Catalyst-controlled wacker-type oxidation of homoallylic alcohols in the absence of protecting groups

Article abstract of DOI:10.1021/jo200462a

Homoallylic alcohols are oxidized to β-hydroxy ketones using a TBHP-mediated Pd-catalyzed Wacker-type oxidation. The use of a bidentate ligand, quinoline-2-oxazoline (Quinox), and TBHP_(aq) as the terminal oxidant provides good yields of the des

Full text of DOI:10.1021/jo200462a

NOTE
pubs.acs.org/joc
Catalyst-Controlled Wacker-Type Oxidation of Homoallylic Alcohols
in the Absence of Protecting Groups
Jessica R. McCombs, Brian W. Michel, and Matthew S. Sigman*
University of Utah, Department of Chemistry, 315 S. 1400 E, Salt Lake City, Utah 84112, United States
S Supporting Information
b
ABSTRACT: Homoallylic alcohols are oxidized to β-hydroxy
ketones using a TBHP-mediated Pd-catalyzed Wacker-type
oxidation. The use of a bidentate ligand, quinoline-2-oxazoline
(
Quinox), and TBHP(aq) as the terminal oxidant provides good
yields of the desired products with reaction times significantly
reduced as compared to the TsujiꢀWacker oxidation. Addition-
ally, bis- and tris-homoallylic alcohols are oxidized to provide
cyclic peroxyketals, presumably via nucleophilic attack of the
methyl ketone product.
n the TsujiꢀWacker oxidation, the oxidation of terminal
olefins to methyl ketones is catalyzed by palladium salts in
I
the presence of a mixed DMF/H O solvent system, which has
2
1
ꢀ4
found widespread application in synthesis.
While simple
alkenes are generally compatible with TsujiꢀWacker oxidation,
the introduction of a proximal heteroatom can lead to unpre-
5
dictable distributions of aldehyde and ketone products. For
example, homoallylic alcohols are a substrate class that offers a
unique set of challenges, as they can undergo intramolecular anti-
Markovnikov cyclization in competition with Markovnikov attack
from water or hydroxide (vida infra). Despite this, homoallylic
alcohols are attractive substrates for the Wacker oxidation, because
they can be easily prepared in enantiomerically enriched form and,
upon Wacker oxidation, yield an aldol product equivalent. The
strategy of aldehyde allylation and subsequent Wacker oxidation
has been commonly employed in synthesis; however, protecting
6,7
groups are usually required.
The selectivity in the TsujiꢀWacker oxidation of homoallylic
alcohols appears to be dependent on numerous factors, including
substitution on the substrate and the precise conditions used.
Highlighting this disparity, Tsuji and co-workers have reported
that homoallylic alcohol substrates such as 1 yield lactol product
8
2
in the presence of CuCl (eq 1), while Yamamoto and co-
workers observed the methyl ketone product 4 from a similar
substrate 3 in the presence of CuCl (eq 2). Additionally, the
selectivity of these reactions can be affected by the choice of
2
In our pursuit of ligand-modulated alkene functionalization
reactions, we recently reported a copper-free catalyst system for
Wacker-type oxidations that utilizes a bidentate ligand (Quinox)
on palladium along with tert-butylhydroperoxide (TBHP) as the
oxidant. This system successfully oxidizes substrates bearing
protected allylic and homoallylic alcohols with high selectivity for
the Markovnikov (i.e., methyl ketone) product (eqs 4 and 5).
The TBHP-mediated Wacker-type oxidation is proposed to
oxidant. For example, the use of the organic oxidant benzoqui-
8
none favors the formation of lactols, such as 2 (eq 3). Further-
12
more, Santelli and co-workers have reported that subtle distal
electronic variations in 11-vinyl-13β-hydroxy steroids affect the
9
ꢀ11
selectivity between aldehyde and ketone products.
Due to
these limitations, we sought to develop general reaction condi-
tions, which predictably provide the ketone product from a
Wacker-type oxidation, and herein we report success in these
efforts.
Received: March 2, 2011
Published: March 29, 2011
r 2011 American Chemical Society
3609
dx.doi.org/10.1021/jo200462a
|J. Org. Chem. 2011, 76, 3609–3613

The Journal of Organic Chemistry
NOTE
proceed through a well-defined syn-oxypalladation that favors
Markovnikov attack due to the coordinatively saturated nature
of palladium (Figure 1a). While protected homoallylic alcohols,
such as 6, are excellent substrates for the Pd(Quinox)ꢀTBHP
system (Figure 1b), unprotected substrates were not previously
evaluated.
