AlCl3-mediated aldol cyclocondensation of 1,6- and 1,7-diones to cyclopentene and cyclohexene derivatives

Article abstract of DOI:10.1021/jo5006137

Exactly 1/3 mol of AlCl₃ is sufficient to cyclize 1 mol of 1,?-dibenzoylbutane (or pentane) to a cyclopentenone (or hexenone) derivative in high yield at room temperature in 40 min to several hours. This condensation is driven by removing elements of water as HCl and Al(OH)₃, and the product enones are exclusively unconjugated, unlike the base-catalyzed condensations providing thermodynamically more stable conjugated enones.

Full text of DOI:10.1021/jo5006137

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Article
The AlCl3-Mediated Aldol Cyclocondensation of 1, 6- and
1, 7-Diones to Cyclopentene and Cyclohexene Derivatives
Yuji Miyahara, and Yoshio N. Ito
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 10 Jun 2014
Downloaded from http://pubs.acs.org on July 3, 2014
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The AlCl -Mediated Aldol Cyclocondensation of 1, 6- and 1, 7-Diones to Cyclopentene
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and Cyclohexene Derivatives
Yuji Miyahara* and Yoshio N. Ito
Department of Chemistry, Faculty of Sciences, Kyushu University
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
*
E-mail: yujimiyahara@kyudai.jp
______________________________________________________________
TOC Graphic Abstract
1
/3AlCl3
(CH ) -
2 n 3
PhCO(CH ) COPh
2
Ph
n
+
HCl
CH Cl
2
2
n = 4.5
O
+ 1/3 Al(OH)3
Ph
______________________________________________________________
ABSTRACT: Exactly 1/3 mole of AlCl is sufficient to cyclize 1 mole of 1,
3
ω-dibenzoylbutane (or pentane) to a cyclopentenone (or hexenone) derivative in high yield
at room temperature in 40 min to several hours. This condensation is driven by removing
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elements of water as HCl and Al(OH) and the product enones are exclusively unconjugated
3
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unlike the base-catalyzed condensations providing thermodynamically more stable
conjugated enones.
_
__________________________________________________________________
INTRODUCTION
1
The aldol condensation is one of the fundamental organic reactions for C-C bond formation.
Although in the infancy of organic chemistry protic acids were used as catalysts for aldol
2
condensation, after discovery of base-catalyzed reaction, acid catalysts have only been
3
4
used sporadically in special cases. Here we report that AlCl can serve as a Lewis acid
3
catalyst as well as a dehydrating agent for aldol cyclocondensation.
RESULTS AND DISCUSSION
A Side Reaction in a Friedel-Crafts reaction. Preparation of 1,4-dibenzoylbutane 1 by
the Friedel-Crafts reaction of adipoyl dichloride with benzene in the presence of AlCl is a
3
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standard Organic Syntheses (OS) procedure, providing 75-81% yield. However, a drastic
a
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decrease in the yield of 1 was observed if the reaction mixture was not quenched after the
specified reaction time of 2 h, when AlCl complex of the product crystallized out, but left
3
standing for an extended period of time. Then, the crystalline complex dissolved to a dark
homogeneous liquid, which gave a tarry material upon aqueous workup. This was nothing
but a failure, but attracted our attention, because the TLC analysis of the product mixture
(SiO , hexane-chloroform-EtOAc 4 : 1 : 0.2) showed a large spot of much less polarity (R
2 f
0.7) in addition to a small spot for the desired dione 1 (R 0.4). Since no mention is made of
f
5a 5b
such a byproduct in the OS procedure or in its original paper, we separated the reaction
mixture by preparative TLC. The compound isolated as colorless needles (mp 99-100 °C)
1 13
was characterized by means of elemental analysis and H and C NMR, IR, and EI-mass
spectral data and found to be 1-phenyl-2-benzoylcyclopentene 2 (Scheme 1), a known
6
compound formed in low yields by base-catalyzed aldol condensation of 1 or by reduction
7
of 1,4-dibromo-1,4-dibenzoylbutane with Zn-NaI.
