"nok": A phytosterol-based amphiphile enabling transition-metal-catalyzed couplings in water at room temperature

Article abstract of DOI:10.1021/jo401744b

The third-generation designer amphiphile/surfactant, "Nok" (i.e., SPGS-550-M; β-sitosterol methoxypolyethyleneglycol succinate), soon to be commercially available from Aldrich, can be prepared in two steps using an abundant plant feedstock and β-sitosterol, together with succinic anhydride and PEG-550-M. Upon dissolution in water, it forms nanomicelles that serve as nanoreactors, which can be characterized by both cryo-TEM and dynamic light scattering analyses. Several transition-metal-catalyzed reactions have been run under micellar conditions to evaluate this surfactant relative to results obtained in nanoparticles composed of TPGS-750-M (i.e., a second-generation surfactant). It is shown that Nok usually affords yields that are, in general, as good or better than those typically obtained with TPGS-750-M, and yet is far less costly.

Full text of DOI:10.1021/jo401744b

Article
pubs.acs.org/joc
“Nok”: A Phytosterol-Based Amphiphile Enabling Transition-Metal-
Catalyzed Couplings in Water at Room Temperature
Piyatida Klumphu and Bruce H. Lipshutz*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: The third-generation designer amphiphile/surfactant, “Nok” (i.e., SPGS-550-M; β-sitosterol methoxypolyethy-
leneglycol succinate), soon to be commercially available from Aldrich, can be prepared in two steps using an abundant plant
feedstock and β-sitosterol, together with succinic anhydride and PEG-550-M. Upon dissolution in water, it forms nanomicelles
that serve as nanoreactors, which can be characterized by both cryo-TEM and dynamic light scattering analyses. Several
transition-metal-catalyzed reactions have been run under micellar conditions to evaluate this surfactant relative to results obtained
in nanoparticles composed of TPGS-750-M (i.e., a second-generation surfactant). It is shown that Nok usually affords yields that
are, in general, as good or better than those typically obtained with TPGS-750-M, and yet is far less costly.
amphiphile should be chosen wisely to align with the “12
Principles of Green Chemistry”;10 that is, it should be “benign
by design”11 and, hence, environmentally innocuous. To meet
these crucial criteria of solvent assistance and environmental
acceptance, our first- and second-generation surfactants were
formulated as (racemic) vitamin E derivatives: initially PTS12
and more recently TPGS-750-M13 (Figure 1). Both, as items of
INTRODUCTION
■
By far the greatest contributor to organic waste, estimated to be
as much as 85% or more, created by the chemical enterprise is
in the form of usually hazardous organic solvents.1 Minimizing
their use in general,2 at any scale, whether at industrial,
governmental, or academic laboratories, is an especially
important goal not only insofar as the teachings of green
chemistry are concerned, but also for sustainability in general.
And while several alternative reaction media exist as options,3
the most generally preferred medium is water.4 Of course,
substrate solubility issues oftentimes preclude use of water as a
true solvent, especially at ambient temperatures, and hence,
significant heating (e.g., via microwave)5 may be necessary.6
One attractive alternative, akin to the approach taken by nature,
is to apply the well-known concepts of micellar catalysis,7 where
an amphiphile is solubilized in water and (above its critical
micelle concentration) spontaneously forms nanoparticles, the
cores of which provide the organic medium in which
homogeneous catalysis can take place. With the spacial capacity
of these nanomicelles being limited (by controlling the amount
of amphiphile used), high concentrations of reactants and
catalyst result, and the chemistry oftentimes ensues without
recourse to heat.8 Reactions run under these very mild
conditions are typically very clean.
Figure 1. Structural comparison of first two generations of surfactants:
PTS (1), TPGS-750-M (2).
Since nanomicelles supply, by virtue of their inner lipophilic
cores, minimum amounts of the reaction solvent, and given the
huge role that organic solvents play in organic reactions,9 the
nature of the surfactant can oftentimes be crucial in
determining the success of a given reaction. Moreover, the
Received: August 8, 2013
© XXXX American Chemical Society
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commerce, enable a growing library of “name” (cross-coupling)
reactions to be conducted in water at room temperature.8 In an
effort to further reduce, in general, the cost of these
amphiphiles by avoiding the high variability in the supply of
racemic vitamin E, we have designed a third-generation
surfactant. In this case, we chose the natural phytosterol β-
sitosterol (Figure 2), which is a cholesterol mimic14 used widely
Figure 4. Neat surfactants; (A) TPGS-750-M, (B) Nok.
are waxy solids at room temperature. Dynamic light scattering
(DLS)15 experiments indicate that Nok and analogue SPGS-
600 (prepared with PEG-600 instead of MPEG-550) lead to
nanoparticles that are similar in size to those found with TPGS-
750-M (Table 1). Elongating the PEG/MPEG chain, on
Table 1. Average Diameter of Surfactants in Water
a
surfactant
average diameter (nm)
TPGS-750-M
TPGS-1000
49
15
46
59
14
25
25
23
10
Nok (SPGS-550-M)
SPGS-600
SPGS-750-M
SPGS-1000
Figure 2. Structures of several common sterols.
b
CPGS-750-M
in the food industry, as the lipophilic portion. Taken together
with a succinate (diester) spacer and MPEG-550 (a
monomethylated polyethylene glycol), the amphiphile β-
sitosterol methoxypolyethyleneglycol succinate (SPGS-550-M)
results, more easily referred to as “Nok” (Figure 3). In this
PTS
c
PSS
a
Micelle size was determined by dynamic light scattering (DLS) at 2
b
wt % concentration in degassed water. Cholesterol methoxypoly-
ethyleneglycol succinate. β-sitosterol polyethyleneglycol sebacate.
c
average, leads to smaller particles. Thus, while the commonly
used excipient TPGS-1000 exists as ca. 15 nm spheres, TPGS-
750-M was engineered to give larger nanomicelles that provide
increased internal volume capacity and greater surface area (and
hence, greater binding constants) for reactions to occur.13
Likewise, Nok was designed to form nanoparticles in the 45−
60 nm range in water, and this was accomplished using MPEG-
550. The larger (M)PEGs, such as MPEG-750 and PEG-1000,
led to smaller nanomicelles (14 and 25 nm, respectively), the
chemistry in which was also, as expected, less effective (vide
infra).
Although the average size of TPGS-750-M and Nok
nanoparticles is roughly comparable (as determined by DLS),
the particle shape for each is remarkably dissimilar. Cryo-TEM
images show that while TPGS-750-M forms mainly spherical
particles,13 Nok forms an intricate array of worm-like micelles
(Figure 5). The difference in cost between the two surfactants
is also nontrivial: thus, while MPEG-550 and MPEG-750 are
comparably priced, β-sitosterol (which is supplied as a mix of
sterols; Figure 2) is far less costly than is racemic vitamin E.
Since the procedure used to make each surfactant leads to high
overall yields, the overriding factor comes down to the choice
of the lipophilic component.
Figure 3. Structure of the third-generation surfactant Nok (average
MW 1056).
report, therefore, we document the design, preparation, and
physical features of Nok, and its direct comparison in terms of
enabling cross-coupling chemistry in aqueous media with its
second-generation precursor TPGS-750-M.
RESULTS AND DISCUSSION
■
Nok vs TPGS-750-M: Distinguishing Features. Both
Nok and TPGS-750-M are composed of a succinic acid spacer
group and an MPEG that balance the lipophilicity of the sterol
and vitamin E residues, respectively. The hydrophilic−lipophilic
balance for Nok is 10, as it is for PTS, while that for TPGS-750-
M is 13, indicative of its somewhat greater hydrophilic
character. Nok relies on a naturally occurring plant steroid,
the hydrocarbon in which is predominantly cyclic in nature,
while the latter contains mainly a linear array of nonpolar
groups. Second, the appearance of neat material is different, as
illustrated in Figure 4, although both TPGS-750-M and Nok
Synthesis of Nok. Nok was synthesized in two steps
(Scheme 1) following the published route used for the
preparation of TPGS-750-M.13 The isolable solid intermediate,
β-sitosterol succinate, was formed initially from treatment of β-
sitosterol with succinic anhydride (1.6 equiv) in the presence of
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Table 2. Surfactant Screening: Olefin Cross-Metathesis
a
entry
surfactant
none
conversion (%)
1
2
3
4
5
6
7
8
9
30
77
76
71
63
63
44
71
62
TPGS-750-M
Nok
SPGS-600
SPGS-750-M
SPGS-1000
CPGS-750-M
PTS
Figure 5. Cryo-TEM image of (A) TPGS-750-M; (B) Nok.