Figure 1. (a) Proposed syn-oxypalladation. (b) Acetate-protected
homoallylic alcohol 6 is converted exclusively to methyl ketone 7 in
high yield.
While the general optimization of the Pd(Quinox)ꢀTBHP
12
system has been reported, 4-hydroxynon-1-ene (8) was used as
a model substrate to determine the optimal conditions for
unprotected homoallylic alcohols (Table 1). It was found that
starting the reaction at 0 °C, as compared to room temperature,
led to higher yields of the methyl ketone product (Table 1,
entries 1ꢀ2). This is in contrast to our previous reports, where
the reaction outcome using various substrates appeared insensi-
tive to temperature. A minimum of 3 mol % catalyst was also
found to be necessary for complete conversion of the starting
material (Table 1, entry 3). It should be noted that the methyl
ketone was the only observed product, and no lactol or aldehyde
products were detected.
Table 1. Optimization of Conditions
mol %
Time
(h)
%
%
a
Entry
Catalyst (X)
Temp
Conversion
Yield
1
2
3
3
3
2
rt
19
5
97
99
64
65
75
42
0 °C
rt
The scope of this transformation was evaluated, and it was
found that, for secondary alcohols, 3 mol % catalyst was sufficient
to achieve good yields in 5 h (Table 2, entry 1). Tertiary alcohols
tended to react slower, where incomplete conversion was ob-
served using 3 mol % catalyst. However, increasing the catalyst
loading to 5 mol % led to efficient reactions (Table 2, entries 2
and 4ꢀ5). Santelli and co-workers observed tertiary alcohol
substrates to yield the aldehyde product via anti-Markovnikov
hydroxypalladation using modified TsujiꢀWacker conditions,
which is in contrast to our observations using Pd(Quinox)ꢀ
4
a
Yields determined by GC based on C12
H
26 (∼10 wt %) internal
standard.
subjected to the standard conditions, Wacker cyclization prod-
ucts were not observed; instead, the products isolated were
identified as cyclic peroxyketals 11 and 13. It is hypothesized
that the methyl ketone is initially formed by TBHP-mediated
Wacker oxidation (Scheme 1). These types of compounds,
however, are known to exist as mixtures of the ketone and cyclic
hemiketal, due to the favorable formation of a five- or six-
9
ꢀ11
TBHP.
For comparison, these tertiary alcohol substrates
were subjected to TsujiꢀWacker conditions, which resulted in
inferior yields (Table 2 entries 3 and 6). A mixture of internal
olefin isomers was also recovered from the reaction mixture,
14
membered ring. The hemiketal is then susceptible to oxygen-
assisted nucleophilic substitution by the excess TBHP in solu-
tion, which yields the peroxyketal products. These interesting
and uncommon products may have applications in targeted
synthesis.
1
as determined by H NMR. For substrates with a secondary
benzylic alcohol, the reaction yielded a complex mixture of prod-
ucts with 62% recovered starting material (Table 2, entry 7).
However, a tertiary benzylic alcohol was compatible, giving 50%
conversion at 5 mol % catalyst, while a catalyst loading of 10 mol %
lead to 100% conversion and 79% isolated yield (Table 2, entries
In conclusion, after modest optimization, it has been demon-
strated that the Pd(Quinox)Cl ꢀTBHP catalyst system can
2
selectively oxidize olefin substrates bearing homoallylic alcohols
to their corresponding methyl ketone products. This is proposed
to be due to the catalyst-controlled nature of this oxidation
system, which is in contrast to the substrate control often ob-
served in the TsujiꢀWacker oxidation. Furthermore, bis- and tris-
homoallylic alcohols are oxidized to interesting cyclic peroxyketal
products. It is proposed that selective Markovnikov oxidation
does occur, but that favorable ring sizes along with the excess
TBHP present in the reaction mixture lead to the formation of
these products. The short reaction times and predictability
afforded by the Pd(Quinox)ꢀTBHP system should allow for
this method to be a useful tool for synthetic chemists in the
preparation of β-hydroxyketones.
8
ꢀ9). When a homoallylic alcohol derived from aldehyde
crotylation was evaluated, the use of 5 mol % catalyst led to a
7% yield, and an average of 32% starting material was recovered
5
13
(
Table 2, entry 10). This result is particularly interesting when
compared with previous examples, where analogous substrates
favor the lactol or ketone product in a condition-dependent
manner (eqs 1 and 2). With the exception of a secondary benzylic
alcohol, the Pd(Quinox)ꢀTBHP catalyst system demonstrates
high selectivity for the desired methyl ketone, regardless of
substitution on the substrates evaluated.