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Scheme 1. A Side Reaction in the Preparation of 1,4-Dibenzoylbutane 1
0
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PhH
Ph
Ph
ClCO(CH ) COCl
2
PhCO(CH ) COPh
2 4
+
4
AlCl3
O
O
Ph
Ph
1
2
3
_
_____________________________________________________________________
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Apparently this side product is formed by an acid-catalyzed aldol condensation of 1. The
product, however, was not the more stable conjugated enone 3, which is the predominant
6c
isomer in the base-catalyzed reaction, but an unconjugated enone 2. Although the use of
9
AlCl as an acid catalyst has been reported for the aldol condensation of benzaldehyde and
3
10
acetophenone or their derivatives, the reactions require a long time (days) for completion,
otherwise suffer from low yields and have been considered useful only when base sensitive
substituents are present. We decided, therefore, to examine the reaction in detail. As
described below the aldol condensation mediated by AlCl is found to have several unique
3
aspects and furnishes cyclopentene and cyclohexene derivatives in high yields in short
reaction times by optimization of the reaction conditions.
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1
The Effect of AlCl3. Although AlCl alone is not soluble in anhydrous CH Cl , when 1
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was added in a molar ratio of 1 : 1 and the mixture was stirred at room temperature, it
dissolved in a few minutes and gave a clear yellow solution of a 1-AlCl complex (If
3
quenched at this stage, 1 was recovered unchanged). After several minutes, a turbidity
appeared and gradually increased to form a white precipitate. In the meantime, TLC analysis
(silica gel / 4 : 1 hexane-EtOAc) showed a new spot for 2, which increased as the reaction
proceeded. At the same time, a small spot was noticed between the two spots, which was
assumed to be that for the intermediate aldol 4, because the spot disappeared when 1 was
consumed after 45 min. Aqueous workup of the reaction mixture and MPLC separation
provided 91% yield of 2.
_
__________________________________________________________________
Scheme 2. Aldol Condensation of Dibnzoylbutane
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AlCl3
Ph
-
HCl Ph
Ph
O
CH Cl
2
2
O HO Ph
O
O
Ph
-Al(OH)3
Ph
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The amount of AlCl was found to have a significant effect on this reaction. Use of 2 molar
3
equivalents of AlCl led to total recovery of 1 even after stirring for 1 day at room
3
temperature. This suggests that the complexation of AlCl occurs with both carbonyl groups
3
rapidly and completely, leaving no free carbonyl group for the next step of the reaction. On
the other hand, a catalytic amount was insufficient, providing only a small amount of 2.
When the amount of AlCl was increased to 1/3 mol equivalent, the reaction was found to be
3
completed in less than 1 h. The best yield (97%, 99% corrected for the recovery of 1) was
obtained when a cold solution of 1 in CH Cl was mixed with 1/3 mol equivalent of AlCl
2
2
3
and stirred at 0 °C for 1 h (only trace of 2 was detected at this stage) and then at room
temperature for 40 min. As the reaction progressed, evolution of HCl and formation of a
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white precipitate were observed. The precipitate was suspected to be Al(OH)3 and its
amount was measured by collecting on a glass filter and drying (100 °C/0.1 mmHg for 48 h)
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until no more loss in weight, providing almost the expected amount (31% excess) as
Al(OH) . Therefore, the water formed in this aldol condensation is removed as Al(OH) and
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3
3
HCl, thus driving the reaction irreversibly. This is in contrast to the usual acid-catalyzed
1
3
aldol condensation, where dehydration is done by heating.
The fact that only one of the three Cl's of AlCl is needed in the condensation for each
3
molecule of 1 led us to examine the reaction using an Al species with only one active Cl. For
this purpose a dialkoxide ClAl(OR) , which can be obtained by reacting AlCl with alcohol
2
3
(ROH), may be used. In order to ensure formation of the bisalkoxide we selected diols,
which are expected to form chelates. We tried chiral ethyl tartarate and binaphthol hoping
for asymmetric induction. Though no enantiomeric excess was observed (HPLC, Chiralpack
AD-H), high yields of 2 were realized in both cases (77% and 94%, respectively). An
interesting finding made in the course of these experiments is the effect of HCl on the
reaction. Namely, when the reagent solution was prepared from AlCl and ethyl tartarate in
3
CH Cl without cooling, the reagent was much less active than the solution made under
2
2
cooling. Since the temperature of the solution was kept below 40 °C by vaporization of
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CH Cl , change in the composition of the Al species seemed unlikely. The difference,
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therefore, was considered to arise from the loss of HCl from the solution as bubbles when the
solution was made without cooling. Conversely, when CH Cl was saturated with HCl, the
2
2
reaction of 1 with AlCl was accelerated considerably. Thus, the necessity of HCl for the
3
reaction is evident, but, since HCl is released in the course of the reaction as described above,
the effect of HCl is noticeable only at the initial stage of the reaction.
Effect of Other Lewis Acids. We examined several other readily available Lewis acids for
this reaction as shown in Table 1.
