Organozinc chemistry enabled by micellar catalysis. Palladium-catalyzed cross-couplings between alkyl and aryl bromides in water at room temperature

Article abstract of DOI:10.1021/om200846h

Negishi-like cross-couplings between (functionalized) alkyl and aryl bromides are described. Despite the fact that organozinc reagents are intolerant of water, their formation as well as their use in an aqueous micellar environment is discussed herein. Each component of this complex series of events leading up to C-C bond formation has an important role which has been determined insofar as the type of zinc, amine ligand, surfactant, and palladium catalyst are concerned. In particular, the nature of the surfactant has been found to be crucial in order to obtain synthetically useful results involving highly reactive, moisture-sensitive organometallics. Neither organic solvent nor heat is required for these cross-couplings to occur; just add water.

Full text of DOI:10.1021/om200846h

Article
pubs.acs.org/Organometallics
Organozinc Chemistry Enabled by Micellar Catalysis.
Palladium-Catalyzed Cross-Couplings between Alkyl and Aryl
Bromides in Water at Room Temperature
Christophe Duplais, Arkady Krasovskiy, and Bruce H. Lipshutz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: Negishi-like cross-couplings between (function-
alized) alkyl and aryl bromides are described. Despite the fact
that organozinc reagents are intolerant of water, their forma-
tion as well as their use in an aqueous micellar environment is
discussed herein. Each component of this complex series of
events leading up to C−C bond formation has an important role which has been determined insofar as the type of zinc, amine
ligand, surfactant, and palladium catalyst are concerned. In particular, the nature of the surfactant has been found to be crucial in
order to obtain synthetically useful results involving highly reactive, moisture-sensitive organometallics. Neither organic solvent
nor heat is required for these cross-couplings to occur; just add water.
rate where, presumably, the rate-determining step is considered
to be zinc insertion into the alkyl halide. On the other hand, in
the presence of far more reactive benzylic chlorides, couplings
can be performed “on water” in only a few hours (3−8 h).13
Initial attempts to utilize less reactive alkyl bromides in cross-
coupling reactions with aryl bromides were unsuccessful, in
contrast to reactions of alkyl iodides (Scheme 2) where
significant byproduct formation was observed under micellar
catalysis. Nonetheless, insertion clearly did take place at
ambient temperature, while in organic solvents direct insertion
of zinc into alkyl bromides occurs, without exception, only with
heating.14 Thus, while after 36 h a 91% yield of product 1 is
obtained starting with 1-iododecane, only a 46% yield could be
isolated after 72 h using 1-bromodecane. Interestingly, under
micellar conditions, competitive zinc insertion takes place with
the activated aryl bromide (ethyl 4-bromobenzoate), leading to
reduction and homocoupling byproducts that take their toll on
the overall isolated yield (Scheme 2).
The effect of varying the surfactant was studied next, choosing
as a model reaction the coupling between bromocyclohexane
and ethyl 4-bromobenzoate in the presence of excess diamine
and zinc dust (Figure 1). Surprisingly, the product was formed
in moderate yield (50%, by GC) even in the absence of
surfactant. Different percentages of several surfactants (2 and
4 wt %), including PTS, solutol, cremophore, and Triton
X-100, all gave comparable results when used in pure water,
whereas CTAC, TPGS, and Brij 35 are actually detrimental to
the formation of the desired product. Using these latter
surfactants, significant amounts of ethyl benzoate and biphenyl
were detected. After intensive further screening, it was found
that inexpensive and commercially available Brij 30, 4 wt % in
INTRODUCTION
■
Cross-couplings between aryl-sp2 and alkyl-sp3 centers have
been intensely studied by many groups, and important advances
have been achieved.1 Traditionally, this type of transformation
has been performed by reacting preformed organometallic
species (zinc,2,3 magnesium,2,4 boron,2,5 tin,2,6 and silicon2,7)
with an appropriate aryl halide (eqs I and II, Scheme 1). More
recently, reductive8 and oxidative9 couplings, as well as C−H
activation10 of arenes (eq III) have been developed. A
conceptually different approach that relies on simultaneous
selective insertion of main-group (Mmg) and transition (Mt)
metals in two different carbon−halogen bonds was presented
recently by von Wangelin (Kumada-like cross couplings in
THF)11 and by our group as well (Negishi-like cross couplings
in water under micellar catalysis12) (eq IV; X = Br, X′ = I).
Chemoselective metal insertion is based on the preferential
reaction of main-group metals with sp3-halogen bonds, while
transition metals tend to react more quickly with sp2-halogen
centers. In order to realize good overall conversions and
isolated yields, we originally used alkyl iodides rather than
alkyl bromides, since the latter react more slowly, if at all, with
zinc metal at room temperature. Herein we wish to report a
study leading to a general solution for cross-coupling reactions
focused on alkyl bromides, with aryl bromides as reaction
partners, in water at room temperature using micellar
nanoparticle technology (eq IV).