To investigate the effect of the position of the alcohol relative
to the olefin, bis- and tris-homoallylic alcohols (10 and 12) were
also evaluated (eqs 6 and 7). When these substrates were
3
610
dx.doi.org/10.1021/jo200462a |J. Org. Chem. 2011, 76, 3609–3613

The Journal of Organic Chemistry
NOTE
Table 2. Scope of TBHP-Mediated Wacker-Type Oxidation
Scheme 1. Proposed Formation of Peroxyketals 11 and 13
compared to substrate). Peak integrations were corrected with a
response factor calculated from samples of known molar ratio.
General Procedure for the Pd(Quinox)Cl ꢀTBHP Oxida-
2
tion. In the dark, AgSbF (25.8 mg, 0.075 mmol, 0.075 equiv) and
6
Pd(quinox)Cl
round bottomed flask with a stir bar. CH
the flask and the mixture was stirred for 10 min, after which time TBHP
1.7 mL, 12 mmol, 12 equiv) was added along with the remaining
CH Cl (6.6 mL), turning the mixture from pale yellow to orange.
The flask was placed in an ice bath, and after 10 min the substrate
1.0 mmol, 1 equiv) was added. The reaction mixture was allowed to
slowly warm to room temperature. Once TLC analysis indicated
complete consumption of the starting material, the reaction was cooled
2 3
to 0 °C and quenched with a saturated solution of Na SO (15 mL) to
2
(11.3 mg, 0.03 mmol, 0.03 equiv) were added to a 25-mL
2
Cl (1.7 mL) was charged to
2
(
2
2
(
a
All yields represent an average of two experiments on at least a 1 mmol
b
scale unless noted otherwise. Experiments conducted using Tsujiꢀ
2
Wacker conditions (10 mol % PdCI , 1 equiv of CuCI, (7:1) DMF/
d
c
2 2
H O, rt, O balloon). Experiment conducted on a 7 mmol scale. An
e f
consume excess TBHP. The mixture was transferred to a separatory
funnel and diluted with hexanes (25 mL). The aqueous layer was
extracted with hexanes (3 ꢁ 25 mL). The combined organic phases
average of 50% starting material was recovered. Single experiment. An
g
average of 35% starting material was recovered. This reaction was
perfromed at room temperature.
were washed with H O (3 ꢁ 10 mL) and brine (25 mL) and then dried
2
over MgSO . After filtration and concentration under reduced pressure,
4
the crude material was purified by flash chromatography and the product
containing fractions were combined and concentrated under reduced
pressure.
Non-1-ene-4-ol (8). This compound was prepared according to the
1
6
17
literature procedure. Analytical data are consistent with the literature.
Non-1-en-4-yl acetate (6). To a 10 mL round bottomed flask
equipped with a stir bar were charged triethylamine (626 μL, 4.5 mmol,
3
0
equiv), 4-N,N-dimethylaminopyridine (DMAP) (18.5 mg, 0.15 mmol,
.1 equiv), and non-1-ene-4-ol 8 (226 mg, 1.5 mmol, 1 equiv). The
mixture was cooled to 0 °C in an ice bath, and acetic anhydride (425 μL,
.5 mmol, 3 equiv) was added in a dropwise fashion. After 1.5 h, TLC
4
analysis showed complete consumption of the starting material. The
reaction was quenched with H O, diluted with Et O (10 mL), and
transferred to a separatory funnel. The aqueous phase was extracted with
2
2
’
EXPERIMENTAL SECTION
Et O (3 ꢁ 10 mL). The combined organics were washed with brine
A procedure for a one-pot synthesis of Quinox is outlined in a recent
2
15
publication. ALTHOUGH NO PROBLEMS OCCURRED DURING
THESE STUDIES, HIGHLY CONCENTRATED SOLUTIONS OF
TBHP IN THE PRESENCE OF TRANSITION METALS CAN BE
EXPLOSIVE.