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Table 1. Effects of Lewis Acids on Reaction with 1 in CH Cl at Room Temperature
2
2
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products, yield (%)
reaction
Lewis acid
entry
mol ratio to 1
time
1
2
4
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1
2
AlCl3
0.33
1.1
40 min
2.0
96.6
91.2
nd
nd
45 min
24 h
2.4
3
ZnCl2 0.5
~100
4
5
6
7
SiCl4 0.6
1.0
48 h
48 h
24 h
3 h
42.6
71.0
84.5
70.4
7.8
4.6
nd
nd
nd
1.2
1.0
6.3
SnCl4 0.3
15.8
8
9
0.3
0.6
24 h
24 h
20.7
15.2
64.9
54.4
tr
nd
tr
1
0
1.0
3 h
3 h
25.4
61.0
46.0
12.2
1
1
TiCl4
0.3
3.4
12
13
0.6
0.6
2 h
64.3
40.0
19.7
33.4
1.1
2.7
24 h
1
4
BF3
0.3
48 h
40.9
45.0
nd
1
1
1
5
6
7
0.6
24 h
24 h
48 h
2 h
56.1
50.1
20.8
3.7
32.7
44.5
68.0
90.7
nd
nd
nd
nd
1.1
0.3*
1.1*
1
8
*
: in HCl saturated CH Cl , nd: not detecte, tr: trace
2 2
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ZnCl formed the precipitate of a complex with 1 and no further changes were observed
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(entry 3). The reaction with SiCl was slow and incomplete after 24 h and gave low yields (at
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best 6%) of 2 (entries 3-6). The use of SnCl (0.3 eq) resulted in 64% yield of 2 after 24 h
4
(entry 6). Further extension of the reaction time or increased amount of SnCl resulted in
4
side reactions. Although BF ·OEt alone (1.1 eq) was inefficient, providing only 45% yield
3
2
1
of 2 with 50% recovery of 1 after 24 h (entry 16), the use of HCl-saturated CH Cl
4
2
2
remarkably accelerated the reaction and 2 was obtained in 91% yield in 2 h (entry 18). This
fact also suggests the participation of HCl in the condensation.
When TiCl was used, 1-TiCl adduct was formed as an orange-colored precipitate and its
4
4
conversion to 2 occurred only slowly, which did not go completion even after 24 h (0.6 eq
TiCl , 33% yield of 2 with 40% recovery of 1, entry 13). TiCl4, however, was found to be
4
useful in the preparation of the intermediate aldol 4. Though TiCl alone gave 4 as colorless
4
needles (mp 100-101 °C) in 3% yield as shown in Table 1, the yield of 4 could be increased
by utilizing a solution of Ti(OEt) Cl prepared by treating a solution of TiCl in
2
2
4
1,2-dichloroethane with 2 eq of EtOH (MeOH was not suitable because the bismethoxide
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precipitated out). In order to reduce the possible effect of HCl on elimination as described
above, the solution was purged with nitrogen. When 1 was added to the light yellow
bisethoxide solution, smooth reaction took place to give an equilibrium mixture of 1 and 4
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(almost 1 : 1 ratio upon TLC analysis) after 1 h. Since the acid sensitive nature of 4 for its
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reversion to 1 was recognized, aqueous workup was conducted under weakly basic
conditions and the product mixture was immediately separated by MPLC. Still, 4 was
obtained in only 8% yield (62% corrected for the recovery of 1). Although 4 is unstable in
1
6
solution, it is stable in crystalline state, allowing its X-ray crystallographic analysis. As
shown in Figure 1, 4 has a C=O ... H-O hydrogen bonded structure, which is the most stable
one by conformational searches and DFT calculations as detailed in Supporting Information.
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Figure 1. The X-ray Structure of Aldol 4.
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Selective Formation of Unconjugated Enones. In this cycloaldol condensation
unconjugated enone 2 is produced exclusively unlike the base-catalyzed condensation where
6
conjugated enone 3 is predominant. This is in accord with the thermodynamic stability
estimated by molecular calculations: 3 is more stable than 2 by 2.1 kcal/mol [Gaussian09,
B3LYP/6-311+G(2d,p), details in Supporting Information].
As a matter of fact, if the reaction conditions were not right (excess Lewis acids and longer
6
reaction times), conjugated 3 was isolated in small amounts as a low melting solid (reported
mp 44 or 54 °C). As shown by the fact that exclusive formation of 2 could be achieved in
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9% yield in short reaction times, 3 was not formed directly, but by acid-catalyzed
1
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isomerization of 2. The effectiveness of AlCl in the catalytic isomerization was low and only
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1
3
2% conversion was observed when a solution of 2 in CH Cl was stirred in the presence of
2 2
0 mol% AlCl at room temperature for 24 h. The most effective reagent for the
3
isomerization was found to be TiCl , which induced complete isomerization of 2 after 20 h,
4
providing 3 in 81% isolated yield.
