Synthesis of tetrahydroanthracen-9-ones by the domino aldol condensation/Diels-Alder cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2012.04.053

A facile protocol toward several substituted 3-aryl-3,4,4a,10-tetrahydro- 2H-anthracen-9-ones 1 starting with substituted 2-allylbenzaldehydes 2 was described. The overall synthetic process was carried out by the domino aldol condensation/Diels-Alder cycloaddition of skeleton 2 with substituted cinnamaldehydes 3 in an alkalic aqueous-methanolic solution followed by base-induced double migration of the resulting cycloadducts. Skeleton 2 was prepared from isovanillin (4) in moderate yield in five-steps via the known procedures with the synthetic sequence of O-allylation, Claisen rearrangement, O-methylation, Grignard methylation, and PCC-mediated oxidation.

Full text of DOI:10.1016/j.tetlet.2012.04.053

Tetrahedron Letters 53 (2012) 3173–3177
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of tetrahydroanthracen-9-ones by the domino aldol
condensation/Diels–Alder cycloaddition
⇑
Meng-Yang Chang , Ming-Hao Wu
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile protocol toward several substituted 3-aryl-3,4,4a,10-tetrahydro-2H-anthracen-9-ones 1 starting
with substituted 2-allylbenzaldehydes 2 was described. The overall synthetic process was carried out by
the domino aldol condensation/Diels–Alder cycloaddition of skeleton 2 with substituted cinnamaldehy-
des 3 in an alkalic aqueous-methanolic solution followed by base-induced double migration of the result-
ing cycloadducts. Skeleton 2 was prepared from isovanillin (4) in moderate yield in five-steps via the
known procedures with the synthetic sequence of O-allylation, Claisen rearrangement, O-methylation,
Grignard methylation, and PCC-mediated oxidation.
Received 8 March 2012
Revised 5 April 2012
Accepted 12 April 2012
Available online 21 April 2012
Keywords:
Claisen rearrangement
Aldol condensation
Ó 2012 Elsevier Ltd. All rights reserved.
Diels–Alder cycloaddition
One-pot combination
Tetrahydroanthracen-9-ones
Introduction
achieving skeleton 1 via a two-component combination of skele-
tons 2 and 3 under the alkaline aqueous-methanolic condition
The Diels–Alder cycloaddition is a useful synthetic tool for con-
structing six-member ring skeletons; it has been successfully ap-
plied to different synthetic fields.1 Most notably, it has been
found that the Diels–Alder reaction is accelerated in a diluted
aqueous solution.2 The related studies on the Diels–Alder reaction
in aqueous solvent present an intriguing history.3,4 In continuing
our efforts in exploring new applications of one-pot combination,5
we wish to develop an environmentally-friendly route of one-pot
domino aldol condensation/Diels–Alder cycloaddition for the syn-
thesis of 3-aryl-3,4,4a,10-tetrahydro-2H-anthracen-9-ones 1 with
substituted 2-allylacetophenones 2 and trans-cinnamaldehydes 3,
under the catalyst-free aqueous condition.
followed by the base-induced double migration of the resulting
cycloadducts. The retrosynthetic analysis of skeleton 1 is shown
in Scheme 1.
Results and discussion
As the key precursors of skeleton 1, 2-allylbenzaldehydes 5a–5d
were prepared from the commercially available isovanillin (4) in
three-steps, according to the standard procedure, with a reaction
sequence of O-allylation, Claisen rearrangement, and O-methyla-
tion.7a As shown in Scheme 2, treatment of isovanillin (4) with
three allyl bromides 6 (6a, R = H; 6b, R = Me; 6c, R = Ph) in the
Molecules with the tricyclic fused carbon skeleton system of
tetrahydroanthracenone are found in nature.6 This wide range of
interesting biological activities has prompted studies on the devel-
opment of efficient methodologies for preparing the benzannulat-
ed tricycle with decalinenone moiety. Based on the literature
reports,7 isovanillin (4) should be chosen as the reasonable starting
material for generating skeleton 1. Recently, isovanillin (4) has pro-
ven to be a useful building block in the preparation of many benz-
annulated heterocycles via some unique approaches.8 While a
great number of synthetic routes have been developed, a one-pot
efficient methodology for constructing novel skeleton is needed.
