Modular synthesis of tetrahydrofluorenones from 5-alkylidene Meldrum's acids

Article abstract of DOI:10.1021/jo0618876

The one-pot synthesis of tetrahydrofluorenones, the core 6-5-6 tricyclic structural motif found in norditerpenoid natural products, from alkylidene Meldrum's acids via thermal Diels-Alder/BF₃·OEt ₂-catalyzed Friedel-Crafts acylation

Full text of DOI:10.1021/jo0618876

Modular Synthesis of Tetrahydrofluorenones
from 5-Alkylidene Meldrum’s Acids
Eric Fillion,* Aaron M. Dumas, and Sylvia A. Hogg
Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario N2L 3G1, Canada
FIGURE 1. Hexahydrofluorene and tetrahydrofluorene natural prod-
ucts.
efillion@uwaterloo.ca
members of the taiwaniaquinoid family via Nazarov cyclization.5
Our own work used a unique trimethylsilyl triflate (TMSOTf)-
promoted tandem intramolecular Friedel-Crafts acylation/
carbonyl R-tert-alkylation reaction in the first total synthesis
of taiwaniaquinol B (3), a highly substituted hexahydrofluo-
renone.6,7 However, for the purpose of SAR studies, a rapid
and modular method to assemble the core 6-5-6 tricyclic
skeleton is desirable. Herein, we describe such an approach
based on the thermal Diels-Alder reaction of 5-alkylidene
Meldrum’s acids followed by in situ BF3‚OEt2-catalyzed
Friedel-Crafts acylation (FC) reaction of the resulting adduct
(Scheme 1).8 (3)
ReceiVed September 12, 2006
Our group has established that Meldrum’s acid derivatives
are powerful and convenient acylating agents in metal triflate-
catalyzed intramolecular FC acylations.9 Thermal Diels-Alder
The one-pot synthesis of tetrahydrofluorenones, the core
6-5-6 tricyclic structural motif found in norditerpenoid natural
products, from alkylidene Meldrum’s acids via thermal
Diels-Alder/BF3‚OEt2-catalyzed Friedel-Crafts acylation
reactions is described. A series of tetrahydrofluorenones was
assembled in good yields, and the Diels-Alder/Friedel-
Crafts acylation protocol allowed modification of the sub-
stitution within the rings.
(5) Liang, G.; Xu, Y.; Seiple, I. B.; Trauner, D. J. Am. Chem. Soc. 2006,
128, 11022-11023.
(6) Fillion, E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127, 13144-13145.
(7) Taiwaniaquinol B isolation and characterization: Lin, W.-H.; Fang,
J.-M.; Cheng, Y.-S. Phytochemistry 1995, 40, 871-873.
(8) For an example of a Lewis acid-promoted intramolecular Diels-
Alder/Friedel-Crafts alkylation sequence: Varseev, G. N.; Maier, M. E.
Angew. Chem., Int. Ed. 2006, 45, 4767-4771.
(9) (a) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J. M. J. Org. Chem.
2005, 70, 1316-1327. (b) Fillion, E.; Fishlock, D. Org. Lett. 2003, 5, 4653-
4656.
Several structurally related diterpenoids and norditerpenoids
have recently been isolated and identified as possible aromatase
inhibitors for the treatment of estrogen-dependent cancers
(Figure 1).1 As such, the total synthesis of these tricyclic natural
products has been an area of considerable recent research. An
intramolecular Heck reaction was key in the preparation of (()-
dichroanal B (1), (()-dichroanone (2), (()-taiwaniaquinones
D and H, and (()-taiwaniaquinol B (3) by Banerjee.2 A similar
strategy was used by Node to accomplish the total synthesis of
(()-dichroanal B (1).3 Stoltz disclosed the first enantioselective
synthesis of (+)-dichroanone (2) using an elegant asymmetric
Tsuji allylation.4 Very recently, Trauner prepared numerous
(10) (a) Andreev, G. N.; Shul’ts, E. E.; Volkov, A. A.; Shakirov, M.