RESULTS AND DISCUSSION
■
Role of the Surfactant. During development of these
couplings between alkyl iodides and aryl bromides, PTS was
chosen as the lead amphiphile, although the surfactant did not
appear to have a major impact on the results obtained.12
However, in the absence of surfactant (i.e., “on water”), the
product is formed to a very limited extent and at a much lower
Received: September 8, 2011
Published: November 21, 2011
© 2011 American Chemical Society
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Scheme 1. Aryl−Alkyl Cross-Couplings
Scheme 2. Comparison Reactions between Iodo- and Bromodecane
Figure 1. Influence of the surfactant on the reaction profile.
water, enables the reaction to proceed with good selectivity and
in high isolated yield (90%).
The major difference between Brij 30 and the other
surfactants examined is the size of its micelles. While all
other surfactants have a size ranging between 10 and 25 nm, as
determined by dynamic light scattering measurements (DLS),
significantly larger micelles are formed in water by Brij 30
(ca. 110 nm), reflecting its shorter hydrophilic portion (Table 1).
These observations include Brij 35, which, notwithstanding the
fact that its lipophilic core is identical with that of Brij 30, leads
to the lowest level of cross-coupling. As is the case for all
surfactants examined in water to date, this larger diameter
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as well as Brij 30 (entries 1, 3, and 6). Secondary alkyl bromides
react faster than do primary bromides, although primary
bromides undergo insertion more rapidly when a functional
group is close to the C−Br bond such that intramolecular
coordination to zinc is possible. Incomplete reactions allowed
for unreacted aryl bromide to be recovered from the reaction
mixture, as little to no byproduct formation is common to these
room-temperature cross-couplings. Excess alkyl halide is
required, since some of the derived organozinc bromide is
inevitably lost as the protio-quenched material. None of the
starting alkyl halide is recovered from these couplings, and only
trace amounts of alkyl homocoupling have been observed.
Unfortunately, complete conversion was not reached
although much effort has to be made to remedy this situation.
Changing the concentration (to between 0.125 and 0.5 M),
heating the reaction (up to 40 °C), or adding catalyst over time
did not improve results and, in some cases, even gave lower
yields of products. Different amines (triethylamine, pyridine,
hexamethylethylenetetramine, piperidine) were tested, but only
traces of product were detected. Eventually, it was postulated
that ZnBr2 formed during the reaction might be interfering with
the course of these cross-couplings. Indeed, addition of only
0.5 equiv of ZnBr2 at the beginning of the reaction decreased
yields significantly. On the other hand, we have shown earlier
that salts can have a positive impact in related Pd-catalyzed
cross-couplings under micellar catalysis.15 Therefore, different
salts were screened, including LiCl, LiBr, KCl, KBr, NaI, and
NaBr, leading to the observation that addition of sodium
chloride (2 equiv) increased the yield in each of the cross-
coupled products 1−3 (Scheme 3).
Effect of the Pd Catalyst. The catalyst PdCl2(Amphos)2
is especially important for the success of this cross-coupling
reaction. It belongs to a new class of air-stable palladium
catalysts synthesized in 2006 by Guram16 at Amgen. Many
other catalysts (e.g., PdCl2(PPh3)2, PdCl2(PCy3)2, and PdCl2-
(DtBPF)2) were screened under optimized conditions, although
each led to the desired product 2 in low yields (Scheme 4).
Modest results were obtained with PdCl2(PR2Ar)2 analogues,
although they were still far less effective than PdCl2(Amphos)2.
No significant difference in reactivity was found between ligands
L1 and L2, whereas substitution of tert-butyl by cyclohexyl (L3)
on phosphorus affected the yield dramatically (18%). Although
the higher reactivity of PdCl2(Amphos)2 relative to that of this
Table 1. Diameter of Micelles Associated with Surfactants in
Water
a
a
entry
surfactant
size of micelles (nm)
1
2
3
4
5
6
7
Triton X-100
Solutol HS 15
Cremophor EL
TPGS
10
13
16
13
PTS-600
25
Brij 35
15
Brij 30
110
a
Measured by dynamic light scattering (DLS).
surfactant in its surface collisions with zinc may be supplying a
greater “payload” of alkyl halide. Its greater diameter may also
provide a more extensive buffering of the newly forming RZnX
to the surrounding water, thereby increasing opportunities for
this water-sensitive reagent to gain entry into the hydrophobic
micellar core.