Herein, we want to describe a facile and efficient route toward
O
O
aldol condensation
R3
H
9
R3
+
O
R
3
MeO
R4
MeO
R4
3
R2
R1
1
R
R2
R1
Diels-Alder cycloaddition
2
Grignard methylation
and oxidation
O-allylation,
R3
CHO
CHO
Claisen rearrangement
and O-methylation
R
MeO
MeO
R2
R1
4
5
OH
⇑
Corresponding author. Tel.: +886 7 3121101x2220.
E-mail address: mychang@kmu.edu.tw (M.-Y. Chang).
Scheme 1. Retrosynthetic analysis of skeleton 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.053

3174
M.-Y. Chang, M.-H. Wu / Tetrahedron Letters 53 (2012) 3173–3177
of the resulting cycloadducts in 83% yield.11 Among the one-pot
CHO
Br
CHO
6, K CO
2
3
reaction procedure, the brilliant reddish color of the reaction
mixture was suddenly generated; it then slowly disappeared. The
stepwise synthetic procedure for the formation of tricyclic tetrahy-
droanthracenone skeleton can be monitored by reaction color or
TLC until the one-pot reaction is completed. Under the abovemen-
tioned condition, fourteen compounds 1a–1n with different elec-
tron-withdrawing or electron-donating aryl substituents were
provided with 63–90% yields, as shown in Table 1.11 Compounds
1a–1d or 1i–1n (R1 = H) with two products of exo and endo diaste-
reoisomers could not be separated by flash column chromatogra-
phy; their related isomer ratios were confirmed on the basis of
1H NMR analysis of vinyl proton (for 1a–1d or 1n) or methyl pro-
tons (R1 group for 1e–1h or R group for 1i–1m). Fortunately, the
further crystal structures of compound 1b with two isomers were
isolated and determined using single-crystal X-ray analytic tech-
nology (Fig. 1).12 Therefore, in the case of compounds 1e–1h
(R1 = Me), only one diastereoisomer was eluted, corresponding to
the steric effects; no other isomer was detected. The structural
assignment of compound 1g was determined using single-crystal
X-ray analysis (Fig. 2).12
R
MeO
MeO
(R =, 6a, H; 6b, Me; 6c, Ph)
OH
O
R
4
7a, R = H (85%)
7b, R = Me (80%)
7c, R = Ph (73%)
CHO
MeO
CHO
1) decalin, reflux
2) MeI, K CO
+
R
MeO
MeO
2
3
(yield of two-steps)
MeO
R
1
5a, R = H (52%)
5b, R = Me (69%)
5c, R = Me (58%)
5d, R = Ph (66%)
1
1
O
O
MeO
1) MeMgBr, THF
+
R
2) PCC, DCM
(yield of two-steps)
MeO
MeO
MeO
R
1
2a, R = H (75%)
2c, R = Me (77%)
2d, R = Ph (69%)
The stereospecific outcome of four compounds 1e–1h may be
influenced by the steric effect, and the methyl group (R1) should
be oriented in an equatorial position in the transition structure I,
as shown in (Eq. 2). We envisioned that the methyl group of dieno-
phile is a key factor to generate the sole exo product with three ste-
reochemical centers during the one-pot domino procedure of aldol
condensation, Diels–Alder cycloaddition, and olefinic migration.
Equation 2: The stereochemical assignment of compounds
1e–1h.
