Reactions of 2,6-dibenzylidenecyclohexanone and its derivatives in high-temperature water

Article abstract of DOI:10.1071/CH06381

The reactivity of derivatives of 2,6-dibenzylidenecyclohexanone was investigated in water at 220?250°C under microwave conditions, without added catalyst. Retro-Claisen?Schmidt processes predominated. Hydrolytic attack at the benzylic position afforded a 2-benzylidenecyclohexanone derivative and liberated an aryl aldehyde. Dienones substituted with electron-withdrawing or -donating groups on the aryl rings were more susceptible to hydrolysis than was the parent 2,6-dibenzylidenecyclohexanone. CSIRO 2006.

Full text of DOI:10.1071/CH06381

Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 883–886
Reactions of 2,6-Dibenzylidenecyclohexanone and its Derivatives
in High-Temperature Water
A
B
B
C,D
Xian-Jun Bi, Luke T. Higham, Janet L. Scott, and Christopher R. Strauss
A
Visiting scholar, Chemical and Engineering College, Yunnan Normal University, Kunming 650092, China.
ARC Special Research Centre for Green Chemistry, Monash University, Clayton VIC 3800, Australia.
CSIRO Molecular and Health Technologies, Private Bag 10, Clayton South VIC 3169, Australia.
Corresponding author. Email: chris.strauss@csiro.au
B
C
D
◦
The reactivity of derivatives of 2,6-dibenzylidenecyclohexanone was investigated in water at 220–250 C under
microwave conditions, without added catalyst. Retro-Claisen–Schmidt processes predominated. Hydrolytic attack
at the benzylic position afforded a 2-benzylidenecyclohexanone derivative and liberated an aryl aldehyde. Dienones
substituted with electron-withdrawing or -donating groups on the aryl rings were more susceptible to hydrolysis
than was the parent 2,6-dibenzylidenecyclohexanone.
Manuscript received: 17 October 2006.
Final version: 10 November 2006.
O
OH
The use of water as a solvent or medium for organic reactions
[
1–5]
H O
has attracted considerable interest since the early 1980s.
2
◦
[4,5]
[7]
At temperatures below 100 C, hydrophobic effects,
250°C (MW), 10 min
[6]
hydrogen bonding, and the high cohesive energy density
of water facilitate processes such as Diels–Alder reactions
and Claisen rearrangements, particularly those with nega-
tive activation volumes. At higher temperatures, however,
the extent of hydrogen bonding diminishes and hydrophobic
effects become less pronounced. The dielectric constant of
9
5% yield
O
O
0
.05% aq NaOH
2
00°C (MW), 5 min
O
8
6% yield
[
8–12]
water decreases but the dissociation constant increases.
Scheme 1. Isoaromatization of carvone[14] and intramolecular
Claisen–Schmidt condensation of 2,5-hexanedione.
In the 1990s, the advent of pressurized microwave reactors
enabled new synthetic protocols that exploited these proper-
[
15]
[
12,13]
ties to be developed.
included the isoaromatization of carvone to carvacrol
the intramolecular Claisen–Schmidt condensation of hexane-
Processes with industrial potential
[
14]
and
predominant process, as exemplified by entries 1–10 in
Table 1, involved hydrolytic cleavage of one of the exo-
cyclic double bonds to afford mono-condensed products 2
and arylaldehydes 3. Although the pathway differed from
that with carvone,
water across a double bond was an early step. With carvone,
water addition to afford 8-hydroxy-p-6-menthen-2-one as a
kinetic product was readily reversible and in the subsequent
elimination step a shift in the position of the isopropenyl dou-
ble bond may have occurred. Isoaromatization would have
ensued through a further shift in the position of that exocyclic
double bond and enolization of the keto group, to afford car-
[
15]
2
,5-dione to 3-methylcyclopent-2-enone (Scheme 1).
