"On water" sp3-sp2 cross-couplings between benzylic and alkenyl halides

Article abstract of DOI:10.1039/c1cc11087j

Organic-solvent-free cross-couplings between benzylic and alkenyl halides have been developed. Various alkenyl halides can be efficiently benzylated by combining the precursor halides in the presence of Zn dust and a Pd catalyst at room temperature, in water as the only medium.

Full text of DOI:10.1039/c1cc11087j

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COMMUNICATION
‘‘On water’’ sp3–sp2 cross-couplings between benzylic and
alkenyl halidesw
Valeria Krasovskaya, Arkady Krasovskiy, Anish Bhattacharjya and Bruce H. Lipshutz*
Received 23rd February 2011, Accepted 18th March 2011
DOI: 10.1039/c1cc11087j
Table 1 Optimization of the reaction between 1-(chloromethyl)-4-
methylbenzene (1) and (E)-1-iodooct-1-enea
Organic-solvent-free cross-couplings between benzylic and alkenyl
halides have been developed. Various alkenyl halides can be
efficiently benzylated by combining the precursor halides in the
presence of Zn dust and a Pd catalyst at room temperature, in
water as the only medium.
Recently, we described a new process for effecting sp2–sp3
cross-coupling reactions that avoids prior preparation of
organozinc reagents. Zinc-mediated, palladium-catalyzed
cross-couplings between two organic halides were accomplished
in water using micellar catalysis,1 and on water2 at room
temperature.
Allylated aromatics (I) are important subunits in organic
synthesis.3 Classically, compounds of general formula I
(Scheme 1) have been accessed via Friedel–Crafts allylation4
of aromatic precursors. More recent strategies involve transition
metal-catalyzed cross-couplings of sp2-organometallics with
activated halides, or allylic organometallics with sp2-halides/
triflates (Scheme 1).5 The corresponding organometallic reagents,
therefore, require preparation in a separate step.6 Based on
our previous work2 it was anticipated that direct ‘on water’
cross-couplings of benzylic halides with alkenyl halides would
provide a 1-step synthesis of functionalized allylated aromatics
(Scheme 1). The important issue of olefin geometry would also
need to be addressed.
Entry
Modification of original conditions
Conversion,%b
1
2
3
4
5
6
None
100
98
77
88
96
90
1.5 equiv of benzylic chloride
TMEDA (0.5)
1 mol% PdCl2(Amphos)2
Zn powder
X = Br
a
Conditions: benzyl chloride (2 mmol), (E)-1-iodooct-1-ene (1 mmol),
zinc dust (3 mmol), PdCl2(Amphos)2 (0.02 mmol), degassed water
b
(3 mL). By GC.
7
temperature, using 2 mol % PdCl2(Amphos)2 along with
Zn dust (3 equiv) and N,N,N0,N0-tetramethylethylenediamine
(TMEDA; 1 equiv).1,2 Modifications (entries 2–5), including
use of a lesser excess of benzylic chloride (entry 2), less
TMEDA (entry 3) or Pd catalyst (entry 4), Zn powder in
place of Zn dust (entry 5), or alkenyl bromide (entry 6),
suggested some flexibility in reagents and/or the standard
stoichiometry. Use of a surfactant for purposes of generating
nanomicelles1 in this reaction type neither enhanced the rate of
reaction, nor improved the overall yield of products.
Initially, 1-(chloromethyl)-4-methylbenzene (2 equiv) was
coupled with (E)-1-iodooctene (1) to afford unsymmetrically
substituted allylated toluene 2 (Table 1). Under optimized
conditions, 1 coupled within six hours, on water at room
As illustrated in Table 2, the substrates that participate in
these cross-couplings leading to allylated aromatics are of
broad scope. In all representative cases examined, >98%
retention of olefin stereochemistry was observed, regardless
of starting olefin geometry. Three equivalents of electron-poor
benzylic chlorides were needed to achieve good isolated yields
due to competitive Zn-insertion and subsequent protio-
quenching by water8 of the in situ-formed benzylic zinc
halides. Unlike cross-couplings with aryl halides,2 switching
