Conformational biasing in 1,3-oxidative rearrangements of dienols

Article abstract of DOI:10.3987/com-07-s(w)62

1-Vinyl-2-cycloalkenols are oxidized to form conjugated dienones in useful yields. Although this oxidative rearrangement is general, severe steric interactions can favor the formation of a conjugated dienal instead of a conjugated dienone. Several heteroc

Full text of DOI:10.3987/com-07-s(w)62

HETEROCYCLES, Vol. 74, 2007
225
HETEROCYCLES, Vol. 74, 2007, pp. 225 - 231. © The Japan Institute of Heterocyclic Chemistry
Received, 1st September, 2007, Accepted, 3rd December, 2007, Published online, 4th December, 2007. COM-07-S(W)62
CONFORMATIONAL
BIASING
§
IN
1,3-OXIDATIVE
REARRANGEMENTS OF DIENOLS
George Majetich,* Hisaya Nishide, Ryan M. Phillips, and Jianhua Yu
Department of Chemistry, The University of Georgia, Athens, Georgia
30602, U.S.A. majetich@chem.uga.edu
Abstract – 1-Vinyl-2-cycloalkenols are oxidized to form conjugated
dienones in useful yields. Although this oxidative rearrangement is
general, severe steric interactions can favor the formation of a conjugated
dienal instead of a conjugated dienone. Several heterocyclic analogues
were also studied.
Since its discovery in the early seventies by Büchi and Egger,1 the oxidative rearrangement of tertiary
allylic alcohols to α,β-unsaturated ketones or aldehydes using chromium trioxide in aqueous 2.6 M
sulfuric acid (Jones reagent) has been widely used in synthesis (Scheme 1).2
Following the
development of less acidic oxidants, such as pyridinium chlorochromate (PCC)3 or pyridinium
dichlorochromate (PDC),4 Dauben and Michno reexamined the oxidation of tertiary allylic alcohols for
the synthesis of a variety of cyclic and acyclic enones.5
In contrast to the use of Jones reagent, the
reaction conditions using PCC are mild enough to tolerate the presence of sensitive functional groups
such as silyl ethers, esters, and isolated double bonds.
Scheme 1
O
CrO3 / H2SO4
(91%)
PCC
OH
OH
(88%)
O
cis-jasmone
Prior to 1989, the study of the 1,3-oxidative rearrangement of substrates in which competing allylic
rearrangements are possible was limited to only two examples (Scheme 2). In 1976, Babler and Coghlin
noted that treatment of 3-methyl-1,4-pentadien-3-ol (1) with PCC afforded a mixture of the
stereoisomeric 3-methyl-2,4-pentadienals (2),6 and methyl vinyl ketone (3), the result of oxidative

226
HETEROCYCLES, Vol. 74, 2007
cleavage.
In the second example, the oxidation of trienol 4 using PCC produces dienone 5 in 38%
yield through the oxidation of intermediate 4i, whereas dienone 6 is produced in 57% yield from
intermediate 4ii, the result of a second allylic transposition.7
Scheme 2
HO-CrO2
PCC
[3,3]-
rearrangement
HO
HO-CrO2
1
HO
4i
4ii
4
PCC
O
O
+
H
O
O
6 (57%)
(no yields reported)
5 (38%)
3
2
These observations prompted us to oxidize a series of bis-allylic alcohols in order to address the
regioselectivity in analogues of 7 (Scheme 3).8 In general, simple vinyl cyclohexenols and vinyl
cyclopentenols rearrange exclusively involving the endocyclic double bond to give good yields of the
β-vinylic cyclohexenone or cyclopentenone;9 however, small amounts (< 5%) of the isomeric dienals
were occasionally isolated. Our recent findings regarding the scope and limitations of this oxidative
rearrangement, as well as additional insight into its mechanism, are reported herein.10
Scheme 3
PCC and Celite
(1.25-1.50 equiv. each)
+
CHO
O
HO
TEA (0.2 equiv.)
CH2Cl2, 8-14 h
7b (trace amounts)
7a (60-81%)
7
Scheme 4 presents twelve dienols which were treated with PDC.11,12 The oxidation of dienols 8-12
confirmed that acetals (cf. 8), vinyl bromides (cf. 11), and esters (cf. 9 and 10) can tolerate the mild
reaction conditions employed. Cyclic dienols 13-17 demonstrated that the introduction of nonbonded
steric interactions increases dienal formation whereas the oxidation of dienols 11, 12, 18 and 19 revealed
that the size of the ring containing the endocyclic double bond influenced the product distribution.
Although a solvolysis mechanism can be envisioned for each of these transformations, we believe these
results are best explained in terms of a [3,3]-sigmatropic mechanism, and that the regioselectivity

