TPGS-750-M: A second-generation amphiphile for metal-catalyzed cross-couplings in water at room temperature

Article abstract of DOI:10.1021/jo101974u

An environmentally benign surfactant (TPGS-750-M), a diester composed of racemic α-tocopherol, MPEG-750, and succinic acid, has been designed and readily prepared as an effective nanomicelle-forming species for general use in metal-catalyzed cross-coupling reactions in water. Several "name" reactions, including Heck, Suzuki-Miyaura, Sonogashira, and Negishi-like couplings, have been studied using this technology, as have aminations, C-H activations, and olefin metathesis reactions. Physical data in the form of DLS and cryo-TEM measurements suggest that particle size and shape are key elements in achieving high levels of conversion and, hence, good isolated yields of products. This new amphiphile will soon be commercially available.

Full text of DOI:10.1021/jo101974u

ARTICLE
pubs.acs.org/joc
TPGS-750-M: A Second-Generation Amphiphile for Metal-Catalyzed
Cross-Couplings in Water at Room Temperature
Bruce H. Lipshutz,* Subir Ghorai, Alexander R. Abela, Ralph Moser, Takashi Nishikata, Christophe Duplais,
and Arkady Krasovskiy
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
Ricky D. Gaston and Robert C. Gadwood*
Kalexsyn, Inc., 4502 Campus Drive, Kalamazoo, Michigan 49008, United States
S Supporting Information
b
ABSTRACT: An environmentally benign surfactant (TPGS-
750-M), a diester composed of racemic R-tocopherol, MPEG-
750, and succinic acid, has been designed and readily prepared
as an effective nanomicelle-forming species for general use in
metal-catalyzed cross-coupling reactions in water. Several
“name” reactions, including Heck, Suzuki-Miyaura, Sonogashira, and Negishi-like couplings, have been studied using this
technology, as have aminations, C-H activations, and olefin metathesis reactions. Physical data in the form of DLS and cryo-TEM
measurements suggest that particle size and shape are key elements in achieving high levels of conversion and, hence, good isolated
yields of products. This new amphiphile will soon be commercially available.
he notion of doing transition-metal-catalyzed organic synth-
esis in water only at ambient temperatures is oftentimes
formed the basis of an enabling technology applied to several
Pd- and Ru-catalyzed reactions performed in HPLC grade water
at room temperature. Thus, several name reactions such as
Heck,8 Suzuki-Miyaura,9 and Sonogashira10 couplings could
all be carried out in e5 wt % PTS/water at room temperature.
Other Pd-catalyzed processes proceeded with comparable suc-
cess, including aminations of aryl halides,11 allylic aminations
of alcohols,12 and silylations of allylic ethers.13 Several types of
Ru-catalyzed metathesis reactions, including cross-14 and ring-
closing,15 were shown to be quite amenable to this medium.
Direct comparisons with existing commercially available (albeit
far less expensive) amphiphiles demonstrated that surfactant make-
up indeed matters and that in most if not all cases, PTS afforded
as good or better results both in terms of yields and reaction rates.
Notwithstanding these successful applications, each surfactant
is anticipated to have distinct characteristics, such as particle
shape(s) (e.g., spherical micelles, rods/worms, vesicles) and size,
functionality (e.g., a linear vs cyclic hydrocarbon interior),1,2 as
well as a specific hydrophilic-lipophilic balance (i.e., the relative
amounts of its hydrophilic to lipophilic components).16 These
factors translate into observed variations in cross-coupling chemistry,
although a full appreciation of the “rules” that precisely match a
surfactant to a chosen reaction type remain elusive. In this report
we disclose a new amphiphile, TPGS-750-M (2), that possesses
several important advantages over PTS: (a) a newly engineered
particle size that apparently better accommodates spacial needs
of substrates/catalysts, leading to greater rates of couplings and
therefore higher levels of conversion and resulting yields, and (b)
T
dismissed out of hand, as most uncharged organic molecules are
simply insoluble. One approach that circumvents this limitation
is the use of catalytic amounts of nanoparticles derived from
amphiphiles that self-aggregate spontaneously in water, thereby
providing a micellar environment within which organic sub-
strates and catalysts may readily interact.1 Such reactions are
technically under homogeneous conditions, taking place within
the lipophilic inner core of the micelle, while the water serves as
the macroscopic medium that drives particle organization due to
entropic factors.2 With limited levels of surfactant present, con-
centrations of reactants are typically quite high, in which case
reaction rates at room temperature can be competitive with those
commonly seen at elevated temperatures in organic solvents.3
One significant outgrowth of this phenomenon is that impurity
profiles may be dramatically altered given the mildness of
reaction conditions.
Over the past few years,4 we have developed the concept of a
“designer” surfactant in recognition of the fact that solvent effects
can be crucial to the success of a reaction. Because the interior of
a micelle serves in this capacity (i.e., as solvent), there is every
reason to suspect that not all surfactants would be equally
effective in metal-catalyzed cross-couplings. Moreover, from
the green chemistry perspective,5 the choice of amphiphile would
ideally be, in the Anastas sense, “benign by design.”6 In other
words, its use on any scale would have minimal environmental
consequences and would ideally be recyclable.
As an initial entry into this area, we have reported a series of
papers in which a first-generation surfactant, PTS (1; Figure 1),7
was identified as a general nanomicelle-forming species that
Received: October 6, 2010
Published: May 09, 2011
r
2011 American Chemical Society
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Scheme 1. Literature Method To Prepare PTS7
Scheme 2. Synthesis of TPGS-750-M
Figure 1. Structural comparisons between PTS, TPGS-750-M, and
TPGS-1000.
a newly streamlined synthesis relative to that used to make PTS,
which offers considerable promise for general utility in transition-
metal-based catalysis. Thus, the overall goal was to provide a
second-generation surfactant, one that offers the community
methodology for metal-catalyzed couplings that take place as
efficiently or more so relative to those in PTS/water, while
simultaneously possessing a much-improved economic profile
with respect to its preparation.
purity levels needed for use in green chemistry. TPGS analogues,
however, regardless of PEG units, benefit considerably from the
succinic anhydride route, where unquestionably the first step leads
to the single ring-opening half acid ester 4 (Scheme 2).19
’ RESULTS AND DISCUSSION
The second important structural change made in the TPGS
series that further streamlines syntheses of such “designer”
surfactants (i.e., analogues of TPGS-1000) is use of a mono-
methylated poly(ethylene glycol) (MPEG), rather than the
corresponding PEG diol. That is, given their similar cost struc-
ture, an MPEG monoalcohol as nucleophilic partner en route to
the corresponding diesters 3 obviates double-ended diesterifica-
tion, commonly seen with PTS due to residual sebacoyl chloride
and the use of diol PEG-600. Hence, not only is the gross
structural feature of a TPGS analogue readily distinguished from
PTS, the workup required due to impurity profile differences
between these amphiphiles is markedly different as well.
Another important distinction between PTS (containing a 10-
carbon linker and PEG-600) and surfactants in the TPGS series
(with a 4-carbon linker and PEG-1000) is that TPGS is more
weighted toward its hydrophilic component, i.e., it has a far
higher hydrophilic lipophilic balance (HLB) of 13 versus 10 for
PTS.14 Longer PEG chains have also been found to decrease
nanoparticle size and to change particle shape; hence, the
nanoenvironment available to a given set of reactants and catalyst
can vary (Table 1), as do the observed experimental results.
Dynamic light scattering (DLS)20 data indicate that PTS forms
on average ca. 24 nm particles,4 whereas modified PTS made with
PEG-1000 (i.e., PTS-1000) leads to 7 nm micelles. On the other
TPGS versus PTS: Distinguishing Features. In search of a
more economically practical alternative to PTS,7 the structurally
similar platform found in commercially available amphiphile
TPGS-100017 (3) emerged as an appealing option for potential
refinements. Like PTS, this related surfactant possesses R-
tocopherol as its main lipophilic component, but differs in the
length of its diester linker and appended PEG chain. Thus, in
place of the longer (10-carbon) sebacic acid residue that joins
PEG-600 to the hydrophobic vitamin E portion of PTS, TPGS-
1000 has a shorter (and significantly less expensive) 4-carbon
succinic acid linker. Not only is the preparation of the initial
adduct, vitamin E succinate, a virtually quantitative reaction, this
intermediate is also commercially available.18 Since the vitamin E
portion, by far, is the most costly of the three ingredients that
would make up any surfactant of this type, the efficient use of this
component is especially noteworthy and significantly enhances
the economic appeal of TPGS-750-M over PTS. As illustrated
in Scheme 1, the existing route to PTS is less than half as efficient,
owing to the lack of regiocontrol in using sebacoyl chloride as the
diester precursor. As expected, the diacid chloride route gener-
ates extensive byproduct formation due to uncontrolled cou-
plings at each end, and ultimately, the desired PTS portion of
the reaction mixture requires very specific protocols to realize
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Table 1. Average Diameter of Surfactants in Water
amphiphile
average diameter (nm)a
PTS with PEG-600 (1)
PTS with PEG-1000
24
7
TPGS-1000 (3)
13
53
65
TPGS-750-M (2)
TPGS-550-M
a Determined by dynamic light scattering (DLS).
hand, TPGS-1000 forms 13 nm micelles in water that would be
expected to increase in size as the PEG chain is shortened. The
newly synthesized TPGS analogues, 550-M, and 750-M, indeed
formed far larger particles, a potentially good omen for their use
in cross-coupling reactions in water.