Optimization of Conditions. The medium of Brij 30 in
water (4 wt %) was then utilized for further optimization
studies with various alkyl bromides (Table 2). Noteworthy are
the observations that lower catalyst loadings (0.5 vs 2 mol %) and
more globally concentrated solutions (0.330 vs 0.125 M) can be
employed for cross-couplings of alkyl bromides compared to
the corresponding iodides.12 Additionally, the Brij 30−H2O
medium is so effective that less TMEDA (activating agent) is
needed to assist with zinc insertion into alkyl bromides relative
to that required with the PTS−H2O system.12 Bromocyclohex-
ane (2.5 equiv) reacted smoothly with zinc powder and
TMEDA (50 mol %) to give the product 2 in 86% yield (entry
1; 2 mmol scale). With additional TMEDA no improvement
was observed. Switching to zinc dust, which is somewhat
more reactive than zinc powder, the yield was decreased slightly,
due to faster consumption of the alkyl halide. With ethyl
4-bromobutyrate, zinc dust is required, and more TMEDA
(1 equiv) is needed to achieve a 72% yield of 3 (entry 3). An
excess of either TMEDA or bromo ester (3 equiv) gave lower
yields of product 3. The same observations were made for ethyl
6-bromohexanoate (entry 5). The reaction with bromodecane
(1.5 equiv) led to 56% of desired product 1 (entry 6) when an
excess of TMEDA (3 equiv) was present. Control experiments
confirm the crucial role of TMEDA (entries 1 vs 2, 3 vs 4, 6 vs 7)
Table 2. Optimization of Conditions
a
b
c
d
6 mmol of zinc was used in all cases. Isolated yield. In the absence of Brij 30. Run over 72 h.
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Scheme 3. Influence of Salts
Scheme 4. Influence of the Catalyst
catalyst’s bis-desamino analogue (L1) might at first be
attributed to electronic effects, this alone cannot account for
the observed results using more electron-rich ligands; the
explanation is obviously unrelated to steric effects (compare
results with Amphos vs L3). Whatever the reason(s) behind the
success based on the Amphos ligand, there may be a correlation
between its dimethylamino group and the facility with which
Et3N mediates several other metal-catalyzed couplings in
aqueous surfactant media.17 Thus, the Me2N residue may be
increasing the polarity of the catalyst, making it more
hydrotropic and, hence, easier for it to negotiate transport
into, and between, micellar arrays. Although PdCl2(Amphos)2
was routinely employed at the 0.5 mol % level (as in Scheme 4),
dropping the catalyst loading to 0.1 mol % did not significantly
decrease yield (80% vs 86%).
Isomerization. Palladium and nickel-catalyzed coupling
reactions of secondary alkyl organometallic compounds are
known to oftentimes give mixtures of linear and branched
products.18 The reaction has been reinvestigated recently by
Molander19 and Buchwald.20 Under our micellar conditions,
using four different secondary alkyl bromides (Table 3), no
undesired linear product was detected by NMR of the crude
reaction mixture. Surprisingly, a mixture of branched products
(ca. 1:1) was obtained with 3-bromopentane as coupling partner
(entry 3). The challenging case of ethyl 4-bromovalerate gave a
single branched product in 82% isolated yield (entry 4). Thus, it
appears that no isomerization between primary and secondary
carbons occurs and that functional groups can suppress any
isomerization between two secondary centers.
Scope. Table 4 illustrates representative aryl bromides that
have been alkylated. As anticipated for organozinc chemistry in
general, functionality present in both reaction partners is
tolerated, including halides (entries 2−4), esters (entries 1, 2,
and 5), nitrile (entry 6), and ketones (entries 3 and 5). The
case of an especially electron-rich aryl bromide (entry 7)
appeared to couple to the same extent as the more electron-
deficient examples studied, suggesting a lack of sensitivity to
oxidative addition as the rate-determining step. In most cases,
the isolated yield is modest as shown, although this reflects the
extent of conversion and not the cleanliness of these reactions.
It is likely that the use of salts in the medium, in particular
NaCl as noted previously (Scheme 3), would afford improved
results.
As for limitations noted to date, several substrates were
found to be unresponsive under these micellar conditions
(Scheme 5). Thus, bromocyclopropane as well as α- and β-
bromo ester derivatives are quantitatively protio-quenched,
with the aryl bromide being fully recoverable. A nitrile residue
on an alkyl bromide is not well tolerated and gives a low yield
of cross-coupled product. All cases examined where an aryl
bromide contains a relatively acidic hydrogen comparable in
pKa to that of water also fail to afford the desired product in
yields >10%. These observations are independent of the
surfactant involved.
Table 3. Couplings of Secondary Alkyl Bromides
CONCLUSIONS
■
In summary, the direct cross-coupling between alkyl and aryl
bromides has been achieved in water at room temperature.
Required for success in these reactions was a switch in
surfactant from PTS to Brij 30, notwithstanding a seemingly
a
b
c
Determined by NMR. NMR yield of the crude reaction. 5 mmol of
d
2-bromopropane was used. Obtained as a 1:1 mixture of branched
products. Isolated yield. Obtained as only one branched product.
e
f
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Table 4. Scope of the Cross-Coupling Reaction
a
b
Isolated yield. 3 equiv of TMEDA were used (72 h).