Scheme 1. Two-Step Synthesis of Nok from β-Sitosterol
PSS
a
Determined by 1H NMR spectroscopy. Conditions: 0.5 mmol alkene,
1.5 mmol MVK (3 equiv).
seen in many related situations.16,17 Nok analogues bearing
longer PEG chains (entries 4−6) gave modest results, although
in all cases slower reactions and lower levels of conversion were
seen. Perhaps most informative is the comparison between Nok
and the structurally related cholesterol-derived amphiphiles
CPGS-750-M (entry 7) and PSS (entry 9), which form ca. 25
nm particles in water and are not as effective notwithstanding
their very similar lipophilic core (Figure 6). Clearly, larger
micelles on the order of ca. 50−60 nm in diameter appear to
afford the best results.
Et3N. The resulting carboxylic acid was then esterified with a
PEG-diol or monomethylated-PEG (MPEG) to afford several
related surfactants varying in their PEG length, including Nok,
SPGS-600, SPGS-750-M, and SPGS-1000. This second step
was performed using a Dean−Stark trap that helped eliminate
water efficiently from the reaction. Couplings with PEG-diols
PEG-600 and PEG-1000 gave the expected lower yields from
double esterification taking place at each terminus of these
1
diols. The structure of each surfactant was elucidated by H
NMR, 13C NMR, MS, and IR data. Although Nok could be
used as obtained from these two steps, it invariably contained
ca. 5+% of β-sitosterol, originating from transesterification of
the initial succinate ester. If desired, this “impurity” could be
removed by simple flushing through a silica gel column with
hexanes followed by 50% v/v of EtOAc/hexanes. Both the silica
gel and recovered mix of solvents could be recycled for this
purpose. Alternatively, its presence in most subsequent
coupling reaction mixtures was of no apparent consequence.
Representative Reactions: Nok vs TPGS-750-M. As
noted earlier (vide supra), Nok was designed to be
economically attractive relative to the vitamin E-based
surfactants PTS and TPGS-750-M. However, as was true for
replacement of PTS by TPGS-750-M, the chemistry in Nok
would have to be, in general, as good or better than that
enabled by its second-generation precursor. Thus, an extensive
study of side-by-side comparison reactions between Nok and
TPGS-750-M was undertaken.
Figure 6. Various amphiphiles studied.
A series of olefin cross- and ring-closing metathesis reactions
was conducted to compare and contrast the quality of these
couplings in each surfactant, with results shown in Table 3.
Under otherwise identical conditions, reactions in 2 wt % Nok/
H2O provide similar yields without additional optimization.
The encouraging results provided an early indication that
nanomicelles composed of Nok can readily replace those
formed by TPGS-750-M, thereby further reducing the cost of
this micellar catalysis. Notably, standard use of chlorinated
reaction solvents can be avoided.18
Olefin Metathesis Reactions. An initial screening in a
challenging cross-metathesis (CM) reaction involving methyl
vinyl ketone (MVK) mediated by the Grubbs-2 catalyst
revealed that both surfactants gave the same level of conversion
under a given set of conditions (in water at rt; Table 2, entries
2, 3). The background reaction “on water” (i.e., in the absence
of a surfactant; entry 1) was minimal and not competitive, as
These reactions undergo a change in appearance over time
(Figure 7). Initially, the mixture appears quite heterogeneous,
becoming brightly colored and pseudohomogeneous with
continued stirring over time. After 4 h, the mixture appears
consistently milky.
The impact of pH on olefin CM reactions under these
aqueous conditions was evaluated, as previously it had been
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Table 3. Cross- and Ring-Closing Metathesis: Nok vs TPGS-750-M
a
b
c
Isolated yield of chromatographically pure materials. Conditions: alkene (0.5 mmol, 1 equiv), MVK (1.5 mmol, 3 equiv). Reaction: alkene (0.5
d
mmol, 1 equiv), acrylate (1.0 mmol, 2 equiv). Reaction: diene (0.25 mmol).
M was made for several Pd-catalyzed cross-couplings involving
both C−C as well as C−heteroatom bond constructions. Thus,
in the former category the following name reactions were
examined: Suzuki−Miyaura, Sonogashira, Heck, Stille, and
Negishi-like couplings. Studies on carbon−heteroatom bond
formation included aminations (C−N) and Miyaura boryla-
tions (C−B). As with prior studies (vide supra), all reactions
were run on the same scale and in water at ambient
temperature (ca. 23 °C).
Suzuki−Miyaura reactions between aryl bromides and
arylboronic acids19 in 2 wt % surfactant in water are shown
in Table 5. Both activated and deactivated substrates provided
nearly quantitative yields of desired products. Reactions in Nok
give results comparable to those seen using TPGS-750-M in all
cases. These reactions are complete in 2−11 h without
byproduct formation at room temperature (other than some
homocoupling from the excess boronic acid present). These
reactions tolerate a variety of functional groups, including
cyano- and trifluoromethyl moieties (entries 1, 4). The reaction
conditions are also applicable to heteroaromatics in both
coupling partners (entry 3).
Figure 7. Appearance of a cross-metathesis reaction (Table 3, entry 1)
at different reaction times.
shown that by lowering the pH to ca. 2−3, the desired alkenes
can be formed at a far greater rate by protonation of a
phosphine ligand, thereby freeing a coordination site on the
ruthenium catalyst.13a Hence, by adding a small amount of
KHSO4 salt (0.02 M) into each reaction mixture, the coupling
rate of the otherwise challenging type II olefin MVK is
significantly enhanced (Table 4). Again, both amphiphiles gave
comparable yields.
Pd-Catalyzed Cross-Couplings. An extensive study compar-
ing aqueous solutions of Nok with those containing TPGS-750-
A similar trend was observed in Sonogashira couplings.
Previously reported comparisons between TPGS-750-M and
PTS were made in 3.0 wt % surfactant/water.20 In this study, all
the reactions have been done with a lower concentration of
amphiphile, at 2.0 wt % surfactant/water, and the yields were
maintained (Table 6). Aromatic and heteroaromatic substrates
bearing electron-donating or electron-withdrawing groups
readily participated. Only with the phenylacetylene/p-bromo-
benzonitrile pair (entry 3) did a lower isolated yield result,
although this is likely due to the highly crystalline nature of the
bromide that can give varying results based on the effectiveness
of stirring from reaction to reaction.
Table 4. Effect of pH on Olefin Cross-Metathesis Reactions
in Water at rt
a
surfactant
time (h)
conversion (%)
2.0 wt % TPGS-750-M
12
12
4
77
76
86
84
2.0 wt % Nok
0.02 M KHSO4/2.0 wt % TPGS-750-M
0.02 M KHSO4/2.0 wt % Nok
4
Heck couplings of both aryl bromides and aryl iodides in 2.0
wt % surfactant/water were also compared. Aryl bromides
reacted more slowly than did aryl iodides, as expected. Thus,
a
Determined by 1H NMR spectroscopy. Conditions: 0.5 mmol alkene
and 1.5 mmol MVK (3 equiv).
D
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Table 5. Suzuki−Miyaura Couplings Reactions: Nok vs TPGS-750-M
a
Isolated yields of chromatographically pure materials. Reaction conditions: alkyl bromide (0.5 mmol, 1 equiv), boronic acid (0.75−1.00 mmol),
triethylamine (3 equiv), catalyst Pd(dtbpf)Cl2 (2 mol %), and 2 wt % of surfactant/H2O.