4
(20 mL), dried over MgSO , filtered, and concentrated under reduced
pressure. The crude mixture was purified by flash chromatography
eluting with 3% Et O in hexanes to yield non-1-en-4-yl acetate 6 (264
mg, 1.43 mmol) as a colorless oil in 90% yield. R = 0.21 (3:97 Et O/
2
f
2
1
General Procedure for Optimization Reactions. In the dark,
AgSbF and Pd(Quinox)Cl were added to a small vial. CH Cl was
Hexanes). H NMR (400 MHz, CDCl
3
) δ 5.70ꢀ5.80 (m, 1H),
5.03ꢀ5.12 (m, 2H), 4.88ꢀ4.95 (m, 1H), 2.24ꢀ2.37 (m, 2H), 2.00
6
2
2
2
added to the vial followed by the desired quantity of TBHP. The
mixtures were allowed to stir for 10 min, and the desired temperature
was established. The substrate was added as a standard solution in
CH Cl . Aliquots (∼100 μL) were taken periodically and passed
(s, 3H), 1.49ꢀ1.57 (m, 2H), 1.20ꢀ1.39 (m, 6H), 0.88 (t, J = 7.0 Hz,
1
3
3H). C NMR (100 MHz, CDCl ) δ 14.2, 21.4, 22.7, 25.2, 31.8, 33.8,
3
38.9, 73.6, 117.7, 134.1, 171.0. IR (neat): 3079 (w), 2931 (m), 2860 (m),
ꢀ1
1737 (s), 1643 (w) cm . HRMS: m/z (ESI/TOF MS Eþ) Calculated
2
2
þ
through a silica pipet, eluting with ethyl acetate. These samples were
then analyzed by gas chromatography, and the amount of product was
measured relative to an internal standard of dodecane (∼10 wt % as
[C11
H
22
O
2
] 185.1542, observed 185.1554.
1-Allylcyclohexanol. This compound was prepared according to the
1
6
18
literature procedure. Analytical data match the literature.
3
611
dx.doi.org/10.1021/jo200462a |J. Org. Chem. 2011, 76, 3609–3613

The Journal of Organic Chemistry
-Methyloct-1-en-4-ol. This compound was prepared according to
NOTE
4
respectively). The crude mixtures were purified by flash chromatography
eluting with 30% Et O and 5% acetone in hexanes to afford 1-(1-
hydroxycyclohexyl)propan-2-one (111 mg, 0.71 mmol and 129 mg, 0.83
f
mmol respectively) as a colorless oil in a 71% average yield. R = 0.21
16
19
the literature procedure. Analytical data match the literature.
-Phenylbut-3-en-1-ol. This compound was prepared according to
2
1
1
6
20
the literature procedure. Analytical data match the literature.
-Phenylpent-4-en-2-ol. This compound was prepared according to
1
2
(65:30:5 Hexanes/Ethyl Acetate/Acetone). H NMR (300 MHz, CDCl )
3
16
21
13
the literature procedure. Analytical data match the literature.
-Methylnon-1-en-4-ol. This compound was prepared according to
δ 3.16 (s, 1H), 2.61 (s, 2H), 2.18 (s, 3H), 1.76ꢀ1.20 (m, 10H). C NMR
3
(75 MHz, CDCl
3
) δ 22.2, 26.0, 32.3, 37.8, 53.13, 70.8, 221.2. IR (neat):
22
23
ꢀ1
the literature procedure. Analytical data match the literature.
Dec-1-en-5-ol (10). Dec-1-en-5-ol was prepared according to the
literature procedure, and analytical data match.
3481 (br m), 2929 (s), 2857 (m), 1697 (s) cm . HRMS: m/z (ESI/TOF
þ
MS Eþ) Calculated [C H O Na ] 179.1048, observed 179.1057.
9
16 2
24
1-(1-Hydroxycyclohexyl)propan-2-one (Table 2, entry 3,
TsujiꢀWacker). In a 10 mL side arm flask, a stir bar, PdCl (18 mg, 0.1
Undec-1-en-6-ol (12). To an oven-dried three-necked 100 mL round
bottomed flask containing a stir bar was weighed freshly ground
magnesium turnings (395 mg, 16 mmol, 4 equiv). A nitrogen atmo-
2
mmol, 0.1 equiv), CuCl (100 mg, 1.0 mmol, 1.0 equiv), and 7:1 DMF/
H O (1.5 mL) were added. The flask was equipped with an O balloon
2
2
sphere was established, and Et
The bromide, 5-bromo-1-pentene (190 μL, 1.6 mmol, 0.4 equiv), was
charged to the flask by syringe addition. The remaining 5-bromo-1-
pentene (760 μL, 6.4 mmol, 1.6 equiv) was dissolved in dry Et O
2
O (8 mL) was cannulated into the flask.