Scheme 5. Substrates That Give Low Yields
EXPERIMENTAL SECTION
■
General Considerations. Reactions were performed in a 10 mL
round-bottom flask under an argon atmosphere containing a Teflon-
coated stir bar and septum. All commercially available reagents were
used without further purification. Water was degassed with argon. Brij
30 (CAS No. 9002-92-0) is available from Acros (Catalog No. 21672).
Zinc powder 99.9% (−325 mesh) and zinc dust 97.5% (−325 mesh)
were purchased from Strem Chemicals (Catalog Nos. 93-3060 and 93-
3056) and stored in a glovebox. PdCl2(Amphos)2 (CAS No. 887919-
35-9) was obtained from Johnson Matthey (Pd-132, Catalog No.
C4138). Column chromatography was preformed using Silicycle Silia-P
60 Å flash silica gel. GC analyses were recorded on a Hewlett-Packard
HP 6890 chromatograph equipped with a capillary column HP-1
(30 m × 0.25 mm
́
× 0.25 mm). 1H and 13C NMR spectra were measured
́
on a Varian Unity Inova-500 (500 and 125 MHz, respectively)
spectrometer at ambient temperature. Proton NMR data are given as
follows: chemical shift in ppm referenced from residual solvent peak
(CDCl3, 7.26 ppm), multiplicity (s = singlet; d = doublet; t = triplet;
q = quartet; quintuplet = qt; sext = sextuplet; spt = septuplet; m =
multiplet), coupling constant (Hz), and integration. 13C chemical
shifts are given in ppm from the solvent resonance employed as the
internal standard (CDCl3, 77.00 ppm). Mass spectral data were
acquired on either a VF Autospec or an analytical VG-70-250 HF
instrument.
Solution of Brij 30. Deionized water (250 mL) was degassed by
bubbling argon through it for 4 h. Brij 30 (10 g) was added into an
empty 250 mL round-bottom flask, and then degassed water (240 mL)
was added to the flask. The solution was stirred overnight under an
argon atmosphere.
modest change in going from alkyl iodides to bromides, an
observation that further attests to our limited understanding of
the vagaries of micellar catalysis in synthesis. Nonetheless,
unprecedented zinc insertion has been found to take place and
was used, to great advantage, under remarkably mild room
temperature conditions in the presence of surfactant Brij 30.
The results obtained from this nanotechnology raise many
questions not only with regard to the possibilities of performing
reactive metal chemistry in water as the gross reaction medium
but also, in a broader sense, just what the new “rules” are for
doing transition-metal-catalyzed couplings under the influence
of the hydrophobic effect.
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General Procedure for Cross-Coupling Reactions between
Alkyl and Aryl Bromides. In a 10 mL round-bottom flask under
argon containing zinc (390 mg, 6 mmol) and PdCl2(Amphos)2 (7 mg,
0.01 mmol) was added a solution of 4 wt % Brij 30 (5 mL). N,N,N′,N′-
Tetramethylethylenediamine (TMEDA, 116−696 mg, 1−6 mmol)
was added at room temperature followed by the addition of the alkyl
halide (3−5 mmol) and the aryl bromide (2 mmol). The flask was
stirred vigorously at room temperature for 48 h unless indicated
otherwise. The reaction mixture was then filtered through a plug of
silica (10 g), completely removing excess zinc, all solids, and the
surfactant, which remains at the top of the absorbent. The column was
washed with diethyl ether (70 mL) into a 100 mL flask containing 2 g
of silica, and the solvents were removed under vacuum. The resulting
dry, crude silica was introduced on top of a silica gel chromatographic
column to purify the product.
4-bromobenzoate. HRMS (C13H18O2): m/z calcd 206.1307, found
206.1308.
Ethyl 4-(Pent-3-yl)benzoate (7). From zinc powder (390 mg,
6 mmol), N,N,N′,N′-tetramethylethylenediamine (TMEDA, 116 mg,
1 mmol), 3-bromopentane (596 mg, 4 mmol), and ethyl 4-bromobenzoate
(458 mg, 2 mmol), the product (378 mg) was obtained in 86% yield as
an inseparable mixture from ethyl 4-bromobenzoate. HRMS
(C14H20O2): m/z calcd 220.1463, found 220.1460.
Ethyl 4-[4-(Ethoxycarbonyl)phenyl]pentanoate (8). From
zinc powder (390 mg, 6 mmol), N,N,N′,N′-tetramethylethylenedi-
amine (TMEDA, 116 mg, 1 mmol), ethyl 4-bromovalerate (836 mg,
4 mmol), and ethyl 4-bromobenzoate (458 mg, 2 mmol), the product
(455 mg) was obtained in 82% yield. 1H NMR (400 MHz): δ 7.95 (d,
J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H),
4.07 (q, J = 7.2 Hz, 2H), 2.78 (sxt, J = 7.3 Hz, 1H), 2.14 (m, 2H), 1.90
(m, 2H), 1.38 (t, J = 7.3 Hz, 3H), 1.27 (d, J = 7.2 Hz, 3H), 1.18 (t, J =
7.2 Hz, 3H). 13C NMR (100 MHz): δ 173.3, 166.4, 151.6, 129.7,
128.5, 126.9, 60.7, 60.2, 39.3, 32.8, 32.3, 21.8, 14.3, 14.1. HRMS
(C16H22O4): m/z calcd 278.1518, found 278.1515.