HETEROCYCLES, Vol. 74, 2007
227
Scheme 4
OH
O
O
O
O
CO2Et
PDC
CO2Et
PDC
O
OH
n = 1 (9) (61%)
= 2 (10) (58%)
(77%)
(CH2)n
(CH2)n
O
8
Br
Br
HO
O
HO
PDC
PDC
O
(70%)
(68%)
12
11
OH
_
CHO
PDC
OCrO2-O-CrO3
(60%)
13
13a (only)
13i
OH
_
CHO
+
OCrO2-O-CrO3
PDC
PDC
O
O
14
15
14b (36%)
14a (32%)
14i
_
OH
OCrO2-O-CrO3
CHO
+
15b (18%)
15a (59%)
15i
_
O3Cr-O-CrO2
CHO
O
+
PDC
PDC
O
OH
16b (21%)
16a (68%)
16
_
O3Cr-O-CrO2
O
+
CHO
O
OH
17b (7%)
17a (47%)
17
CHO
CHO
OH
PDC
OH
+
PDC
+
O
O
18
19
19b (16%)
19a (13%)
18a (43%)
18b (21%)

228
HETEROCYCLES, Vol. 74, 2007
observed is the result of conformational biasing. For example, the chromate ester derived from the
bis-allylic alcohol 7, the simplest substrate studied, should adopt a conformation in which the chromate
group resides in a pseudoequatorial position (cf. 7i, Scheme 5). However, in this conformation
nonbonded steric interactions between the chromate ester and the vinyl group would cause the vinyl
susbstituent to rotate away from the chromate moiety (cf. 7ii). Once the chromate ester adopts a rotamer
in which it is above the endocyclic double bond (cf. 7iii), a [3,3]-sigmatropic rearrangement produces
intermediate 7iv, the further oxidation of which irreversibly produces conjugated dienone 7a. In the
case of the acyclic dienol 13, the disubstituted double bond of chromate ester 13i is much more hindered
than the vinyl group, hence only dienal formation is observed. Similarly, significant steric interactions
between the chromate ester and the indicated methyl group of 14i disfavors the sigmatropic
rearrangement with the endocyclic double bond and dienal 14a is the major product. In contrast, the
geminal dimethyl groups present in substrates 15, 16, and 17 do not interact with the chromate ester
resulting in the preferred formation of the conjugated dienones.
Scheme 5
_
_
_O3Cr
O3Cr
O3Cr O
O
O
Cr
O
O
O
Cr
O
O
Cr
O
O
O
O
7iii
7ii
7i
[3,3]-sigmatropic
rearrangement
_
[3,3]-sigmatropic
rearrangement
_
O3Cr
O3Cr-O
O
Cr
O
7a
Cr O
7b
O
O
O
O
7iv
7v
Conformational biasing also accounts for the trend that larger cyclic dienols produce more dienals. In
particular, the nearly planar, rigid conformer 12i has few non-bonded steric interactions between the
carbocyclic methylene units and the chromate ester to destabilize this conformation (Scheme 6).
Scheme 6
_
_
O3Cr O
O
H
O3Cr O
O
H
_
OCrO3
O
O
O
_
OCrO3
O
H
Cr
H
H
Cr
H
H
H
O
Cr
O
Cr
O
O
H
O
O
19i
12i
18i
7iii

HETEROCYCLES, Vol. 74, 2007
229
A chair-like conformation of 7iii also has few significant nonbonded steric interactions. In contrast, the
more flexible cycloheptenol and cyclooctenol rings can adopt multiple conformations, several of which
introduce significant steric congestion (e.g. 18i and 19i), thereby favoring the formation of the dienal.
Additional support for endocyclic selectivity in the [3,3]-sigmatropic rearrangement can be found in the
oxidation of 3-methyl-1-vinyl-2-cyclohexenol (20) which can only undergo irreversible oxidation at the
terminal carbon of the vinyl substituent (Scheme 7). Although a 23% yield of the E and Z isomers of
acetaldehyde 20b is produced, tertiary alcohol 20a nevertheless predominates (56%).
Scheme 7
H
PDC
+
O
CH3
CH3
CH3
8-12 h
OH
OH
20b (23%)
20a (56%)
20
The oxidation of allylsilane 21 could form annulation products 22a and 22b if discrete carbocation
intermediates (cf. 21i and 21ii) were involved. However, treatment of allylsilane 21 with two
equivalents of PCC gave a mixture of products from which dienone 23 was isolated in only 14% yield
and heterocycle 24 was isolated in 53% yield (Scheme 8). In contrast, treatment of 21 with PDC cleanly
afforded dienone 23 in 57% yield. We believe that bicyclic heterocycle 24 is the result of the
protonation of the allylsilane moiety by capricious acid present in the PCC (cf. 21iii). When PDC was
employed, the buffered reaction medium prevented furan formation and the dienone was produced in
good yield.
Scheme 8
+
+
PCC
OH
21
(CH3)3Si
Si(CH3)3
Si(CH )
and/or
3 3 21ii
22b
22a
21i
PDC
(57%)
P
C
C
furan
formation
O
O
OH
(CH3)3Si
53% of 24
and
14% of 23
+
24
(CH3)3Si
23
Si(CH3)3
21iii