Table 6. Sonogashira Couplings: Nok vs TPGS-750-M
a
Isolated yields of chromatographically pure materials. Reaction conditions: alkyl bromide (0.5 mmol, 1 equiv), boronic acid (0.65−1.00 mmol),
XPhos (2.5 mol %), triethylamine (3 equiv), catalyst Pd(CH3CN)2Cl2 (2 mol %), and 2 wt % of surfactant/H2O.
while the coupling shown in Table 7 (entry 5) required 72 h to
reach completion in 2 wt % Nok/H2O, the reaction time was
reduced to 19 h (Table 8, entry 4) with 5 wt % Nok in water
and the trivial addition of NaCl. Both acrylate and styrene-type
partners react smoothly in both surfactants, giving comparable
yields. As with PTS and TPGS-750-M, the presence of NaCl in
Nok/water leads to a “salting out” effect,21 which increases
reaction rates in Heck couplings.12 This may be due to
increased particle size and the resulting opportunity for educts
and catalyst to spend more time within the lipophilic cores of
these nanoparticles and less time exchanging between smaller
micelles (i.e., have greater binding constants). The specific
impact on Nok is illustrated in Figure 8, documenting (via
DLS) that with increasing levels of salt concentration, particle
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Table 7. Heck Couplings in Nok vs TPGS-750-M
a
Isolated yields of chromatographically pure materials. Reaction conditions: alkyl bromide (0.5 mmol, 1 equiv), acrylate/styrene (1.00 mmol, 2
equiv), triethylamine (3 equiv), catalyst, Pd(t-Bu3P)2 (2 mol %), and 2 wt % of surfactant/H2O.
surrogates25 (entries 3, 4) are presented in Table 11. The
Table 8. Effect of NaCl Concentration on a Heck Reaction
of an Aryl Bromide
former proceed as observed previously at room temperature to
give unsymmetrical diarylamines,24 while the latter were
conducted at 50 °C. By increasing the catalyst loading from
0.5 to 2 mol % and increasing the ligand from 2 to 4 mol %,
aminations with ammonia equivalents, such as a carbamate, can
be conducted in water at room temperature.25 Use of an in-situ-
generated base derived from KOH/TIPSOH helps to further
accelerate this reaction, leading to full conversion in 15 h.
Identical results were obtained in either surfactant, Nok or
TPGS-750-M (Table 12).
a
entry
NaCl concentration (M)
yield (%)
1
2
3
4
0
1
2
3
29
57
76
90
a
Isolated yield of chromatographically pure materials. Reaction
Another example of a valued Pd-catalyzed cross-coupling is
that between an aryl and alkyl halide, mediated by in-situ-
generated organozinc halides (i.e., Negishi-like couplings), as
we previously reported (Table 13).13a In order to avoid prior
formation of an organozinc halide, portion-wise addition of an
alkyl halide partner to the Pd catalyst, Zn dust, and TMEDA
leads to the desired cross-coupling reaction in both surfactants
over 48 h. Dehalogenated byproducts were observed by GCMS,
albeit in less than 5%. After chromatographic purification, 85
and 86% of the product was obtained in TPGS-750-M and
Nok, respectively.
Recycling of Nok. To assess the opportunity to recycle the
aqueous phase containing Nok, a Suzuki−Miyaura coupling was
examined as a representative reaction. Each cycle was followed
by a standard in-flask extraction of the product using minimal
amounts of an organic solvent (e.g., EtOAc, 3 times). To the
aqueous phase remaining in the flask, fresh catalyst, base, and
coupling partner were reintroduced. After six cycles, the
reaction afforded the same full conversion to the desired
product (Table 14), confirming that the surfactant remains
conditions: bromobenzene (0.5 mmol, 1 equiv), t-butyl acrylate
(1.00 mmol, 2 equiv), triethylamine (3 equiv), catalyst, Pd(t-Bu3P)2 (2
mol %), NaCl, and 5 wt % of surfactant/H2O.
size goes up correlating with, in the case of Heck reactions in 5
wt % Nok, an increasing rate of reaction: no NaCl, 1 M, 2 M,
and 3 M gave 29, 57, 76, and 90% yield, respectively (Table 8).
Stille couplings22 proceeded smoothly with full conversion in
relatively short periods of time, using either surfactant. Similar
to Heck reactions (vide supra), the presence of NaCl
accelerates these couplings. A variety of substrates has been
examined (Table 9), with most leading to high yields of the
desired products. The enol ether obtained in moderate yield
(entry 3) reflects its volatility on isolation and not the extent of
conversion or the quality of bond formation.
For carbon−heteroatom bond formations, Miyaura boryla-
tions23 and aminations were selected as representative
examples. Borylations of aryl bromides with B2pin2 afford
good yields using either TPGS-750-M or Nok (Table 10).
Amination reactions using either aryl amines24 or ammonia
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Figure 8. Particle size of Nok in water as a function of wt % and NaCl concentration.
Table 9. Comparison of Nok vs TPGS-750-M in Stille Couplings
a
Isolated yields of chromatographically pure materials. Conditions: aryl bromide (0.25 mmol, 1 equiv), stannyl reagent (0.275 mmol, 1.1 equiv),
catalyst Pd(t-Bu3P)2 (2 mol %), base DABCO (3 equiv), NaCl (1 equiv) and 2 wt % surfactant/H2O.
available in the water for continuous service in this micellar
catalysis.
tinely run in water-miscible solvents, and hence, the wastewater
produced contains organic waste. Moreover, calculation of an
associated E Factor can lead to insight as to how low these
numbers can be even when water is included, since these
reactions typically run at high global concentrations. As
illustrated in Scheme 2, the E Factors are very low, reflecting
both the high yield of the coupling and the minimum
investment of both organic solvent and water in the overall
process. Clearly, with options for recycling of the aqueous
reaction medium, E Factors that include water go down even
further. By way of comparison, typical E Factors (organic
E Factor Determination. As an indication of the potential
environmental savings these couplings offer insofar as organic
waste is concerned, an E Factor4,26 determination was made
using a Suzuki−Miyaura coupling as a model case (Scheme 2)
on the basis of (1) the total organic solvent used in the reaction
and extractive workup, and (2) the combined organic solvent
use and water associated with the coupling. Although this latter
number is historically not part of the E Factor calculation given
the oftentimes large volumes of water involved,4 it is useful
nonetheless since Suzuki−Miyaura cross-couplings are rou-
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Table 10. Nok vs TPGS-750-M in Miyaura Borylations
Table 12. Amination in Nok vs TPGS-750-M
a
surfactant
yield (%)
TPGS-750-M
98
Nok (SPGS-550-M)
98
a
Isolated yields.
Table 13. Negishi-like Coupling in Nok vs TPGS-750-M
a
surfactant
yield (%)
TPGS-750-M
85
Nok (SPGS-550-M)
86
a
Isolated yields.
a
Isolated yields of chromatographically pure materials. Conditions:
successive esterification reactions of inexpensive β-sitosterol
with succinic anhydride, followed by esterification of the
resulting acid with MPEG-550. The resulting surfactant, which
is currently an item of commerce (Aldrich catalog number
776033), forms nanometer-sized micelles in water that
accommodate various types of Ru- and Pd-catalyzed coupling
reactions, almost all of which take place at room temperature.
These studies document that the newly engineered surfactant
Nok can substitute in most types of reactions for the second-
generation amphiphile TPGS-750-M that is based on the more
expensive (racemic) vitamin E.
aryl bromide (0.5 mmol, 1 equiv), B2pin2 (0.55 mmol, 1.1 equiv),
catalyst Pd(t-Bu3P)2 (3 mol %), KOAc (3 equiv), and 2 wt % of
surfactant/H2O.
solvent only) in the pharmaceutical industry range from 25 to
100.4
CONCLUSIONS
■
The third-generation sterol-based surfactant, Nok (SPGS-550-
M), has been efficiently prepared in two steps via two
Table 11. Nok vs TPGS-750-M in Amination Reactions
a
b
Isolated yields. Reaction conditions: aryl bromide (1.00 mmol, 1 equiv), toluidine (1.20 mmol, 1.2 equiv), catalyst [(π-allyl)PdCl]2 (0.5 mol %),
c
cBRIDP (2 mol %), K-O-t-Bu (1.5 equiv), and 2 wt % of surfactant/H2O, at rt. Na-O-t-Bu (1.5 equiv); reaction was run at 50 °C, 24 h using [(π-
allyl)PdCl]2 (0.5 mol %), cBRIDP (2 mol %), K-O-t-Bu (1.5 equiv) and 2 wt % of surfactant/H2O. Reaction conditions: aryl bromide (1.00 mmol,
1 equiv), t-butyl carbamate (1.50 mmol, 1.5 equiv). Reaction conditions: aryl bromide (0.50 mmol, 1 equiv), ethyl carbamate (0.60 mmol, 1.2
d
e
equiv).
