Carboannulation reactions of cyclohexenone derivatives: Synthesis of functionalized α-tetralones

Article abstract of DOI:10.1055/s-0029-1217159

The base-mediated cyclocondensation reactions of 3- (ethoxycarbonylmethylene)- and 3-(cyanomethylene)cyclohexenones with ethoxymethylenemalonate derivatives lead to two functionalized α-tetralones with selectivities which depend on the stoichiometric rati

Full text of DOI:10.1055/s-0029-1217159

LETTER
1405
Carboannulation Reactions of Cyclohexenone Derivatives: Synthesis of
Functionalized a-Tetralones
S
a
ynthesis of Functiona
o
lized
a
-Tetra
h
lones amed Tabouazat,a,b Ahmed El Louzi,a Mohammed Ahmar,b Bernard Cazes*b
b
Received 10 December 2008
ously considered by Wiemann and Cyrot who studied the
magnesium oxide catalyzed condensation in the vapor
phase between isophorone 1 and conjugated aldehydes or
ketones (Scheme 1).18 They obtained differently alkyl-
Abstract: The base-mediated cyclocondensation reactions of 3-
(ethoxycarbonylmethylene)- and 3-(cyanomethylene)cyclohexen-
ones with ethoxymethylenemalonate derivatives lead to two func-
tionalized a-tetralones with selectivities which depend on the
stoichiometric ratio of the reactants. a-Tetralones are selectively substituted a-tetralones 2 and 3. However, the selectivi-
obtained when excess Michael acceptor is used.
ties and yields were modest. Later, Loupy, Fkih–Tétouani
and co-workers described a straightforward access to aryl
substituted a-tetralones 4 from isophorone and chalcones
via Michael addition and subsequent Robinson annulation
reactions followed by a base-induced oxidative dehydro-
genation (Scheme 1).19
Key words: carboannulation, Michael additions, condensation,
carbocycles, a-tetralones.
The a-tetralone skeleton is the basic core of numerous nat-
ural products such as (–)-arnottin II,1 (–)-regiolone,2
berchemiaside A and B,3 or pyrolone A and B.4 Some of
them have been demonstrated to present interesting bio-
logic activities. Xylarenone and hypoxylonol B, both iso-
lated from xylariaceous fungus PSU-A80, displayed good
radical scavenging potency,5 and daldinone C and D are
cytotoxic against SW1116 cells.6 The a-tetralone struc-
ture is also the basic unit of numerous synthetic bioactive
compounds such as the antitumor 2-arylidene-1-
tetralones7 and QF0104B,8 an 4-amino-1-tetralone antag-
onist of dopamine D2 and serotonin 5-HT2 receptors.
Thus, a-tetralones still remain prime targets and have be-
come valuable synthetic intermediates for the preparation
of numerous biologically active substances and their ana-
logues.9 In industry, a-tetralones are important in different
chemical areas such as agrochemistry (pest control as
antifeedants against spruce budworm10) or fragrances.11
R1
R1
O
R1
O
O
R2
+
base
O
R2
2
3
Ar
O
Ar
1
O
Ph
base
Ph
4
Scheme 1 Carboannulation reactions of isophorone 1 with enones
Consequently, we expected that the base-mediated cyclo-
condensation of 3-methylcyclohexenones
I
with
ethoxymethylenemalonate derivatives 5 might lead to
new functionalized a-tetralones II and/or III (Scheme 2),
and now report herein our preliminary results.
However, synthetic routes to a-tetralones are scarce. The
most classic access to these compounds is based on the
intramolecular Friedel–Crafts reaction of arylbutyric
acids and its variants.12 Other routes include Diels–Alder
reactions between cyclohexenones and various dienes,13
the tandem Michael addition–Dieckmann condensation,14
the aryne condensation of a,b-unsaturated ketone eno-
lates,15 the aluminum- and nickel-mediated cyclotrimer-
ization of cyclohexenone with alkynes16 or the radical
cyclization of g-phenacyl xanthates to olefins.17
Our first experiments demonstrated that the base-
catalyzed reactions (20 mol% piperidine or 10 mol%
DMAP) of isophorone 1 with diethyl ethoxymethylene-
malonate 5a gave no cyclocondensation product of type II
or III in refluxing ethanol or even at 180 °C without sol-
vent.20 However, when the reaction was carried out in re-
fluxing ethanol in the presence of 2 equivalents of sodium
hydride, we could isolate the keto-malonate 6 in 20%
yield (Scheme 3).