Recently, we have employed various media including
[16]
solvent-free conditions and dimethylammonium dimethyl
carbamate[ in condensations of non-enolizable arylaldehy-
des and cyclic ketones. The products all have at least one
enone functionality and we consider 2-benzylidenecyclo-
hexanone (2a) and 2,6-dibenzylidenecyclohexanone (1a)
as parents. The range now includes unsymmetrically
17]
[14]
it seems that in both cases, addition of
[18]
substituted bis(arylidene)alkanones
and dienone-based
macrocycles.[ Palladium-catalyzed isoaromatization has
19]
afforded a new family of compounds possessing motifs with
,6-disubstituted phenols.[
20–22]
[14]
2
vacrolasthethermodynamicproduct. Contrastingly, inthe
The earlier success with carvone and hexane-2,5-
dione encouraged us to investigate reactions of 2,6-
dibenzylidenecyclohexanone (1a) in high-temperature water
see Scheme 2 and Table 1). Isoaromatization was not
present study it appears that putative Markovnikov addition
of water was followed by a rapid retro-aldol addition instead
of by an elimination which would have afforded the starting
material or an isomer thereof. Activation energy barriers for
aldol additions typically are relatively low and the energy
(
observed under any of the conditions employed. The
©
CSIRO 2006
10.1071/CH06381
0004-9425/06/120883

8
84
X.-J. Bi et al.
O
O
O
R1
R2
H O
R
R
2
ϩ
ϩ
O
2
20–250°C (MW),
0.5–8 h
12
3
4
1
2
a: R ϭ R ϭ H
a: R ϭ H
a: R ϭ H
1
2
b: R ϭ R ϭ 4-OCH
b: R ϭ 4-OCH3
c: R ϭ 2-OCH3
d: R ϭ 4-NO2
b: R ϭ 4-OCH3
c: R ϭ 2-OCH3
d: R ϭ 4-NO2
3
1
2
c: R ϭ R ϭ 2-OCH
3
1
2
d: R ϭ H, R ϭ 4-OCH
3
1
2
e: R ϭ H, R ϭ 4-NO
2
Scheme 2. Reactions of 2,6-dibenzylidenecyclohexanones in high-temperature water.
Table 1. Reactions of benzylidenecyclohexanones in high-temperature water
◦
Product composition [%]A
Entry
Substrate
Temp. [ C]
Time [h]
SMB
2a
2b
2c
2d
3a
3b
3c
3d
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1d
1d
1d
1e
2a
2a
220
240
250
220
220
220
220
220
220
220
220
220
220
220
220
220
220
0.5
0.5
0.5
2
4
6
8
4
3
4
0.5
1.5
4
4
2
96
93
54
54
46
16
0
2
3
—
—
—
—
—
—
—
16
—
—
0
—
—
—
—
—
—
—
—
16
14
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
12
—
—
—
2
5
—
—
—
—
—
—
—
84
—
—
6
—
—
—
—
—
—
—
—
—
—
—
23
19
17
27
12
—
—
—
6
23
27
37
57
88
—
—
—
0
—
—
—
—
0
C
31
28
88
70
0
48
50
D
0
1
2
3
4
5
6
7
—
—
—
—
10
2
34
5
5
10
—
—
—
—
—
—
E
<0.5
—
—
—
—
49
12
13
15
—
44
—
—
—
—
F
7
26
—
—
—
G
87
85
—
—
G
6
2
H
I
5J
3a + 4
95
A
1
Calculated from integrated area of signals measured by GC or by H NMR spectroscopy. Ketone 4 could not be analyzed reliably and was not
included.
B
Unreacted benzylidenecyclohexanone.
Salicylaldehyde accounted for 4%.
Salicylaldehyde accounted for 8%.
p-Hydroxybenzaldehyde accounted for 5%.
Unidentified compounds accounted for 8%.
Starting material was 2a.
C
D
E
F
G
H
1
:1 Mixture.
I
Benzaldehyde (3a).