230
HETEROCYCLES, Vol. 74, 2007
It is well known that pyrroles are more reactive than furans, which in turn are more reactive than
thiophenes. We were curious whether the tertiary alcohols 24-26 would oxidize the C(3) positions of
the aromatic rings or produce the corresponding functionalized enals (Scheme 9). Treatment of pyrrole
derivative 24 with PDC (and buffer) might have produced 2-alkylidenepyrrolinone 24a or enal 24b, but
these products rapidly decomposed.13 Treatment of furan derivative 25 with PDC did not produce
furanone 25a; instead enal 25b was isolated in 60% yield. Finally, since thiophenes are the most
aromatic in character of these three heterocycles, it was not surprising that oxidation of thiophene
derivative 26 only produces enal 26a in 70% yield.
Scheme 9
O
CHO
PDC
and / or
X
X
X
OH
x = NH (24b) decomposes
= O (25b) (60%)
= S (26b) (70%)
x = NH (24a) decomposes
= O (25a) (0%)
= S (26a) (0%)
x = NH (24)
= O (25)
= S (26)
In conclusion, the above results are most consistent with this type of oxidation occurring via a
[3,3]-sigmatropic rearrangement mechanism whereby the formation of the conjugated dienone
predominates unless there are severe steric interactions present in the transition state, which leads to the
formation of significant quantities of the conjugated dienal.
ACKNOWLEDGEMENTS
We thank the National Science Foundation (CHE-0506486) for support of this research.
REFERENCES AND NOTES
§
In honor and celebration of the 75th birthday of Professor Ekkehard Winterfeldt of the University
of Hannover.
1.
2.
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7.
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HETEROCYCLES, Vol. 74, 2007
231
8.
9.
G. Majetich, S. M. Condon, K. Hull, and S. Ahmad, Tetrahedron Lett., 1989, 30, 1033.
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10.
11.
All yields are isolated yields. The spectroscopic data obtained for all new compounds were fully
consistent with the assigned structures.
The optimum conditions for these oxidations consist of using 1.25 to 1.50 equivalents of
pyridinium dichromate (PDC) with an amount of dry Celite equal to the number of equivalents
of the oxidant and 0.20 equivalents of triethylamine as an acid scavenger. The reagents were
added to dry CH Cl and stirred at rt for 8 to 14. Standard ethereal workup, followed by
2 2
chromatography, provided the yields cited.
12.
The preparation of 3-ethenyl-2-cyclohexen-1-one is a representative example of this oxidative
protocol: A 50-mL flame-dried two-neck round-bottom flask under a positive pressure of dry
nitrogen was charged with 4.54 g of PDC (12.09 mmol), 4.50 g of Celite, 225 mL of dry
triethylamine (1.61 mmol) and 15 mL of anhydrous CH2Cl2. To this mixture was added a
solution containing 1.00 g of ethenyl-2-cyclohexen-1-ol (8.00 mmol) in 10 mL of anhydrous
CH2Cl2. The resulting mixture was stirred at ambient temperature and monitored by TLC
analysis until the starting material was completely consumed (~12 h). The reaction mixture was
diluted with Et2O (100 mL) and filtered through a plug of glass wool. The solids were washed
with Et2O (20 mL). The filtrate was washed once with brine, dried over anhydrous magnesium
sulfate, filtered and concentrated. The crude residue was chromatographed on silica gel 60
(230-400 mesh ASTM) using freshly distilled reagent grade solvents (elution with hexanes/ Et2O,
4:1) to provide 803 mg (81% yield) of 3-ethenyl-2-cyclohexenone which was homogeneous by
TLC.
13.
B. Capon and F.-C. Kwok, Tetrahedron Lett., 1986, 27, 3275.