H
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Nok (SPGS-550-M; <10 g scale). β-Sitosterol succinate (4.00 g,
7.77 mmol), MPEG-550-M (6.41 g, 11.7 mmol), and p-TsOH (0.21g,
1.11 mmol) were added into a 100 mL round-bottom flask. Toluene
(40 mL) was added via syringe, and then the mixture was refluxed
using a Dean−Stark trap until complete. After cooling to rt, the
mixture was poured into saturated aqueous NaHCO3 and extracted
with DCM. The combined organic extracts were washed with
saturated aqueous NaHCO3 (3 × 50 mL), brine (2 × 80 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure to
afford a pale yellow, viscous liquid. The oil was poured on top of a
silica gel bed and then first eluted with 50% v/v EtOAc/hexane to
remove an impurity, followed by 10% MeOH/DCM to obtain the
product. Concentration under vacuum followed by storage under high
vacuum overnight afforded Nok as an off-white waxy solid (7.61 g,
92%): IR (neat) 2935, 2868, 1731, 1465, 1345, 1280, 1242, 1107,
1030, 1003, 963, 843, 668, 556 cm−1; 1H NMR (400 MHz, CDCl3) δ
5.37−5.33 (d, J = 3.7 Hz, 1H), 4.66−4.54 (m, 1H), 4.28−4.18 (t, J =
4.6 Hz, 2H), 3.74−3.51 (m, PEG), 3.39 (s, 3H), 2.66−2.56 (m, 4H),
2.32−2.26 (d, J = 7.6 Hz, 2H), 2.02−0.61 (m, 45H); 13C NMR (500
MHz, CDCl3) δ; 171.85, 171.10, 139.15, 122.23, 73.85, 71.54, 70.18,
68.65, 63.37, 58.57, 56.28, 55.64, 49.62, 45.41, 41.91, 39.33, 37.67,
36.58, 36.17, 35.74, 33.54, 31.55, 29.00, 28.66, 27.85, 27.34, 25.70,
23.90, 22.68, 20.05, 19.47, 18.92, 18.71, 18.43, 11.61, 11.49; MS (ESI)
m/z 1079 [M + Na]+.
Table 14. Recycling of Nok in Water
a
cycle (% conversion)
1
2
3
4
5
6
>99
>99
>99
>99
>99
>99
a
Determined by 1H NMR spectroscopy at 400 MHz. Reaction
conditions: alkyl bromide (0.5 mmol, 1 equiv), boronic acid (1.00
mmol), triethylamine (3 equiv), Pd(dtbpf)Cl2 (2 mol %), and 2 wt %
of surfactant/H2O.
Scheme 2. E Factor Model Reaction
General Procedure for Cross-Metathesis (Table 3). Grubbs
second-generation catalyst (8.5 mg, 0.010 mmol) was charged under
an Ar atmosphere into a 2−5 mL microwave vial containing a
magnetic stir bar and Teflon-lined septum. The alkene (0.50 mmol)
and acrylate (1.00 mmol) or ketone (1.50 mmol) were added
sequentially into the vial, and then an aliquot of surfactant solution
(1.0 mL, 2 wt % in degassed water) was added via syringe under a
positive flow of Ar. The reaction was allowed to vigorously stir for 12−
18 h at rt. The reaction mixture was then diluted with EtOAc and
passed through a silica gel bed and further washed with EtOAc to
collect the coupling product. All volatile solvents were removed in
vacuo to obtain crude product, which was further purified by flash
chromatography on silica gel.
(E)-5-(2-((t-Butyldimethylsilyl)oxy)phenyl)pent-3-en-2-one (Table
3, entry 1). Following the general procedure using (2-allylphenoxy)(t-
butyl)dimethylsilane (124 mg, 0.50 mmol), methyl vinyl ketone (106
mg, 1.50 mmol), and Grubbs second-generation catalyst (8.5 mg,
0.010 mmol), the reaction was allowed to stir for 12 h. After column
chromatography, the product was obtained as a colorless liquid (110
mg, 74%): 1H NMR (400 MHz, CDCl3) δ 7.15−7.09 (td, J = 7.6, 1.7
Hz, 1H), 7.09−7.06 (dd, J = 7.6, 1.7 Hz, 1H), 6.98−6.85 (m, 2H),
6.83−6.78 (dd, J = 9.0, 1.0 Hz, 1H), 6.03−5.95 (dt, J = 1.7, 16.1 Hz,
1H), 3.54−3.48 (dd, J = 8.0, 1.5 Hz, 2H), 2.21 (s, 3H), 0.98 (s, 9H),
0.26 (s, 6H).13a
(E)-t-Butyl 4-(2-((t-butyldimethylsilyl)oxy)phenyl)but-2-enoate
(Table 3, entry 2). Following the general procedure using (2-
allylphenoxy)(t-butyl)dimethylsilane (124 mg, 0.50 mmol), t-butyl
acrylate (128 mg, 1.00 mmol), and Grubbs second-generation catalyst
(8.5 mg, 0.010 mmol), the reaction was allowed to stir for 12 h. After
column chromatography, the product was obtained as a colorless
liquid (149 mg, 86%): 1H NMR (400 MHz, CDCl3) δ 7.16−7.08 (m,
2H), 7.05−6.96 (dt, J = 15.4, 6.6 Hz, 1H), 6.94−6.88 (td, J = 7.5, 1.2
Hz, 1H), 6.84−6.79 (dd, J = 7.9, 1.2 Hz, 1H), 5.72−5.65 (dt, J = 15.6,
1.7 Hz, 1H), 3.50−3.45 (dd, J = 6.5, 1.7 Hz, 2H), 1.47 (s, 9H), 1.01 (s,
9H), 0.25 (s, 6H).16
t-Butyl (E)-4-(4-methoxyphenyl)but-2-enoate (Table 3, entry 3).
Following the general procedure using 1-allyl-4-methoxybenzene (74
mg, 0.50 mmol), t-butyl acrylate (128 mg, 1.00 mmol), and Grubbs
second-generation catalyst (8.5 mg, 0.010 mmol), the reaction was
allowed to stir for 24 h. After column chromatography, the product
could not be fully separated from excess acrylate; it was obtained as a
colorless liquid (105 mg, 84%): 1H NMR (400 MHz, CDCl3) δ 7.13−
7.07 (d, J = 8.5 Hz, 2H), 7.03−6.94 (dt, J = 15.6, 6.6 Hz, 1H), 6.89−
6.84 (d, J = 8.5 Hz, 2H), 5.75−5.68 (d, J = 15.6 Hz, 1H), 3.80 (s, 3H),
3.47−3.42 (d, J = 6.6 Hz, 2H), 1.48 (s, 3H).16
EXPERIMENTAL SECTION
■
β-Sitosterol succinate (<10 g scale). A 100 mL round-bottom
flask with magnetic stir bar and septum was charged with β-sitosterol
(≥70% purity) (8.33 g, 20.00 mmol) and succinic anhydride (3.20 g,
32.00 mmol). A rubber septum was put on, and toluene (40 mL) was
added via syringe as solvent. To this well-stirring mixture, triethyl-
amine (0.7 mL, 5.00 mmol) was added via syringe, the reaction flask
was placed in a 60 °C oil bath, and the stirring continued until the
reaction reached completion (followed by TLC). The resulting
solution was allowed to warm to rt, at which point it was treated with
water and extracted with DCM. The combined organic extracts were
washed with 2 M HCl (3 × 50 mL), water (3 × 50 mL), and brine (80
mL) and then dried over anhydrous Na2SO4. Concentration of the
solvent in vacuo was followed by exposure to a high vacuum overnight
to afford β-sitosterol succinate (10.16 g, 98%) as a white solid. The
structure of this intermediate was confirmed: mp 150−151 °C, lit27
mp 151−153 °C; IR (neat) 2938, 2867, 1731, 1711, 1466, 1442, 1378,
1179, 1033, 802 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.32−5.28 (d, J
= 4.6 Hz, 1H), 4.62−4.51 (m, 1H), 2.64−2.57 (t, J = 6.1 Hz, 2H),
2.57−2.50 (t, J = 6.1 Hz, 2H), 2.78−2.21 (d, J = 7.6 Hz, 2H), 1.97−
0.51 (m, 45H); 13C NMR (500 MHz, CDCl3) δ; 177.92, 171.51,
139.52, 122.72, 74.54, 56.68, 56.04, 50.00, 45.83, 42.30, 39.71, 38.00,
36.94, 36.57, 36.15, 33.92, 31.85, 28.77, 28.23, 27.68, 26.09, 24.28,
23.06, 21.02, 19.81, 19.30, 19.03, 18.77, 11.89; MS (ESI) m/z 537 [M
+ Na]+; HRMS (ESI) calcd for C33H54O4Na [M + Na]+ 537.3920,
found 537.3909 (Δ = 1.1 mDa, 2.0 ppm).