M.; Bagryyanskaya, I. Yu.; Gatilov, Yu. V.; Tolstikov, G. A. Russ. J. Org.
Chem. 2004, 40, 854-865. (b) Ramachary, D. B.; Barbas, C. F., III Chem.s
Eur. J. 2004, 10, 5323-5331. (c) Ramachary, D. B.; Chowdari, N. S.;
Barbas, C. F., III Angew. Chem., Int. Ed. 2003, 42, 4233-4237. (d) Zitsane,
D. R.; Ravinya, I. T.; Riikure, I. A.; Tetere, Z. F.; Gudrinietse, E. Yu.;
Kalei, U. O. Russ. J. Org. Chem. 1999, 35, 1457-1460. (e) Benvegnu, T.;
Martelli, J.; Gre´e, R.; Toupet, L. Tetrahedron Lett. 1990, 31, 3145-3148.
(f) Kraus, G. A.; Liras, S. Tetrahedron Lett. 1989, 30, 1907-1908. (g)
Eberle, M.; Lawton, R. G. HelV. Chim. Acta 1988, 71, 1974-1982. (h)
Kraus, G. A.; Krolski, M. E. J. Org. Chem. 1986, 51, 3347-3350. (i) Kunz,
F. J.; Polansky, O. E. Monatsh. Chem. 1969, 100, 920-927. Diels-Alder
with methylene Meldrum’s acid: (j) White, J. D.; Wang, G.; Quaranta, L.
Org. Lett. 2003, 5, 4983-4986. (k) Zia-Ebrahimi, M.; Huffman, G. W.
Synthesis 1996, 215-218. (l) Tolstikov, G. A.; Tolstikova, T. G.; Shultz,
EÄ . EÄ .; Mukhametyanova, T. Sh.; Popov, V. G.; Davydova, V. A.; Lazareva,
D. N.; Zarudii, F. S.; Spirikhin, L. V.; Chertanova, L. F.; Gazikasheva, A.
A. Pharm. Chem. J. 1992, 26, 834-842. (m) Buzinkai, J. F.; Hrubowchak,
D. M.; Smith, F. X. Tetrahedron Lett. 1985, 26, 3195-3198. (n) Brown,
R. F. C.; Eastwood, F. W.; McMullen, G. L. Aust. J. Chem. 1977, 30, 179-
193. (o) Brown, R. F. C.; Eastwood, F. W.; McMullen, G. L. J. Am. Chem.
Soc. 1976, 98, 7421-7422. Diels-Alder forming two contiguous all-carbon
quaternary centers: (p) Benzing, M.; Vilsmaier, E.; Martini, H.; Michels,
G.; Anders, E. Chem. Ber. 1989, 122, 1277-1284. (q) Bell, V. L.; Holmes,
A. B.; Hsu, S.-Y.; Mock, G. A.; Raphael, R. A. J. Chem. Soc., Perkin Trans.
1 1986, 1507-1514. (r) Bell, V. L.; Holmes, A. B. Synth. Commun. 1982,
12, 323-326. (s) Mock, G. A.; Holmes, A. B.; Raphael, R. A. Tetrahedron
Lett. 1977, 4539-4540. (t) Dauben, W. G.; Kozikowski, A. P.; Zimmerman,
W. T. Tetrahedron Lett. 1975, 515-517. Diels-Alder with photoenols of
o-methylbenzaldehyde and related compounds: (u) Tsuno, T.; Sugiyama,
K. In Trends in Heterocyclic Chemistry; Ramachandran, U., Ed.; Research
Trends: Trivandrum, India, 2001; Vol. 7, pp 91-106. (v) Tsuno, T.;
Sugiyama, K. Heterocycles 1991, 32, 1989-2004.
