Novel PDC catalyzed oxidative rearrangement of tertiary allylic alcohols to β-substituted enones

Article abstract of DOI:10.1016/j.tetlet.2015.09.046

Novel pyridinium dichromate (PDC) catalyzed oxidative rearrangement for the conversion of tertiary allylic alcohols to ?-substituted enones is described. Using a catalytic amount of PDC with PhI(OAc)₂ as a co-oxidant in the presence of magnesium sulfate and water under oxygen was found effective for this rearrangement.

Full text of DOI:10.1016/j.tetlet.2015.09.046

Tetrahedron Letters 56 (2015) 5941–5944
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Tetrahedron Letters
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Novel PDC catalyzed oxidative rearrangement of tertiary allylic
alcohols to b-substituted enones
⇑
Kazuma Matsunaga, Hironori Hirajima, Atsushi Kishida, Kazuhiko Takatori, Hiroto Nagaoka
Meiji Pharmaceutical University, Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel pyridinium dichromate (PDC) catalyzed oxidative rearrangement for the conversion of tertiary
allylic alcohols to ß-substituted enones is described. Using a catalytic amount of PDC with PhI(OAc)2
as a co-oxidant in the presence of magnesium sulfate and water under oxygen was found effective for this
rearrangement.
Received 3 August 2015
Revised 3 September 2015
Accepted 15 September 2015
Available online 21 September 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
PDC
Iodosylbenzene diacetate
Oxidation
Rearrangement
Tertiary allylic alcohol
The oxidative rearrangement of tertiary allylic alcohols is a fun-
damental means for the preparation of b-substituted ,b-unsatu-
oxidation of various tertiary allylic alcohols. However, no suitable
reagent for the conversion of cyclohex-2-enols 14a9 bearing a
bulky substituent at the 6-position to b-substituted enone 14b
has been found in our studies on natural product synthesis.
To develop a more effective reagent than PCC or PDC but with
less toxicity, an investigation was made of PDC catalyzed oxidative
rearrangement of tertiary allylic alcohols. Studies on several oxo-
chromium(VI) catalyzed oxidations have indicated chromium(VI)
oxide (CrO3) to catalyze the oxidation of primary and secondary
allylic alcohols with alkyl hydroperoxide,10 CrO3 to catalyze the
oxidation of primary and secondary alcohols, benzylic C–H bonds,
and arenes with periodic acid (H5IO6),11 and the (salen)chromium
complex catalyzed oxidation of primary and secondary allylic
(or benzyl) alcohols with PhIO12 or iodosylbenzene diacetate
(PhI(OAc)2).12 But to date, no application of these reagents to the
oxidative rearrangement of tertiary allylic alcohols has been made
to our knowledge.
In the present study, the effective transformation of tertiary
allylic alcohols to a,b-unsaturated ketones using catalytic amounts
of PDC and PhI(OAc)2 as a terminal oxidant was successfully car-
ried out.
The reaction conditions for the PDC catalyzed oxidation of
1-butylcyclohex-2-enol (1a) with PhI(OAc)2 to give 3-butylcyclo-
hex-2-enone (1b) is shown in Table 1. Reaction of 1a with
0.01 equiv of PDC and 3.0 equiv of PhI(OAc)2 in CH2Cl2 (0.2 M)
for 24 h at room temperature under argon atmosphere gave 1b
in 84% yield (entry 1). In this reaction, air or oxygen was found
to promote the reactivity of the reagent remarkably, but in all
a
rated ketones in natural product synthesis.1 An oxochromium(VI)
based reagent such as pyridinium chlorochromate (PCC) and pyri-
dinium dichromate (PDC) is the first choice for the rearrangement.2
The pathway of the reaction is considered to quite likely be that
shown in Scheme 1. First, tertiary allylic alcohol I reacts with
oxochromium(VI) based reagent to form chromate II. The allylic
rearrangement of II produces the chromate of secondary alcohol
III, which is then transformed to enone IV and oxochromium(IV).