Ethyl 4-[4-(Ethoxycarbonyl)phenyl]pentanoate (9). From
zinc dust (390 mg, 6 mmol), N,N,N′,N′-tetramethylethylenediamine
(TMEDA, 232 mg, 2 mmol), ethyl 5-bromovalerate (627 mg, 3 mmol),
and ethyl 4-bromobenzoate (458 mg, 2 mmol), the product (372 mg)
was obtained in 67% yield. 1H NMR (400 MHz): δ 7.95 (d, J = 8.2 Hz,
2H), 7.24 (d, J = 8.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 4.11 (q, J =
7.2 Hz, 2H), 2.66 (t, J = 7.3 Hz, 2H), 2.30 (t, J = 7.3 Hz, 2H), 1.62
(m, 4H), 1.37 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz): δ 173.7, 166.8, 147.7, 129.8, 128.5, 128.3, 60.9, 60.4, 35.8,
34.3, 30.7, 24.7, 14.5, 14.4. HRMS (C16H22O4): m/z calcd 278.1518,
found 278.1520.
Ethyl 4-Decylbenzoate (1). From zinc dust (390 mg, 6 mmol),
N,N,N′,N′-tetramethylethylenediamine (TMEDA, 696 mg, 6 mmol),
1-bromodecane (660 mg, 3 mmol), and ethyl 4-bromobenzoate (458 mg,
2 mmol), the product (324 mg) was obtained in 56% yield in 72 h. By
adding NaCl (224 mg, 4 mmol) to the reaction mixture in water,
1
the product (394 mg) was obtained in 68% yield after 72 h. H NMR
(400 MHz): δ 7.95 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 4.35
(q, J = 7.2 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 1.62 (m, 3H), 1.39 (t,
J = 7.2 Hz, 3H), 1.25 (m, 14H), 0.89 (t, J = 7.2 Hz, 2H). 13C NMR
(100 MHz): δ 166.9, 148.6, 129.7, 128.5, 128.1, 60.9, 36.2, 32.1, 31.8,
29.8, 29.7, 29.6, 29.5, 29.4, 22.9, 14.5, 14.3. HRMS (C19H30O2): m/z
calcd 290.2246, found 290.2252.
Ethyl 4-Cyclohexylbenzoate (2). From zinc powder (390 mg,
6 mmol), N,N,N′,N′-tetramethylethylenediamine (TMEDA, 116 mg,
1 mmol), bromocyclohexane (818 mg, 5 mmol), and ethyl 4-bromobenzoate
(458 mg, 2 mmol), the product (400 mg) was obtained in 86% yield.
When NaCl (224 mg, 4 mmol) was added to the reaction mixture
in water, the product (417 mg) was obtained in 90% yield. The
corresponding spectroscopic data matched those reported in the
literature for ethyl 4-cyclohexylbenzoate.21 HRMS (C15H20O2): m/z
calcd 232.1463, found 232.1468.
Ethyl 4-[4-(Ethoxycarbonyl)phenyl]butanoate (3; CAS No.
38632-65-4). From zinc dust (390 mg, 6 mmol), N,N,N′,N′-
tetramethylethylenediamine (TMEDA, 232 mg, 2 mmol), ethyl
4-bromobutyrate (780 mg, 4 mmol), and ethyl 4-bromobenzoate
(458 mg, 2 mmol), the product (380 mg) was obtained in 72% yield.
When NaCl (224 mg, 4 mmol) was added to the reaction mixture in
water, the product (443 mg) was obtained in 84% yield. HRMS
(C15H20O4): m/z calcd 264.1362, found 263.1355. The corresponding
spectroscopic data matched those reported in the literature for ethyl
4-[4-(ethoxycarbonyl)phenyl]butanoate.22
5-[4-(Ethoxycarbonyl)phenyl]chloropentane (10). From zinc
dust (390 mg, 6 mmol), N,N,N′,N′-tetramethylethylenediamine
(TMEDA, 232 mg, 2 mmol), 1-bromo-5-chloropentane (742 mg,
4 mmol), and ethyl 4-bromobenzoate (458 mg, 2 mmol), the product
1
(396 mg) was obtained in 78% yield. H NMR (400 MHz): δ 7.96
(d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H),
3.52 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 1.81 (qt, J = 7.2 Hz,
2H), 1.64 (qt, J = 7.2 Hz, 2H), 1.52 (qt, J = 7.2 Hz, 2H), 1.37 (t, J =
7.2 Hz, 3H). 13C NMR (100 MHz): δ 166.9, 148.6, 129.7, 128.5,
128.1, 60.9, 45.2, 36.0, 32.6, 31.1, 28.6, 14.3. HRMS (C14H19ClO2):
m/z calcd 254.1074, found 254.1079.