(1) (a) Chang, C.-I.; Chang, J.-Y.; Kuo, C.-C.; Pan, W.-Y.; Kuo, Y.-H.
Planta Med. 2005, 71, 72-76. (b) Chang, C.-I.; Chien, S.-C.; Lee, S.-M.;
Kuo, Y.-H. Chem. Pharm. Bull. 2003, 51, 1420-1422. (c) Minami, T.;
Iwamoto, M.; Ohtsu, H.; Ohishi, H.; Tanaka, R.; Yoshitake, A. Planta Med.
2002, 68, 742-745. (d) Iwamoto, M.; Ohtsu, H.; Tokuda, H.; Nishino, H.;
Matsunaga, S.; Tanaka, R. Bioorg. Med. Chem. 2001, 9, 1911-1921. (e)
Ohtsu, H.; Iwamoto, M.; Ohishi, H.; Matsunaga, S.; Tanaka, R. Tetrahedron
Lett. 1999, 40, 6419-6422. (f) Kawazoe, K.; Yamamoto, M.; Takaishi,
Y.; Honda, G.; Fujita, T.; Sezik, E.; Yesilada, E. Phytochemistry 1999, 50,
493-497. (g) Lin, W.-H.; Fang, J.-M.; Cheng, Y.-S. Phytochemistry 1996,
42, 1657-1663.
(2) (a) Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee, A. Kr.
J. Org. Chem. 2006, 71, 2787-2796. (b) Banerjee, M.; Makhopadhyay,
R.; Achari, B.; Banerjee, A. Kr. Org. Lett. 2003, 5, 3931-3933.
(3) Planas, L.; Mogi, M.; Takita, H.; Kajimoto, T.; Node, M. J. Org.
Chem. 2006, 71, 2896-2898.
(4) McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738-
7739.
10.1021/jo0618876 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/18/2006
J. Org. Chem. 2006, 71, 9899-9902
9899

TABLE 1. One-Pot Tetrahydrofluorenone Synthesis
SCHEME 1. One-Pot Tetrahydrofluorenone Synthesis:
General Strategy
reactions of 5-alkylidene Meldrum’s acids as dienophiles occur
readily, as well.10,11
We began our investigation using butadiene generated in situ
from butadiene sulfone 5a and Meldrum’s acid 4a. The Diels-
Alder reaction of alkylidene 4a bearing an electron-rich 3,5-
dimethoxybenzene moiety is unprecedented, but 4a was ratio-
nally selected to facilitate the search for effective catalyst and
reaction conditions in the subsequent FC acylation reaction.
Spiro Meldrum’s acid 6a was isolated in 82% yield from 10
equiv of 5a and 5-[(3,5-dimethoxyphenyl)methylene] Meldrum’s
acid (4a) after 16 h at 100 °C in CH3NO2 in a sealed tube
(Scheme 2). The reaction conditions were then applied to 2,3-
dimethylbutadiene (5b) and 4a. In this case, only 1.1 equiv of
the diene was necessary to furnish a quantitative yield of the
[4 + 2] cycloadduct 6b (Scheme 2).
a 5 equiv of diene was used. b Adduct 7c and its regioisomer were
obtained in a >20:1 ratio.
amined, and BF3‚OEt2 (10 mol %) in (CH2Cl)2 at 100 °C was
found to provide tricycle 7b in 91% yield from 6b (Scheme
2).13
With this set of optimal conditions in hand, the development
of a one-pot protocol was explored. Carrying out the Diels-
Alder reaction in (CH2Cl)2 at 100 °C for 16 h followed by the
addition of BF3‚OEt2 (10 mol %) generated 7b in 86% yield
(Table 1, entry 2) from 4a and 5b.14 Similar results were
obtained with 5a and 4a (entry 1). Excellent regioselectivity
was observed when 4a was reacted with isoprene 5c (entry 3).15
SCHEME 2. Initial Studies
The π-nucleophilicity of the aromatic moiety and its impact
on the FC acylation were investigated for a series of alkylidene
Meldrum’s acids using 2,3-dimethylbutadiene (5b). As shown
in Table 2, the electron-rich 3,4-dimethoxyphenyl and 3,4,5-
trimethoxyphenyl substituted alkylidenes 4b and 4c provided
excellent yields of tetrahydrofluorenones 7d and 7e, respectively
(Table 2, entries 1 and 2). Alkylidene 4d furnished a mixture
of regioisomers 7f and 7g. Of note, 5-(phenylmethylene) and
5-[(4-methoxyphenyl)methylene] Meldrum’s acids 4h and 4i
were ineffective in the one-pot transformation; both gave good
conversion to the Diels-Alder cycloadduct, but the FC acylation
failed.