Proposed Mechanism. Evidently, the conventional mechanism of aldol condesnation in
hydroxylic solvents cannot be applied for this reaction in the non-hydroxylic solvent CH Cl ,
2
The experimental facts described above led to a tentative mechanistic proposal shown in
Scheme 3.
2
_
_______________________________ _____________________________________
Scheme 3. Proposed Mechanism for the Condensation
-
Cl
HCl
Ph
Ph
Ph
H
Ph
H
Ph
O
Ph
O
Ph
+
O
O
Cl
O
O
Al
Al
O
Al
H
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Cl AlOH
2
A
B
C
D
_
____________________________________________________________________
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 2. DFT (B3LYP/LANL2DZ)-optimized Structure for the Al Aldolate 5.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Al
Hb
Cl
Ha
______________________________________________________________________
After complexation of AlCl with one of the carbonyl groups of 1 occurs to give A, an Al
3
enolate B is formed with releasing HCl. Then, the enolate moiety adds intramolecularly on
the other carbonyl group to form a five-membered ring. The process is apparently assisted by
coordination to the Al ion as an Al aldolate 5 (C). The structure of 5 is assumed to be similar
to that of 4 in Figure 1, showing the presence of C=O ... H-O hydrogen bonding. Actually,
the most favored configuration of 5 as optimized by DFT calculations (B3LYP/LANL2DZ)
from several possible starting structures was that shown in Figure 2 (see, Supporting
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Information). In the next elimination step, the two hydrogens, Ha and Hb, which are anti
periplanar to the C-O bond to be cleaved, are candidates for abstraction by a base (Figure 2),
leading to unconjugated or conjugated enone, respectively. However, Ha is less hindered and,
thus, the formation of unconjugated 2 is kinetically favored over the thermodynamically
more stable conjugated 3. Since involvement of HCl in the reaction is suggested as described
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
above, Cl is assumed to be the species attacking at Ha of the protonated Al aldolate as
depicted in C.
Extension to 6-Membered Ring Formation. This cyclocondensation reaction was
successfully extended to construct a 6-membered ring, though the reaction was considerably
slower. Thus, the reaction of 1,5-dibenzoylpentane 6 with 1/3 AlCl was almost complete
3
1
7
after 6 h to give unconjugated 7 (colorless needles, mp 107-108 °C) in yield of 90% without
formation of conjugated 8. Acceleration effect of HCl was also present and the reaction time
was shortened to 2 h to give 87% yield of 7. In contrast to the acid sensitive 5-membered
ring aldol 4, 6-membered ring aldol 9 (colorless plates, mp 127-128 °C), which has been
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
isolated in small amount by base-catalyzed aldol condensation), was readily prepared in
8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
4% yield by using TiCl . The structure of 9 is predicted to be that shown with a C=O ...
4
H-O hydrogen bond by molecular calculations (conformational searches and DFT
optimizations) which were remarkably successful in reproducing the X-ray structure of 4
(Supporting Information),
_________________________________________________________________
Scheme 4. The Cycloaldol Condensation to Form 6-Membered 7
Ph
1/3AlCl Ph
3
Ph
Ph
O
CH Cl
2
O
2
O
Ph
O
Ph
Ph
HO
O
Ph
6
7
8
9
_
________________________________________________________________
In contrast to the thermodynamically favored 5- and 6-membered ring formation, attempts
to form strained rings with 4, 7, and 8 members gave either only recovery of most of the
starting diones under the mild conditions as for the 5- and 6-membered rings, or complex
mixtures of products under forcing conditions (heating for a prolonged time).
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Intermolecular Condensation. Intermolecular self-condensation of acetophenone did not
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
proceed at all. However, the reaction of acetophenone with benzaldehyde proceeded at room
temperature in the presence of 0.36 eq of AlCl . After 20 h, the reaction gave a mixture
3
1
9
containing a chloride 10 (isolable in 15% yield), 11, and the starting materials (Scheme 5).
Due to the thermal instability of 10, distillation of the product mixture gave 11 in 61% yield.
The formation of chloride 10 is assumed to be formed by nucleophilic attack of a chloride ion
on the Al aldolate (E).