Figure 3. (A) Neat PTS; (B) neat TPGS-750-M.
in the TPGS series, TPGS-750-M gave the most synthetically
useful cross-couplings (vide infra). Thus, while it is far from
obvious why larger nanoparticles (spherical or otherwise) offer as
good or better quality cross-couplings relative to PTS, it appears
that micelles on the order of 50þ nm best accommodate the
components associated with Pd- and Ru-catalyzed couplings
described to date.
Designing a Better Micelle for Cross-Couplings. Although
surfactants PTS, TPGS-750-M, and TPGS-1000 appear to be
very similar in structural makeup, the extent of the cross-
couplings occurring within each of their spontaneously formed
nanoparticles in water can be quite varied. Hints that size and
nature of the particles formed can be important factors come
from DLS data. However, these numbers represent average
values and offer little insight into individual particle shape or
size. On the other hand, cryo-TEM analysis21 is extremely useful
for this purpose, and hence, these experiments were performed
on each of these three surfactants (Figure 2). Cryo-TEM data on
PTS show that it is composed of two types of nanoparticles:
8-10 nm spheres, and rods of highly variable lengths (A). By
contrast, TPGS-1000 (C) appears to form only spherical parti-
cles (13 nm). The change to shorter PEG lengths by using
MPEG-550 and -750 (thereby leading to surfactants TPGS-
550-M, and -750-M) altered particle size significantly, with DLS
data suggestive of particles averaging 53-65 nm. Relative to PTS
and TPGS-1000, TPGS-750-M led to a higher percentage of
larger rod-like particles (B). Among the three lower homologues
Synthesis of TPGS Analogues: Spotlight on TPGS-
750-M. To meld the convenience of preparing surfactants in the
TPGS series with the established chemical versatility of PTS,4 the
HLB of commercially available TPGS-1000 was tuned by balanc-
ing the length of its PEG chain. Accordingly, TPGS variants with
MPEG molecular weights of approximately 550 (n = ca. 11) and
750 (n = ca. 15) were synthesized via the straightforward two-step
route outlined in Scheme 2. Under optimized conditions on a
laboratory scale of <10 g, as illustrated for TPGS-750-M, each
of the two steps affords a nearly quantitative yield of the desired
product. Ring-opening of succinic anhydride (1.5 equiv) by
R-tocopherol in warm toluene (0.5 M) takes place smoothly
in 5 h. The resulting acid is then put through a standard workup
and filtration throughsilica gel to give knownwhite solid4.22 Treat-
ment of ester 4 with MPEG-750 in the usual way (cat. TsOH,
toluene, Δ, Dean-Stark trap) gave the desired, previously unknown
amphiphile 2 as a waxy solid (Figure 3B). This sequence could be
smoothly scaled to >170 g, with comparable yields for each step
(97% and 98%, respectively). In a similar fashion, both TPGS-600
and TPGS-550-M were prepared as viscous liquid materials. All
could be stored indefinitely in vials at ambient temperatures.
Cross-Couplings in Aqueous TPGS-750-M. To compare
and contrast these newly designed amphiphiles for promoting
cross-couplings in water relative to those previously studied using
commercially available PTS23 (1) and TPGS-1000,24 two olefin
metathesis reactions were initially examined (Table 2). Both
olefin cross- and ring-closing metathesis proceed smoothly in
2.5 wt % PTS/water (entries 1, 6) and in TPGS-750-M (entries
4, 9), although notably inferior results are seen in both cases
using 2.5 wt % TPGS-1000/water (entries 5, 10). With methyl
vinyl ketone and olefin 5, in the presence of the second
generation Grubbs catalyst, product 6 was formed to the extent
of 64% conversion after 4 h at room temperature in PTS/H2O,
whereas in aqueous TPGS-1000 under otherwise identical con-
ditions only 35% conversion had occurred (entry 5). The best
result (74%) was observed using TPGS-750-M (entry 4). Diene
7 also underwent ring-closing metathesis in PTS to produce an
85% isolated yield of seven-membered ring product 8 (entry 6),
whereas in micellar TPGS-1000 only a 40% level of conversion
was noted (entry 10). For both test reactions, all three of the new
Figure 2. Cryo-TEM image of (A) aqueous PTS 1 (50 nm scale), (B)
TPGS-750-M (50 nm scale), and (C) TPGS-1000 (20 nm scale).
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Table 2. Screening of Surfactants: Representative Olefin
Metathesis Reactions in Water
Table 3. Cross- and Ring-Closing Metathesis Reactions in
PTS versus TPGS-750-M in Water
a Isolated yield of chromatographically pure materials. b Reaction run for
3 h.
TPGS variants gave results that were significantly superior to
those of TPGS-1000. The best results were obtained using
TPGS-750-M (entries 4, 9), affording results that are equal or
superior to those obtained using PTS.
Table 4. Effect of pH on Olefin Metathesis Reactions
To examine the generality of TPGS-750-M, a broader survey
of olefin metathesis reactions was carried out. As shown in
Table 3, reactions conducted in 2.5% TPGS-750-M/water gave,
in all examples, yields equal to or slightly better than those
obtained in PTS/water. These results were especially encoura-
ging in that they demonstrated the potential for TPGS-750-M to
replace PTS on two key fronts: (1) equal or superior efficiency
in reactions, and (2) far greater efficiency in its preparation.
Importantly, TPGS-750-M can be directly substituted for
PTS under already established protocols,4 without additional
optimization.
An interesting and potentially very useful experimental observa-
tion was made from a reaction in which the pH of the aqueous
phase had been lowered to between 2 and 3 by virtue of the
addition of small amounts of KHSO4 (0.02 M). As had been shown
previously by Grubbs and co-workers, ring-opening metathesis
polymerization (ROMP) reactions in aqueous acid are accelerated
as a result of protonation of the catalyst-containing phosphine
moiety, thereby freeing a coordination site on Ru.25 By simply using
PTS or TPGS-750-M in the presence of this salt, rates of olefin
metathesis reactions using even a challenging partner in methyl
vinyl ketone were significantly enhanced (Table 4).
surfactant
TPGS-750-M
time (h)
yield (%)a
12
4
74
93
91
0.02 M KHSO4 TPGS-750-M
0.02 M KHSO4 PTS
a Isolated yield of chromatographically pure materials.
4
Although results for Ru-catalyzed metathesis reactions were
encouraging, a more extensive study for comparison purposes
between amphiphiles involving Pd-catalyzed cross-couplings was
undertaken. These transformations included Heck, Suzuki-
Miyaura, and Sonogashira couplings, as well as Buchwald-Hartwig
aminations. Results are shown in Table 5 and clearly suggest that
the more conveniently accessed surfactant TPGS-750-M relative
to PTS promotes the same variety of valued C-C bond-forming
reactions under identical conditions: in water at room temperature.
Heck couplings with aryl iodides (entries 1, 2) have been
previously studied in PTS/water,8 requiring typically high
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Table 5. Pd-Catalyzed Cross-Couplings with TPGS-750-M and PTS in Water at Room Temperature
a Isolated yield of chromatographically pure materials. b Reactions carried out for 4-12 h using aryl iodide (1 equiv), acrylate or styrene (2 equiv),
triethylamine (3 equiv), catalyst Pd(P(t-Bu)3)2 (2 mol %), and 5 wt % of surfactant/H2O. c Reactions carried out for 2-24 h using aryl bromide (1
equiv), arylboronic acid (1.5-2 equiv), triethylamine (3 equiv), catalyst PdCl2(dtbpf) (2 mol %), and 2 wt % of surfactant/H2O. d Reactions carried out
for 21-25 h using aryl bromide (1 equiv), alkyne (1.5 equiv), triethylamine (2 equiv), catalyst Pd(CH3CN)2Cl2 (1 mol %), X-Phos (2.5 mol %), and 3
wt % of surfactant/H2O. e Reactions carried out for 19-20 h using aryl bromide (1 equiv), aryl amine (1.2 equiv), KO-t-Bu (1.5 equiv), catalyst [(π-
allyl)PdCl]2 (0.5 mol %), cBRIDP (2 mol %), and 2 wt % of surfactant/H2O.
surfactant loading (15 wt %) when using PdCl2(dtbpf ) as
catalyst (Figure 4). Subsequent catalyst screening revealed that
PTS loading could be dropped to 5% by switching to Pd(P(t-
Bu)3)2 as the source of palladium.26 Trials revealed that this
reduced loading could be maintained with TPGS-750-M/H2O,
and slightly higher yields could be obtained as compared to
those using PTS. Similarly, improved yields for Suzuki-Miyaura
cross-couplings could be realized, for both straightforward
(entry 3) and more sterically challenging (entry 4) substrate
combinations with 2% aqueous TPGS-750-M under otherwise
identical conditions (2 wt % PTS in water). A similar trend was
seen with Sonogashira couplings in 3 wt % surfactant/water,
with a moderately yielding substrate combination showing
improvement (entry 5), and a coupling involving an enyne
elevated to nearly quantitative yield (entry 6). Generation of
unsymmetrical diarylamines in water also appears to benefit
from a change in amphiphile from PTS to TPGS-750-M (entries
7, 8). The same aniline-forming reaction (entry 7) using TPGS-
1000 led to only a 39% yield of the desired derivative versus a
98% yield using TPGS-750-M.
