromoanisole reacted in 84% isolated yield with a cis/trans of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
28/72 (entry 3).
CONCLUSION
We have developed convenient and efficient protocols for the palladium-catalyzed coupling of zinc
enolates of esters with aryl bromides. The zinc enolates of esters for this process can be the isolated
Reformatsky reagents generated in situ by reactions of α-bromoesters with Rieke’s activated zinc, or the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
related zinc enolate generated in situ by quenching the alkali metal enolates with ZnCl . These coupling
2
reactions were conducted with palladium catalysts bearing hindered monophosphines that allow fast
oxidative addition of electronically varied aryl bromides and coupling reactions at room temperature.
The scope of the reaction of zinc ester enolates encompasses aryl bromides with functionality that does
not tolerate the strongly basic or nucleophilic alkali metal enolates, such as ketones with enolizable
hydrogens, esters, nitriles, and nitro groups. The scope of esters encompasses acyclic acetates,
propionates, and isobutyrates, α-alkoxyesters, and lactones. Considering the high functional group
tolerance of zinc enolates, the use of relatively nonpolar solvents for this coupling process, and the high
yields of monoarylation products and absence of diarylation products from the reactions of zinc ester
enolates, we anticipate that these procedures will provide valuable routes to a wide range of α-aryl
carboxylic acid derivatives, including a series of such compounds that were inaccessible through
coupling of the alkali metal enolates.
EXPERIMENTAL SECTION
General Methods. All reactions were performed in a nitrogen-filled dry box or with Schlenk techniques
under N . THF and toluene were distilled from sodium/benzophenone. Dichloromethane was distilled
2
from calcium hydride. Anhydrous dioxane was purchased from commercial suppliers and was used and
stored in a nitrogen-filled dry box. All aryl bromides, α-bromo esters, bases, zinc halides, lithium, and
naphthalene were obtained from commercial suppliers and used without further purification. Zinc metal
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6
7
(
granular, 20 mesh) was obtained from Mallinckrodt, activated according to literature procedures. P(t-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Bu) and Pd(dba) was purchased from Strem and other ligands were purchased from commercial
3
2
1
13
1
suppliers. {[P(t-Bu) ]PdBr} was obtained as a gift from Johnson-Matthey. H and C{ H} NMR
3
2
spectra were recorded on 400 or 500 MHz spectrometers, with shifts reported in parts per million
1
13
downfield from tetramethylsilane and referenced to residual protiated ( H) or deuterated solvent ( C).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure for the Arylation of the Reformatsky Reagents of Esters. In a dry box, a 4-mL
screw-capped vial was charged with Pd(dba) (2.9 mg, 5.0 μmol), Q-phos (3.6 mg, 5.0 μmol), aryl
2
halide (0.500 mmol), the corresponding Reformatsky reagent (0.550 mmol), THF (2 mL), and a
magnetic stirring bar. The vial was sealed with a cap containing a PTFE septum and removed from the
dry box. The reaction mixture was then stirred at room temperature or 70 °C for 4–24 h. The reaction
mixture was then adsorbed onto silica gel, loaded on a silica column, and eluted with a mixture of ethyl
acetate in hexanes. The compounds obtained after column chromatography are generally pale yellow or
clear oils. Detailed procedures on the purification and data on characterization of products were listed
below.
General Procedure for the Arylation of the Reformatsky Reagents of Esters with Bromophenols.
In a dry box, a solution of bromophenol (86.5 mg, 0.500 mmol) in THF (1 mL) was added to KH (21.1
mg, 0.525 mmol). Gas evolution occurred immediately. The suspension was stirred at room temperature
for 10 min and then transferred to a 4-mL screw-capped vial containg {[P(t-Bu) ]PdBr} (2.0 mg, 2.5
3
2
μmol), the corresponding Reformatsky reagent (0.550 mmol), THF (1 mL), and a magnetic stirring bar.
The vial was sealed with a cap containing a PTFE septum and removed from the dry box. The reaction
mixture was stirred at room temperature for 4 h. The reaction mixture was then adsorbed onto silica gel,
loaded on a silica column, and eluted with 20% ethyl acetate in hexanes. The compounds obtained after
column chromatography are generally pale yellow or clear oils.
General Procedure for the Arylation of the Reformatsky Reagents of Esters with Bromoanilines.
In a dry box, a solution of bromoaniline (86.0 mg, 0.500 mmol) in THF (1 mL) was added to KH (21.1
mg, 0.525 mmol). Gas evolution occurred immediately. The suspension was stirred at room temperature
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for 30 min and then transferred to a 4-mL screw-capped vial containing {[P(t-Bu) ]PdBr} (2.0 mg, 2.50
3
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
μmol), the corresponding Reformatsky reagent (0.550 mmol), THF (1 mL), and a magnetic stirring bar.