______________________________________________________________________
Scheme 5
-
Cl
1
/3AlCl3
Ph
Ph
PhCOCH +
3
OHCPh
PhCOCH CHClPh + PhCOCH=CHPh
2
2
CH Cl2
O
O
Al
Cl2
+
-
HCl
11
H
1
0
E
ꢀ
_
_____________________________________________________________________
Cyclization of PhCO(CH ) COR. In order to extend the scope of this condensation, we
2
4
studied the cases where one of the Ph groups of 1 was replaced with an alkyl group R (Me or
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Et) as shown in Scheme 6 and the results are collected in Table 2.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
_
_______________________________________________________________
Scheme 6. The reaction of PhCO(CH ) COR 12 with AlCl in CH Cl
2 4
3
2
2
R
R
Ph
Ph
R
(Ph)
1/3AlCl
3
+
+
+
O
CH Cl2
2
O
O
O
O
Ph
13
Ph
14
R
R
O
Ph
(
R)
15
16
1
2
Minor
Major
____________________________________________________________________
Table 2. Aldol condensation of PhCO(CH ) COR 12 with 1/3 AlCl in HCl-satd CH Cl
2
2
4
3
2
reation time
(h at RT )
yield (%)
13 + 14 (ratio)
entry
R
15
16
7
1.9 (56 : 44)
1
2
3
4
Me
Me
Me
Me
5
--
--
4.8
--
5
68.9 (61 : 39)
5
7
6
3.7 (65 : 35)
5.1 (67 : 33)
--
--
2.7
3.3
--
4.5
2
3
27.4 (60 : 40)
73.1 (79 : 21)
87.0 (80 : 20)
--
5
6
7
Et
Et
Et
4
5
--
--
2.5
--
--: A mixture of compounds in a trace amount.
_____________________________________________________________________
_
Since the reaction of PhCO(CH ) COR 12 (R = Et) with 1/3 eq AlCl in CH Cl was found to
2
2
4
3
2
be much slower than that of 1 or 6 in a preliminary experiment, the reaction was conducted in
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HCl-saturated CH Cl at room temperature. However, 12 did not disappear completely after
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
h by TLC analysis and then the mixture was stirred overnight (23 h). After aqueous workup,
the product mixture was separated by MPLC. The major product, eluted as overlapping
peaks after a small peak, was found to be a mixture of unconjugated 13 and conjugated 14,
1
13
both having a RCO group instead of PhCO, in a ratio of 60 : 40 by H and C NMR analysis
(entry 5). The poor selectivity for the unsubstituted 13 was considered to be due to the long
reaction time, because, if the reaction is slow, 13 formed in the course of the reaction would
be isomerized to 14 by remaining AlCl as discussed above. Therefore, the later reactions
3
were quenched after 4-5 h, when a small spot of 12 was still detected by TLC analysis. Then
the ratios were much improved to ca. 80 : 20 (entries 6 and 7), though complete control could
not be made. On the other hand, in the cases of 12 (R = Me) the ratios of unconjugated to
conjugated were lower and at best ca. 65 : 35 (entries 3 and 4) under the same reaction
conditions. Thus, in contrast to the almost complete selectivity for unonjugated 2 and 7, the
ratio for 13 decreased from Et to Me. These results may be understood in terms of decrease
in hindrance to the approach of a Cl ion to Hb in the Al aldolate 5 (Figure 2) when its PhCO
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
group is replaced with a less bulky EtCO or even smaller MeCO group.
As shown in Table 2, the other possible isomers with a PhCO group were also obtained in
small amounts (3% yields) as a peak preceding the major peaks of 13 and 14 in MPLC
separation. The only assignable compounds were 16 for R = Me and 15 for R = Et, because
the minor products were obtained in only small amounts and often as a mixture of several
compounds.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Since both PhCO- and RCO-containing isomers were obtained for PhCO(CH ) COR, this
2
4
aldol cyclization reaction may also be applied to bis(alkanoyl)butanes RCO(CH ) COR'.
4
2
Unfortunately, we have not confirmed this possibility as yet because of rather difficult
2
0
accessibility of 1,6-diones, particularly with dissimilar alkyl groups.
Autoxidation of the Unconjugated Enones. To be noted is the unexpectedly high
susceptibility of 13 and 14 toward oxygen. Though the enone mixtures (R = Me and Et)
were obtained as colorless mobile liquids right after separation, they turned to gel-like
materials after a day, if not stored with exclusion of air. The decomposed samples were
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1
complex mixtures without 13 and 14 as revealed by H NMR spectroscopy. In fact, at the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
beginning of the studies on the reaction of 12 we were not aware of this susceptibility
problem and puzzled by the low yield of 27% for 13 and 14 (entry 5).