1
2b, R = Me (80%)
1
Scheme 2. Synthetic routes of substituted 2-allylacetophenones 2.
presence of K2CO3 in acetone at reflux for 8 h afforded compounds
7a–7c with good yields. Under the general Claisen rearrangement
condition (in decalin, 190–200 °C, 8 h)9 and O-methylation condi-
tion (in refluxing acetone, 8 h), compounds 5a, 5c, and 5d were
provided as the sole isomers from compounds 7a–7c with modest
yields of two-steps. By controlling the heating time of compound
7b at 3 or 6 h, a compound with one rearrangement and its dou-
ble-rearranged isomer were isolated in nearly a ratio of almost 3/
1 or 1/3 under the abovementioned boiling condition. After O-
methylation of the two resulting rearranged products, compounds
5b and 5c were yielded in different ratios from adjusting the reac-
tion time. Furthermore, compounds 2a–2d were provided in mod-
erate yields from two-steps of Grignard methylation of 5a–5d with
methylmagnesium bromide followed by the oxidation of the
resulting secondary alcohols with PCC. With compounds 2a–2d
in hand, the investigation of the domino aldol reaction/Diels–Alder
reaction continued.10
MeO
MeO
OMe
OMe
O
O
2b
+
H
ð2Þ
1e-1h
Me
equatorial
Me
3a-3d
H
H
H
H
R4
R4
I
With the results in hand, two analogues 2e and 2f were synthe-
sized as the next precursor for exploring the one-pot application.
As shown in Scheme 3, compound 2e (R5 = Ph) or 2f (R5 = Me)
was yielded via the two-step route of Grignard addition of com-
pound 5a with benzylmagnesium bromide or ethylmagnesium
bromide, followed by the oxidation of the resulting secondary alco-
hols with PCC, respectively. However, when the NaOH-mediated
reaction of compound 2e or 2f was treated with compound 3b or
3c, the aldol product 8a, 8b, or 8c with the mixture of E and Z iso-
mers was only isolated with 80%, 84% or 77% yield. Attempts to
form the cycloadduct failed under a number of conditions (e.g.,
prolonged time, reaction vessel, reagent equivalent, etc) due to
the steric hindrance of the phenyl or methyl substituent (R5 group)
of diene moiety. Furthermore, attempts to expand the one-pot pro-
tocol to the reaction of compound 5a with crotonaldehyde 3f
(R4 = Me, an aliphatic substituent) are unsuccessful as compound
3f was unstable under this basic condition.13
In the following investigation, the tricyclic benzofused skeleton
of tetrahydrofluorene 9 was chosen as the next target (Scheme 4).
Using the three-step protocol, a reasonable precursor 11 with
diene and dienophile groups was easily synthesized via the Wittig
reaction of compound 5a with Ph3P@CHCO2Et, DIBALH-mediated
reduction, and olefination of compound 10, with an overall 58%
yield of three-steps. Unfortunately, attempts to realize compound
9 by the ring-closure of compound 11 were unsuccessful in the
sealed tube due to the ring strain of the five-member ring.
Equation 1: The reaction procedure of compound 1a.