Oxochromium(VI) appears to be the most suitable reagent since
it acts at both the stage of rearrangement and oxidation. But these
reactions require stoichiometric amounts of oxochromium(VI)
based oxidants all of which possess considerable toxicity.
Recently, alternative methods have been reported for the reac-
tions shown above. These reactions may be classed as either those
caused through use of stoichiometric amounts of oxidant or cat-
alytic amounts of a reagent with co-oxidant. Oxoammonium salts
of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO+XÀ) oxidation3
and 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX) oxida-
tion4 are of the first type reaction while the second type involves
combinations of TEMPO and NaIO4–SiO2,5 TEMPO, iodosylbenzene
(PhIO) and Bi(OTf)3,6 TEMPO and copper(II) chloride (CuCl2),6
2-iodoxybenzenesulfonic acid (IBS) and OxoneÒ (2KHSO5ÁKHSO4Á
K2SO4),7 and Pt black and H2O2.8 These reagents were used for the
⇑
Corresponding author. Tel./fax: +81 42 495 8819.
E-mail address: nagaoka@my-pharm.ac.jp (H. Nagaoka).
http://dx.doi.org/10.1016/j.tetlet.2015.09.046
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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K. Matsunaga et al. / Tetrahedron Letters 56 (2015) 5941–5944
Table 2
Combinations of oxidant and base for chromium(IV) oxide catalyzed oxidative
rearrangement of allylic alcohol 1a
Entry
CrO2
Base (equiv)
Oxidant
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
0.1
0.1
2.0
2.0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
Pyridine (0.1)
—
—
Phl(OAc)2
Phl(OAc)2
—
0.5
1
1
1
1
1
1
1
1
94
0b
0b
0b
0b
0b
0b
0b
0b
0b
90
Pyridine (2.0)
2,6-Lutidine (0.1)
DMAP (0.1)
NaHCO3 (0.1)
MS4A
Pyridine (0.1)
Pyridine (0.1)
Pyridine (0.1)
—
Phl(OAc)2
Phl(OAc)2
Phl(OAc)2
Phl(OAc)2
PhlO
Scheme 1. The reaction pathway of the oxidative rearrangement of tertiary allylic
alcohol I to form a,b-unsaturated ketone IV by oxochromium(VI) based reagent.
10
11
NalO
IBX
1
15
cases, a small amount of 1a was recovered (entries 2 and 3). Using
0.05 equiv of PDC and 1.5 equiv of PhI(OAc)2 under oxygen
increased the reaction rate and an optimum yield of 1b was 94%
(entry 4). Reproducibility of the reaction, however, was not satis-
factory. The addition of 1 equiv of H2O in this reaction condition
was found to improve reproducibility, but the yield of 1b was
slightly less than without H2O (entry 5). This problem was solved
by the addition of 1 equiv of MgSO4, which increases the yield of
1b to 96% (entry 6). It seems that gradual supply of H2O is effective
for this reaction. However, the exact reason for the effectiveness of
a combination of H2O, MgSO4, and O2 is not clear. This condition is
superior to that commonly used for PDC oxidation in nearly all
respects (entry 7). It should be pointed out that the oxidation of
1a with 1.5 equiv of PhI(OAc)2 without PDC did not occur (entry 8).
The chromium(IV) generated in the above reactions should be
reoxidized to chromium(VI) by PhI(OAc)2. A study was thus made
using a combination of chromium(IV) oxide (CrO2), base, and PhI
(OAc)2 instead of PDC in combination with PhI(OAc)2 and the
results are shown in Table 2. Using 0.1 equiv of CrO2, 0.1 equiv of
pyridine and 1.5 equiv of PhI(OAc)2 in CH2Cl2 (0.5 M) under oxygen
atmosphere for the reaction of 1a provided results essentially the
same as for the oxidation described above. Enone 1b was obtained
in 94% yield (entry 1). The oxidation did not proceed without pyr-
a
Isolated yield.
No reaction occurred.
b
idine and/or PhI(OAc)2 (entries 2–4). Pyridine was essential and
could not be replaced with 2,6-lutidine, N,N-dimethylaminopy-
ridine (DMAP), NaHCO3, or MS4A (entries 5–8). Neither PhIO nor
NaIO4 was found to function as a co-oxidant (entries 9 and 10).