Perhaps the most remarkable result obtained using PTS tech-
nology was the development of a new zinc-mediated Negishi-like
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Table 6. Room Temperature Negishi-like Couplings with
TPGS-750-M versus PTS in Water
Figure 4. Palladium catalysts and ligands employed.
coupling between aryl and alkyl halides, performed in water at
room temperature.27 Although organozinc halides are notor-
iously moisture-sensitive,28 they can be formed in situ on the
surface of zinc dust or powder from an alkyl or vinylic halide,
which then reacts with an aryl or vinylic halide under palladium
catalysis within the hydrophobic core of a nanoparticle. In the
presence of a stabilizing ligand for the transient RZnX, e.g., tetra-
methylethylenediamine (TMEDA), this sequence takes place in
an aqueous medium leading to a variety of primary and secondary
alkyl-substituted aromatics and olefins. Crucial to success are the
relative rates of organozinc halide formation, transmetalation
to palladium, and aqueous protonation of RZnX, all controlled
such that RZnX is not formed in situ too rapidly so as to avoid
quenching by eventual exposure to the nanoparticle-surrounding
water. The surfactant likely plays dual critical roles by both
helping to insulate the nascent organozinc species from water,
thereby extending lifetime, as well as by acting as a general
solubilizing agent.
On the basis of several comparison examples (Table 6),
TPGS-750-M appears to best accommodate the multiple species
involved leading to competitive or superior yields of the coupling
products relative to PTS under otherwise identical conditions.
Primary and secondary alkyl halides, including both bromides
and iodides, can serve as the organozinc halide precursor. A
range of functionality, such as esters (entries 1-3), is likely to
be tolerated under these mild conditions. In addition to aryl
bromides as coupling partners (entries 1-3), alkenyl halides also
work well in these reactions (entries 4-6). Interestingly, not
only are the yields of cross-coupled products as good or better
using aqueous TPGS-750-M, the levels of stereoretention are
higher in this medium relative to those observed in PTS/water.
Another exciting development in the pursuit of new, more
efficient, and atom-economical strategies in micellar catalysis
focuses on C-H activation reactions of aromatic hydrogens.29
While this class of reactions is appealing as a direct route to aryl
substitution, the relative inertness of the sp2 C-H bond in most
aromatics has generally necessitated relatively harsh reaction
conditions, including high temperatures and oftentimes strongly
acidic media. Most strategies rely on directing groups to enhance
reactivity, although where applicable, issues of regiocontrol and
monosubstitution can arise.30
a Isolated yield of chromatographically pure materials. b Using 1%
Pd(Amphos)2Cl2, 4 equiv of Zn powder, and 5 equiv of TMEDA.
left). Akin to other reaction types described herein, the process
was found to be easily adaptable to use of TPGS-750-M.
Similarly, C-H arylation reactions of aryl ureas with aromatic
iodides could also be achieved in water at room temperature, with
the aid of a surfactant (Scheme 3, right). In this case, a cationic
palladium species had to be generated in situ, necessitating use
of HBF4. While under optimized conditions the surfactant Brij 35
gave the highest yields (e.g., 76% vs 68%), results with PTS were
matched by TPGS-750-M.
Beyond metathesis and aromatic cross-coupling reactions,
allylic substitution chemistry has also been developed in PTS/
water and would benefit from adaptation to the more practical
TPGS-750-M surfactant. Procedures that take advantage of micellar
catalysis have led to use of less common allylic alcohols12 and
allylic ethers13 as viable coupling partners. Developing condi-
tions for reactions with these relatively inert substrates toward Pd
catalysis is appealing in a number of ways: (1) it streamlines synthetic
planning by minimizing prior derivatization; (2) it allows more
readily stored (and often less expensive) precursors to be
employed; and (3) it expands options in terms of orthogonal
reactivity, improving opportunities for selectivity when there are
multiple functionalities present that could potentially participate
in a Pd-catalyzed reaction.
In the case of a model allylic alcohol (Table 7, entry 1), it was
found that a palladium-catalyzed amination reaction could be
effected in 2% PTS/water at room temperature in the presence of
methyl formate, an additive that apparently enhances the leaving-
group ability of the allylic alcohol (although not by prior trans-
esterification).12 These mild conditions, when utilized with
TPGS-750-M as surfactant, gave the same product in competitive
Prior studies in our laboratory in this timely arena showed that
such chemistry occurs in water at room temperature, including
the Fujiwara-Moritani reaction.31 It was found that by using a
commercially available cationic palladium catalyst, ortho-directed
couplings of acrylate and anilide derivatives could, indeed, be
performed in 2% PTS/water at ambient temperatures (Scheme 3,
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Scheme 3. C-H Activation Reactions: PTS versus
TPGS-750-M in Water at Room Temperature
Table 8. Additional Reactions of Allylic Phenyl Ethers in
Water
Table 7. Aminations of Allylic Alcohols and Ethers in Water
at Room Temperature
a Isolated yield of chromatographically pure materials. b Using catalyst
PdCl2(dtbpf) (6 mol %).
Table 9. Recycling of TPGS-750-M
cycle
1
2
3
4
5
6
7
8
>99
>99
>99
>99
>99
>99
99
99
a Determined by 1H NMR spectroscopy.
Recycling TPGS-750-M. By design, the preferred solubility of
TPGS-750-M in water, as opposed to common organic solvents
used for extraction (e.g., hydrocarbons, Et2O, and EtOAc), allows
for recycling of the aqueous phase. A ring-closing metathesis
reaction was studied, where each cycle was followed by a standard
in-flask extraction of the product using minimal amounts of
Et2O (3 times), after which fresh substrate and catalyst were
introduced. As illustrated in Table 9, after eight recycles, essen-
tially complete conversion to the desired trisubstituted olefinic
product 9 can be realized.
a Isolated yield of chromatographically pure materials.
yield. A related amination developed for allylic phenyl ethers32
also translated well from PTS to TPGS-750-M (entries 2-4).
Although C-N bond formation proceeds smoothly under con-
ditions similar to those used for aminations of allylic alcohols,
allylic ethers are far less prone to react relative to allylic carbonates
and acetates under typical Pd-catalyzed allylation conditions.
Couplings of allylic phenyl ethers with either boronic acids
(Table 8, entries 1-3)33 or silanes13 (entries 4-6) in water at
room temperature have also been developed. These protocols
were readily subject to replacement of PTS with TPGS-750-M
as surfactant, as similar yields were achieved under otherwise
identical conditions.
’ CONCLUSION
A new “designer” surfactant, TPGS-750-M, an unsymmetrical
diester of succinic acid, has been prepared very efficiently in two
steps and shown to form nanomicelles in water. These particles
readily accommodate a variety of substrates and catalysts lead-
ing to efficient Pd- and Ru-catalyzed cross-couplings at room
temperature. In the many cases studied and described herein,
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second-generation TPGS-750-M is oftentimes a superior choice
to first-generation surfactant PTS, usually insofar as both yields
are concerned, and especially in terms of economics of prepara-
tion and levels of purity.34
Concentration of the solvent in vacuo followed by storage under high
vacuum overnight affords 82.56 g of a faintly yellow semisolid containing
4 wt % EtOAc (79.26 g actual, 96.9%). NMR (CDCl3) was consistent
with the desired product. Used as is for the next reaction.
TPGS-750-M (2). DL-R-Tocopherol succinate (79.26 g, 149.3 mmol)
was dissolved in toluene (560 mL, 5.3 mol) in a 1 L 3-necked
round-bottom flask under a stream of nitrogen. MPEG 750 (104.5 g,
141.9 mmol) was added to the reaction mixture followed by the addition
ofp-toluenesulfonic acid monohydrate (3.01 g, 15.8 mmol) which caused a
slight lightening of the solution. The flask was fitted with a Dean-Stark
trap (receiver filled with toluene) and a condenser. The reaction
mixture was heated to reflux for 5 h. HPLC indicates that starting
material still remains. The reaction mixture was cooled to room
temperature, additional MPEG-750 (5.00 g, 6.78 mmol) was added,
and the reaction was heated to reflux for an additional 5 h. HPLC
indicated that almost all of the starting material was gone. The reaction
mixture was cooled to room temperature and concentrated on a rotary
evaporator to afford a viscous dark brown oil. The oil was passed
through a pad of basic aluminum oxide (600 g in a 0.2 L filter funnel)
eluting with methylene chloride (3 L). The solvent was removed in
vacuo to afford a faintly yellow waxy solid. The material was placed
under high vacuum keeping the material at 50 °C (the waxy solid
liquefies at this temperature) until removal of the residual toluene and
methylene chloride was complete. After cooling and resolidification,
174.11 g (98.2%) of material was obtained that was identical in all
aspects (HPLC, 1H NMR, 13C NMR) with the sample prepared on a
smaller scale.
’ EXPERIMENTAL SECTION
DL-r-Tocopherol Succinate (4), <10 g Scale. To a solution of
DL-R-tocopherol (4.30 g, 10.00 mmol) and succinic anhydride (1.50 g,
15.00 mmol) in toluene (20 mL) was added Et3N (0.35 mL, 2.50 mmol)
at 22 °C with stirring, and the stirring was continued at 60 °C for 5 h.