With the aim of developing an alternative approach to
a-tetralones, we focused our attention on the possible
carboannulation reactions of 3-methylcyclohexenones
with activated olefins. This methodology has been previ-
So, in order to favor the enolization of the 3-methylcyclo-
hexenone structure and of the presumed reaction interme-
diates, it seemed advantageous to start from activated
substrates such as 3-(ethoxycarbonyl)methylene21 or 3-
cyanomethylenecyclohexenones 7a–c.22 This turned out
SYNLETT 2009, No. 9, pp 1405–1408
x
x.
x
x.
2
0
0
9
Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217159; Art ID: D40908ST
© Georg Thieme Verlag Stuttgart · New York

1406
M. Tabouazat et al.
LETTER
EtO2C
CO2Et
OEt
O
OH
Z
O
O
CO2Et
CO2Et
OH
5a
+
R
R
R
base
Z
Z
I
(Z = H or EWG)
II
III
Scheme 2 New approach to a-tetralones II and III
to be fruitful since we observed the formation of two a- in refluxing THF led to no cyclocondensation product
tetralones 8 and/or 9 (Table 1).
(Table 1, entry 1). However, in DMF it afforded a-tetra-
lone 8a in a low 9% yield (Table 1, entry 2). The DMAP-
catalyzed reaction of 7a with 5a (1 equiv) at 180 °C with-
The reaction of cyclohexenone 7a with diethyl ethoxy-
methylenemalonate 5a in the presence of sodium hydride
Table 1 Cyclocondensations of 3-Methylcyclohexenones 7a–c with Ethoxymethylenemalonate 5a
O
O
O
OH
EtO2C
CO2Et
OEt
CO2Et
CO2Et
base
+
+
R
R
R
R
R
R
Z
Z
Z
7a R = Me Z = CO2Et
7b R = H Z = CO2Et
7c R = Me Z = CN
5a
(n equiv)
8a–c
9a–c
Entry
Cyclohexenone
7a–c
5a
(n equiv)
Base
Solvent Temp
(°C)
Time (h) Products Yield of 8 Yield of 9
8 and 9 (%)a
(%)a
O
1
1.2
NaH (1.1 equiv)
NaH (2 equiv)
THF
66
9
n.r.
CO2Et
7a
7a
2
3
4
5
6
1.2
1
DMF
85
9
1
1
1
1
8a
9
7a
7a
7a
7a
O
DMAP (10 mol%)
DMAP (10 mol%)
–
–
–
–
180
180
180
180
8a, 9a
9a
62
2
2
43
53
62
2
NaH (1 equiv) + DMAP (10 mol%)
NaH (1 equiv) + DMAP (10 mol%)
8a, 9a
9a
15
4
7
1
DMAP (10 mol%)
–
180
1
8b, 9b 30
10
CO2Et
7b
7b
8
9
2
2
4
DMAP (10 mol%)
–
–
–
180
180
180
1
1
1
9b
9b
9b
41
50
60
7b
7b
NaH (1 equiv) + DMAP (10 mol%)
NaH (1 equiv) + DMAP (10 mol%)
10
O
11
2
DMAP (10 mol%)
–
–
145
145
1
1
9c
9c
30
45
CN
7c
7c
12
2
NaH (1 equiv) + DMAP (10 mol%)
a Refers to yield of isolated product after flash chromatography.
Synlett 2009, No. 9, 1405–1408 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized a-Tetralones
1407
perature, because of presumed unwanted polycondensa-
tion reactions of the comparatively less sterically
demanding cyano group (Table 1, entries 11 and 12). a-
Tetralone 9c was then obtained in an optimal 45% yield.
EtO2C
CO2Et
OEt
O
O
5a (2 equiv)
CO2Et
CO2Et
This carboannulation reaction of activated 3-methyl-
enecyclohexenones 7a–c was extended to the use of a-
cyano-b-ethoxyacrylate 5b as Michael acceptor. Thus,
several reactions of cyclohexenone 7a with 5b were car-
ried out under similar conditions which are summarized in
Scheme 5. They all gave a-tetralone 13 as a single product
which was obtained in an optimized 65% yield when four
equivalents of acrylate 5b were used.