IBX, however, was found to serve as a co-oxidant, but with a lower
reaction rate (entry 11). IBX treatment of 1a in CH2Cl2 without the
presence of CrO2 did not cause the oxidative rearrangement.
CrO2 is thus shown to function as a catalyst for the oxidation in
the presence of pyridine and PhI(OAc)2 (or IBX) under oxygen.
The PDC catalyzed oxidative rearrangement to various sub-
strates was consequently investigated. Allylic alcohols 2a–5a each
bearing a tert-butyldimethylsilyloxy, acetyloxy, methoxymethoxy,
or benzyloxy group could be converted to the corresponding
enones 2b–5b in good yields (Table 3, entries 2–5). In the cases
of benzyl alcohol 6a and ester 7a, the standard reaction conditions
were ineffective for completing the oxidation and the yields of
enones 6b and 7b were only moderate (entries 6 and 7). 3 equiv
of PhI(OAc)2 and the addition of 11 equiv of pyridine in the case
of 6a or 3 equiv of PhI(OAc)2 in the case of 7a, were found to
improve the yields of 6b and 7b. Allylic alcohol 8a bearing a qua-
ternary carbon center at the 4-position smoothly underwent con-
version to enone 8b in high yields (entry 8). The substituent at
the 2-position in cyclohex-2-enol 9a was found to hinder the oxi-
dation and the yield of 9b was somewhat low (entry 9). Neither
transformation of 11a bearing a cycloheptene ring, 12a bearing a
cyclooctene ring nor acyclic allylic alcohol 13a to corresponding
enones 11b–13b gave satisfactory results, but cyclopent-2-enol
10a was easily oxidized to 10b (entries 10–13). PDC and PhI
(OAc)2 in combination were effective for bringing about the oxida-
tion of allylic alcohols each possessing a bulky group at the 6-po-
sition. The oxidation of 14a9 having a number of acid sensitive
groups produced enone 14b in 70% yield (entry 14). The usual
PDC oxidation of 14a gave low yield of 14b and a small amount
of 14a was recovered. Alcohols 15a with 2-(trimethylsilyloxy)pro-
pan-2-yl group and 16a with 2-(methoxymethoxy)propan-2-yl
group gave 76% yield of 15b and 92% yield of 16b, respectively
(entries 15 and 16). TEMPO catalyzed oxidation5 of 15a with
NaIO4–SiO2 was seen to cause desilylation to give 15c and the oxi-
dation of 16a provided 16b in moderate yields.
Table 1
Optimization of the reaction conditions for the oxidative rearrangement of allylic
alcohol 1a with pyridinium dichromate in the presence of PhI(OAc)2
Entry PDC
Phl
Additive
(equiv)
Condition Concn
(M)
Time
(h)
Yielda
(%)
(equiv) (OAc)2
(equiv)
1
2
3
4
5
6
0.01
0.01
0.01
0.05
0.05
0.05
3.0
3.0
3.0
1.5
1.5
1.5
—
—
—
—
Ar
0.2
0.2
0.2
0.5
0.5
0.5
24
1.5
1
84
Air
O2
O2
88b
88b
0.25 94c
H20 (1.0) O2
H20 (1.0) O2
MgSO4
0.25 86
0.25 96
(1.0)
7
8
2.0
—
—
1.5
—
—
Air
Air
0.2
0.2
3
5
91
0d
The typical experimental procedure for the PDC catalyzed oxida-
tive rearrangement of tertiary allylic alcohol with PhI(OAc)2 is
shown in the following. To a solution of alcohol 1a (77.1 mg,
0.500 mmol) in CH2Cl2 (1.0 mL, 0.5 M) was added MgSO4 (60.2 mg,
a
b
c
Isolated yield.
A small amount of 1a was recovered.
The best yield, but low reproducibility.