to zinc powder instead of zinc dust did not impact yields.
Attempts to control the rate of Zn-insertion by employing
Scheme 1 Synthetic approaches to benzylic-alkenyl cross-couplings.
Department of Chemistry & Biochemistry, University of California,
Santa Barbara, California 93106, USA.
E-mail: lipshutz@chem.ucsb.edu; Fax: (805) 893-8265;
Tel: (805) 893-2521
w Electronic supplementary information (ESI) available: Experimental
section and spectroscopic data. See DOI: 10.1039/c1cc11087j
c
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Table 2 Representative benzylic-alkenyl cross-couplingsa
Entry Product (Yield)b
Entry Product (Yield)b
1
2
2 (82%)
3 (91%)
3
4
4 R = CF3 (84%)
5 R = Cl (89%)
5
6
6 R = H (95%)
7 R = OMe (81%)
7
9
8
8 (90%)
9 (85%) E/Z 83/17c
Scheme 2 Competition experiments (rt, 6 h), and a 1-pot, double
benzylation (1st step 6 h, 2nd step 18 h at rt).
10
10 (77%) E/Z 92/8d
11 (95%)
was successfully coupled on water with a functionalized benzyl
chloride at room temperature (entry 15).
To probe for potential differences in reactivity in these
cross-couplings between sp2-aryl and sp2-alkenyl halides,
several competition experiments were conducted (Scheme 2).
The representative case of unfunctionalized bromobenzene
and b-bromostyrene was chosen. Remarkably, both Z-
and E-alkenyl bromides reacted far more rapidly, and with
complete stereocontrol, than did bromobenzene with 1-(chloro-
methyl)-4-methylbenzene (equations 1, 2). Additionally, the
E-isomer reacted faster than did Z-b-bromostyrene (equation 3),
as expected.9 These results suggested that selective, sequential
cross-couplings on dibromide 17 should be possible. In the event,
use of just 1.1 equivalents of 1-(chloromethyl)-4-methylbenzene
led to cross-coupled product 18 with very good chemoselectivity
and in good isolated yield. Hence, the corresponding 1-pot,
stepwise dibenzylation of 17 could also be achieved to form the
unsymmetrically derivatized product 19, without introduction of
additional Pd(II) catalyst in the second step.
11
13
12
14
12 (92%)
14 (83%)
13 (96%)
15 (79%)e
15
16 (82%)
a
Conditions: benzylic chloride (2–3 mmol), alkenyl halide (X = I, for
entries 1–6, 10, 12, 15, and X = Br for entries 7–9, 11, 13–14; 1 mmol),
zinc dust (3–4 mmol), PdCl2(Amphos)2 (0.02 mmol), degassed water
b
c
(3 mL), rt, 6 h. Isolated yield. From commercially available
d
= 87/13. From commercially available
b-bromo-styrene, E/Z
(2-bromovinyl)trimethylsilane, E/Z
In summary, new technology for preparing functionalized
allylated benzenes has been developed. These reactions proceed
in a green chemistry sense: in the absence of organic solvents,
and without heating or cooling; i.e., in water only, and at room
temperature, to afford the targeted products without erosion of
olefin geometries and in high chemical yields.
e
93/7. From commercially
=
available 90% technical grade a-bromostyrene.
only 0.25 equivalents of TMEDA with two equivalents of an
electron-poor benzylic chloride led to full consumption of
starting alkenyl halide; however, 10–30% of diene formation
occurred, leading to poor isolated yields of final products. This
coupling does tolerate b,b-disubstituted alkenyl iodides (entry 11),
as well as secondary benzylic chlorides (entries 13 and 14).
Nevertheless, sterically crowded 2-(chloromethyl)-1,3,5-tri-
methylbenzene did not afford the desired product, and under
a variety of conditions, no product was detected using benz-
hydryl chloride. a-Benzylated styrene 15 could be efficiently
prepared starting from commercially available a-bromostyrene
(entry 14). A highly lipophilic, solanesol-derived alkenyl halide
We are grateful to the NIH for financial support (GM
86485), and to Johnson Matthey for generously supplying
palladium catalyst PdCl2(Amphos)2 (Pd-132, catalog #C4138).
Notes and references
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Chem. Commun., 2011, 47, 5717–5719 5719