6-(4′-Acetophenone)chlorohexane (11). From zinc dust (390
mg, 6 mmol), N,N,N′,N′-tetramethylethylenediamine (TMEDA, 232
mg, 2 mmol), 1-bromo-6-chlorohexane (798 mg, 4 mmol), and 4′-
bromoacetophenone (398 mg, 2 mmol), the product (380 mg) was
1
obtained in 80% yield. H NMR (400 MHz): δ 7.83 (d, J = 8.2 Hz,
Ethyl 4-[4-(Ethoxycarbonyl)phenyl]hexanoate (4). From zinc
dust (390 mg, 6 mmol), N,N,N′,N′-tetramethylethylenediamine
(TMEDA, 232 mg, 2 mmol), ethyl 6-bromohexanoate (669 mg,
3 mmol), and ethyl 2-bromobenzoate (458 mg, 2 mmol), the product
2H), 7.26 (d, J = 8.2 Hz, 2H), 3.52 (t, J = 7.2 Hz, 2H), 2.68 (t, J = 7.2
Hz, 2H), 2.57 (s, 3H), 1.75 (qt, J = 7.2 Hz, 2H), 1.64 (qt, J = 7.2 Hz,
2H), 1.47 (qt, J = 7.2 Hz, 2H), 1.35 (qt, J = 7.2 Hz, 2H). 13C NMR
(100 MHz): δ 198.0, 148.6, 135.2, 128.6, 128.7, 45.2, 36.0, 32.6, 31.1,
28.6, 26.8, 26.7. HRMS (C14H19ClO): m/z calcd 238.1124, found
238.1120.
Ethyl 4-(4-Chlorophenyl)butanoate (12; CAS 3435-98-1). From
zinc dust (390 mg, 6 mmol), N,N,N′,N′-tetramethylethylenediamine
(TMEDA, 232 mg, 2 mmol), ethyl 4-bromobutyrate (780 mg, 4 mmol),
and 4-bromochlorobenzene (398 mg, 2 mmol), the product (339 mg)
was obtained in 75% yield. The corresponding spectroscopic data
matched those reported in the literature for ethyl 4-(4-chlorophenyl)-
butanoate.12a HRMS (C12H15ClO2): m/z calcd 226.0761, found
226.0767.
7-[4-(Ethoxycarbonyl)phenyl]2-methylheptan-3-one (13). From
zinc dust (390 mg, 6 mmol), N,N,N′,N′-tetramethylethylenediamine
(TMEDA, 232 mg, 2 mmol), 7-bromo-2-methylheptan-3-one (824 mg,
4 mmol), and ethyl 4-bromobenzoate (458 mg, 2 mmol), the product
(463 mg) was obtained in 84% yield. 1H NMR (400 MHz): δ 7.94 (d,
J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H),
2.67 (t, J = 7.2 Hz, 2H), 2.56 (spt, J = 7.2 Hz, 1H), 2.45 (t, J = 7.2 Hz,
2H), 1.60 (m, 4H), 1.38 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 7.2 Hz, 6H).
13C NMR (100 MHz): δ 216.2, 166.8, 147.9, 129.8, 128.5, 60.9, 41.0,
1
(379 mg) was obtained in 65% yield. H NMR (400 MHz): δ 7.95
(d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H),
4.11 (q, J = 7.2 Hz, 2H), 2.66 (t, J = 7.3 Hz, 2H), 2.27 (t, J = 7.3 Hz,
2H), 1.66 (m, 4H), 1.37 (m, 5H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz): δ 173.8, 166.8, 148.1, 128.8, 128.5, 128.9, 60.9, 60.4, 35.9,
34.4, 30.9, 28.8, 24.9, 14.5, 14.4. HRMS (C17H24O4): m/z calcd
292.1675, found 292.1670.
Ethyl 4-Isopropylbenzoate (5; CAS No. 19024-50-1). From
zinc powder (390 mg, 6 mmol), N,N,N′,N′-tetramethylethylenedi-
amine (TMEDA, 116 mg, 1 mmol), 2-bromopropane (615 mg,
5 mmol) and ethyl 4-bromobenzoate (458 mg, 2 mmol), the product
(265 mg) was obtained in 69% yield as an inseparable mixture from
ethyl 4-bromobenzoate. The corresponding spectroscopic data
matched those reported in the literature for ethyl 4-isopropylben-
zoate.9 HRMS (C12H16O2): m/z calcd 192.1150, found 192.1152.