No reaction.
d

K. Matsunaga et al. / Tetrahedron Letters 56 (2015) 5941–5944
5943
Table 3
Pyridinium dichromate catalyzed oxidative rearrangement of allylic alcohols with iodosobenzene diacetate
Entry
1
Substrate
Product
Time (h)
0.25
Yielda (%)
Entry
9
Substrate
Product
Time (h)
Yielda (%)
96
1
49
2
3
1
1
87
81
10
11
0.5
1
84
43
4
5
1
1
86
77
12
13
1
1
38
Trace
0.5
1.5
41
24
12
70c
38e
6
14
84b
3
24
51
1
1
76f
7
8
15
16
69c
0g,h
1
1
92
0.5
90
57g,i
a
b
c
d
e
f
Isolated yield.
PDC (0.05 equiv), Phl(OAc)2 (3.0 equiv), pyridine (11 equiv), MgSo4 (1.0 equiv), O2 (balloon), CH2Cl2 (0.2 M).
PDC (0.05 equiv), Phl(OAc)2 (3.0 equiv), H20 (1.0 equiv), O2 (balloon), CH2Cl2 (0.1 M).
A 7:1 diastereomeric mixture.
PDC (3 equiv), MS4A, CH2Cl2 (0.2 M).
14% of 15a was recovered.
TEMPO (0.01 equiv), NaIO4–SiO2 (2 equiv), CH2Cl2 (0.1 M).
Diol 15c was obtained quantitatively.
35% of 16a was recovered.
g
h
i
0.500 mmol), H2O (9.0
0.750 mmol) and PDC (9.4 mg, 25
l
L, 9.0 mg, 0.50 mmol), PhI(OAc)2 (242 mg,
chromatography on silica gel (hexane/ether = 3.5:1) to give 1b
(73.0 mg, 0.480 mmol, 96%).
lmol) with stirring. The resulting
dark brown mixture was stirred for 15 min at room temperature
under oxygen (balloon). This was followed by the addition of satu-
rated aqueous NaHCO3 and 20% aqueous Na2S2O3. After been stirred
for 15 min, the suspension was diluted with Et2O. The organic layer
was washed with brine, dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The residue was purified by flash
In summary, PDC was found an effective catalyst for the oxidative
rearrangement of cyclic tertiary allylic alcohols with PhI(OAc)2,
MgSO4, and H2O in CH2Cl2. By this method, various 1-alkylcyclo-
hex-2-enols, cyclohex-2-enol bearing a quaternary carbon center
at the 4-position and 1-alkylcyclopent-2-enol could be smoothly
converted to the corresponding enones and even cyclohex-2-enol

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K. Matsunaga et al. / Tetrahedron Letters 56 (2015) 5941–5944
2. For recent reviews on oxochromium(VI)-based oxidants, see: (a) Luzzio, F. A. In
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6. (a) Vatèle, J.-M. Synlett 2008, 1785–1788; (b) Vatèle, J.-M. Synlett 2009, 2143–
2145; (c) Vatèle, J.-M. Tetrahedron 2010, 66, 904–912.
14a bearing a bulky group at the 4-position, the usual PDC oxidation
of which gave only low yield of 14b, could be oxidized to enone 14b
in good yields. CrO2 could also be used as a catalyst for the oxidative
rearrangement in the presence of pyridine and PhI(OAc)2.
Acknowledgment
7. Uyanik, M.; Fukatsu, R.; Ishihara, K. Org. Lett. 2009, 11, 3470–3473.
8. Nagamine, T.; Kon, Y.; Sato, K. Chem. Lett. 2012, 41, 744–746.
9. Allylic alcohol 14a was prepared from (R)-2,2-dimethyl-1,3-dioxolane-4-
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) from Japan Society for the Promotion of Science (No.
23590022).
carbaldehyde in 5 steps: (1) cyclohexanone, L-proline, THF, H2O, rt, 17 h, 97%;
(2) TMSCl, Et3N, DMAP, THF, 0 °C to rt, 1 h; (3) LDA then TMSCl, THF, À78 °C,
30 min; (4) Pd(OAc)2, O2, DMSO, rt, 15 h, 82% (3 steps); (5) AcOEt, LDA, THF,
À78°C, 30 min, 90%.
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