J
1
a not detected.
wells for the starting materials and the aldol adducts are
of comparable magnitude.[ These circumstances facilitate
ready reversibility of aldol addition processes.
strongly suggested that under the conditions 2a was more
stable than 1a and that an equilibrium involving 2a, ben-
zaldehyde (3a), and cyclohexanone (4) had become estab-
lished. That conclusion was reinforced when aldehyde 3a
23]
Difficulties associated with mono-condensation of an ary-
laldehyde with cyclohexanone (4) to afford products 2 are
well documented.[ With base catalysis in particular, mono-
condensed products 2 typically are more reactive than 4
toward arylaldehydes and reactions tend to afford disubsti-
◦
and ketone 4 partially condensed in water at 220 C to give 2-
17]
benzylidenecyclohexanone (2a) with no detectable 1a (entry
17). It was also consistent with results of Zhu et al., who
recently reported that aldehydes including 3a and 3b con-
tuted products 1.[ Here, 2,6-dibenzylidenecyclohexanone
17]
◦
densed with 4 in water at 250 and 280 C to form primarily
[24]
(
1a) underwent gradual hydrolytic degradation in high-
the mono-condensed products 2a and 2b, respectively.
◦
temperature water. Its half-life was ∼4 h at 220 C (entry
Next, the influence of electron-withdrawing or -donating
groups on the aryl moieties was explored with regard to the
hydrolytic behaviour of compounds 1. Two symmetrically
substituted dienones, 1b and 1c as well as two unsymmetri-
cally substituted dienones, 1d and 1e were employed. These
5
, Table 1) and somewhat surprisingly, 2-benzylidene-
cyclohexanone (2a) was a significant product (e.g. entries
◦
3
and 5). In water at 220 C, after 2 and 6 h (entries 15
and 16), 87% and 85% respectively, of 2a remained. Ben-
zaldehyde (3a) was the only product detected. These results
◦
substrates were heated in water at 220 C under microwave

2
,6-Dibenzylidenecyclohexanone in High-Temperature Water
885
conditions for up to 4 h (entries 8–14). Hydrolysis of 1b,
which contained two electron-donating groups, was facile
and neared completion after 4 h (entry 8). That of 1c pro-
helium was used as the carrier gas with a flow rate of 0.8 mL min 1
−
.
Microwave experiments were conducted in a MicroSYNTH (Microwave
◦
Organic Synthesis Labstation, Milestone) that was operable up to 250 C
and that could withstand reaction pressures of at least 5 MPa. Com-
ceeded less readily, probably because the sterically bulky
[25]
[17]
[26]
[27]
pounds 1a–1c,
2a–2b,
2c,
and 2d
were prepared according
ꢀ
2
and 2 -methoxy groups inhibited attack of water at the
to literature methods. Dienones 1d–1e were prepared by reaction of 2-
benzylidenecyclohexanone (2a) with aldehyde (3b or 3d) in 4% NaOH
in 95% EtOH at rt overnight. All compounds were known and had satis-
benzylic positions. Minor changes in composition between
reaction mixtures after 3 h (entry 9) and 4 h (entry 10), again
suggested the establishment of an equilibrium. Interestingly,
hydrolytic cleavage of the methoxy group of 3c was also
apparent, as salicylaldehyde was present among the products
after 4 h (entry 10).
Unsymmetrically substituted dienone 1d underwent com-
plete hydrolysis after 4 h (entry 13) to give aldehydes 3a
and 3b predominantly. Shorter reaction times returned con-
siderable amounts of starting material (entries 11 and 12).
After a lag phase, 4-hydroxybenzaldehyde was detected as
a minor component and it appears that it acid-catalyzed the
hydrolysis.
When the electron-donating methoxy group of 1d was
replaced with an electron withdrawing nitro group, the
resultant unsymmetrical dienone 1e also was prone to hydrol-
ysis (entry 14). Aqueous attack occurred readily and more
regioselectively than was the case for 1d, preferentially at
the benzylic position proximal to the electron withdrawing
group. Consequently, p-nitrobenzaldehyde (3d) and enone
[
17,25–29] 1
13
factory physical and spectral characteristics.
