Organic Letters
Letter
highly crystalline nature, although solubility can be improved
with the addition of cosolvents.13
A variety of carbon nucleophiles, such as doubly activated
cases including 1,3-dicarbonyl-containing compounds such as α-
nitroketones, malonates, etc., readily participated (Scheme 3).
hydrolyzed, in situ-formed allylic alcohol to react with an allylic-
O-LG; for example, cinnamyl-O-Boc produced the cinnamyl-O-
cinnamyl dimer as the major product. However, cinnamyl-O-Bz
gave the desired unsymmetrical ether 3d in 85% yield.
Therefore, in such cases, it became necessary to diversify leaving
groups beyond the more typically seen acetates and methyl
carbonates. Allylic O-Bz derivatives were ultimately found to
give greatly enhanced yields without dimerization. Use of an
OBz leaving group may be fortuitous, as inclusion of byproduct
potassium benzoate (when K2CO3 is used as base) has
previously been found to promote Tsuji−Trost reactions in
water.11d,e
a
Scheme 3. Reactions of Carbon Nucleophiles
Whereas many intramolecular variations of this reaction have
been reported in organic solvents, they have been conspicuously
absent from reports on Tsuji−Trost reactions in water. This led
us to pursue the synthesis of various types of heterocycles via this
method. Several cyclizations could be achieved under these
aqueous conditions, each based on literature precedent in
organic solvents.14 These cyclizations occurred smoothly at 1000
ppm of Pd catalyst, forming vinyl-substituted heterocycles such
as piperazine, morpholine, dihydrofuran, and tetrahydrovinyl-
quinoxaline-containing rings in typically moderate to high yields
(Scheme 5).
a
Scheme 5. Intramolecular Cyclization Reactions
a
Reaction conditions: nucleophile (1.0 equiv, b1.1 equiv), electrophile
c
d
e
f
(1.1 equiv, 1.0 equiv, 1.5 equiv), K2CO3 (1.5 equiv, 1.0 equiv, 2.5
equiv), 2.5 equiv), 2 wt % TPGS-750-M/H2O (1.0 M reaction
concentration) catalyst stock solution prepared in toluene, 45 °C,
argon. Pd(OAc)2/PPh3 used as Pd catalyst, h1.0 equiv of methyl
g
i
j
formate added, Et3N (3.0 equiv) instead of K2CO3, [Pd(allyl)Cl]2/
ligand added as solids, (S,S)-DACH-naphthyl used as ligand instead
of DPEphos, 0.5 M (reaction concentration).
k
l
In addition, one asymmetric example using a carbon nucleophile
(2g) was explored; however, in limited testing, amine
nucleophiles failed to give significant enantioselectivities. Similar
to allylic aminations, substrates bearing additional substitution
on the allylic partner may require higher loadings of catalyst.
Although phenols proved to be competent nucleophiles at
parts per million levels of Pd, alcohols with higher pKa values
(e.g., chrysanthemyl alcohol) failed to react at those loadings
(Scheme 4). In the case of primary alcohols, the nature of the
leaving group is crucial due to the potential for dimerization of
a
Reaction conditions: nucleophile (1.0 equiv), electrophile (1.0
equiv), Et3N (3 equiv, b2.0 equiv), methyl formate (1 equiv), 2 wt %
TPGS-750-M/H2O (0.33 M, c0.25 M, d0.4 M reaction concentration),
catalyst stock solution prepared in toluene, 45 °C, argon.
a
Scheme 4. Reactions of Oxygen Nucleophiles
To demonstrate the potential for use of this method at scale
(∼25 mmol), a multigram reaction was conducted at the 1000
ppm level of palladium in water at 45 °C after precomplexing the
catalyst in a minimum of toluene (4e; Scheme 5). This trial
proceeded with a yield (4.2 g, 84%) similar to that obtained from
the initial scale trial run on 0.5 mmol.
In addition to traditional allyl alcohols, acetates, and
carbonates, vinyl epoxides were also found to be suitable
electrophiles for Tsuji−Trost couplings in water (Scheme 6).
Reactions with various nucleophiles furnish allylic alcohols that
can be further functionalized. Most combinations were
amenable under 1000 ppm Pd catalysis.
An example of a tandem two-step, one-pot sequence is shown
in Scheme 7 (top). Whereas indole gave a mixture of N-allylated
and C3-allylated products and required fairly high loadings of
palladium to achieve good conversion, indoline is especially
a
Reaction conditions: nucleophile (1.0 equiv), electrophile (1.1 equiv,
b1.2 equiv, c1.5 equiv), K2CO3 (1.5 equiv, d1.0 equiv), 2 wt % TPGS-
750-M/H2O (1.0 M reaction concentration), catalyst stock solution
d
prepared in toluene, 45 °C, argon. Methyl formate (1 equiv) added,
e[Pd(allyl)Cl]2/DPEphos added as solids.
C
Org. Lett. XXXX, XXX, XXX−XXX