O
2a
+
1a
ð1Þ
3a
MeO
MeO
(reddish intermediate)
A
The syntheses of 3-aryl-3,4,4a,10-tetrahydro-2H-anthracen-9-
ones 1a–1n are summarized in Table 1 via the facile one-pot
domino aldol condensation/Diels–Alder cycloaddition combination
of substituted 2-allylacetophenones 2a–2d and trans-cinnamalde-
hydes 3a–3e. The conjugated dienone A was first provided by
NaOH-mediated aldol condensation of model substrate 2a with
cinnamaldehyde 3a (1.05 equiv) in the co-solvent of MeOH and
water (v/v = 2/1) at reflux (Eq. 1). Then, compound 1a with deca-
linenone skeleton was generated from the subsequent intramolec-
ular ring-closure of the resulting product with the dienone motif
and 2-allyl group, followed by the base-induced double migration

M.-Y. Chang, M.-H. Wu / Tetrahedron Letters 53 (2012) 3173–3177
3175
Table 1
Synthesis of dimethoxy-3-aryl-3,4,4a,10-tetrahydro-2H-anthracen-9-ones 1a,b,c
O
O
R3
H
R3
NaOH (aq), MeOH
R
+
O
MeO
MeO
R4
R2 R1
R4
R2 R1
R
3a, R4 = Ph
2a, R2 = OMe, R = R1 = R3 = H
1
3b, R4 = 4-F-Ph
2b, R2 = OMe, R1 = Me, R = R3 = H
2c, R3 = OMe, R = Me, R1 = R2 = H
2d, R3 = OMe, R = Ph, R1 = R2 = H
3c, R4 = 4-MeO-Ph
3d, R4 = 4-Me2N-Ph
3e, R4 = 2-MeO-Ph
Entry
Substrates 2/3
Product 1/yield (ratio)
Entry
Substrates 2/3
Product 1/yield (ratio)
O
O
1
2a/3a
2a/3b
2a/3c
2a/3d
8
2b/3d
2c/3a
2c/3b
2c/3c
MeO
MeO
H
H
Me
OMe
MeO
NMe
2
1a / 83% (2.2 : 3.2)
1h / 84% (sole)
O
O
MeO
MeO
2
3
4
9
MeO
MeO
MeO
H
H
OMe
Me
F
1i / 63% (2.7 : 3.4)
1b / 85% (2.4 : 3.5)
O
O
MeO
MeO
10
H
H
OMe
Me
OMe
F
1c / 90% (2.3 : 3.0)
1j / 66% (2.5 : 3.0)
O
O
MeO
MeO
11
H
H
OMe
Me
NMe
OMe
2
1k / 70% (1.9 : 3.0)
1d / 88% (2.8 : 3.4)
O
O
MeO
MeO
5
2b/3a
12
2c/3d
MeO
H
H
Me
MeO
Me
NMe
2
1e / 80% (sole)
1l / 73% (3.1 : 4.0)
O
O
MeO
MeO
OMe
6
2b/3b
13
2c/3e
MeO
MeO
H
H
Me
MeO
Me
F
1m / 80% (3.5 : 4.1)
1f / 72% (sole)
O
O
MeO
MeO
H
7
2b/3c
14
2d/3a
H
Me
MeO
OMe
1g / 82% (sole)
1n / 63% (3.6 : 4.2)
a
b
c
For the best one-pot reaction conditions: skeleton 2 (1.0 equiv), skeleton 3 (1.05 equiv), NaOH (2.5 equiv), MeOH/H2O (v/v = 2/1, 15 mL), reflux, 2 h.
The isolated products were >95% pure as determined by 1H NMR analysis.
The ratio of the related isomers was determined by the 1H NMR analysis of vinyl proton (for 1a–1d or 1n) or methyl protons (R1 group for 1e–1h or R group for 1i–1m).

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M.-Y. Chang, M.-H. Wu / Tetrahedron Letters 53 (2012) 3173–3177
CHO
Ph P=CHCO Et
1) Ph P=CHCO Et
3
2
3
2
5a
MeO
2) DIBALH, THF
toluene, reflux
OMe
10 (66%)
CO Et
2
CO Et
2
MeO
MeO
11 (88%)
9 (No detected)
OMe
OMe
Scheme 4. Synthesis of compound 11.
one-pot combination-promoted aldol condensation/Diels–Alder
cycloaddition/double bond migration under the alkaline aqueous-
methanolic condition. Further studies on the one-pot combination
are actively underway in laboratories.
Acknowledgment
Figure 1. X-ray structures of compound 1b and its isomer.
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-
037-006-MY3).
Supplementary data
Supplementary data (scanned photocopies of 1H and 13C NMR
(CDCl3) spectral data) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
053.
References and notes
1. For recent reviews on the Diels–Alder reaction, see: (a) Corey, E. J. Angew.
Chem., Int. Ed. 2002, 41, 1650; (b) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668; c Tietze, L. F.;
Kettschau, G. In Topics in Current Chemistry; Springer: Berlin, 1997; Vol. 189, (d)
Boger, D. L.; Trost, B. M.; Flemming, I.; Paquette, L. A. In Comprehensive Organic
Synthesis; Pergamon: Oxford, 1991; Vol. 5, pp 451–512; (e) Fringuelli, F.;
Taticchi, A. Dienes in the Diels–Alder Reaction; Wiley: New York, 1990.
2. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159; (b) Breslow, R.; Maitra, U.; Rideout,
D. Tetrahedron Lett. 1901, 1983, 24; (c) Blokzijl, W.; Blandamer, M. J.; Engberts,
J. B. F. N. J. Am. Chem. Soc. 1991, 113, 4241; (d) Otto, S.; Engberts, J. B. F. N. Pure
Appl. Chem. 2000, 72, 1365.
3. (a) Grieco, P. A. Organic Synthesis in Water; Blackie: London, 1998; (b) Li, C.-J.
Chem. Rev. 1993, 93, 2023; (c) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751.
4. Breslow, R.; Rideout, D. J. Am. Chem. Soc. 1980, 102, 7816.
Figure 2. X-ray structure of compound 1g.
5. Chang, M.-Y.; Lee, N.-C. Synlett 2012, 23, 867.
6. (a) Singh, V.; Iyer, S. R.; Pal, S. Tetrahedron 2005, 61, 9197; (b) Silveira, C. C.;
Braga, A. L.; Kaufman, T. S.; Lenardao, E. J. Tetrahedron 2004, 60, 8295.
7. (a) Tsai, J.-C.; Li, S.-R.; Chen, L.-Y.; Chen, P. Y.; Jhong, J. Y.; Shu, C.-J.; Lo, Y.-F.; Lin,
C.-N.; Wang, E.-C. J. Chin. Chem. Soc. 2008, 55, 1317; (b) Chen, L.-Y.; Li, S.-R.;
Chen, P.-Y.; Tsai, I.-L.; Hsu, C.-L.; Lin, H.-P.; Wang, T.-P.; Wang, E.-C. Tetrahedron
Lett. 2009, 50, 5748; (c) Li, S.-R.; Chen, P.-Y.; Chen, P.-Y.; Lo, Y.-F.; Tsai, I.-L.;
Wang, E.-C. Tetrahedron Lett. 2009, 50, 2121.
8. For galanthamine, see: (a) Chandrasekhar, S.; Basu, D.; Sailu, M.; Kotamraju, S.
Tetrahedron Lett. 2009, 50, 4882; For pulverolide, see: (b) Yang, W.; Liu, J.;
Zhang, H. Tetrahedron Lett. 2010, 51, 4874; For benzofurans, see: (c) van Otterlo,
W. A. L.; Morgans, G. L.; Madeley, L. G.; Kuzvidza, S.; Moleele, S. S.; Thornton,
N.; de Koning, C. B. Tetrahedron 2005, 61, 7746; For benzosuberenes, see: (d)
Chen, Z.; O’Donnell, C. J.; Maderna, A. Tetrahedron Lett. 2012, 53, 64; (e) de
Koning, C. B.; Giles, R. G. F.; Green, I. R.; Jahed, N. M. Tetrahedron Lett. 2002, 43,
4199; For benzopyrans, see: (f) van Otterlo, W. A. L.; Ngidi, E. L. N.; Kuzvidza, S.;
Morgans, G. L.; Moleele, S. S.; de Koning, C. B. Tetrahedron 2005, 61, 9996.
9. For reviews on the Claisen rearrangement, see: (a) Castro, A. M. Chem. Rev.
2004, 104, 2939; (b) Nubbemeyer, U. Synthesis 2003, 961; (c) Hiersemann, M.;
Abraham, L. Eur. J. Org. Chem. 2002, 1461; (d) Chai, Y.; Hong, S.; Lindsay, H. A.;
MaFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905.