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The Journal of Organic Chemistry
Article
1
General Procedure for Ring-Closing Metathesis (Table 3).
Grubbs second-generation catalyst (3.4 mg, 0.004 mmol) was charged
under an Ar atmosphere in a 2−5 mL microwave vial with magnetic
stir bar and Teflon-lined septum. Diene (0.20 mmol) was added to the
vial, and then an aliquot of surfactant solution (2.0 mL, 2 wt % in
degassed water) was added via syringe under positive flow of Ar. The
reaction was allowed to vigorously stir for 6−18 h at rt. The reaction
mixture was then diluted with EtOAc and passed through silica gel bed
and further washed with EtOAc to collect the coupling product. All
volatile solvent was removed in vacuo to obtain crude product that was
further purified by flash chromatography on silica gel.
obtained as a white solid (152 mg, 99%): mp 68−70 °C; H NMR
(400 MHz, CDCl3) δ 7.81−7.75 (m, 3H), 7.73 (s, 1H), 7.62−7.56 (t, J
= 7.3 Hz, 1H), 7.53−7.49 (t, J = 7.3 Hz, 1H), 7.46−7.40 (t, J = 6.8 Hz,
2H), 7.22−7.18 (m, 2H), 3.96 (s, 3H); 13C NMR (500 MHz, CDCl3)
δ ; 157.97, 135.13, 133.79, 132.38, 131.27, 129.65, 128.30, 127.69,
127.26, 126.13, 126.1, 119.24, 105.61, 55.37; HRMS (FI) calcd for
C18H13F3O [M]+ 302.0918, found 302.0905 (Δ = 1.3 mDa, 4.3 ppm).
General Procedure for Sonogashira Couplings (Table 6).
Pd(CH3CN)2Cl2 catalyst (1.3 mg, 0.005 mmol) and XPhos ligand (6.2
mg, 0.013 mmol) were combined under an Ar atmosphere in a 5.0 mL
microwave vial with magnetic stir bar and Teflon-lined septum. Aryl
bromide (0.50 mmol), alkyne (0.65−1.00 mmol), triethylamine (0.14
mL, 1.00 mmol), and surfactant solution (1.0 mL, 2 wt % in degassed
water) were added, respectively, via syringe into the reaction under
flow of Ar. The reaction was allowed to stir vigorously for 4−28 h. The
reaction mixture was then diluted with EtOAc, passed through silica
gel bed, and further washed with EtOAc to collect the coupling
product. All volatile solvent was removed in vacuo to obtain crude
product that was further purified by flash chromatography on silica gel.
2-(Dodec-1-yn-1-yl)-1-methyl-4-nitrobenzene (Table 6, entry 1).
Following the general procedure using 2-bromo-1-methyl-4-nitro-
benzene (109 mg, 0.50 mmol) and 1-dodecyne (109 mg, 0.65 mmol)
the reaction was allowed to stir for 24 h. After column
chromatography, the product was obtained as a brown liquid (150
1-Tosyl-1,2,3,6-tetrahydropyridine (Table 3, entry 4). Following
the general procedure using N-allyl-N-(but-3-en-1-yl)-4-methylbenze-
nesulfonamide (53 mg, 0.20 mmol), the reaction was allowed to stir
for 6 h. After column chromatography, the product was obtained as a
1
white solid (47 mg, 88%): H NMR (400 MHz, CDCl3) δ 7.70−7.66
(d, J = 8.0 Hz, 2H), 7.35−7.30 (d, J = 8.0 Hz, 2H), 5.79−5.73 (m,
1H), 5.65−5.59 (m, 1H), 3.60−3.56 (m, 2H), 3.20−3.15 (t, J = 5.7
Hz, 2H), 2.44 (s, 3H), 2.25−2.19 (m, 2H).28
3-Methyl-1-tosyl-2,5-dihydro-1H-pyrrole (Table 3, entry 5).
Following the general procedure using N-allyl-4-methyl-N-(2-
methylallyl)benzenesulfonamide (53 mg, 0.20 mmol), the reaction
was allowed to stir for 18 h. After column chromatography, the
1
product was obtained as a white solid (46 mg, 96%): H NMR (400
1
mg, 98%): H NMR (400 MHz, CDCl3) δ 8.24−8.19 (d, J = 2.0 Hz,
MHz, CDCl3) δ 7.75−7.71 (d, J = 8.0 Hz, 2H), 7.35−7.30 (d, J = 8.0
Hz, 2H), 5.27−5.23 (m, 1H), 4.11−4.05 (m, 1H), 4.00−3.95 (m, 2H),
2.45−2.42 (s, 3H), 2.44 (s, 3H), 1.66 (s, 3H).29
1H), 8.04−7.98 (dd, J = 8.6, 2.2 Hz, 1H), 7.36−7.30 (d, J = 8.6 Hz,
1H), 2.51 (s, 3H), 2.50−2.45 (t, J = 6.8 Hz, 2H), 1.69−1.59 (m, 2H),
1.53−1.42 (m, 2H), 1.40−1.20 (m, 12H), 0.93−0.85 (t, J = 6.7 Hz,
3H).22
General Procedure for Suzuki−Miyaura Couplings (Table 5).
Arylboronic acid (0.75−1.00 mmol) and Pd(dtbpf)Cl2 (6.5 mg, 0.01
mmol) were added under an Ar atmosphere in a 5.0 mL microwave
vial with magnetic stir bar and Teflon-lined septum. Aryl bromide
(0.50 mmol), triethylamine (0.21 mL, 1.50 mmol), and surfactant
solution (1.0 mL, 2 wt % in degassed water) were sequentially added
into the reaction under a flow of Ar. The reaction was allowed to stir
vigorously for 2−11 h. The reaction mixture was then diluted with
EtOAc, passed through a silica gel bed, and further washed with
EtOAc to collect the coupling product. All volatile solvent was
removed in vacuo to obtain crude product that was further purified by
flash chromatography on silica gel.
1-Methoxy-4-(phenylethynyl)benzene (Table 6, entry 2). Follow-
ing the general procedure using 1-bromo-4-methoxybenzene (94 mg,
0.50 mmol) and ethynylbenzene (77 mg, 0.75 mmol) the reaction was
allowed to stir for 28 h. After column chromatography, the product
was obtained as a brown solid (99 mg, 95%): H NMR (400 MHz,
CDCl3) δ 7.54−7.45 (m, 4H), 7.36−7.30 (m, 3H), 6.92−6.85 (d, J =
1
8.8 Hz, 2H), 3.84 (s, 3H).33
4-(Phenylethynyl)benzonitrile (Table 6, entry 3). Following the
general procedure using 4-bromobenzonitrile (91 mg, 0.50 mmol) and
ethynylbenzene (77 mg, 0.75 mmol) the reaction was allowed to stir
for 2 h. After column chromatography, the product was obtained as a
yellow solid (89 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 7.67−7.60
(m, 4H), 7.58−7.52 (m, 2H), 7.41−7.37 (m, 3H).34
3-(6-Chlorohex-1-yn-1-yl)quinoline (Table 6, entry 4). Following
the general procedure using 3-bromoquinoline (104 mg, 0.50 mmol)
and 6-chlorohex-1-yne (117 mg, 1.00 mmol) the reaction was allowed
to stir for 15 h. After column chromatography, the product was
[1,1′-Biphenyl]-3-carbonitrile (Table 5, entry 1). Following the
general procedure using 3-bromobenzonitrile (91 mg, 0.50 mmol) and
phenylboronic acid (91 mg, 0.75 mmol) the reaction was allowed to
stir for 2 h. After column chromatography, the product was obtained
1
as a colorless liquid (61 mg, 99%): H NMR (400 MHz, CDCl3) δ
7.89−7.86 (t, J = 1.5 Hz, 1H), 7.85−7.80 (dt, J = 7.8, 1.5 Hz, 1H),
7.66−7.62 (dt, J = 7.8, 1.5 Hz, 1H), 7.60−7.54 (dt, J = 8.0, 1.5 Hz,
3H), 7.52−7.46 (tt, J = 7.3, 1.5 Hz, 2H), 7.46−7.40 (tt, J = 7.3, 1.5 Hz,
1H).30
1
obtained as a yellow liquid (113 mg, 93%): H NMR (400 MHz,
CDCl3) δ 8.90−8.86 (d, J = 2.0 Hz, 1H), 8.20−8.17 (d, J = 2.0 Hz,
1H), 8.11−8.07 (d, J = 8.6 Hz, 1H), 7.80−7.75 (d, J = 8.1 Hz, 1H),
7.74−7.68 (m, 1H), 7.59−7.53 (m, 1H), 3.67−3.61 (t, J = 6.5 Hz,
2H), 2.58−2.52 (t, J = 7.0 Hz, 2H), 2.06−1.97 (m, 2H), 1.91−1.79
(m, 3H). 13C NMR (500 MHz, CDCl3) δ 152.59, 146.81, 138.28,
129.96, 129.54, 127.64, 127.54, 127.38, 118.16, 93.16, 78.80, 44.66,
31.89, 26.02, 19.02; HRMS (FI) calcd for C15H14ClN [M]+ 243.0815,
found 243.0806 (Δ = 0.9 mDa, 3.7 ppm).