Although 2 is much more stable than 13 and 14, its sample stored for several years was
found to contain a new compound together with brown decomposed matter. The structure of
this compound, isolated as colorless needles (mp 155-156 °C), was elucidated by X-ray
16 21
crystallography to be 2-phenyl-3-benzoylcyclopentanone 17 as shown in Figure 3.
2
2
Apparently 2 was oxidized with singlet oxygen formed by activation with light. As a
preliminary experiment, the solution of 2 in benzene was exposed to sunlight for 2 days until
most of 2 disappeared. Though the reaction was not efficient with formation of many
unidentifiable products, 17 was obtained in 44% yield.
_
_____________________________________________________________
Figure 3. X-ray Structure of Air-oxidation Product 17
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
O
O
Ph
1
7
_
_______________________________________________________________
CONCLUSION
The examination of the side product in the Friedel-Crafts reaction led to a new efficient
aldol condensation for cyclization to 5- and 6-membered rings under mild reaction
conditions as summarized in Table 3.
_
_______________________________________________________________
Table 3. Results for the AlCl -mediated* Aldol Cyclocondensation in CH Cl
2
3
2
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9
reation time
product(s) (yield)
entry
dione
(
at RT)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
0 min
2 (97%)
1
2
3
1
6
6
h (2 h**)
7
(90%, 87%**)
5
5
h**
h**
PhCO(CH ) COMe
2 4
13 + 14 (R = Me, 65 : 35) (74%)
13 + 14 (R = Et, 80 : 20) (87%)
4
PhCO(CH ) COEt
2
4
*
1/3 molar amount of AlCl per mole of the dione was used.
3
**In HCl-saturated CH Cl .
2
2
_____________________________________________________________________
Though the reaction is not catalytic, it requires inexpensive AlCl in only 1/3 molar amount.
3
Particularly noteworthy is the fact that thermodynamically less stable unconjugated enones 2
and 7 were formed selectively unlike the base-catalyzed aldol condensation.
EXPERIMENTAL SECTION
Starting materials.
1
,4-Dibenzoylbutane 1 and 1,5-dibenzoylpentane 6. Prepared according to the OS
5
procedure by using adipic acid and pimelic acid, respectively, and recrystallized from EtOH.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1-Phenylheptane-1,6-dione (PhCO(CH ) COMe). Prepared by Raney Ni reduction of
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22
-benzoyl-5-acetylthiophene, colorless needles mp 45-46 °C (lit. mp 44-45°C). H NMR
1
2
(270 MHz, CDCl3) δ 7.99-7.92 (m, 2H), 7.60-7.50 (m, 1H), 7.50-7.42 (m, 2H), 2.99 (t, J =
1
3
6
.9 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 2.15 (s, 3H), 1.82-1.60 (m, 4H). C NMR (67.8 MHz,
CDCl3) δ 208.7, 199.9, 136.8, 132.9, 128.5, 127.9, 43.4, 38.2, 29.8, 23.6, 23.3.
1-Phenyloctane-1,6-dione (PhCO(CH ) COEt): Prepared by Raney Ni reduction of
2
4
2
-benzoyl-5-propanoylthiophene, distilled at 100 °C/0.2 mmHg, colorless platelets, mp
2
33-34 °C (lit. mp 84 °C). Anal. Calcd. for C H O : C, 77.03; H, 8.31. Found C 76.92
3
1
4
18
2
1
H 8.28. H NMR (270 MHz, CDCl ) 7.99-7.91 (m, 2H), 7.60-7.51 (m, 1H), 7.51-7.42 (m,
δ
3
2
4
1
H), 2.99 (t,
J
= 6.9 Hz, 2H), 2.47 (t,
J
= 6.9 Hz, 2H), 2.44 (q,
J
= 7.3 Hz, 2H), 1.81-1.60 (m,
211.3, 199.9, 136.8, 132.9,
1
3
= 7.3 Hz, 3H). C NMR (67.8 MHz, CDCl )
H), 1.05 (t,
J
δ
3
28.5, 127.9, 42.1, 38.2, 35.8, 23.6, 23.4, 7.7.