Water was added to the reaction mixture, which was then extracted with
CH2Cl2. The combined organic layers were washed with 1 N HCl (3 ꢀ
50 mL) and water (2 ꢀ 30 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo affording a yellow liquid, which was purified by
flash column chromatography on silica gel eluting with a 10% EtOAc/
hexane to 35% EtOAC/hexanes gradient to afford DL-R-tocopherol
succinate (5.25 g, 99%) as a white solid, mp 68-71 °C, lit.22 mp 64-
67 °C. IR (neat) 2926, 1757, 1714, 1576, 1463, 1455, 1415, 1377, 1251,
1224, 1151, 1110, 1078, 926 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.94
(t, J = 6.8 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.59 (t, J = 6.8 Hz, 2H), 2.09
(s, 3H), 2.02 (s, 3H), 1.98 (s, 3H), 1.85-1.71 (m, 2H), 1.56-1.50 (m,
3H), 1.43-1.05 (m, 21H), 0.88-0.84 (m, 12H); 13C NMR (100 MHz,
CDCl3) δ 178.6, 171.0, 149.7, 140.7, 126.9, 125.1, 123.2, 117.6, 75.2,
39.6, 37.8, 37.7, 37.6, 37.5, 33.0, 32.9, 31.3, 29.2, 28.8, 28.2, 25.0, 24.6,
24.0, 22.9, 22.8, 21.2, 20.8, 19.95, 19.88, 13.0, 12.2, 12.0; MS (ESI) m/z
554 (M þ Na); HRMS (ESI) calcd for C33H54O5Na [M þ Na]þ
553.3869, found 553.3876.
General Procedure for Cross Metathesis (Table 3). Alkene
(0.50 mmol), acrylate (1.00 mmol)/ketone (1.50 mmol), and Grubbs-2
catalyst (8.5 mg, 0.010 mmol) were sequentially added into a Teflon-
coated stir-bar-containing Biotage 2-5 mL microwave reactor vial at rt,
and then the vial was sealed with a septum. An aliquot of TPGS-750-M/
H2O (1.0 mL; 2.5% TPGS-750-M by weight; all cross-coupling reac-
tions were conducted at 0.5 M unless stated otherwise) was added
via syringe, and the resulting solution was allowed to stir at rt for 12 h.
The homogeneous reaction mixture was then diluted with EtOAc
(2 mL) and filtered through a bed of silica gel, and the bed was further
washed (3 ꢀ 5 mL) with EtOAc to collect all of the cross-coupled
material. The volatiles were removed in vacuo to afford the crude product
that was subsequently purified by flash chromatography on silica gel.
(E)-tert-Butyl 4-(2-(tert-Butyldimethylsilyloxy)phenyl)-2-
butenoate (Table 3, entry 1). The representative procedure above
was followed using tert-butyl(2-allylphenoxy)dimethylsilane (124 mg,
0.50 mmol), tert-butyl acrylate (128 mg, 1.00 mmol), and Grubbs-2
catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel
(eluting with 3% EtOAc/hexanes) afforded the product as a colorless
oil (158 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.15-7.10 (m, 2H),
7.00 (dt, J = 15.6, 6.4 Hz, 1H), 6.91 (dt, J = 7.6, 1.2 Hz, 1H), 6.82 (dd,
J = 8.0, 0.8 Hz, 1H), 5.68 (dt, J = 15.6, 1.6 Hz, 1H), 3.48 (dd, J = 6.4, 1.6
Hz, 2H), 1.46 (s, 9H), 1.01 (s, 9H), 0.25 (s, 6H).14
(E)-5-(2-(tert-Butyldimethylsilyloxy)phenyl)pent-3-en-2-one
(Table 3, entry 2). The representative procedure above was followed
using tert-butyl(2-allylphenoxy)dimethylsilane (124 mg, 0.50 mmol),
methyl vinyl ketone (106 mg, 1.50 mmol), and Grubbs-2 catalyst (8.5
mg, 0.01 mmol). Column chromatography on silica gel (eluting with 3%
EtOAc/hexanes) afforded the product as a colorless oil (107 mg, 74%).
IR (neat) 3062, 3034, 2932, 2894, 2859, 1699, 1676, 1626, 1599, 1582,
1492, 1472, 1452, 1422, 1390, 1361, 1254, 1182, 1108, 1043, 982, 929
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.15 (td, J = 7.6, 1.6 Hz, 1H), 7.11
(dd, J = 7.6, 1.6 Hz, 1H), 6.95 (dt, J = 16.0, 6.4 Hz, 1H), 6.92 (td, J = 7.6,
1.2 Hz, 1H), 6.84 (dd, J = 7.6, 1.2 Hz, 1H), 6.03 (dt, J = 16.0, 1.6 Hz, 1H),
3.54 (dd, J = 6.4, 1.6 Hz, 2H), 2.24 (s, 3H), 1.01 (s, 9H), 0.26 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 198.8, 153.7, 146.8, 132.0, 130.7, 128.4,
128.1, 121.4, 118.6, 33.7, 26.9, 25.9, 18.4, -4.0; EI-MS m/z (%) 275
TPGS-750-M (2). A mixture containing DL-R-tocopherol succinate
(2.97 g, 5.60 mmol), poly(ethylene glycol) monomethylether-750 (4.00
g, 5.33 mmol) and p-TsOH (0.15 g, 0.79 mmol) in toluene (20 mL) was
refluxed for 5 h using a Dean-Stark trap. After cooling to rt, the mixture
was poured into saturated aqueous NaHCO3 solution and extracted with
CH2Cl2. The combined organic layers were washed with saturated
NaHCO3 (3 ꢀ 50 mL), brine (2 ꢀ 30 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo to afford the title compound (6.60 g,
98%) as a waxy solid. IR (neat) 2888, 1755, 1739, 1465, 1414, 1346,
1281, 1245, 1202, 1109, 947, 845 cm-1; 1H NMR (400 MHz, CDCl3) δ
4.28-4.26 (m, 2H), 3.71-3.54 (m, PEG), 3.38 (s, 3H), 2.93 (t, J = 7.2
Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 2.08 (s, 3H),
2.01 (s, 3H), 1.97 (s, 3H), 1.84-1.70 (m, 2H), 1.55-1.04 (m, 24H),
0.87-0.83 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 172.2, 170.9,
149.5, 140.6, 126.7, 125.0, 123.0, 117.4, 94.5, 75.1, 72.0, 70.64, 70.56,
69.1, 64.0, 59.0, 39.4, 37.6, 37.5, 37.4, 37.3, 32.8, 32.7, 31.1, 29.2, 28.9,
28.0, 24.8, 24.5, 22.8, 22.7, 21.1, 20.6, 19.8, 19.7, 13.0, 12.1, 11.8; MS
(ESI) m/z 1272 (M þ Na).
DL-r-Tocopherol Succinate (4), >150 g Scale. DL-R-Toco-
pherol (66.4 g, 154.1 mmol) and methylene chloride (300 mL) were
charged under nitrogen into a 1 L single necked round-bottom flask that
had been oven-dried and cooled under vacuum. Succinic anhydride
(23.1 g, 231 mmol) was added to the clear yellow solution followed by
the addition of 4-dimethylaminopyridine (9.4 g, 77.1 mmol) and finally
triethylamine (21.5 mL, 154 mmol). The reaction mixture was stirred at
23 °C overnight during which time the reaction mixture became a dark
purplish solution. HPLC and TLC (3:7 EtOAc/hexanes, Rf = 0.3)
indicated the reaction was complete. The reaction mixture was poured
into a 1 L separatory funnel, and the flask was rinsed with methylene
chloride (300 mL). The organic layer was washed with 1 M HCl
(160 mL) (ꢀ 3), water (100 mL) (ꢀ 2), and saturated aqueous sodium
chloride solution (250 mL). The organic layer was dried over Na2SO4
and filtered, and the solvent was emoved in vacuo affording a dark,
viscous oil. The oil was poured onto a pad of silica gel (600 g in a 1.2 L
filter funnel) and then eluted first with methylene chloride (1.5 L) (to
remove impurity) followed by elution with 1:1 EtOAc/hexanes (3 L).
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(M - CH3þ, 2), 233 (M - C4H9þ, 100), 215 (20), 151 (8), 75 (42);
HRMS (EI) calcd for C13H17O2Si [M -C4H9]þ 233.0998, found 233.1006.
(E)-2-Adamantyl 4-(4-methoxyphenyl)-2-butenoate (Table 3,
entry 3). The representative procedure was followed using 4-allylani-
sole (74 mg, 0.50 mmol), 2-adamantyl acrylate (206 mg, 1.00 mmol),
and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chromatography
on silica gel (eluting with 5% EtOAc/hexanes) afforded the product as a
colorless oil (134 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 7.16-7.08
(m, 3H), 6.88 (d, J = 8.8 Hz, 2H), 5.84 (dt, J = 15.2, 1.2 Hz, 1H), 4.99 (br
s, 1H), 3.80 (s, 3H), 3.47 (dd, J = 6.8, 1.2 Hz, 2H), 2.05-2.01 (m, 4H),
1.90-1.74 (m, 8H), 1.58-1.56 (m, 2H).14
(E)-tert-Butyl 3-(2,4-Dimethylphenyl)acrylate (Table 3,
entry 4). The representative procedure was followed using 2,4-dimethyl-
1-vinylbenzene (66 mg, 0.50 mmol), tert-butyl acrylate (128 mg, 1.00
mmol), and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chroma-
tography on silica gel (eluting with 2% EtOAc/hexanes) afforded the
product as a colorless oil (86 mg, 74%). 1H NMR (400 MHz, CDCl3) δ
7.87 (d, J = 15.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.03-7.01 (m, 2H),
6.29 (d, J = 15.6 Hz, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.55 (s, 9H).14
(E)-tert-Butyl 11-(tert-Butyldimethylsilyloxy)-2-undecenoate
(Table 3, entry 5). The representative procedure was followed using
tert-butyl(dec-9-enyloxy)dimethylsilane (135 mg, 0.50 mmol), tert-
butyl acrylate (128 mg, 1.00 mmol), and Grubbs-2 catalyst (8.5 mg,
0.01 mmol). Column chromatography on silica gel (eluting with 2%
EtOAc/hexanes) afforded the product as a colorless oil (176 mg, 95%).