1-Methyl-4-phenylnaphthalene (Table 5, entry 2). Following the
general procedure using 1-bromo-4-methylnaphthalene (111 mg, 0.50
mmol), and phenylboronic acid (122 mg, 1.00 mmol), the reaction
was allowed to stir for 2 h. After column chromatography, the product
1
was obtained as a colorless liquid (109 mg, 99%): H NMR (400
MHz, CDCl3) δ 8.14−8.06 (dd, J = 8.5, 0.5 Hz, 1H), 7.98−7.91 (dd, J
= 8.3, 0.5 Hz, 1H), 7.63−7.32 (m, 8H), 2.77 (s, 3H).31
General Procedure for Heck Couplings (Table 7). Under an Ar
atmosphere, Pd(t-Bu3P)2 (5.1 mg, 0.010 mmol) was weighed into a
5.0 mL microwave vial containing a magnetic stir bar and Teflon-lined
septum. An aryl halide (0.50 mmol) and acrylate/styrene (1.00 mmol)
were added under a positive flow of Ar followed by surfactant solution
(1.0 mL of 2 wt % in degassed water). Triethylamine (0.21 mL, 1.50
mmol) was then added via syringe as the stoichiometric base. The
mixture was stirred vigorously for 4−72 h and then diluted with
EtOAc, passed through a silica gel bed, and washed with EtOAc to
collect the product. All volatile solvent was removed in vacuo to obtain
the crude product that was further purified by flash chromatography
on silica gel.
3-(Thiophen-3-yl)quinoline (Table 5, entry 3). Following the
general procedure using 3-bromoquinoline (105 mg, 0.50 mmol) and
thiophen-3-ylboronic acid (96 mg, 0.75 mmol) the reaction was
allowed to stir for 4 h. After column chromatography, the product was
obtained as a white solid (102 mg, 95%): 1H NMR (400 MHz,
CDCl3) δ 9.25−9.20 (d, J = 2.0 Hz, 1H), 8.34−8.30 (d, J = 2.2 Hz,
1H), 8.18−8.11 (d, J = 8.3 Hz, 1H), 7.90−7.85 (d, J = 7.8 Hz, 1H),
7.75−7.70 (m, 1H), 7.70−7.67 (dd, J = 2.9, 1.5 Hz, 1H), 7.62−7.57
(m, 1H), 7.56−7.53 (dd, J = 5.1, 1.5 Hz, 1H), 7.53−7.50 (dd, J = 5.1,
2.9 Hz, 1H).32
2-Methoxy-6-(2-(trifluoromethyl)phenyl)naphthalene (Table 5,
entry 4). Following the general procedure using 1-bromo-2-
(trifluoromethyl)benzene (113 mg, 0.50 mmol) and (6-methoxynaph-
thalen-2-yl)boronic acid (152 mg, 0.75 mmol) the reaction was
allowed to stir for 4 h. After column chromatography, the product was
(E)-t-Butyl 3-(4-methoxyphenyl)acrylate (Table 7, entry 1).
Following the general procedure using 1-iodo-4-methoxybenzene
(117 mg, 0.50 mmol), t-butyl acrylate (128 mg, 1.00 mmol) the
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The Journal of Organic Chemistry
Article
reaction was allowed to stir for 4 h. After column chromatography, the
product was obtained as a brown liquid (117 mg, 99%): H NMR
Hz, 1H), 7.44−7.33 (m, 4H), 7.32−7.28 (d, J = 9.0 Hz,1H), 4.08 (s,
3H).41
1
(400 MHz, CDCl3) δ 7.58−7.52 (d, J = 16.1 Hz, 1H), 7.49−7.44 (dt, J
= 8.6, 2.0 Hz, 2H), 6.93−6.87 (dt, J = 8.8, 2.0 Hz, 2H), 6.28−6.22 (d, J
= 16.1 Hz, 1H), 3.84 (s, 3H), 1.54 (s, 9H).35
(Z)-2-(2-Ethoxyvinyl)-1,3-dimethylbenzene (Table 9, entry 3).
Following the general procedure using 2-bromo-1,3-dimethylbenzene
(47 mg, 0.25 mmol) and (Z)-tributyl(2-ethoxyvinyl)stannane (99 mg,
0.275 mmol), the reaction was allowed to stir for 8 h. After column
chromatography, the product was obtained as a yellow liquid (24 mg,
56%): 1H NMR (400 MHz, CDCl3) δ 7.10−7.00 (m, 3H), 6.25−6.16
(d, J = 6.8 Hz, 1H), 5.26−5.19 (d, J = 7.0 Hz, 1H), 3.93−3.84 (q, J =
7.0 Hz, 2H), 2.29 (s, 6H), 1.31−1.21 (d, J = 7.0 Hz, 3H); 13C NMR
(500 MHz, CDCl3) δ 145.11, 136.69, 133.96, 127.00, 126.27, 103.26,
68.02, 20.68, 15.39; HRMS (EI) calcd for C12H16O [M]+ 176.1201,
found 176.1209 (Δ = 0.8 mDa, 4.5 ppm).
(E)-2-Ethylhexyl 3-(4-methoxyphenyl)acrylate (Table 7, entry 2).
Following the general procedure using 1-iodo-4-methoxybenzene (117
mg, 0.50 mmol) and 2-ethylhexyl acrylate (184 mg, 1.00 mmol), the
reaction was allowed to stir for 5 h. After column chromatography, the
product was obtained as yellow-brown liquid (135 mg, 93%): 1H
NMR (400 MHz, CDCl3) δ 7.68−7.60 (d, J = 16.1 Hz, 1H), 7.53−
7.45 (dt, J = 8.6, 2.0 Hz, 2H), 6.95−6.87 (dt, J = 8.8, 2.0 Hz, 2H),
6.36−6.28 (d, J = 15.9 Hz, 1H), 4.16−4.07 (m, 2H), 3.85 (s, 3H),
1.71−1.55 (m, 1H), 1.48−1.24 (m, 8H), 0.99−0.86 (t, J = 7.3 Hz,
6H).36
2-Ethylhexyl cinnamate (Table 7, entry 3). Following the general
procedure using iodobenzene (102 mg, 0.50 mmol) and 2-ethylhexyl
acrylate (184 mg, 1.00 mmol), the reaction was allowed to stir for 5 h.
After column chromatography, the product was obtained as colorless
liquid (129 mg, 99%): 1H NMR (400 MHz, CDCl3) δ 7.72−7.65 (d, J
= 15.9 Hz, 1H), 7.58−7.51 (m, 2H), 7.42−7.36 (m, 2H), 6.50−6.43
(d, J = 15.9 Hz, 1H), 4.15−4.12 (m, 2H), 1.72−1.60 (m, 1H), 1.49−
1.26 (m, 9H), 0.98−0.87 (m, 6H).37
(E)-1-Chloro-2-(4-methoxystyryl)benzene (Table 7, entry 4).
Following the general procedure using 1-iodo-4-methoxybenzene
(58.5 mg, 0.25 mmol) and 1-chloro-2-vinylbenzene (69 mg, 0.50
mmol), the reaction was allowed to stir for 5 h. After column
chromatography, the product was obtained as yellow liquid (61 mg,
99%, 77:23 E/Z): 1H NMR (400 MHz, CDCl3) δ 7.69−7.64 (dd, J =
7.8, 1.3 Hz, 1H), 7.52−7.47 (d, J = 8.8 Hz, 2H), 7.42−7.34 (dd, J =
11.7, 3.4 Hz, 2H), 7.23−7.33 (m, 2H), 7.21−7.14 (m, 1H), 7.07−7.00
(d, J = 16.3 Hz, 1H), 6.94−6.89 (d, J = 8.8 Hz, 2H), 6.85−6.81 (d, J =
8.8 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H).38
(Z)-1-(2-Ethoxyvinyl)-4-methylnaphthalene (Table 9, entry 4).