Ethyl 4-sec-Butylbenzoate (6; CAS No. 860695-72-3). From
zinc powder (390 mg, 6 mmol), N,N,N′,N′-tetramethylethylenediamine
(TMEDA, 116 mg, 1 mmol), 2-bromobutane (548 mg, 4 mmol)
and ethyl 4-bromobenzoate (458 mg, 2 mmol), the product (321 mg)
was obtained in 78% yield as an inseparable mixture from ethyl
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Article
40.2, 36.0, 30.9, 23.5, 18.4, 14.5. HRMS (C17H24O3): m/z calcd
276.1725, found 276.1722.
UCSB: the Harold J. Plous Award in 1984 given each year to a single
Assistant Professor, and a Distinguished Faculty Teaching Award in
2002. Most of the research done in the Lipshutz group has been in the
areas of synthetic methods development and natural products partial
or total synthesis. However, over the past five years, much of the
group’s effort has turned to green chemistry, focused in particular on
“designer” surfactants that enable reactions to be run in water at room
temperature under micellar catalysis conditions. These reactions
include transition-metal-catalyzed cross-couplings, as well as
processes based on organocatalysis, where the goal is to get organic
solvents out of organic reactions. The promise offered by this
technology, that industrial labs will consider switching from massive
usage of organic solvents as reaction media to water as the gross
medium, has very recently been acknowledged in the form of a 2011
Presidential Green Chemistry Challenge Award, given by the U.S.
Environmental Protection Agency.
4-Cyclohexylbenzonitrile (14; CAS 27634-88-4). From zinc
powder (390 mg, 6 mmol), N,N,N′,N′-tetramethylethylenediamine
(TMEDA, 116 mg, 1 mmol), bromocyclohexane (818 mg, 5 mmol),
and 4-bromobenzonitrile (364 mg, 2 mmol), the product (255 mg)
was obtained in 69% yield. 1H NMR (400 MHz): δ 7.57 (d, J = 8.1 Hz,
2H), 7.30 (d, J = 8.1 Hz, 2H), 2.55 (m, 1H), 1.84 (m, 4H), 1.38 (m,
4H), 1.26 (m, 2H). 13C NMR (100 MHz): δ 153.7, 132.4, 127.8,
119.4, 109.7, 44.9, 34.2, 26.8, 26.1. HRMS (C13H15N): m/z calcd
185.1204, found 185.1201. The corresponding spectroscopic data
matched those reported in the literature for 4-cyclohexylbenzonitrile.23
5-Heptyl-1,2,3-trimethoxybenzene (15). From zinc dust (390
mg, 6 mmol), N,N,N′,N′-tetramethylethylenediamine (TMEDA, 448
mg, 3 mmol), 1-bromoheptane (716 mg, 4 mmol), and 5-bromo-1,2,3-
trimethoxybenzene (494 mg, 2 mmol), the product (372 mg) was
obtained in 70% yield. 1H NMR (400 MHz): δ 6.54 (s, 2H), 3.83 (s, 9H),
2.40 (t, J = 7.2 Hz, 2H), 1.65−1.55 (m, 2H), 1.48−1.28 (m, 8H), 0.90
(t, J = 7.0 Hz, 3H). 13C NMR (100 MHz): δ 153.2, 137.7, 105.8, 60.8,
56.1, 36.0, 31.8, 31.2, 29.3, 29.2, 22.7, 14.3. HRMS (C16H26O3): m/z
calcd 266.1881, found 266.1881.
ACKNOWLEDGMENTS
■
We are grateful to the NIH for support (GM 86485) and
Johnson Matthey for generously supplying several palladium
catalysts, including PdCl2(Amphos)2 (Pd-132, Catalog No.
C4138). Dr. S. Ghorai is warmly acknowledged for providing
DLS data.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figures giving product spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
REFERENCES
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu.
■
(1) de Meijere, A.; Diederich, F. Metal Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, Germany, 2004.
(2) (a) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346,
1525. (b) Frisch, A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674.
(c) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656.
(d) Nakamura, M.; Ito., S In Modern Arylation Methods; Ackermann., L.,
Ed.; Wiley-VCH: Weinheim, Germany, 2009; p 155.
Biography
(3) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340.
(b) Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594. (c) Arp,
F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. (d) Smith, S. W.;
Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645. (e) Nakamura, M.; Ito,
S.; Matsuo, K.; Nakamura, E. Synlett 2005, 1794.
(4) (a) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199. (b) Furstner,
̈
A.; Leitner, A.; Men
́
dez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124,
13856. (c) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41,
609. (d) Martin, R.; Furstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955.
̈
̈
(e) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc.
2004, 126, 3686. (f) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(g) Bedford, R. B.; Bruce, D. W.; Frost, R.; M. Hird, M. Chem.
Commun. 2005, 4161. (h) Bedford, R. B.; Betham, M.; Bruce, D. W.;
Danopoulos, A. A.; Frost, R.; Hird, M. J. Org. Chem. 2006, 71, 1104.
(i) Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew. Chem., Int.