1
-Phenyl-5-benzoylcyclopentene 2. The best procedure: To a solution of 1,
4-dibenzoylbutane 1 (799.0 mg, 3.0 mmol) in 10 mL CH Cl cooled in an ice bath was added
2
2
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9
powdered AlCl (144 mg 1.08 mmol) in one portion. After stirring for 10 min all AlCl3
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
dissolved to form a pale yellow solution. After 1.5 h only a small spot for 2 appeared on
TLC analysis. The bath was removed and the reaction mixture was allowed to reach room
temperature. After 10 min a white granular precipitate was formed. After 40 min the
precipitate began to assume a greenish yellow tinge and TLC indicated the disappearance of
1. Then, the reaction was quenched by addition of water and extracted with chloroform.
After drying (MgSO ), the extract was filtered through a short column of silica gel,
4
concentrated, and separated by MPLC (silica gel, 4:1:0.25 hexane-chloroform-EtOAc) to
6a
give 719.3 mg (96.6% yield) of 2 as colorless needles (hexane), mp 99-100 °C (lit. mp
9
8 °C). From the later fractions 1 (15.8 mg, 2.0%) was recovered, making the yield of 2,
corrected for the recovery, 98.6%. Anal. Calcd. for C H O: C, 87.06; H, 6.49. Found: C,
8
1
16
1
6.99; H, 6.47. H NMR (270 MHz, CDCl )
8
δ
8.06 (d,
J
= 6.9 Hz, 2H), 7.63-7.55 (m, 1H),
3
7.55-7.43 (m, 2H), 7.36-7.12 (m, 5H), 6.47 (m, 1H), 4.95 (m, 1H), 2.78-2.45 (m, 3H), and
13
.19-2.05 (m, 1H). C NMR (67.8 MHz, CDCl ) 201.1, 141.6, 136.5, 135.6, 133.1, 130.1,
2
δ
3
128.7, 128.4, 127.1, 125.8, 53.5, 32.4, 30.1.
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Large scale preparation: To 1, 4-dibenzoylbutane 1 (7.99 g, 30 mmol) in 50 mL CH Cl2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
cooled in an ice water bath was added AlCl (powdered, 1450 mg, 10.9 mmol). After 10 min
3
the yellow solution was allowed to warm to room temperature. After 5 min, the solution
became reddish in color and a white precipitate started to form. After 30 min 1 disappeared
as judged by TLC (SiO , 4:1 hexane-EtOAc). The reaction was quenched by addition of
2
water and the product was extracted with chloroform (2x). The combined extract was dried
(MgSO ), passed through a short column of silica gel, and evaporated. The residue was
4
crystallized from hexane-acetone to form colorless needles (4.149 g), The mother liquor was
separated by MPLC (There was no peak for 1 and, therefore, simple recrystallization is
sufficient.) to give 2.615 g, making total of 6.764 g (90.8%).
Isomerization of 2 to 3 with TiCl . To a solution of 2 (300 mg, 1.21 mmol) in CH Cl (5
4
2
2
mL) was added TiCl (50 ꢁL, 0.46 mmol, 0.38 eq) in one portion at room temperature.
4
Immediate deep brown coloration occurred. After 20 h, the dark brown solution was
quenched with water and extracted with chloroform (3x). A brown extract was dried
(MgSO ), filtered through a short column of silica gel, and subjected to MPLC separation to
4
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2
3
4
5
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7
8
9
give a pale brown liquid (solidified on cooling, 244 mg, 81.3%), which was identical with 3
10
11
12
13
14
15
16
17
18
19
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22
23
24
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28
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36
37
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6c 1
prepared by base-catalyzed reaction of 1. H NMR (270 MHz, CDCl3)
δ
7.74 (d, J = 6.9 Hz,
2
H), 7.41-7.31 (m, 1H), 7.30-7.19 (m, 2H), 7.19-6.99 (m, 5H), 3.07-2.87 (m, 4H), and 2.20
1
2.04 (m, 2H). C NMR (67.8 MHz, CDCl3) 198.4, 146.1, 137.4, 136.5, 135.9, 132.7,
3
-
δ
1
29.2, 128.1, 127.9, 127.8, 127.6, 37.9, 37.6, 22.5.