6
1
piperidine (20 mol%), EtOH, reflux, 3 h n.r.
DMAP (10 mol%), 180 °C, 2 h
NaH (2 equiv), EtOH, reflux, 2 h
n.r.
20%
Scheme 3 Reactions of isophorone 1 with 5a
out any solvent gave a-tetralones 8a (62%) and 9a (2%;
Table 1, entry 3). The former product 8a was one of the
expected cyclocondensation products (type II a-tetra-
lone). The latter product 9a seemed to result from the
cyclocondensation of cyclohexenone 7a with two mole-
cules of the activated olefin 5a. A plausible mechanism
depicted in Scheme 4 would involve the formation of
intermediates 10–12, the latter 12 giving access to a-tetra-
lone 9a via elimination of the anion of tri(ethoxycarbon-
yl)methane. A similar reaction using two equivalents of
5a gave only a-tetralone 9a (Table 1, entry 4). By using a
more basic system (1 equiv NaH and 10 mol% DMAP) we
observed the formation of a-tetralone 9a as the major cy-
clocondensation product (53% yield; Table 1, entry 5).23
The yield of 9a was optimized to 62% by carrying out the
reaction with four equivalents of 5a (Table 1, entry 6).
EtO2C
CN
O
O
OEt
CN
5b
CO2Et
CO2Et
13
7a
5b (2 equiv), DMAP (10 mol%), 180 °C, 3 h
5b (2 equiv), NaH (1 equiv), DMAP (10 mol%), 180 °C, 1 h
5b (4 equiv), NaH (1 equiv) DMAP (10 mol%), 180 °C, 1 h
20%
62%
65%
Scheme 5 Cyclocondensation reactions of cyclohexenone 7a with
5b
In summary, we have shown that the cyclocondensation
of activated 3-methylenecyclohexenones 7a–c with
ethoxymethylenemalonate derivatives 5 gives a-tetra-
lones 8 and 9 with selectivities which mainly depend on
the number of equivalents of the derivative 5. This opens
an attractive route to polyfunctionalized a-tetralones 9
which are obtained in one step as single products when ex-
cess of the Michael acceptor 5 is used. Further study on
the cyclocondensation reactions of cyclohexenone deriv-
atives with other activated olefins is in progress in our lab-
oratory.
Analogous results were obtained for the reactions of
cyclohexenone 7b with ethoxymethylenemalonate 5a
(Table 1, entries 7–10). Thus, both a-tetralones 8b and 9b
were obtained for the reaction of 7b with one equivalent
of 5a in the presence of 10 mol% of DMAP (Table 1, en-
try 7). Use of increased amounts of ethoxymethylene-
malonate 5a provided only a-tetralone 9b (Table 1,
entries 8–10) which was obtained in an optimal 60% yield
(entry 10).
The cyclocondensation reactions of 3-cyanomethylene-
cyclohexenone 7c were performed at a lower 145 °C tem-
CO2Et
OEt
EtO2C
5a
O
O
OH
Z
O
EtO2C
CO2Et
CO2Et
base
– EtO–
hydrolysis
– EtO–
Z
8
10
Z
7a (Z = CO2Et)
5a
– EtOH
O
O
O
EtO2C
O
Z
CO2Et
–
OEt
Z
–
– C(CO2Et)3
Z
Z
–
Z
Z
Z
Z
Z
11
12
9
Scheme 4 Mechanism of formation of a-tetralones 8 and 9
Synlett 2009, No. 9, 1405–1408 © Thieme Stuttgart · New York

1408
M. Tabouazat et al.
LETTER
(16) Mori, N.; Ikeda, S.-I.; Sato, Y. J. Am. Chem. Soc. 1999, 121,
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(17) Liard, A.; Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z.
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Acknowledgment
One of us (M.T.) thanks Région Rhône-Alpes for a doctoral fel-
lowship (MIRA program).
(18) (a) Cyrot, E.; Wiemann, J. Tetrahedron Lett. 1971, 12, 53.
(b) Cyrot, E. Ann. Chim. (Paris) 1971, 6, 413; Chem. Abstr.
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References and Notes
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M.; Fkih-Tétouani, S. Eur. J. Org. Chem. 2002, 2518.
