alcohol. Similar chemoselectivity was also seen with
methyl 4-acethylbenzoate (entry 25).
Table 2. Screening Halides as Deoxgyenation Additives
Entries 27-32 show that the chlorobenzene effect can
be seen during the hydrogenolysis of a variety of C-O
bonds.15 In the presence of PhCl, benzyl bornyl ether
(entry 29) underwent deprotection in 67% yield in less
than 1 h. In the absence of PhCl, only 15% of isobornyl
alcohol was formed in 1 h, and over 8 h was needed for the
reaction to give a comparable yield. Not surprisingly, the
rateacceleration thatoccurscourtesyof PhClcould impact
the reactions negatively. For example, the benzyl ether of
1-phenylethanol (entry 27) undergoes hydrogenolysis of
both C-O bonds when PhCl is present, whereas without
PhCl the reaction was regioselective for hydride delivery to
the least substituted benzyl, affording toluene and sec-
phenethyl alcohol in nearly quantitative yields. It should
also be noted that the presence of a basic nitrogen inhibited
the deoxygenation (entry 17), affording only the alcohol,
presumably due to HCl sequestration.
To evaluate the regio- and stereoselectivity of the reduc-
tion, a stereodefined benzylic epoxide (entry 31) was sub-
jected to the conditions. Here, the 1,2-diol was generated in
high yield and 95% de.16 Reaction of the epoxide without
PhCl also afforded the 1,2-diol quantitatively, but with
decreased de (entry 32). A stereodefined17 tertiary benzylic
alcohol (entry 33) afforded (S)-3-phenyl-1-butanol with no
loss of enantiomeric excess and retention of configuration.18
Finally, as evidenced by entries 8 vs 7, 11 vs 10, 20 vs 19,
and 26 vs 25, changing the aryl chloride additive from
chlorobenzene to 4-chloroanisole enabled the deoxygena-
tion of some of the more difficult substrates.
More work is needed to secure a mechanism for this
process, as well as to determine how the additives impact
the nature of the Pd nanoparticles. That said, the observed
memory of chirality (Table 3, entry 33) and cyclobutane
stability (Table 3, entries 6-9) argue against the presence
of benzyl radicals. On the basis of these and other data, we
favor a mechanism were the ketone is first reduced to the
alcohol by Pd-catalyzed hydrosilylation. In the interim, a
reduction of chlorobenzene affords benzene and a chlor-
osiloxane. The chlorosiloxane is then hydrolyzed by water
present in the reaction to form HCl and the silanol. The
HCl then facilitates12,19 Pd-catalyzed transfer hydrogeno-
lysis of the benzylic C-O bond, where the hydrogen is in
part formed from the PMHS and water.6 This last step is
% yielda
entry
ArCl
neutralizing agent (A/B/sm)
1
2
chlorobenzene
21/77/-
13/74/-
39/46/ -
32/28/10
-/13/85
38/61/-
30/66/2
2-chloro-m-xylene
4-chloroanisole
3
4
4-chlorobenzo-trifluoride
2-chloropyridine
o-dichlorobenzene
hexachlorobenzene
4-chloroanisole
5
6
7
8
2,6-lutidineb
DTBMPc,d
proton-sponged
propylene oxided
-/94/1
9
4-chloroanisole
28/65/-
-/98/-
37/57/-
10
11
4-chloroanisole
4-chloroanisole
a Average isolated yield over two runs. b 0.1 equiv. c 2,6-di-tert-butyl-
4-methylpyridine. d 0.5 equiv.
In addition to these reactions being mechanistically
curious, chlorobenzene represents a unique and attractive
additive. Even relative to TMSCl, chlorobenzene is cheap,
stable, and otherwise inert. For these reasons we presented
these conditions to a variety of substrates bearing benzylic
C-O bonds (Table 3). Substrate screening was carried out
with 10 mol % of PhCl, 5 mol % of Pd(OAc)2, 1.5-4.0
equiv of PMHS, and 4 equiv of KF in 5:2 THF/H2O at
room temperature for 1 h.13,14 We found that increasing
the steric environment about the carbonyl hindered the
deoxygenation (entries 6, 10, and 12-14), with substitution
at both ortho positions completely shutting down a second
reduction (entries 15 and 16). To evaluate the chemo-
selectivity of the system, 4-(4-acetylphenyl)butan-2-one
(entries 18-21) was prepared and subjected to the reac-
tion conditions, resulting in reduction of only the
benzylic ketone. Likewise, subjecting 1-phenylbutane-
1,3-dione to the reaction conditions (entries 22-24)
resulted in deoxygenation of the benzylic carbonyl,
along with some reduction of the 3-carbonyl to the
(13) Typical procedure: Into a 25 mL round-bottom flask that had
been purged with nitrogen was charged Pd(OAc)2 (0.05 mmol, 11 mg),
freshly distilled THF (5 mL), and then the ketone (1.0 mmol). The flask
was fitted with a balloon of nitrogen. A solution of potassium fluoride (4
mmol, 232 mg) in degassed water (2 mL) was added via syringe into the
reaction, followed by chlorobenzene (0.1 mmol, 0.01 mL). PMHS (2.5
mmol, 0.15 mL) was then dropwise added via syringe into the reaction
mixture. The resulting reaction was stirred for one hour. Ether was
added to the reaction mixture, the layers were separated, and the
aqueous layer was back-extracted with ether. The combined organics
were concentrated and subjected to flash chromatography. (Caution:
Rapid addition of PMHS can result in vigorous gas evolution! For
reactions run on large scale, it is recommended that the reaction flask be
fitted with a reflux condenser.)
(15) For other Pd-mediated reductions of benzylic C-O bonds, see:
(a) Felpin, F.-X.; Fouquet, E. Chem.;Eur. J. 2010, 16, 12440–12445.
(b) Mirza-Aghayan, M.; Boukherroub, R.; Rahimifard, M. Tetrahedron
Lett. 2009, 50, 5930–5932. (c) Thiery, E.; Le Bras, J.; Muzart, J. Green
Chem. 2007, 9, 326–327. (d) Coleman, R. S.; Shah, J. A. Synthesis 1999,
1399–1400. (e) Keinan, E.; Greenspoon, N. J. Org. Chem. 1983, 48, 3545–
3548. (f) Lipowitz, J; Bowman, S. A. J. Org. Chem. 1973, 38, 162–165.
(16) 3-Phenyl-1-butanol (3%) was also isolated.
(17) The % ee and absolute configuration of the starting material were
determined by derivation to Mosher’s ester with (S)-(þ)-MTPA-Cl. See:
Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
(18) The % ee and absolute configuration of the product were
determined by derivation with (R)-MPA. See: Trost, B. M.; Curran,
D. P. Tetrahedron Lett. 1981, 22, 4929–4932.
(14) As little as 1 mol % of Pd(OAc)2 can be used provided the
amounts of PMHS and KF are raised to 5 and 10 equiv, respectively.
However, increasing the amount of PMHS can make purifications more
difficult as PMHS can undergo sol-gel processes.
(19) Consistent with this proposal is the quantitative deoxygenation
of sec-phenethyl alcohol and its TBS ether in the presence of catalytic
HCl.
586
Org. Lett., Vol. 13, No. 4, 2011