1-Phenyl-2-benzoylcyclopentanol 4: Addition of EtOH (360 ꢁL, 6.2 mmol) to a solution of
TiCl (340 ꢁL, 3.1 mmol, 1.03 eq) in 5 mL of ClCH CH Cl at room temperature resulted in
4
2 2
an immediate exothermic reaction with evolution of HCl. The HCl dissolved in the solution
was purged by bubbling nitrogen for 5 min. To the light yellow solution was added 1 (799.0
mg, 3.0 mmol) in 10 mL of ClCH CH Cl. The reaction mixture was stirred for 1 h at room
2
2
temperature and then cooled in an ice-water bath for 1 h before quenching with a cold
saturated NaHCO solution. The product was extracted with chloroform and the extract was
3
dried (Na SO instead of acidic MgSO ) and passed through a short column of silica gel and
2
4
4
evaporated. The crystalline residue was recrystallized from hexane-chloroform to remove
most of 1 (286.2 mg). The mother liquor was immediately separated by MPLC (SiO2,
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2
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
hexane-chloroform-EtOAc 3:1:0.25) to give 2 (7.7 mg, 1.0%), 4 (65.0 mg, 8.1%), and 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(408.4 mg, total of 694.6 mg, 86.9%). Recrystallization of 4 from hexane gave colorless
needles, mp 100-101 °C. Anal. Calcd. for C H O : C, 81.17; H, 6.81. Found C, 81.20; H,
18 18 2
1
.78. H NMR (270 MHz, CDCl ) 7.86 (d, J = 6.9 Hz, 2H), 7.61-7.36 (m, 5H), 7.33-7.23
6
δ
3
(m, 2H), 7.23-7.10 (m, 1H), 5.40 (d, J =1.0 Hz, 1H, OH, exchangeable with D O), 4.09 (dd,
2
1
3
= 10.2, 10.6 Hz, 1H), 2.42-1.89 (m, 6H). C NMR (67.8 MHz, CDCl3) 205.4, 145.2,
J
1
δ
36.8, 133.7, 128.6, 128.3, 128.1, 126.7, 124.9, 84.5, 54.6, 42.7, 30.4, 22.7.
1-Phenyl-6-benzoycyclohexene 7: To 1,5-dibenzoylpentane 6 (841.1 mg, 3.0 mmol) in 10
mL of HCl-saturated CH Cl cooled in an ice bath was added powdered AlCl (143 mg 1.07
2
2
3
mmol, 0.357 eq). After 5 min all AlCl was dissolved to give a faintly yellow solution with
3
slight turbidity, Then the bath was removed and the reaction was allowed to reach room
temperature. After 2 h the reaction was complete judging from TLC. Then the reaction was
quenched with water. and the product was extracted with chloroform. The extract was
washed with water, dried (MgSO ), passed through a short column of silica gel. After
4
evaporation of the solution, the residue was separated by MPLC (SiO2,
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7
8
9
hexane-chloroform-EtOAc 3:1:0.25) to give 7 as colorless needles (681.5 mg, 86.6%), mp
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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46
47
48
49
50
51
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53
54
55
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57
58
59
60
16b
07-108 °C (lit. mp 107-108 °C). H NMR (270 MHz, CDCl )
1
1
7
J
δ
8.01 (d, J = 7.3 Hz, 2H),
3
.60-7.51 (m, 1H), 7.51-7.40 (m, 2H), 7.30-7.08 (m, 5H), 6.39 (t,
J
= 3.7 Hz, 1H), 4.72 (br t,
1
= 4.9 Hz, 1H), 2.45-2.20 (m, 2H), 2.20-1.95 (m, 2H), 1.76-1.61 (m, 2H). C NMR (67.8
3
MHz, CDCl3)
δ
201.0, 141.6, 136.1, 135.1, 132.9, 128.7, 128.5, 128.3, 126.7, 125.3, 45.1,
27.3, 25.6, 18.7.
16b
-Phenyl-2-benzoylcyclohexene 8: Prepared in 28.4% yield according to Gao et al. for
1
6b
1
comparison purpose. Colorless plates (hexane-acetone), mp 79-80 °C (lit. 78-79 °C). H
NMR (270 MHz, CDCl3)
δ
7.68 (d, J = 7.3 Hz, 2H), 7.35-7.27 (m, 1H), 7.25-7.16 (m, 2H),
1
3
7
2
1
.11-7.94 (m, 5H), 2.56-2.40 (m, 4H), 1.98-1.71(m, 4H).
C NMR (67.8 MHz, CDCl3)
δ
01.3, 141.7, 139.8, 136.7, 135.2, 132.3, 129.1, 127.9, 127.8, 127.1, 30.8, 28.0, 22.8, 22.0.
-Phenyl-2-benzoylcyclohexanol 9: To 1,5-dibenzoylpentane 6 (841.1 mg, 3.0 mmo) in 10
mL of HCl-saturated CH Cl , To this solution was added TiCl (150 ꢁL, 1.36 mmol, 0.45 eq)
2
2
4
at room temperature. The immediate orange coloration faded in 5 min to deep yellow. After
20 min TLC showed considerable formation of 9 (ca. 1:1 area ratio as compared to 6). After
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