and allowed to stir vigorously for 1 h, during which time the mixture
turned from black to green. Substrate (142 mg, 1.0 mmol, 1.0 equiv) was
then charged to the flask, and the reaction mixture was allowed to stir for
30 h before being quenched with 25% HCl (15 mL). The mixture was
2
(40 mL) and was slowly cannulated to the flask containing the
transferred to a separatory funnel with Et O and separated. The aqueous
2
magnesium turnings. The mixture was heated to 45 °C in an oil bath
and refluxed for 1 h, at which point it was cooled to room temperature. In
an oven-dried 250 mL round bottomed flask with a stir bar were charged
portion was extracted with ether (3 ꢁ 15 mL), and the combined organic
portions were washed with NaHCO (20 mL) and brine (20 mL) before
3
being dried over MgSO . The organic phase was filtered and concen-
4
1
-hexanal (480 μL, 4 mmol, 1 equiv) and Et
2
O (18 mL). This flask was
trated under reduced pressure. The crude material was purified by silica
gel flash chromatography eluting with 15% ethyl acetate in hexanes to
yield 1-(1-hydroxycyclohexyl)propan-2-one in a 34% yield (53 mg, 0.34
mmol) and 11% recovered isomerized starting material (16 mg).
cooled in a dry ice/isopropanol bath, and the Grignard solution was can-
nulated to this flask in a dropwise fashion. The reaction mixture was
subsequently allowed to warm to room temperature. TLC analysis con-
firmed the consumption of the aldehyde after 5 h which was quenched at
4-Hydroxy-4-methyloctan-2-one (Table 2, entry 4). The
0
°C with 1 M HCl solution. The aqueous portion was extracted with
2
general procedure for the TBHP-mediated Wacker oxidation was used
for 4-methyloct-1-en-4-ol with the modifications that 0.05 equiv of
Pd(Quinox)Cl and 0.125 equiv of AgSbF were found to be necessary
2 6
for full consumption of the substrate. The reactions were performed with
142 mg (1.00 mmol) and 143 mg (1.01 mmol) of 4-methyloct-1-en-4-ol
respectively. The crude mixture was purified by flash chromatography
Et O (3 ꢁ 35 mL). The combined organics were washed with brine
(
50 mL), dried over MgSO
pressure. The crude mixture was purified by flash chromatography with
0% Et O in hexanes to provide undec-1-en-6-ol 12 (504 mg, 2.96
4
, filtered, and concentrated under reduced
2
2
mmol) as a colorless oil in 74% yield. R
f
= 0.20 (5:25:70 Acetone/Et
Hexanes). H NMR (300 MHz, CDCl
): δ 5.75ꢀ5.86 (m 1H), 4.94
dd, J = 16 Hz, 1H), 3.52ꢀ3.63 (m, 1H), 1.95ꢀ2.15 (m, 2H), 1.57ꢀ1.07
2
O/
1
3
2
eluting with 50% Et O in hexanes to afford 4-hydroxy-4-methyloctan-2-one
(
(
as a colorless oil in 84% average yield (130 mg, 0.82 mmol and 136 mg, 0.86
13
1
m, 12H), 0.86 (t, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl ) δ 14.2,
3
mmol). R = 0.21 (30:5:65 Et O/Acetone/Hexanes). H NMR (400 MHz,
f
2
2
2.8, 25.1, 25.5, 32.1, 34.0, 37.1, 37.7, 72.0, 114.7, 139.0. IR (neat): 3335
3
CDCl ) δ 3.69 (s, 1H), 2.67 (d, 1H J = 17.3 Hz), 2.60 (d, J = 17.0 Hz, 1H),
ꢀ1
(
(
1
br m), 3077 (w), 2927 (s), 2858 (m), 1641 (w) cm . HRMS: m/z
ESI/TOF MS Eþ) Calculated [C H O ] 171.1749, observed
2
.19 (s, 3H), 1.52ꢀ1.48 (m, 6H), 1.34ꢀ1.29 (m, 3H), 1.21 (s, 3H), 0.91
þ
13
11
23
(t, J = 7.3 Hz, 3H). C NMR (75 MHz, CDCl ) δ 13.9, 23.0, 26.0, 26.6,
3
71.1749.
2
3
2
1.8, 41.5, 52.1, 71.5, 211.0. IR (neat): 3463 (br w), 2957 (m), 2933 (m),
ꢀ1
-Oxononan-4-yl Acetate (7). The general procedure for the TBHP-
mediated Wacker oxidation was followed using non-1-en-4-yl acetate 6
197 mg, 1.07 mmol) and purified by flash chromatography eluting with
863 (m), 1699 (s) cm . HRMS: m/z (ESI/TOF MS Eþ) Calculated
þ
[
C
9
H
18
O
2
Na ] 181.1204, observed 181.1214.