Complex benzocyclic ketones were generated from alkylidene
Meldrum’s acids 4a and 4e-g and o-quinodimethane generated
in situ from sultine 5d (Table 3). In order for SO2 to escape,
the one-pot process was carried out in an open vessel.16 As a
result, longer reaction times were required for the FC acylations
to go to completion. The products were formed in good to
excellent yields, and the process was compatible with an aryl
The Friedel-Crafts acylation of 6a was studied initially.
Tetrahydrofluorenone 7a was obtained in 79% yield after 2.5 h
at 100 °C when catalyzed by Sc(OTf)3 in CH3NO2, which were
the optimal conditions in our previous FC acylations.9 Triflic
acid (10 mol %) provided a 49% yield, and TMSOTf (10 mol
%) yielded 85% of 7a (Scheme 2).12 However, when the FC
acylation conditions were applied to 6b, decomposition was
observed, which was attributed to the high π-nucleophilicity of
the tetrasubstituted alkene. The reaction conditions were reex-
(13) BF3‚OEt2 (10 mol %) in MeNO2 gave 7b after 10 min, which was
contaminated with numerous alkene isomers. Sc(OTf)3, Cu(OTf)2, Al(OTf)3,
and Sn(OTf)2 gave unsactifactory results. Mg(OTf)2 was effective under
stoichiometric conditions. Zn(OTf)2 in (CH2Cl)2 cleanly converted 6b to
7b. CH3CN, toluene, and benzene were unsuitable solvents for the FC
acylation reactions.
(14) The development of a BF3‚OEt2-catalyzed Diels-Alder/Friedel-
Crafts acylation protocol was unsuccessful. In most cases, the alkylidene
Meldrum’s acid was recovered and the diene polymerized.
(15) Analysis of the 1H NMR of the crude revealed a 9:1 ratio of
regioisomers after the initial Diels-Alder reaction.
(11) Functionalized tetrahydrofluorenones are generally prepared via
multistep sequences: Lomberget, T.; Bentz, E.; Bouyssi, D.; Balme, G.
Org. Lett. 2003, 5, 2055-2057 and references therein
(12) The one-pot procedure furnished tricycle 7a in 79% yield when 5a
(10 equiv) was heated in the presence of 4a in CH3NO2 for 16 h followed
by the addition of TMSOTf (10 mol %).
(16) In a closed vessel, o-quinodimethane was rapidly trapped by SO2
to generate a cyclic sulfone, and a large excess of sultine was required for
the cycloaddition to go to completion, making purification of the FC
acylation product tedious.
9900 J. Org. Chem., Vol. 71, No. 26, 2006

TABLE 2. Scope of the Alkylidene Meldrum’s Acids
SCHEME 3. Reaction of 1-((E)-Buta-1,3-dienyl)benzene
with 4a
of the cycloadducts in the FC acylation allowed for the isolation
of tricycle 7l in 53% yield as a single diastereomer from 4a
and 5e; unreacted endo-adduct 6c was obtained in 29% yield
(Scheme 3).18 On the basis of the X-ray structure of 6c, it seems
likely that the two aryl groups flanking the Meldrum’s acid
moiety encumber Lewis acid complexation, preventing activa-
tion of the electrophile.