1H NMR (400 MHz, CDCl3) δ 6.85 (dt, J = 15.6, 7.2 Hz, 1H), 5.73 (dt,
J = 15.6, 1.2 Hz, 1H), 3.61 (t, J = 7.2 Hz, 2H), 2.17 (qd, J = 7.2, 1.2 Hz,
2H), 1.52-1.42 (m, 4H), 1.48 (s, 9H), 1.32-1.30 (m, 8H), 0.90 (s,
9H), 0.05 (s, 6H).14
General Procedure for Ring-Closing Metathesis (Table 3).
Diene (0.20 mmol) and Grubbs-2 catalyst (3.4 mg, 0.004 mmol) were
both added into a Teflon-coated stir-bar-containing Biotage 2-5 mL
microwave reactor vial at rt, and the vial was sealed with a septum. An
aliquot of TPGS-750-M/H2O was added via syringe (2.0 mL; 2.5%
TPGS-750-M by weight; all RCM reaction were conducted at 0.1 M
unless stated otherwise), and the resulting solution was allowed to stir at
rt for 3 h. The homogeneous reaction mixture was then diluted with
EtOAc (2 mL) and filtered through a bed of silica gel, and the bed was
further washed (3 ꢀ 5 mL) with EtOAc to collect all of the cyclized
material. The volatiles were removed in vacuo to afford the crude
product, which was subsequently purified by flash chromatography
using silica gel.
1-Tosyl-1,2,5,6-tetrahydropyridine (Table 3, entry 6). The
representative procedure was followed using N-allyl-N-(but-3-enyl)-4-
methylbenzenesulfonamide (53 mg, 0.20 mmol) and Grubbs-2 catalyst
(3.4 mg, 0.004 mmol). Column chromatography on silica gel (eluting
with 5% EtOAc/hexanes) afforded the product as a white solid (47 mg,
99%). 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.0 Hz, 2H), 7.32 (d,
J = 8.0 Hz, 2H), 5.77-5.72 (m, 1H), 5.63-5.58 (m, 1H), 3.58-3.55 (m,
2H), 3.16 (t, J = 6.0 Hz, 2H), 2.42 (s, 3H), 2.24-2.18 (m, 2H).35
1-Tosyl-2,5,6,7-tetrahydro-1H-azepine (Table 3, entry 7).
The representative procedure was followed using N-allyl-4-methyl-
N-(pent-4-enyl)benzenesulfonamide (56 mg, 0.20 mmol) and Grubbs-2
catalyst (3.4 mg, 0.004 mmol). Column chromatography on silica gel
(eluting with 5% EtOAc/hexanes) afforded the product as a white solid
(44 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.0 Hz, 2H),
7.28 (d, J = 8.0 Hz, 2H), 5.79-5.74 (m, 1H), 5.67-5.62 (m, 1H), 3.83-
3.82 (m, 2H), 3.38 (t, J = 6.0 Hz, 2H), 2.42 (s, 3H), 2.20-2.15 (m, 2H),
1.82-1.76 (m, 2H).36
1.50 mmol), and acrylate/styrene (1.0 mmol) were added by syringe,
and the resulting mixture was allowed to stir at rt for 4-12 h. The
homogeneous reaction mixture was then diluted with EtOAc (2 mL)
and filtered through a bed of silica gel, and the bed was further washed
(3 ꢀ 5 mL) with EtOAc to collect all of the coupled material. The
volatiles were removed in vacuo to afford the crude produc, which was
subsequently purified by flash chromatography on silica gel.
(E)-tert-Butyl 3-(4-Methoxyphenyl)acrylate (Table 5, entry
1). Following the general procedure using 4-methoxyiodobenzene
(117 mg, 0.50 mmol) and tert-butyl acrylate (145 μL, 1.00 mmol), the
reaction was stirred for 4 h at rt. Column chromatography on silica gel
(eluting with 3% EtOAc/hexanes) afforded the product as a colorless oil
(113 mg, 97%). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 16.0 Hz,
1H), 7.47 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.25 (d, J = 16.0
Hz, 1H), 3.84 (s, 3H), 1.54 (s, 9H).37
(E)-1-(2,4-Dimethylstyryl)-2-methoxynaphthalene (Table 5,
entry 2). Following the general procedure using 1-iodo-2-methoxy-
naphthalene (142 mg, 0.50 mmol) and 2,4-dimethylstyrene (132 μL, 1.0
mmol), the reaction was stirred for 12 h at rt. Column chromatography
on silica gel (eluting with 5% EtOAc/hexanes) afforded the product as a
tan semisolid (137 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.30 (d,
J = 8.7 Hz, 1H), 7.81 (t, J = 7.8 Hz, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.47 (t,
J = 7.2 Hz, 1H), 7.40-7.30 (m, 4H), 7.10 (d, J = 8.2 Hz, 1H), 7.05 (s,
1H), 3.98 (s, 3H), 2.40 (s, 3H), 2.37 (s, 3H).8
General Procedure for Suzuki-Miyaura Coupling (Table 5).
Arylboronic acid (0.50-1.00 mmol), aryl bromide (0.50 mmol), and
Pd(dtbpf)Cl2 (6 mg, 0.01 mmol) were added to a reaction tube
equipped with a magnetic stir bar. Under a positive flow of argon while
stirring, surfactant solution (1.0 mL, 2 wt % TPGS-750-M in water),
and Et3N (0.21 mL, 1.5 mmol) were added by syringe and stirred
vigorously for 2-24 h. The reaction mixture was then diluted with brine
and extracted with EtOAc. The solution obtained was dried over
anhydrous MgSO4 and concentrated by rotary evaporation. The residue
was purified by flash column chromatography on silica gel to afford the
title compounds.
3-Phenylbenzonitrile (Table 5, entry 3). Following the
general procedure using 3-bromobenzonitrile (91 mg, 0.5 mmol) and
phenylboronic acid (91 mg, 0.75 mmol), the reaction was stirred for 2 h
at rt. Column chromatography on silica gel (eluting with 20% CH2Cl2/
hexanes) afforded the product as a slightly yellow oil (83 mg, 93%). 1H
NMR (400 MHz, CDCl3) δ 7.84-7.79 (m, 2H), 7.62-7.38 (m, 7H).38
4-Methoxy-20,40,60-tri-isopropylbiphenyl (Table 5, entry
4). Following the general procedure using 4-methoxy-phenylboronic
acid (152 mg, 1.00 mmol) and 2,4,6-tri-iso-propylbromobenzene
(126 μL, 0.50 mmol) the reaction was stirred for 24 h at rt. Column
chromatography on silica gel (eluting with 5% CH2Cl2/hexanes)
afforded the product as a white solid (137 mg, 88%). 1H NMR
(400 MHz, CDCl3) δ 7.17 (d, J = 8.7 Hz, 2H), 7.13 (s, 2H), 7.01 (d,
J = 8.7 Hz, 2H), 3.92 (s, 3H), 3.01 (sept, J = 6.9 Hz, 1H), 2.73 (sept, J =
6.9 Hz, 2H), 1.38 (d, J = 6.9 Hz, 6H), 1.15 (d, J = 6.9 Hz, 12H).39
General Procedure for Sonogashira Coupling (Table 5). The
catalyst Pd(CH3CN)2Cl2 (1.3 mg, 0.005 mmol) and XPhos (6.2 mg,
0.013 mmol) were added under argon into a 5.0 mL microwave vial
equipped with a large stir bar and Teflon-lined septum. An aliquot of
TPGS-750-M/H2O (1.0 mL; 3.0% TPGS-750-M by weight) solution,
triethylamine (140 μL, 1.00 mmol), aryl bromide (0.50 mmol), and
alkyne (0.75 mmol) were added by syringe, and the resulting solution
was allowed to stir at rt for 21-25 h. The homogeneous reaction mixture was
then diluted with EtOAc (2 mL),and filtered through a bed of silica gel, and the
bed was further washed (3 ꢀ 5 mL) with EtOAc to collect all of the coupled
material. The volatiles were removed in vacuo to afford the crude product,
which was subsequently purified by flash chromatography on silica gel.
1-(6-Chlorohex-1-ynyl)-4-methoxybenzene (Table 5, en-
try 5). Following the general procedure using 4-bromoanisole (60 mg,
General Procedure for Heck Coupling (Table 5). The cata-
lyst Pd[P(t-Bu)3]2 (5.1 mg, 0.01 mmol) and aryl iodide (0.50 mmol)
were added under argon into a 5.0 mL microwave vial equipped with a
large stir bar and Teflon-lined septum. An aliquot of TPGS-750-M/H2O
solution (1.0 mL; 5.0% TPGS-750-M by weight), triethylamine (208 μL,
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0.48 mmol) and 6-chloro-1-hexyne (90 μL, 0.74 mmol), the reaction
was stirred for 25 h at rt. Column chromatography on silica gel (eluting
with 1% EtOAc/hexanes) afforded the product as a pale yellow oil (70
mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.8 Hz, 2H), 6.83
(d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.62 (t, J = 6.6 Hz, 2H), 2.45 (t, J = 7.0
Hz, 2H), 2.02-1.94 (m, 2H), 1.81-1.71 (m, 2H).10
3 mmol), PdCl2(Amphos)2 (3.5 mg, 0.005 mmol), 2 wt % of TPGS-750-
M (3 mL), TMEDA (116 mg, 1 mmol), ethyl 4-bromobutanoate (390 mg,
2 mmol), and ethyl bromobenzoate (229 mg, 1 mmol), the reaction was
stirred for 48 h at rt. Column chromatography on silica gel (eluting with
1
10% Et2O/petroleum ether) afforded the product (187 mg, 71%). H
NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz,
2H), 4.35 (q, J = 7.5 Hz, 2H), 4.11 (q, J = 7.5 Hz, 2H), 2.69 (t, J = 7.5 Hz,
2H), 2.30 (t, J = 7.5 Hz, 2H), 1.95 (quint, J = 7.5 Hz, 2H), 1.37 (t,
J = 7.5 Hz, 3H), 1.24 (t, J = 7.5 Hz, 3H).42
2-(Cyclohexenylethynyl)naphthalene (Table 5, entry 6).