(
1
9
4-Hydroxy-4-methyloctan-2-one (Table 2, entry 5). The
5% ethyl acetate in hexanes to afford 2-oxononan-4-yl acetate 7 in a
4% yield (202 mg, 1.01 mmol). R = 0.26 (15:85 Ethyl Acetate/
general procedure for the TBHP-mediated Wacker oxidation was used
for 4-methyloct-1-en-4-ol with the modifications that 0.05 equiv of
Pd(Quinox)Cl and 0.125 equiv of AgSbF were found to be necessary
f
1
Hexanes). H NMR (300 MHz, CDCl ) δ 5.19ꢀ5.28 (m, 1H), 2.47
3
2
6
(dd, 1H J = 16.1, 7.42 Hz), 2.60 (dd, 1H J = 16.2, 5.36 Hz), 2.17 (s, 3H),
for full consumption of the substrate. The reactions were performed with
981 mg (6.9 mmol) of 4-methyloct-1-en-4-ol. The crude mixture was
2
3
3
1
.03 (s, 3H), 1.51ꢀ1.62 (m, 2H), 1.20ꢀ1.40 (m, 6H), 0.89 (t, J = 6.9 Hz,
13
H). C NMR (75 MHz, CDCl
3
) δ 14.1, 21.3, 22.6, 25.0, 30.6, 31.7,
purified by flash chromatography eluting with 50% Et O in hexanes to
2
4.2, 40.1, 70.4, 170.6, 206.0. IR (neat): 2931 (m), 2861 (m), 1735 (s),
afford 4-hydroxy-4-methyloctan-2-one as a colorless oil in 83% yield
(908 mg, 5.74 mmol).
ꢀ1
717 (s) cm . HRMS: m/z (ESI/TOF MS Eþ) Calculated
þ
[C
11
H
20
O
3
Na ] 223.1310, observed 223.1313.
4-Hydroxy-4-methyloctan-2-one (Table 2, entry 6, Tsujiꢀ
4
-Hydroxynonan-2-one (Table 2, entry 1, 9). The general
Wacker). In a 10 mL side arm flask, a stir bar, PdCl (18 mg, 0.1 mmol,
2
procedure for the TBHP-mediated Wacker oxidation was followed using
non-1-en-4-ol 8 (142 mg, 1.00 mmol and 152 mg, 1.07 mmol respec-
tively). The crude mixtures were purified by flash chromatography
eluting with 33% ethyl acetate in hexanes to afford 4-hydroxynonan-2-
one 9 (132 mg, 0.83 mmol and 123 mg, 0.78 mmol respectively) as a
colorless oil in an 81% average yield. The spectral data were in
0.1 equiv), CuCl (99 mg, 1.0 mmol, 1.0 equiv), and 7:1 DMF/H O
2
(1.5 mL) were added. The flask was equipped with an O balloon and
2
allowed to stir vigorously for 1 h during which the mixture turned from
black to green. Substrate (140 mg, 0.98 mmol, 1.0 equiv) was then
charged to the flask, and the reaction mixture was allowed to stir for 30 h
before being quenched with 25% HCl (15 mL). The mixture was
25
accordance with the previous report.
-(1-Hydroxycyclohexyl)propan-2-one (Table 2, entry 2).
The general procedure for the TBHP-mediated Wacker oxidation was
followed with the exception that 0.05 equiv of Pd(Quinox)Cl and 0.125
equiv of AgSbF were found to be necessary for the oxidation of
-allylcyclohexanol (145 mg, 1.03 mmol and 158 mg, 1.13 mmol
transferred to a separatory funnel with Et O and separated. The aqueous
2
1
portion was extracted with ether (3 ꢁ 15 mL), and the combined organic
portions were washed with NaHCO (20 mL) and brine (20 mL) before
3
2
4
being dried over MgSO . The organic phase was filtered and concen-
trated under reduced pressure. The crude material was purified by silica
6
1
gel flash chromatography eluting with 25:5:70 Et O/Acetone/Hexanes
2
3
612
dx.doi.org/10.1021/jo200462a |J. Org. Chem. 2011, 76, 3609–3613

The Journal of Organic Chemistry
NOTE
to yield 4-hydroxy-4-methyloctan-2-one in a 26% yield (40 mg, 0.25
mmol) and 15% recovered isomerized starting material (22 mg).
’ AUTHOR INFORMATION
Corresponding Author
*
4
-Hydroxy-4-phenylpentan-2-one (Table 2, entry 8). The
general procedure for the TBHP-mediated Wacker oxidation was used
with the modification that 0.05 equiv of Pd(Quinox)Cl and 0.125 equiv
of AgSbF were used. The reactions were performed with 163 mg
1.00 mmol) and 161 mg (0.99 mmol) of 2-phenylpent-4-en-2-ol respec-
tively. The crude mixture was purified by flash chromatography eluting with
5% Et O and 5% acetone in hexanes to afford 4-hydroxy-4-phenylpentan-2-
one as a colorless oil in 44% average yield (80 mg, 0.45 mmol and 78 mg, 0.44
Email: sigman@chem.utah.edu.