The steric argument was tested by the reaction of trans-
piperylene 5f with 4a, which gave a similar exo/endo ratio, but
the difference in reactivity in the FC acylation step was far less
pronounced. After treatment with BF3‚OEt2 (10 mol %), a small
amount of unreacted endo-isomer 6d was recovered, along with
a 69:31 mixture of 7m/7n in 83% yield (Scheme 4).19
a Compounds 7f and 7g were obtained in a 67:33 ratio.
TABLE 3. Reaction of Alkylidene Meldrum’s Acids with
o-quinodimethane
SCHEME 4. Reaction of trans-Piperylene with 4a
In order to make later derivatization as diverse as possible,
the placement of the alkene in the tetrahydrofluorenone was
modified by simply incorporating the most reactive π-nucleo-
phile in the diene (Table 4). Reacting diene 5g with alkylidene
4h provided tricycle 7o in 58% yield, in addition to a 20% yield
of endo cycloadduct 6e.20 The one-pot process was then applied
to a variety of alkylidene Meldrum’s acids 4h-k as depicted
in Table 4. Arylbutadiene 5h reacted similarly with 4h, yielding
7s as a single regioisomer (entry 5).
a FC acylation reaction times are in parentheses. b 2.0 equiv of sultine
was used.
(17) Once again, 5-(phenylmethylene) Meldrum’s acid 4h underwent
[4 + 2] cycloaddition but the acylation failed, likely due to the low
π-nucleophilicity of the phenyl moiety.
(18) The exo and endo cycloadducts were separated and their respective
structures determined by nOe’s experiments. The structure of the endo
adduct 6c was further confirmed by X-ray crystallography. See the
Supporting Information.
bromide (entry 3). 5-(2-Naphthylmethylene) Meldrum’s acid
(4g) furnished pentacycle 7k in 71% yield (entry 4).17
(19) The diastereomers were separated by flash chromatography for
characterization; see Supporting Information.
(20) Preliminary experiments have shown that the conversion of the endo
adducts to the corresponding tetrahydrofluorenone is slow. For example, a
50% conversion for 6e after 8 h at 100 °C was observed.
Functionalization of the cyclohexene moiety was then inves-
tigated by reacting alkylidene Meldrum’s acid 4a with 1-((E)-
buta-1,3-dienyl)benzene (5e). The stereoselectivity of the Diels-
Alder reaction was modest, but the large reactivity difference
J. Org. Chem, Vol. 71, No. 26, 2006 9901

TABLE 4. Reactivity of 1-Arylbutadienes 5g and 5h
was washed into the tube with (CH2Cl)2 (0.2 M relative to the
alkylidene). The tube was sealed, heated in an oil bath at 100 °C
for 16 h, and removed from the bath to cool to rt. A 50 µL aliquot
was removed and concentrated to determine conversion and endo/
1
exo ratio (where applicable) of the Diels-Alder reaction by H
NMR. A solution of BF3‚OEt2 in (CH2Cl)2 (0.1 equiv/100 µL) was
washed into the tube with sufficient (CH2Cl)2 to bring the total
concentration to 0.15 M. The tube was reheated to 100 °C for 30
min and cooled to rt, and the contents were transferred into a
separatory funnel with CH2Cl2 (Caution: A small amount of
pressure builds up in the tube during the FC acylation as CO2 is
eVolVed.) The organic phase was washed with brine, dried with
MgSO4, filtered, and concentrated. Purification by flash chroma-
tography eluting with EtOAc/hexanes solvent mixtures yielded the
product.