Following the general procedure using 2-bromonaphthalene (103 mg,
0.50 mmol) and 1-ethynylcyclohex-1-ene (100 μL, 0.85 mmol), the
reaction was stirred for 21 h at rt. Column chromatography on silica gel
(eluting with 1% EtOAc/hexanes) afforded the product as an off-white
Ethyl 4-Decylbenzoate (Table 6, entry 3). Following the
general procedure, using zinc powder (260 mg, 4 mmol), PdCl2-
(Amphos)2 (7 mg, 0.01 mmol), 2 wt % of TPGS-750-M (6 mL),
TMEDA (580 mg, 5 mmol), iododecane (804 mg, 3 mmol), and ethyl
bromobenzoate (229 mg, 1 mmol), the reaction was stirred for 36 h at rt.
Column chromatography on silica gel (eluting with 1% Et2O/petroleum
ether) afforded the product (258 mg, 89%). 1H NMR (500 MHz,
CDCl3) δ 7.95 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.35 (q, J =
7.5 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 1.63-1.60 (m, 2H), 1.38 (t, J = 7.5
Hz, 3H), 1.27-1.25 (m, 14H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (125
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) calcd
290.2246, found 290.2252.
(E)-((Dodec-4-en-1-yloxy)methyl)benzene (Table 6, entry
4). Following the general procedure, using zinc powder (260 mg, 4
mmol), PdCl2(Amphos)2 (7 mg, 0.01 mmol), 2 wt % of TPGS-750-M
(6 mL), TMEDA (580 mg, 5 mmol), 1-iodoheptane (678 mg, 3 mmol),
and (E)-(((5-iodopent-4-en-1-yl)oxy)methyl)benzene (302 mg, 1 mmol,
Z/E = 1/99), the reaction was stirred for 16 h at rt. Column
chromatography on silica gel (eluting with 5% EtOAc/petroleum ether)
afforded the product (231 mg, 84%, Z/E = 1/99). 1H NMR (400 MHz)
δ 7.35-7.34 (m, 4H), 7.30-7.27 (m, 1H), 5.45-5.36 (m, 2H), 4.50 (s,
2H), 3.48 (t, J = 6.6 Hz, 2H), 2.08 (q, J = 6.7 Hz, 2H), 1.97 (q, J = 6.7 Hz,
2H), 1.68 (quint, J = 7.0 Hz, 2H), 1.35-1.27 (m, 10H), 0.89 (t, J = 6.9
Hz, 3H); 13C NMR (100 MHz) δ 138.9, 131.3, 129.6, 128.6, 127.9,
127.7, 73.1, 70.1, 32.8, 32.1, 29.9, 29.8, 29.4, 29.4, 29.4, 22.9, 14.4;
HRMS (C19H30O) calcd 274.2297, found 274.2293.
1-((Z)-Non-1-enyl)benzene (Table 6, entry 5). Following the
general procedure, using zinc powder (260 mg, 4 mmol), PdCl2-
(Amphos)2 (7 mg, 0.01 mmol), 2 wt % of TPGS-750-M (6 mL),
TMEDA (580 mg, 5 mmol), 1-iodoheptane (678 mg, 3 mmol), and
1-((Z)-2-bromovinyl)benzene (183 mg, 1 mmol, Z/E = 99/1), the
reaction was stirred for 16 h at rt. Column chromatography on silica gel
(eluting with petroleum ether) afforded the product (182 mg, 90%,
Z/E = 88/12). 1H NMR (400 MHz) δ 7.34 (t, J = 7.7 Hz, 2H), 7.27 (d,
J = 6.9 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 6.40 (brd, J = 11.7 Hz, 1H), 5.67
(dt, J = 11.7, 7.3 Hz, 1H), 2.34 (dq, J = 7.5, 1.5 Hz, 2H), 1.47-1.42 (m,
2H), 1.31-1.26 (m, 8H), 0.88 (t, J = 7.1 Hz, 3H).43
(Z)-Ethyl Dodec-5-enoate (Table 6, entry 6). Following the
general procedure, using zinc powder (260 mg, 4 mmol), PdCl2-
(Amphos)2 (7 mg, 0.01 mmol), 2 wt % of TPGS-750-M (6 mL),
TMEDA (580 mg, 5 mmol), (Z)-1-bromooct-1-ene (181 mg, 1 mmol,
Z/E = 99/1), and ethyl 4-bromobutanoate (390 mg, 2 mmol), the
reaction was stirred for 12 h at rt. Column chromatography on silica gel
(eluting with 5% EtOAc/petroleum ether) afforded the product (196
mg, 87%, Z/E = 99/1). 1H NMR (400 MHz) δ 5.43-5.30 (m, 2H), 4.12
(q, J = 7.1 Hz, 2H), 2.28 (q, J = 7.6 Hz, 2H), 2.06 (q, J = 7.4 Hz, 2H), 2.00
(q, J = 7.7 Hz, 2H), 1.70-1.65 (m, 2H), 1.34-1.23 (m, 11H), 0.88 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz) δ 174.0, 131.3, 128.6, 60.4, 34.0,
32.0, 29.9, 29.2, 27.4, 26.7, 25.1, 22.9, 14.5, 14.3; HRMS (C14H26O2)
calcd 226.1933, found 226.1934.
1
solid (115 mg, 99%). H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H),
7.82-7.76 (m, 3H), 7.50-7.45 (m, 3H), 6.29-6.27 (m, 1H), 2.30-
2.26 (m, 2H), 2.21-2.16 (m, 2H), 1.75-1.62 (m, 4H).10
General Procedure for Buchwald-Hartwig Amination
(Table 5). The catalyst [(π-allyl)PdCl]2 (2.1 mg, 0.006 mmol), ligand
cBRIDP (Takasago; 7.6 mg, 0.022 mmol), KO-t-Bu (184 mg, 1.56
mmol), and amine (1.20 mmol) were added under argon into a 5.0 mL
microwave vial equipped with a large stir bar and Teflon lined septum.
An aliquot of TPGS-750-M/H2O (1.0 mL; 2.0% TPGS-750-M by
weight) solution and aryl bromide (1.00 mmol) were added by syringe,
and the resulting solution was allowed to stir at rt for 19-20 h. The
homogeneous reaction mixture was then diluted with EtOAc (2 mL)
and filtered through a bed of silica gel, and the bed was further washed (3
ꢀ 5 mL) with EtOAc to collect all of the coupled material. The volatiles
were removed in vacuo to afford the crude product that was subsequently
purified by flash chromatography on silica gel.
N-(m-Tolyl)-3-aminopyridine (Table 5, entry 7). Following
the general procedure using 3-bromotoluene (121 μL, 1.00 mmol) and
3-aminopyridine (113 mg, 1.20 mmol), the reaction was stirred for 20 h
at rt. Column chromatography on silica gel (eluting with 40% EtOAc/
hexanes) afforded the product as an off-white solid (180 mg, 98%). 1H
NMR (400 MHz, CDCl3) δ 8.39 (br s, 1H), 8.17 (br s, 1H) 7.41 (dd, J =
8.4, 1.6 Hz, 1H), 7.21-7.17 (m, 2H), 6.91 (s, 1H), 6.90 (d, J = 8.4 Hz,
1H), 6.83 (d, J = 7.2 Hz, 1H), 5.81 (br s, 1H), 2.33 (s, 3H).40
2,6-Dimethyl-N-(m-tolyl)aniline (Table 5, entry 8). Follow-
ing the general procedure using 3-bromotoluene (121 μL, 1.00 mmol)
and 2,6-dimethylaniline (148 μL, 1.20 mmol), the reaction was stirred
for 19 h at rt. Column chromatography on silica gel (eluting with 30%
EtOAc/hexanes) afforded the product as an off-white solid (196 mg,
93%). 1H NMR (400 MHz, CDCl3) δ 7.15-7.09 (m, 3H), 7.06 (t, J =
7.6 Hz, 1H), 6.59 (d, J = 7.2 Hz, 1H), 6.36 (s, 1H), 6.32 (d, J = 8.0 Hz,
1H), 5.15 (br, 1H), 2.26 (s, 3H), 2.23 (s, 6H).11
General Procedure for Negishi Coupling (Table 6). In a
5 mL round-bottom flask under argon containing zinc dust/powder and
PdCl2(Amphos)2 was added a solution of 2 wt % of TPGS-750-M. N,N,
N0,N0-Tetramethylethylenediamine (TMEDA) was added at rt followed
by the addition of alkyl halide (2.0-3.0 mmol) and aryl or alkenyl
bromide (1 mmol). The flask was stirred vigorously at rt for 12-48 h.