(20) For few reports on such carboannulation reactions giving
access to condensed structures, see: (a) Deady, L. W.;
Werden, D. M. J. Org. Chem. 1987, 52, 3930. (b) Radl, S.;
Kovarova, L. Collect. Czech. Chem. Commun. 1992, 57,
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(23) Typical Experimental Procedure (Table 1, entry 5) –
Synthesis of Diethyl 5,6,7,8-Tetrahydro-7,7-dimethyl-4-
hydroxy-5-oxo-1,3-naphthalenedicarboxylate (8a) and
Diethyl 5,6,7,8-Tetrahydro-7,7-dimethyl-5-oxo-1,3-
naphthalenedicarboxylate (9a)
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Sodium hydride (50% oil, 48 mg, 1 mmol) was added to a
mixture of ester 7a (211 mg, 1 mmol), DMAP (12 mg, 0.1
mmol) and diethyl ethoxymethylenemalonate (433 mg, 2
mmol) stirred at 0 °C under nitrogen. The reaction mixture
immediately became yellow with release of hydrogen. After
stirring for 10 min at r.t., the mixture was heated at 180 °C
for 1 h. After cooling at r.t., the mixture was diluted with
CH2Cl2 and hydrolyzed with sat. aq NH4Cl. Workup gave an
oil which was purified by flash chromatography (SiO2, PE–
Et2O, 80:20) to afford a-tetralone 8a (50 mg, 15%) and
a-tetralone 9a (170 mg, 53%).
Compound 8a: mp 62–64 °C. TLC (SiO2, PE–Et2O, 50:50):
Rf = 0.39. IR (KBr film): 2950, 1717, 1701, 1635, 1605,
1443, 1228, 1208, 1191, 1150, 867, 774, 683 cm–1. 1H NMR
(300 MHz, CDCl3): d = 14.18 (s, 1 H, OH), 8.62 (s, 1 H, H-
2), 4.32 (q, 3J = 7.1 Hz, 4 H, 2 × OCH2CH3), 3.25 (s, 2 H,
H-8), 2.55 (s, 2 H, H-6), 1.38 (t, 3J = 7.1 Hz, 6H, 2 ×
OCH2CH3), 1.06 [s, 6 H, gem-(CH3)2]. 13C NMR (75.5 MHz,
CDCl3): d = 206.1 (C=O), 166.1 (OC=O), 166.0 (OC=O),
165.0 (C-4), 151.9 (C-8a), 141.4 (C-2), 120.7 (C-1), 117.9
(C-4a), 117.6 (C-3), 61.7 (OCH2CH3), 61.6 (OCH2CH3),
52.0 (C-6), 42.2 (C-8), 33.1 (C-7), 28.5 [gem-(CH3)2], 14.7
(OCH2CH3), 14.6 (OCH2CH3). ESI-HRMS: m/z calcd for
C18H22O6 [MNa+]: 357.1314; found: 357.1320.
Compound 9a: mp 78 °C. TLC (SiO2, PE–Et2O, 50:50):
Rf = 0.56. IR (KBr film): 2977, 2958, 2870, 1715, 1691,
1605, 1466, 1449, 1418, 1389, 1225, 1195, 1148, 1022, 755
cm–1. 1H NMR (300 MHz, CDCl3): d = 8.81 (d, 3J = 1.8 Hz,
1 H, H-4), 8.68 (d, 3J = 1.8 Hz, 1 H, H-2), 4.32 (q, 3J = 7.1
Hz, 4 H, 2 × OCH2CH3), 3.24 (s, 2 H, H-8), 2.54 (s, 2 H, H-
6), 1.42 (t, 3J = 7.1 Hz, 3 H, OCH2CH3), 1.40 (t, 3J = 7.1 Hz,
3 H, OCH2CH3), 1.07 [s, 6 H, gem-(CH3)2]. 13C NMR (75.5
MHz, CDCl3): d = 197.5 (C=O), 166.6 (OC=O), 166.5
(OC=O), 148.4 (C-8a), 136.3 (C-4a), 133.6 (C-2), 131.9
(C-4), 131.7 (C-1), 129.2 (C-3), 61.9 (2 × OCH2CH3), 52.0
(C-6), 42.0 (C-8), 33.3 (C-7), 29.0 [gem-(CH3)2], 14.7
(OCH2CH3), 14.6 (OCH2CH3). ESI-HRMS: m/z calcd for
C18H22O5 [MNa+]: 341.1359; found: 341.1357.
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