The vial was sealed with a cap containing a PTFE septum and removed from the dry box. The reaction
mixture was then stirred at room temperature for 12-24 h and then diluted with Et O (30 mL). The
2
resulting solution was washed with 0.1 N HCl (7 mL), with saturated NaHCO aqueous solution (20
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
mL), and then with H O (20 mL). The organic phase was dried over MgSO , filtered, and concentrated
2
4
at reduced pressure. The crude product was then adsorbed onto silica gel, loaded on a silica column, and
eluted with 20% ethyl acetate in hexanes. The compounds obtained after column chromatography are
generally pale yellow or clear oils.
Procedure for the Arylation of Zinc Enolates Generated from tert-Butyl Bromoacetate and tert-
Butyl Bromopropionate with Rieke Activated Zinc. In a nitrogen-filled dry box, Rieke activated zinc
dust (49.0 mg, 0.750 mmol) was suspended in THF (1 mL) in a 4 mL screw-capped vial containing a
stir bar. To this suspension was added dropwise the α-bromoester (0.550 mmol) by syringe, and the vial
was sealed. The mixture was stirred at room temperature for 10 min. To the resulting suspension was
added a solution of aryl bromide (0.500 mmol), Pd(dba) (2.9 mg, 5.0 μmol), and Q-phos (3.6 mg, 5.0
2
μmol) in THF (1 mL). The vial was sealed with a cap containing PTFE septum and removed from the
dry box. The mixture was stirred at room temperature for 4 h. The crude product was adsorbed on silica
gel, loaded on a silica column, and eluted with a mixture of ethyl acetate and hexanes. The compounds
obtained after column chromatography are generally pale yellow or clear oils. Detailed procedures on
the purification and data on characterization of products were listed below.
Procedure for the Arylation of Zinc Enolate Generated from Methyl 2-Bromoisobutyrate with
Rieke Activated Zinc. In a nitrogen-filled dry box, Rieke activated zinc dust (49.0 mg, 0.750 mmol)
was suspended in THF (1 mL) in a 4 mL screw-capped vial containing a stir bar. To this suspension was
added dropwise 2-bromoisobutyrate (99.6 mg, 0.550 mmol) by syringe, and the vial was sealed. The
mixture was stirred at room temperature for 30 min. To the resulting suspension was added a solution of
aryl bromide (0.500 mmol) and {[P(t-Bu) ]PdBr} (9.7 mg, 12.5 µmol) in THF (1 mL). The vial was
3
2
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sealed with a cap containing PTFE septum and removed from the dry box. The resulting solution was
stirred at room temperature for 4 h. The crude product was adsorbed on silica gel, loaded on a silica
column, and eluted with a mixture of ethyl acetate and hexanes. The compounds obtained after column
chromatography are generally pale yellow or clear oils. Detailed procedures on the purification and data
on characterization of products were listed below.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure for the Arylation of the Zinc Enolate of tert-Butyl Acetate by Quenching of the
Lithium Enolate with ZnCl . The reactions were conducted under a nitrogen atmosphere. In a
2
nitrogen-filled dry box, a 10 mL round bottom flask was charged with LiHMDS (92.0 mg, 0.550 mmol),
toluene (4 mL), and a magnetic stirring bar. The flask was sealed with a rubber septum, removed from
the dry box, connected to a supply of nitrogen, and cooled at -78 °C. The this solution was added tert-
butyl acetate (75 µL, 0.55 mol) dropwise at -78 °C and the mixture was stirred at this temperature for 1
h. To the resulting suspension of lithium enolate was added a solution of ZnCl (150 mg, 1.10 mmol) in
2
THF (2 mL), and the resultant mixture was stirred for 30 min at -78 °C. To the suspension of zinc
enolate was added a solution of aryl bromide (0.500 mmol), Pd(dba) , and Q-phos in toluene (1 mL).
2
The amounts of catalyst components are provided in the Table 8 in the Results and Discussion section.
The reaction mixture was allowed to warm to room temperature and stirred at room temperature or at 70
°
C for 4 h. The crude product was adsorbed on silica gel, loaded on a silica column, and eluted with a
mixture of ethyl acetate and hexanes. The compounds obtained after column chromatography are
generally pale yellow or clear oils. Detailed procedures on the purification and data on characterization
of products were listed below.
General Procedure for the Arylation of Zinc Enolate of tert-Butyl Propionate by Quenching
Sodium Enolate with ZnCl . The reactions were conducted under a nitrogen atmosphere. In a nitrogen-
2
filled dry box, a 10 mL round bottom flask was charged with NaHMDS (119 mg, 0.650 mmol), toluene
(
2 mL), and a magnetic stirring bar. The flask was sealed with a rubber septum, removed from the dry
box, connected to a supply of nitrogen, and cooled at 0 °C. The this solution was added tert-butyl
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