The reaction mixture was then filtered through a plug of silica (10 g)
and washed with diethyl ether (70 mL) into a 100 mL flask containing 2 g
ofsilica. Solvents wereremovedundervacuum. The residuewasloadedon
silica gel and purified by flash chromatography to afford the product.
Ethyl 4-Cyclohexylbenzoate (Table 6, entry 1). Following
the general procedure, using zinc dust (195 mg, 3 mmol), PdCl2-
(Amphos)2 (3.5 mg, 0.005 mmol), 2 wt % of TPGS-750-M (3 mL),
TMEDA (116 mg, 1 mmol), bromocyclohexane (407 mg, 2.5 mmol),
and ethyl bromobenzoate (229 mg, 1 mmol), the reaction was stirred
for 48 h at rt. Column chromatography on silica gel (eluting with 1% Et2O/
petroleum ether) afforded the product (174 mg, 75%). 1H NMR (500 MHz,
CDCl3) δ 7.97 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.37 (q, J = 7.0
Hz, 2H), 2.56-2.55 (m, 1H), 1.87-1.84 (m, 4H), 1.43-1.38 (m, 9H).41
Ethyl 4-[(4-Ethoxycarbonyl)phenyl]butanoate (Table 6,
entry 2). Following the general procedure, using zinc dust (195 mg,
(E)-n-Butyl 3-(2-Acetamido-4-methoxyphenyl)acrylate.
N-(3-Methoxyphenyl)acetamide (41 mg, 0.25 mmol), n-butyl acrylate
(64 mg, 0.50 mmol), 1,4-benzoquinone (27 mg, 0.25 mmol), AgNO3
(85 mg, 0.5 mmol), and [Pd(MeCN)4](BF4)2 (11 mg, 0.025 mmol)
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ARTICLE
were sequentially added under air to a reaction tube equipped with a stir
bar and a septum. A degassed aqueous solution containing TPGS-750-M
(1.0 mL, 2 wt %) was added by syringe, and the resulting mixture was
vigorously stirred for 20 h. After this time, the contents of the flask
were quenched with aqueous NaHCO3 and extracted with EtOAc. The
solution obtained was filtered through the plug of silica gel and
anhydrous MgSO4 and then concentrated by rotary evaporation. The
residue was purified by flash chromatography, eluting with 50%
EtOAc/hexanes to afford the product as an off-white solid (60 mg,
83%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 15.6 Hz, 1H), 7.50 (d,
J = 8.8 Hz, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.37 (br s, 1H), 6.74 (dd, J = 8.8,
1.7 Hz, 1H), 6.30 (d, J = 15.6 Hz, 1H), 4.19 (t, J = 6.7 Hz, 2H), 3.83 (s,
3H), 2.25 (s, 3H), 1.68 (quint, J = 6.7 Hz, 4H), 1.42 (sext, J = 7.4 Hz,
2H), 0.96 (t, J = 7.4 Hz, 3H).31c
4.03 (d, J = 14.2 Hz, 1H), 3.75 (dd, J = 8.2, 7.2 Hz, 1H), 3.62 (d, J = 14.2
Hz, 1H), 3.52 (ddd, J = 14.5, 4.9, 1.8 Hz, 1H), 3.28 (ddd, J = 14.5, 7.8, 0.6
Hz, 1H), 3.11 (dd, J = 13.7, 7.2 Hz, 1H), 2.98 (dd, J = 13.7, 8.2 Hz, 1H),
1.27 (t, J = 7.2 Hz, 3H).32
N-Methyl-N-(2-methallyl)-1-naphthylmethylamine (Table 7,
entry 3). Following the general procedure using (2-methylallyloxy)-
benzene (74 mg, 0.50 mmol) and N-methyl-N-naphthylmethylamine
(128 mg, 0.75 mmol), the reaction was stirred for 1 h at rt. Column
chromatography on silica gel (eluting with 10% EtOAc/hexanes)
1
afforded the product as a colorless liquid (88 mg, 80%). H NMR
(400 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 7.1, 2.3 Hz,
1H), 7.75 (d, J = 8.0 Hz, 1H), 7.51-7.37 (m, 4H), 4.92 (s, 1H), 4.85 (s,
1H), 3.87 (s, 2H), 2.96 (s, 2H), 2.14 (s, 3H), 1.73 (s, 3H).32
(E)-N,N-Dibenzyl-3-phenylprop-2-en-1-amine (Table 7,
entry 4). Following the general procedure using cinnamyloxybenzene
(105 mg, 0.50 mmol) and dibenzylamine (148 mg, 0.75 mmol), the
reaction was stirred for 0.5 h at rt. Column chromatography on silica gel
(eluting with 8% EtOAc/hexanes) afforded the product as a pale yellow
liquid (145 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.41-7.15 (m,
15H), 6.52 (d, J = 15.9 Hz, 1H), 6.29 (dt, J = 15.9, 11.4 Hz, 1H), 3.63 (s,
4H), 3.22 (d, J = 11.4 Hz, 2H).45
General Procedure for Suzuki-Miyaura Coupling with
Allylic Ethers (Table 8). An allylic phenyl ether (0.25 mmol),
arylboronic acid (0.38 mmol), and PdCl2(DPEphos) (0.005 mmol,
3.6 mg) (or PdCl2(dtbpf) were sequentially added under air to a
reaction tube equipped with a stir bar and a septum. Degassed TPGS-
750-M solution (0.8 mL, 2 wt %), and Et3N (0.75 mmol, 0.1 mL) were
added by syringe and vigorously stirred for 5-20 h. After the reaction,
the contents of the flask were diluted with brine and extracted with
EtOAc. The solution obtained was dried over anhydrous MgSO4,
filtered, and concentrated by rotary evaporation. The residue was
purified by flash chromatography, eluting with hexane/EtOAc to
afford the product.
3-(4,40-Dimethoxybiphenyl-2-yl)-1,1-dimethylurea. 3-(3-
Methoxyphenyl)-1,1-dimethylurea (49 mg, 0.25 mmol), 1-iodo-4-meth-
oxybenzene (117 mg, 0.50 mmol), AgOAc (0.5 mmol, 83 mg), and
Pd(OAc)2 (0.025 mmol, 5.6 mg) were sequentially added under air
to a reaction tube equipped with a stir bar and septum. An aliquot of
TPGS-750-M/H2O (1.0 mL; 2.0% TPGS-750-M by weight) solution
and 48 wt % aqueous HBF4 solution (1.25 mmol, 0.16 mL) were added
by syringe and stirred vigorously for 24 h. After the reaction, the contents
of the flask were quenched with NaHCO3 and extracted with EtOAc.
The solution obtained was dried over anhydrous MgSO4 and concen-
trated by rotary evaporation. The residue was purified by flash chroma-
tography eluting with 1:1 EtOAc/hexanes to afford the product (51 mg,
68%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 2.6 Hz,
1H), 7.27 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.6 Hz,
2H), 6.61 (dd, J = 8.3, 2.6 Hz, 1H), 3.84 (s, 6H), 2.81 (s, 6H).31b
N-Cinnamyl-N-methylaniline (Table 7, entry 1). Cinnamyl
alcohol (100 mg, 0.75 mmol), N-methylaniline (53 mg, 0.50 mmol), dppf
(14 mg, 0.025 mmol), K2CO3 (207 mg, 1.5 mmol), and [Pd(allyl)Cl]2
(4.5 mg, 0.0125 mmol) were sequentially added under argon to a reac-
tion tube equipped with a stir bar and a septum. Degassed TPGS-750-M
solution (1.0 mL, 2 wt %) and HCO2Me (0.12 mL, 2.0 mmol) were
added by syringe and vigorously stirred for 20 h. After the reaction, the
contents of the flask were diluted with brine and extracted with EtOAc.
The solution obtained was dried over anhydrous MgSO4, filtered, and
concentrated by rotary evaporation. The residue was purified by flash
chromatography eluting with 10% EtOAc/hexanes to afford the product
as a pale yellow liquid (102 mg, 92%). 1H NMR (400 MHz, CDCl3) δ
7.36-7.34 (m, 2H),7.32-7.28 (m, 2H), 7.27-7.21(m, 3H), 6.78(dd, J=
8.8, 0.8 Hz, 2H), 6.72 (td, J = 7.3, 0.8 Hz, 1H), 6.51 (d, J = 15.9 Hz, 1H),
6.25 (dt, J= 15.9, 5.5 Hz, 1H), 4.08 (dd, J=5.5, 1.6Hz, 2H), 3.02(s,3H).44
General Procedure for Aminations with Allylic Ethers
(Table 7). An allylic phenyl ether (0.5 mmol), amine (0.75 mmol),
DPEphos (0.005 mmol, 2.7 mg), K2CO3 (0.75 mmol, 103 mg), and
[Pd(allyl)Cl]2 (0.0025 mmol, 0.9 mg) were sequentially added under air
to a reaction tube equipped with a stir bar and a septum. Degassed
TPGS-750-M solution (1.0 mL, 2 wt %), and HCO2Me (2.0 mmol, 0.12
mL) were added by syringe and vigorously stirred for 0.5 - 2.5 h. Upon
completion of the reaction, the contents of the flask were diluted with
brine and extracted with EtOAc. The solution obtained was dried over
anhydrous MgSO4, filtered, and concentrated by rotary evaporation.
The residue was purified by flash chromatography, eluting with hexane/
EtOAc to afford the product.