2
6
(
’
ACKNOWLEDGMENT
This work was supported by the National Institutes of Health
(NIGMS RO1 GM63540).
2
2
26
mmol). The spectral data were in accordance with the previous reports.
4
-Hydroxy-4-phenylpentan-2-one (Table 2, entry 9). The
general procedure for the TBHP-mediated Wacker oxidation was used with
the modification that 0.10 equiv of Pd(Quinox)Cl and 0.25 equiv of AgSbF
’
REFERENCES
2
6
(
1) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Ruttinger,
R.; Kojer, H. Angew. Chem. 1959, 71, 176–182.
2) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, A.
Angew. Chem. 1962, 74, 93–102.
3) Tsuji, J. Synthesis 1984, 369–384.
were used. The reaction was performed with 162 mg (1.00 mmol) of
-phenylpent-4-en-2-ol. The crude mixture was purified by flash chroma-
2
(
tography eluting with 25% Et O and 5% acetone in hexanes to afford 4-
2
hydroxy-4-phenylpentan-2-one as a colorless oil in 79% yield (140.8 mg, 0.79
(
26
mmol). The spectral data were in accordance with the previous reports.
-Hydroxy-3-methylnonan-2-one (Table 2, entry 10). The
general procedure for the TBHP-mediated Wacker oxidation was used
with the modification that 0.05 equiv of Pd(Quinox)Cl and 0.125 equiv
of AgSbF were used. The reactions were performed with 159 mg
(4) Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241–243.
(5) Muzart, J. Tetrahedron 2007, 63, 7505–7521.
(6) Shioiri, T.; McFarlane, N.; Hamada, Y. Heterocycles 1998,
4
47, 73–76.
7) Takacs, J. M.; Jiang, X.-t. Curr. Org. Chem. 2003, 7, 369–396.
8) Nokami, J.; Ogawa, H.; Miyamoto, S.; Mandai, T.; Wakabayashi,
S.; Tsuji, J. Tetrahedron Lett. 1988, 29, 5181–5184.
9) Pellissier, H.; Michellys, P.-Y.; Santelli, M. Tetrahedron Lett.
2
(
(
6
(1.02 mmol) and 155 mg (0.99 mmol) of 3-methylnon-1-en-4-ol
respectively. Purified by flash chromatography eluting with 50% Et
2
O
(
in hexanes to afford the title compound as a colorless oil in 57% average
yield (93.9 mg, 0.55 mmol and 103 mg, 0.60 mmol). The spectral data
1
5
5
994, 35, 6481–6484.
(10) Pellissier, H.; Michellys, P.-Y.; Santelli, M. Tetrahedron 1997,
3, 7577–7586.
27
were in accordance with the previous report.
-(tert-Butylperoxy)-2-methyl-5-pentyltetrahydrofuran
11). The general procedure for the TBHP-mediated Wacker oxidation
was followed using dec-1-en-5-ol 10. The reactions were performed with
55.0 mg (0.99 mmol) and 155.9 mg (1.00 mmol) of 10 respectively. The
crude product was purified by flash chromatography eluting with 20%
Et O in hexanes to afford 2-(tert-butylperoxy)-2-methyl-5-pentyltetrahy-
drofuran 11 as a colorless oil in 83% average yield (200 mg, 0.82 mmoland
2
(
11) Pellissier, H.; Michellys, P.-Y.; Santelli, M. Tetrahedron 1997,
3, 10733–10742.
12) Michel, B. W.; Camelio, A. M.; Cornell, C. N.; Sigman, M. S.
(
(
1
J. Am. Chem. Soc. 2009, 131, 6076–6077.
(13) The diastereomeric ratio was not affected during oxidation.
(14) (a) Schwartz, B. D.; Moore, C. J.; Rahm, F.; Hayes, P. Y.;
Kitching, W.; De Voss, J. J. J. Am. Chem. Soc. 2008, 130, 14853–14860.
(b) Martín-Matute, B.; Edin, M.; B €a ckvall, J. Chem.—Eur. J. 2006,
12, 6053–6061. (c) Holt, T.; Atkinson, R.; Arey, J. J. Photochem.
Photobiol., A 2005, 176, 231–237.