R
4
O
O
1) PhCH MgBr
2
NaOH,
R
5
or EtMgBr, THF
3b or 3c
5a
R
5
2) PCC, DCM
MeO
MeO
OMe
OMe
2e, R = Ph (70%)
2f, R = Me (53%)
R
= Ph
5
5
5
8a, R = 4-F-Ph (80%)
4
4
8b, R = 4-MeO-Ph (84%)
R
= Me
5
8c, R = 4-F-Ph (77%)
4
Scheme 3. Reaction of compound 2e or 2f.
10. For intramolecular Diels–Alder reaction, see: (a) He, Y.; Funk, R. L. Org. Lett.
2006, 8, 3689; (b) Zou, Y.; Che, Q.; Snider, B. B. Org. Lett. 2006, 8, 5605; (c) Port,
M.; Lett, R. Tetrahedron Lett. 2006, 47, 4671; (d) Shintani, R.; Duan, W.-L.; Park,
S.; Hayashi, T. Chem. Commun. 2006, 3646; (e) Chung, S.-I.; Seo, J.; Cho, C.-G. J.
Org. Chem. 2006, 71, 6701.
Conclusion
A synthetic methodology for producing a series of methoxy tet-
rahydroanthracenones 1 has been successfully presented from
substituted 2-allylacetophenones 2 and cinnamaldehydes 3 using
11. A representative procedure of skeleton 1 is as follows: A solution of NaOH (40 mg,
1.0 mmol) in water (5 mL) was added to a solution of skeleton 2 (0.4 mmol) in

M.-Y. Chang, M.-H. Wu / Tetrahedron Letters 53 (2012) 3173–3177
3177
MeOH (10 mL). Skeleton 3 (0.42 mmol) was added to the reaction mixture at rt.
The reaction mixture was stirred at reflux. The overall synthetic procedure had
to be monitored by TLC until the reaction was completed within a period of 2 h.
10% HCl (1 mL) was added to the reaction mixture and the solvent was
concentrated. The residue was diluted with water (10 mL) and the mixture was
extracted with EtOAc (3 ꢀ 20 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated to yield crude compound.
Purification on silica gel (hexanes/EtOAc) afforded skeleton 1. For compound
1g: Yield 82% (124 mg); White solid; Mp = 175–177 °C (recrystallized from
hexanes and EtOAc); HRMS (ESI, M++1) calcd for C24H27O4 379.1909, found
379.1916; 1H NMR (400 MHz): d 7.88 (d, J = 8.8 Hz, 1H), 7.47–7.45 (m, 1H),
7.13–7.10 (m, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.82–6.79 (m, 2H), 3.91 (s, 3H), 3.84
(s, 3H), 3.76 (s, 3H), 3.31–3.28 (m, 1H), 3.21–3.19 (m, 1H), 2.75–2.67 (m, 2H),
2.57–2.50 (m, 1H), 2.10–2.03 (m, 1H), 2.00–1.96 (m, 1H), 1.12 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz): d 185.36, 157.85, 156.65, 144.20, 143.91, 138.25,
137.05, 135.00, 127.85 (2ꢀ), 125.84, 125.54, 113.65 (2ꢀ), 110.28, 60.89, 55.72,
55.17, 35.60, 35.00, 33.77, 31.88, 31.34, 17.76; Anal. Calcd for C24H26O4 : C,
76.17; H, 6.92. Found: C, 76.40; H, 7.13. Single-crystal X-Ray diagram: crystal
of compound 1g was grown by slow diffusion of EtOAc into a solution of
compound 1g in CH2Cl2 to yield colorless prism. The compound crystallizes in
the monoclinic crystal system, space group P 1 21/c 1, a = 12.9405(16) Å,
b = 7.3738(8) Å, c = 20.306(3) Å, V = 1909.8(4) Å3, Z = 4, dcalcd = 1.316 g/cm3,
F(000) = 808, 2h range 1.60–26.41°,
R indices (all data) R1 = 0.0834,
wR2 = 0.2078.
12. CCDC 867572 (1b) and 867571 (1g) contain the supplementary
crystallographic data for this Letter. This data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: 44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).
13. Guthrie, J. P. Can. J. Chem. 1974, 52, 2037.