Following the general procedure using 1-bromo-4-methylnaphthalene
(55 mg, 0.25 mmol) and (Z)-tributyl(2-ethoxyvinyl)stannane (99 mg,
0.275 mmol), the reaction was allowed to stir for 18 h. After column
chromatography, the product was obtained a yellow liquid (44 mg,
1
84%): H NMR (400 MHz, CDCl3) δ 8.19−8.11 (t, J = 4.9 Hz, 1H),
8.03−7.98 (t, J = 4.9 Hz, 1H), 7.98−7.94 (d, J = 7.6 Hz, 1H), 7.56−
7.47(t, J = 4.9 Hz, 2H), 7.35−7.29 (d, J = 7.6 Hz, 1H), 6.45−6.40 (d, J
= 7.1 Hz, 1H), 5.91−5.87 (d, J = 7.1 Hz, 1H), 4.06−3.95 (q, J = 7.1
Hz, 2H), 2.69 (s, 3H), 1.43−1.30 (t, J = 7.1 Hz, 3H); 13C NMR (500
MHz, CDCl3) δ 146.79, 132.73, 132.35, 131.19, 130.04, 126.47,
126.44, 125.15, 125.10, 124.55, 124.46, 101.47, 68.93, 19.57, 15.43;
HRMS (EI) calcd for C15H16O [M]+ 212.1201, found 212.1203 (Δ =
0.2 mDa, 0.9 ppm).
2-(2-Methoxynaphthalen-1-yl)furan (Table 9, entry 5). Following
the general procedure using 1-bromo-2-methoxynaphthalene (59 mg,
0.25 mmol) and tributyl(furan-2-yl)stannane (98 mg, 0.275 mmol),
the reaction was allowed to stir for 4 h. After column chromatography,
1
the product was obtained as a brown liquid (55 mg, 97%): H NMR
(400 MHz, CDCl3) δ 7.94−7.89 (d, J = 9.0 Hz, 1H), 7.89−7.84 (d, J =
8.3 Hz, 1H), 7.84−7.80 (d, J = 8.1 Hz, 1H), 7.69−7.64 (t, J = 1.5 Hz,
1H), 7.48−7.42 (td, J = 6.8, 1.5 Hz, 1H), 7.40−7.33 (td, J = 6.8, 1.2
Hz, 2H), 6.65−6.62 (d, J = 1.5 Hz, 2H), 3.94 (s, 3H).24
t-Butyl cinnamate (Table 7, entry 5). Following the general
procedure using bromobenzene (78 mg, 0.50 mmol) and t-butyl
acrylate (128 mg, 1.00 mmol), the reaction was allowed to stir for 72
h. After column chromatography, the product was obtained as a
General Procedure for Miyaura Borylations (Table 10). The
catalyst (Pd(t-Bu3P)2, 7.7 mg, 0.015 mmol) was added under an Ar
atmosphere in a 5.0 mL microwave vial with magnetic stir bar and
Teflon-lined septum. B2pin2 (140 mg, 0.55 mmol) and KOAc (147
mg, 1.50 mmol) were added under a positive flow of Ar followed by
1.0 mL of surfactant solution (2 wt % in degassed water). The mixture
was stirred vigorously for about 10 min, and then the aryl bromide
(0.50 mmol) was added followed by an additional 1.0 mL of surfactant
solution. The reaction was allowed to stir vigorously for 4−26 h. The
reaction mixture was then diluted with EtOAc and passed through
silica gel bed and washed with EtOAc to collect the product. All
volatile solvent was removed in vacuo to obtain the crude product that
was further purified by flash chromatography on silica gel.
Methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(Table 10, entry 1). Following the general procedure using methyl
3-bromobenzoate (109 mg, 0.50 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-
2,2′-bi(1,3,2-dioxaborolane) (140 mg, 0.55 mmol), the reaction was
allowed to stir for 4 h. After column chromatography, the product was
obtained as a yellow solid (125 mg, 94%): 1H NMR (400 MHz,
CDCl3) δ 8.48 (s, 1H), 8.17−8.09 (dt, J = 7.8, 1.6 Hz, 1H), 8.03−7.95
(dt, J = 7.3, 1.2 Hz, 1H), 7.50−7.40 (t, J = 7.6 Hz, 1H), 3.92 (s, 3H),
1.36 (s, 12H).42
2-(4-Methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(Table 10, entry 2). Following the general procedure using 1-bromo-4-
methoxybenzene (93 mg, 0.50 mmol) and 4,4,4′,4′,5,5,5′,5′-
octamethyl-2,2′-bi(1,3,2-dioxaborolane) (140 mg, 0.55 mmol), the
reaction was allowed to stir for 4 h. After column chromatography, the
product was obtained as a yellow liquid (97 mg, 83%): 1H NMR (400
MHz, CDCl3) δ 7.79−7.73 (dt, J = 8.6, 2.0 Hz, 2H), 6.93−6.88 (dt, J
= 8.8 Hz, 2.0 Hz, 2H), 3.84 (s, 3H), 1.34 (s, 12H).43
2-(2,6-Dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(Table 10, entry 3). Following the general procedure using 2-bromo-
1,3-dimethylbenzene (93 mg, 0.50 mmol) and 4,4,4′,4′,5,5,5′,5′-
octamethyl-2,2′-bi(1,3,2-dioxaborolane) (140 mg, 0.55 mmol), the
1
colorless liquid (81 mg, 79%): H NMR (400 MHz, CDCl3) δ 7.63−
7.56 (d, J = 16.1 Hz, 1H), 7.55−7.49 (m, 2H), 7.42−7.34 (m, 3H),
6.41−6.35 (d, J = 16.1 Hz, 1H), 1.55 (s, 9H).39
General Procedure for Stille Couplings (Table 9). Pd(t-Bu3P)2
catalyst (2.6 mg, 0.005 mmol) and DABCO base (84 mg, 0.75 mmol)
were added under an Ar atmosphere in a 5.0 mL microwave vial
containing a magnetic stir bar and Teflon-lined septum. NaCl (15 mg,
0.25 mmol) was added as an additive under a positive flow of Ar,
followed by aryl halide (0.25 mmol), stannyl reagent (0.275 mmol),
and surfactant solution (0.5 mL of 2 wt % in degassed water),
respectively. The mixture was allowed to stir vigorously for 2−18 h.
After confirming full conversion by TLC, the reaction mixture was
then diluted with 2.0 mL of EtOAc and 0.25 mL of triethylamine. The
mixture was passed through a silica gel bed and washed with EtOAc to
collect the product. All volatile solvent was removed in vacuo to obtain
the crude product that was further purified by flash chromatography
on silica gel.
1-Methoxy-3-(phenylethynyl)benzene (Table 9, entry 1). Follow-
ing the general procedure using 1-bromo-3-methoxybenzene (47 mg,
0.25 mmol) and tributyl(phenylethynyl)stannane (108 mg, 0.275
mmol) the reaction was allowed to stir for 2 h. After column
chromatography, the product was obtained as a yellow liquid (52 mg,
99%): 1H NMR (400 MHz, CDCl3) δ 7.58−7.52 (m, 2H), 7.40−7.33
(m, 3H), 7.29−7.25 (t, J = 7.6 Hz, 1H), 7.17−7.12 (d, J = 7.6 Hz, 1H),
7.10−7.06 (s, 1H), 6.94−6.88 (dd, J = 8.3, 2.4 Hz, 1H), 3.84 (s, 3H).40
2-Methoxy-1-(phenylethynyl)naphthalene (Table 9, entry 2).