1-Cinnamyl-2-methylbenzene (Table 8, entry 1). Following
the general procedure using cinnamyloxybenzene (53 mg, 0.25 mmol),
o-tolylboronic acid (51 mg, 0.38 mmol), and PdCl2(DPEphos) (0.005
mmol, 3.6 mg), the reaction was stirred for 5 h at rt. Column
chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded
1
the product as a colorless liquid (51 mg, 99%). H NMR (400 MHz,
CDCl3) δ 7.34-7.25 (m, 4H), 7.19-7.14 (m, 5H), 6.39-6.32 (m, 2H),
3.51 (d, J = 4.8 Hz, 2H), 2.32 (s, 3H).33
(E)-1-(3-(4-Methoxyphenyl)allyl)-2-methylbenzene (Table 8,
entry 2). Following the general procedure using (E)-1-methoxy-4-(3-
phenoxyprop-1-enyl)benzene (60 mg, 0.25 mmol), o-tolylboronic acid
(51 mg, 0.38 mmol), and PdCl2(DPEphos) (0.015 mmol, 11 mg), the
reaction was stirred for 6 h at rt. Column chromatography on silica gel
(eluting with 3% EtOAc/hexanes) afforded the product as a colorless
liquid (51 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz,
2H), 7.22-7.14 (m, 4H), 6.84 (d, J = 8.8 Hz, 2H), 6.33 (d, J = 15.8 Hz,
1H), 6.20 (dt, J = 15.8, 6.5 Hz, 1H), 3.80 (s, 3H), 3.52 (dd, J = 6.4, 1.1
Hz, 2H), 2.34 (s, 3H).33
1-Chloro-4-cinnamylbenzene (Table 8, entry 3). Following
the general procedure using cinnamyl-oxybenzene (53 mg, 0.25 mmol),
4-chlorophenylboronic acid (58 mg, 0.38 mmol), and PdCl2(Dt-BPF)
(0.015 mmol, 9.8 mg), the reaction was stirred for 20 h at rt. Column
chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded
1
(E)-N-Benzyl-N-(3-phenyl-2-propenyl)-3-phenylalanine Ethyl
Ester (Table 7, entry 2). Following the general procedure using
cinnamyloxybenzene (105 mg, 0.50 mmol) and ethyl 2-(benzylamino)-
3-phenylpropanoate (212 mg, 0.75 mmol), the reaction was stirred for
2.5 h at rt. Column chromatography on silica gel (eluting with 10%
EtOAc/hexanes) afforded the product as a pale yellow liquid (190 mg,
95%). 1H NMR (400 MHz, CDCl3) δ 7.33-7.11 (m, 15H), 6.47 (d, J =
16.2 Hz, 1H), 6.04 (ddd, J = 16.2, 7.8, 5.0 Hz, 1H), 4.24-4.10 (m, 2H),
the product as a colorless liquid (43 mg, 75%). H NMR (400 MHz,
CDCl3) δ 7.38 (d, J = 7.9 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 7.30 (d, J =
8.2 Hz, 2H), 7.26 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.42 (d, J =
15.8 Hz, 1H), 6.29 (dt, J = 15.8, 6.8 Hz, 1H), 3.49 (d, J = 6.7 Hz, 2H).33
General Procedure for Silylation with Allylic Ethers
(Table 8). A 1 dram vial containing a strong magnetic stir bar was
loaded with PdCl2(DPEphos) (6 mol %, 10.8 mg, 15 μmol) and an
allylic phenyl ether (0.25 mmol) and brought into a glovebag. After an
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The Journal of Organic Chemistry
ARTICLE
atmosphere of argon was applied, hexamethyldisilane (77 μL, 0.38
mmol)/1,2-diphenyltetramethyldisilane (101.4 mg, 0.38 mmol), NEt3
(139 μL, 1.0 mmol), and 2% TPGS-750-M/H2O (1.5 mL) were added.
The vial was immediately closed with a Teflon-coated cap and vigorously
stirred for 20 h at rt. The reaction mixture was poured into brine (2 mL)
and extracted with EtOAc (3 ꢀ 2 mL). All organic phases were collected,
dried over anhydrous Na2SO4 and filtered through a short plug of silica
gel, and the solvent was removed by a constant stream of argon. The
residue was loaded on silica gel and purified by flash chromatography
eluting with hexanes/EtOAc to afford the product.
Cinnamyldimethyl(phenyl)silane (Table 8, entry 4). Fol-
lowing the general procedure, using (E)-cinnamyl phenyl ether (52.6
mg, 0.25 mmol) and 1,2-diphenyltetramethyldisilane (101.4 mg, 0.38
mmol), silica gel chromatography (hexanes) yielded the product as a
colorless oil (57.4 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.55-7.13
(m, 10H), 6.27-6.17 (m, 2H), 1.90 (dd, J = 4.8, 2.0 Hz, 2H), 0.32 (s,
6H).13
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu; rcgadwood@kalexsyn.com.
’ ACKNOWLEDGMENT
Financial support provided by the NIH is warmly acknowl-
edged. We also thank Dr. Thomas J. Colacot (Johnson Matthey)
and Dr. Richard Pederson (Materia) for supplying the palladium
catalyst and Grubbs catalyst, respectively, used in this study; Dr.
Wei Zhang (University of Minnesota) for help with the cryo-
TEM experiments; Wyatt Technologies for assistance with DLS
measurements; and Eastman for generously supplying TPGS-
1000.
’ REFERENCES
(E)-(3-(2-Methoxyphenyl)allyl)dimethyl(phenyl)silane
(Table 8, entry 5). Following the general procedure, using (E)-1-
methoxy-2-(3-phenoxyprop-1-enyl)benzene (60.1 mg, 0.25 mmol) and
1,2-diphenyltetramethyldisilane (101.4 mg, 0.38 mmol), silica gel chro-
matography (0-10% EtOAc/hexanes) yielded the product as a color-
less oil (62.8 mg, 89%). 1H NMR (500 MHz, CDCl3) δ 7.59-7.34 (m,
6H), 7.19-7.16 (m, 1H), 6.92-6.85 (m, 2H), 6.59 (d, J = 15.5 Hz, 1H),
6.22 (dt, J = 15.5, 8.5 Hz, 1H), 3.84 (s, 3H), 1.96 (dd, J = 8.5, 1.5 Hz,
2H), 0.35 (s, 6H).13
(E)-(3-(3-Methoxyphenyl)allyl)trimethylsilane (Table 8,
entry 6). Following the general procedure, using (E)-1-methoxy-
3-(3-phenoxyprop-1-enyl)benzene (60.1 mg, 0.25 mmol) and hexa-
methyldisilane (77 μL, 0.38 mmol), silica gel chromatography (0-10%
EtOAc/hexanes) yielded the product as a colorless liquid (48.5 mg,
88%). 1H NMR (500 MHz, CDCl3) δ 7.25-7.20 (m, 1H), 6.94-6.73
(m, 3H), 6.28 (dt, J = 16.0, 7.5 Hz, 1H), 6.22 (d, J = 16.0 Hz, 1H), 3.83
(s, 3H), 1.69 (d, J = 7.0 Hz, 2H), 0.07 (s, 9H).13
(1) (a) Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed.
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(2) Malmsten, M. Surfactants and Polymers in Drug Delivery; Marcel
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(3) Fendler, J. H.; Fendler, E. J. Catalysis in Micellar and Macro-
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(4) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008, 41, 59–72.
(5) Sheldon, R. A.; Arends, I. W. C. E.; Hanefeld, U. Green Chemistry
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(6) Anastas, P. T., Farris, C. A., Eds.; Benign by Design: Alternative
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Borowy-Borowski, H.; Sikorska-Walker, M.; Walker, P. R. Water-
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(8) Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329–1332.
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(10) Lipshutz, B. H.; Chung, D. W.; Rich, B. Org. Lett. 2008, 10,
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(11) Lipshutz, B. H.; Chung, D. W.; Rich, B. Adv. Synth. Catal. 2009,
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Recycling of TPGS-750-M (Table 9). N-Allyl-4-methyl-N-(2-
methylallyl)benzenesulfonamide (26.5 mg, 0.10 mmol) and Grubbs-2
catalyst (1.7 mg, 0.002 mmol) were both added into a Teflon-coated stir-
bar-containing Biotage 5 mL microwave reactor vial at rt, and the vial was
sealed with a septum. An aliquot of TPGS/H2O (1.0 mL; 2.5% TPGS by
weight) was added via syringe, and the resulting solution was allowed to
stir at rt for 2 h. Et2O (3 mL) was then added to the reaction mixture and
stirred for 10 s. The reaction mixture was then allowed to separate, and
the upper (Et2O) layer was removed by pipet. The aqueous layer was
successively washed with Et2O (3 ꢀ 3 mL). The combined Et2O extracts
layers were evaporated to afford the crude product, which was examined
by 400 MHz 1H NMR spectroscopy to reveal complete conversion of
1
diene and clean formation of the corresponding cyclized product. H
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz,
2H), 5.25-5.24 (m, 1H), 4.07-4.05 (m, 2H), 3.97-3.95 (m, 2H), 2.42
(s, 3H), 1.65 (s, 3H).46 For the second run, the diene (26.5 mg, 0.10
mmol) and Grubbs-2 catalyst (1.7 mg, 0.002 mmol) were both added
again to the same reaction vessel and stirred at rt for another 2 h. The
workup was conducted in exactly the same way as described for the first
cycle. This reaction was repeated six more times, each using the above
diene (26.5 mg, 0.10 mmol) and Grubbs-2 catalyst (1.7 mg, 0.002
mmol).
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’ ASSOCIATED CONTENT
Supporting Information. Copies of H and 13C NMR
1
S
b
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.
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