Ed. 2007, 46, 4364. (j) Cahiez, G.; Duplais, C.; Moyeux, A. Org. Lett.
Photo provided by Bruce Lipshutz
2007, 9, 3253. (k) Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008, 41,
1500. (l) Vechorkin, O.; Hu, X. J. Am. Chem. Soc. 2009, 131, 9756.
(m) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264.
(5) (a) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett.
1992, 691. (b) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340.
̈
Bruce Lipshutz was born on December 10, 1951, in the Washington
Heights section of Manhattan. He attended the Bronx High School of
Science (1969) and then went upstate as an undergraduate at Harpur
College within the State University of New York at Binghamton. His
instructor for sophomore organic chemistry was Howard Alper, with
whom he eventually did senior honors research, defending his thesis in
1973. Ph.D. studies were subsequently carried out at Yale with Harry
Wasserman (1977), prior to a two-year stint as an American Cancer
Society Postdoctoral Fellow at Harvard in the labs of E. J. Corey. At
age 27, he began his professorial career at UC Santa Barbara in 1979
and was promoted to Associate Professor in 1984 and Professor in
1987. During these early years he received several awards for research,
including those in 1984 from the Alfred P. Sloan Foundation, and the
Camille & Henry Dreyfus Foundation (Teacher-Scholar Award). In
1997, he received an American Chemical Society Cope Scholar Award.
He has also been the recipient of the two top teaching awards at
́
(c) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360.
(d) Duncton, M. A. J.; Estiarte, M. A.; Tan, D.; Kaub, C.; O’Mahony,
D. J. R.; Johnson, R. J.; Cox, M.; Edwards, W. T.; Wan, M.; Kincaid, J.;
Kelly, M. G. Org. Lett. 2008, 10, 3259. (e) Saito, B.; Fu, G. C. J. Am.
Chem. Soc. 2007, 129, 9602. (f) Saito, B.; Fu, G. C. J. Am. Chem. Soc.
2008, 130, 6694. (g) Lundin, P. M.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 11027.
(6) Powell, D. A.; Maki, T.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
510.
(7) (a) Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788.
(b) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew. Chem., Int. Ed.
2007, 46, 3556. (c) Dai, X.; Strotman, N. A.; Fu, G. C. J. Am. Chem.
Soc. 2008, 130, 3302.
6096
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Article
(8) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010,
132, 920.
(9) Cahiez, G.; Foulgoc, L.; Moyeux, A. Angew. Chem., Int. Ed. 2009,
48, 2969.
(10) (a) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q.
J. Am. Chem. Soc. 2006, 128, 78. (b) Deng, G.; Zhao, L.; Li, C.-J.
Angew. Chem., Int. Ed. 2008, 47, 6278. (c) Ackermann, L.; Novak
́
, P.;
Vincente, R.; Hofman, N. Angew. Chem., Int. Ed. 2009, 48, 6045.
(11) Czaplik, W. M.; Mayer, M.; von Wangelin, A. J. Angew. Chem.,
Int. Ed. 2009, 48, 607.
(12) (a) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc.
2009, 131, 15592. (b) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. Org.
Lett. 2010, 12, 4742.
(13) (a) Duplais, C.; Krasovskiy, A.; Wattenberg, A.; Lipshutz, B. H.
Chem. Commun. 2010, 562. (b) Krasovskaya, V.; Krasovskiy, A.;
Bhattacharjya, A.; Lipshutz, B. H. Chem. Commun. 2011, 5717.
(c) Krasovskaya, V.; Krasovskiy, A.; Lipshutz, B. H. Chem. Asian
J. 2011, 6, 1974.
(14) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040.
(15) Lipshutz, B. H.; Ghorai, S.; Leong, W. Y.; Taft, B. R.; Krogstad,
D. V. J. Org. Chem. 2011, 76, 5061.
(16) (a) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel,
L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli,
M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787. (b) Guram, A. S.; Wang, X.;
Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J. J. Org. Chem.
2007, 72, 5104.
(17) Lipshutz, B. H.; Ghorai, S. Aldrichim. Acta 2008, 41, 59.
(18) (a) Tamao, K.; Kiso, Y.; Sumitani, K.; Kumada, M. J. Am. Chem.
Soc. 1972, 94, 9268. (b) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada,
M.; Higuchi, T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158.
(19) Dreher, S. D.; Dormer, P.; Sandrock, D.; Molander, G. A. J. Am.
Chem. Soc. 2008, 130, 9257.
(20) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532.
(21) Luo, X.; Zhang, H.; Duan, H.; Liu, Q.; Zhu, L.; Zhang, T.; Lei, A.
Org. Lett. 2007, 9, 4571.
(22) Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S. Bull.
Chem. Soc. Jpn. 1972, 45, 1825.
(23) Itou, T.; Yoshimi, Y.; Morita, T.; Hatanaka, M.; Tokunaga, Y.
Tetrahedron 2009, 65, 263.
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