H and C NMR
spectral data of dienones 1d and 1e are presented for the first time,
below.
Typical Procedure for the Reaction of Benzylidenecyclohexanones
in High-Temperature Water
The substrate (1.5 mmol) and water (40 mL) were placed in a pressure-
resistant microwave reaction vessel (100 mL capacity).The mixture was
stirred and rapidly microwave-heated for 3 min to the desired temp (220–
◦
2
50 C), held at this temp for the designated time (0.5–8 h) and cooled.
The product mixture was extracted with an organic solvent and the com-
bined organic phase was dried (anhyd. MgSO4) and concentrated for
1
analysis by GC, GC-MS, and H NMR spectroscopy.
2
-Benzylidene,6-(4-methoxybenzylidene)cyclohexanone (1d): δH
7
7
.79 (1H, t, J 2, CH), 7.77 (1H, t, J 2, CH), 7.48–7.45 (4H, m, Ar),
.42–7.38 (2H, m, Ar), 7.35–7.31 (1H, m, Ar), 6.96–6.92 (2H, m, Ar),
3.85 (3H, s, OCH ), 2.95–2.91 (4H, m, CCH ), 1.83–1.77 (2H, m, CH ).
3
2
2
δC 190.4, 160.2, 137.2, 137.1, 136.6, 136.5, 136.3, 134.4, 132.5, 130.5,
30.5, 128.9, 128.6, 128.5, 55.5, 28.8, 28.6, 23.2.
-Benzylidene,6-(4-nitrobenzylidene)cyclohexanone (1e): δH 8.25
2H, m, Ar), 7.82 (1H, t, J 2, CH), 7.77 (1H, t, J 2, CH), 7.58 (2H, m,
1
2
(
Ar), 7.49–7.46 (2H, m, Ar), 7.44–7.40 (2H, m, Ar), 7.37–7.34 (1H, m,
Ar), 2.97–2.94 (2H, m, CCH ), 2.92–2.88 (2H, m, CCH ), 1.85–1.79
2
a were the two major products.
To summarize, when heated in water at 220–250 C,
2
2
◦
(2H, m, CH2). δC 189.8, 147.3, 142.7, 139.5, 138.1, 135.8, 135.8, 133.9,
30.9, 130.6, 129.1, 128.6, 123.7, 28.6, 28.5, 22.9.
1
dienones 1 underwent hydrolytic attack at the benzylic posi-
tions to afford 2-benzylidenecyclohexanone derivatives 2 and
arylaldehydes 3. 2,6-Dibenzylidenecyclohexanone (1a) was
more reactive than the mono-substituted enone 2a. The pres-
ence of either electron withdrawing or donating groups at the
ortho or para positions on the aryl rings of 1, rendered substi-
tuted dienones 1b–1e more susceptible to hydrolysis than the
unsubstituted parent molecule 1a. In some cases, equilibria
were readily established and these appeared to influence the
product distributions. These preliminary experiments further
demonstrate the chemoselectivities possible with reactions
in high-temperature water and the multiple roles that water
can play including as solvent/medium, reactant and catalyst
depending upon the conditions.
Acknowledgments
We thank Angela Ziebell and Dr Ulf Kreher for conducting
a preliminary experiment, Anthony Rosamilia for provid-
ing a sample of 2b, the Australian Research Council (ARC)
for funding this research through the ARC Special Research
Centre for Green Chemistry, and an Australian Postgraduate
Award (to L.T.H.), The People’s Republic of China for sup-
porting sabbatical leave (for X.J.B.), and Milestone (Italy)
for the loan of microwave reactors and ancillary equipment.
Drs Carl Braybrook and Jo Cosgriff of CSIRO Molecular &
Health Technologies are thanked for performing GC-MS
analyses.
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13
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◦
◦
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