Following the general procedure using 1-bromo-2-methoxynaphtha-
lene (59 mg, 0.25 mmol) and tributyl(phenylethynyl)stannane (108
mg, 0.275 mmol), the reaction was allowed to stir for 4 h. After
column chromatography, the product was obtained as a pale yellow
solid (63 mg, 99%): 1H NMR (400 MHz, CDCl3) δ 8.40−8.35 (d, J =
8.3 Hz, 1H), 7.88−7.83 (d, J = 9.0 Hz, 1H), 7.83−7.79 (d, J = 8.1 Hz,
1H), 7.72−7.67 (dd, J = 8.1, 1.7 Hz, 2H), 7.61−7.55 (td, J = 8.3, 1.2
K
dx.doi.org/10.1021/jo401744b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
reaction was allowed to stir for 26 h. After column chromatography,
the product was obtained as a yellow liquid (92 mg, 82%): H NMR
pale yellow solid (63 mg, 98%): H NMR (400 MHz, CDCl3) δ 8.86
(s, 1H), 7.89−7.80 (dd, J = 8.4, 2.3 Hz, 1H), 7.31−7.27 (d, J = 8.3 Hz,
1H), 6.41 (s, 1H), 2.35 (s, 3H), 1.56 (s, 9H).49
1
(400 MHz, CDCl3) δ 7.16−7.10 (t, J = 7.6 Hz, 1H), 6.98−6.92 (d, J =
7.8 Hz, 2H), 2.40 (s, 6H), 1.40 (s, 12H).44
In Situ-Derived Organozinc Halide-Mediated Cross-Couplings:
Ethyl 4-cyclohexylbenzoate (Table 13). In a 5.0 mL microwave vial
under Ar containing zinc dust (65 mg, 1 mmol) and PdCl2(Amphos)2
(1.2 mg, 0.0017 mmol), a surfactant solution (1.0 mL of 2 wt % in
degassed water) and N,N,N′,N′-tetramethylethylenediamine
(TMEDA) (39 mg, 0.33 mmol) were added at rt followed by the
addition of bromocyclohexane (136 mg, 0.83 mmol) and ethyl 4-
bromobenzoate (77 mg, 0.33 mmol). The flask was stirred vigorously
at rt for 24 h. Another portion of Zn dust (22 mg, 0.33 mmol),
PdCl2(Amphos)2 (0.6 mg, 0.00085 mmol), TMEDA (39 mg, 0.33
mmol) and bromocyclohexane (26 mg, 0.16 mmol) were added to the
reaction mixture, and the reaction was continuously stirred for another
24 h. The reaction mixture was then filtered through a plug of silica gel
and washed with diethyl ether, after which the solvents were removed
under a vacuum. After column chromatography on silica gel, the
2-([1,1′-Biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(Table 10, entry 4). Following the general procedure using 4-bromo-
1,1′-biphenyl (117 mg, 0.50 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-
2,2′-bi(1,3,2-dioxaborolane) (140 mg, 0.55 mmol), the reaction was
allowed to stir for 24 h. After column chromatography, the product
1
was obtained as a pale yellow solid (133 mg, 95%): H NMR (400
MHz, CDCl3) δ 7.92−7.87 (d, J = 8.3 Hz, 2H), 7.65−7.60 (m, 4H),
7.49−7.42 (t, J = 7.8 Hz, 2H), 7.40−7.34 (m, 1H), 1.37 (s, 12H).45
General Procedure for Aminations (Table 11). [(π-allyl)PdCl]2
catalyst (1.8 mg, 0.005 mmol), cBRIDP ligand (7.0 mg, 0.020 mmol),
and KO-t-Bu as base (168 mg, 1.50 mmol) were added under an Ar
atmosphere into a 5.0 mL microwave vial containing a magnetic stir
bar and Teflon-lined septum. p-Toluidine (1.20 mmol) was added
under a positive flow of Ar, followed by surfactant solution (1.0 mL of
2 wt % in degassed water), and aryl bromide (1.00 mmol),
respectively. The mixture was stirred vigorously for 3−24 h. The
reaction mixture was then diluted with EtOAc, passed through a silica
gel bed, and further washed with EtOAc to collect the coupling
product. All volatile solvent was removed in vacuo to obtain the crude
product that was further purified by flash chromatography on silica gel.
4-Methoxy-N-(p-tolyl)aniline (Table 11, entry 1). Following the
general procedure using 1-bromo-4-methoxybenzene (187 mg, 1.00
mmol) and p-toluidine (129 mg, 1.20 mmol), the reaction was allowed
to stir for 21 h. After column chromatography, the product was
1
product was obtained as a white solid (66 mg, 86%): H NMR (400
MHz, CDCl3) δ 8.00−7.91 (d, J = 8.3 Hz, 2H), 7.30−7.20 (d, J = 8.1
Hz, 2H), 4.43−4.27 (q, J = 7.2 Hz, 2H), 2.62−2.46 (m, 1H), 1.92−
1.78 (m, 4H), 1.48−1.31 (m, 9H).50
ASSOCIATED CONTENT
* Supporting Information
Copies of MS and IR spectra of all new compounds, copies of
1H and 13C NMR spectra of all new compounds, and copies of
1H NMR spectra of all known compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
1
obtained as an off-white solid (195 mg, 91%): H NMR (400 MHz,
CDCl3) δ 7.08−7.00 (m, 4H), 6.90−6.82 (m, 4H), 5.41 (s, 1H), 3.80
(s, 3H), 2.29 (s, 3H).46
N-(p-Tolyl)naphthalen-2-amine (Table 11, entry 2). Following the
general procedure using 2-bromonaphthalene (207 mg, 1.00 mmol)
and p-toluidine (129 mg, 1.20 mmol), the reaction was allowed to stir
for 10 h. After column chromatography, the product was obtained as
AUTHOR INFORMATION
Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu.
Notes
■
1
an off-white solid (176 mg, 75%): H NMR (400 MHz, CDCl3) δ
The authors declare no competing financial interest.
7.75−7.71 (d, J = 8.8 Hz, 2H), 7.65−7.60 (d, J = 8.3 Hz, 1H), 7.42−
7.36 (td, J = 6.8, 1.2 Hz, 2H), 7.31−7.27(td, J = 6.8, 1.2 Hz, 1H),
7.21−7.17 (dd, J = 8.8, 2.4 Hz, 1H), 7.17−7.08 (q, J = 8.3, 4H), 5.96
(s, 1H), 2.35 (s, 3H).24
ACKNOWLEDGMENTS
■
We would like to warmly thank the NIH for support of our
program in green chemistry (GM 86485), and Drs. Thomas J.
Colacot (Johnson Matthey) and Richard Pederson (Materia)
for supplying the palladium catalysts and Grubbs catalyst,
respectively, used in this study. The cryo-TEM experiments
were performed by Dr. Wei Zhang (University of Minnesota),
for which we are most appreciative.
Ethyl 4-((t-butoxycarbonyl)amino)benzoate (Table 11, entry 3).
The general procedure was followed using ethyl 4-bromobenzoate
(231 mg, 1.00 mmol), t-butyl carbamate (176 mg, 1.50 mmol), and
Na-O-t-Bu (144 mg, 1.50 mmol) as base. The reaction was allowed to
stir in oil bath at 50 °C for 24 h. After column chromatography, the
1
product was obtained as a white solid (228 mg, 85%): H NMR (400
MHz, CDCl3) δ 8.01−7.96 (d, J = 8.8 Hz, 2H), 7.46−7.40 (d, J = 8.8
Hz, 2H), 6.66 (s, 1H), 4.39−4.32 (q, J = 7.2 Hz, 2H), 1.54 (s, 9H),
1.42−1.36 (t, J = 7.2 Hz, 3H).47
DEDICATION
■
Ethyl (4-benzoylphenyl)carbamate (Table 11, entry 4). The
general procedure was followed using (4-bromophenyl)(phenyl)-
methanone (131 mg, 0.50 mmol), ethyl carbamate (53 mg, 0.60
mmol), and Na-O-t-Bu 72 mg, 0.75 mmol) as base. The reaction was
allowed to stir in oil bath at 50 °C for 24 h. After column
chromatography, the product was obtained as a yellow solid (126 mg,
93%): mp 187−189 °C, lit48 mp 189 °C; 1H NMR (400 MHz,
CDCl3) δ 7.85−7.81 (d, J = 8.8 Hz, 2H), 7.80−7.76 (d, J = 8.6 Hz,
2H), 7.62−7.56 (tt, J = 7.3, 1.2 Hz, 1H), 7.53−7.46 (m, 4H), 6.81 (s,
1H), 4.31−4.24 (q, J = 7.1 Hz, 2H), 1.38−1.32 (t, J = 7.1 Hz, 3H); 13C
NMR (500 MHz, CDCl3) δ 195.62, 153.17, 142.14, 137.95, 132.11,
131.78, 129.81, 128.23, 117.47, 61.63, 14.49; HRMS (ESI) calcd for
C16H15NO3 [M + Na]+ 292.0950, found 292.0946 (Δ = 0.4 mDa, 1.4
ppm).
Dedicated to the memory of Professor Harry H. Wasserman.
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