2
1
2
06 mg, 0.84 mmol). R
f 2
= 0.67 (20:80 Et O/Hexanes). H NMR (500
MHz, CDCl
3
) δ 4.11ꢀ4.17 (m, 1H), 2.00ꢀ2.10 (m, 2H), 1.80ꢀ1.87 (m,
2
0
2
H), 1.58ꢀ1.66 (m, 2H), 1.48 (s, 3H), 1.16ꢀ1.51 (m, 6H), 1.22 (s, 9H),
13
(
15) Michel, B. W.; McCombs, J. R.; Winkler, A.; Sigman, M. S.
.86 (t, J = 6.8 Hz, 3H). C NMR (125 MHz, CDCl ) δ 14.4, 23.0, 23.8,
3
Angew. Chem., Int. Ed. 2010, 49, 7312–7315.
5.8, 27.0, 31.2, 32.3, 35.6, 35.8, 79.5, 80.2, 111.5. IR (neat): 2976 (m), 2957
ꢀ1
(16) Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970–8972.
(17) Feng, J.-P.; Shi, Z.-F.; Li, Y.; Zhang, J.-T.; Qi, X.-L.; Chen, J.;
Cao, X.-P. J. Org. Chem. 2008, 73, 6873–6876.
(
(
(m), 2930 (s), 2861 (w), 1460 (m) cm . HRMS: m/z (ESI/TOF MS
þ
Eþ) Calculated [C H O Na ] 267.1936, observed 267.1945
14 28 3
2
-(tert-Butylperoxy)-2-methyl-6-pentyltetrahydro-2H-pyran
13). The general procedure for the TBHP-mediated Wacker oxidation was
used for undec-1-ene-6-ol 12. The reactions were performed with 158 mg
0.93 mmol) and 169 mg (0.99 mmol) of 12 respectively. The crude
18) Zhao, H.; Cai, M.-Z. Chin. J. Chem. 2006, 24, 1669–1673.
19) Fujita, T.; Watanabe, S.; Suga, K.; Inaba, T. J. Chem. Technol.
(
Biotechnol. 1979, 29, 100–106.
20) Guijarro, D.; Mancheno, B.; Yus, M. Tetrahedron 1992,
48, 4593–4600.
21) Zhou, C.-L.; Zha, Z.-G.; Wang, Z.-Y.; Wu, J.-H.; Zhang, J.-H.
(
(
mixture was purified by flash chromatography eluting with 25% Et O in
2
hexanes to afford 2-(tert-butylperoxy)-2-methyl-6-pentyltetrahydro-2H-
(
pyran 13 as a colorless oil in 81% average yield (196 mg, 0.76 mmol and
Chin. J. Chem. 2002, 20, 718–721.
1
2
04 mg, 0.79 mmol). R
f
= 0.70 (20:80 Et
2
O/Hexanes). H NMR (500
(22) Thorn, D. L. J. Am. Chem. Soc. 1980, 102, 7109–7110.
(23) Margot, C.; Rizzolio, M.; Schlosser, M. Tetrahedron 1990,
46, 2411–2424.
MHz, CDCl , ppm) δ 3.81ꢀ3.88 (m, 1H), 1.79ꢀ1.65 (m, 4H), 1.61ꢀ1.39
3
(
3
(
3
m, 2H), 1.38 (s, 3H), 1.36ꢀ1.25 (m, 4H), 1.23 (s, 9H), 0.87 (t, J = 7.8 Hz,
13
H). C NMR (125 MHz, CDCl
), 25.3 (CH ), 27.0 (CH ), 27.2 (CH
3.6 (CH ), 36.3 (CH ), 70.3 (CH), 78.8 (C), 101.5 (C). IR (neat): 2977
3
, ppm) δ 14.4 (CH
3
), 19.9 (CH
2
), 23.0
(24) Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010,
132, 1474–1475.
CH
2
2
2
3
), 30.7 (CH
2
), 32.1 (CH
2
),
(
25) Ohwa, M.; Kogure, T.; Eliel, E. L. J. Org. Chem. 1986,
2
2
ꢀ
1
51, 2599–2601.
(26) Stahl, I.; Gosselck, J. Synthesis 1980, 561–563.
(
(m), 2934 (s), 2871 (m), 1457 (m) cm . HRMS: m/z (ESI/TOF MS
þ
Eþ) Calculated [C15
H
30
O
3
Na ] 281.2093, observed 281.2101.
27) Colobert, F.; Obringer, M.; Solladie, G. Eur. J. Org. Chem.
2
006, 1455–1467.
’
ASSOCIATED CONTENT
Supporting Information. Copies of NMR Spectra. This
S
b
information is available free of charge via the Internet at http://
pubs.acs.org
3
613
dx.doi.org/10.1021/jo200462a |J. Org. Chem. 2011, 76, 3609–3613