yield of (7) yield of (6)
entry
Ar (4)
Ph (4h)
4-MeOPh (4i) 5g
diene (5) exo/endoa
(%)b
(%)b
Synthesis of Benzotetrahydrofluorenones 7h-k (Procedure
B). A flame-dried round-bottom flask equipped with a condenser
under N2 with an outlet for SO2 was charged with alkylidene
Meldrum’s acid (200 mg, 1.0 equiv). Sultine 5d22 (1.1 equiv) was
weighed into a vial and rinsed into the flask with (CH2Cl)2 (0.2 M
relative to the alkylidene). The contents were heated to reflux for
16 h and cooled to rt before removing a 50 µL aliquot to check the
1
2
3
4
5
5g
66:34
69:31
65:35
64:36
65:35
58 (7o)
42 (7p)
55 (7q)
51 (7r)
45 (7s)
20 (6e)
24 (6f)
23 (6g)
24 (6h)
21 (6i)
3-ClPh (4j)
4-ClPh (4k)
4h
5g
5g
5h
a Determined by analysis of the 1H NMR of the crude Diels-Alder
reaction mixture. b R1 and R2 identical to 5g or 5h, respectively.
1
reaction progress by H NMR. A solution of BF3‚OEt2 (CH2Cl)2
in (0.1 equiv/100 µL) was added to the flask, as well as enough
(CH2Cl)2 to bring the total volume to 0.15 M. The reaction was
heated to reflux for the indicated times and then cooled to rt. The
remainder of the procedure is identical to procedure A.
A common feature of these natural products is the gem-
dimethyl group (Figure 1), which can be introduced using
alkylidene 4l. An 81% yield of tricycle 7t was obtained with
electron-rich diene 5h, but the less reactive diene 5g provided
a 26% yield of 7u (Scheme 5).21
Synthesis of Tetrahydrofluorenones 7t-u (Procedure C). An
oven-dried Schlenk tube cooled under N2 was charged with 5-(1-
methylethylidene) Meldrum’s acid 4l (100 mg, 0.54 mmol, 1.0
equiv). The arylbutadiene (2.2-3.0 equiv) was weighed into a vial,
then transferred into the tube with (CH2Cl)2 (0.4 M). The tube was
sealed and heated to 100 °C for 16 h and then cooled to rt. A 50
SCHEME 5. Gem-Dimethyl Substituted
Tetrahydrofluorenones
1
µL aliquot was removed to check conversion by H NMR, then a
solution of BF3‚OEt2 in (CH2Cl)2 (0.1 equiv/100 µL) was washed
into the tube with sufficient (CH2Cl)2 to bring the concentration to
0.15 M. The reaction was reheated to 100 °C for 30 min, cooled to
rt, and worked up as in procedure A. Flash chromatography eluting
with 1:9 to 1:4 EtOAc/hexanes afforded a yellow powder, which
was recrystallized from Et2O to remove colored impurities.
a Diels-Alder reaction 89% complete. bDiels-Alder reaction 78%
Acknowledgment. This work was supported by the Natural
Sciences and Engineering Research Council of Canada (NSERC),
the Canadian Foundation for Innovation, the Ontario Innovation
Trust, and the University of Waterloo. We gratefully acknowl-
edge the Merck Frosst Centre for Therapeutic Research,
Boehringer Ingelheim (Canada) Ltd. (Young Investigator Award
to E.F.), and AstraZeneca Canada Inc. (AstraZeneca Award to
E.F.) for unrestricted support of this research. We thank Dr.
Nicholas J. Taylor of the University of Waterloo for X-ray
crystal structure determination. A.M.D. thanks the Government
of Ontario for OGS scholarships.
complete.
In summary, a modular strategy for the expedient assembly
and modification of structurally diverse tetrahydrofluorenones
from alkylidene Meldrum’s acids was described.
Experimental Section
Synthesis of Tetrahydrofluorenones 7a-g, 7o-s (Procedure
A). An oven-dried Schlenk tube cooled under N2 was charged with
alkylidene Meldrum’s acid (200 mg, 1.0 equiv) and the diene (1.1
equiv, 5.0 equiv of butadiene sulfone for the preparation of 7a) and
Supporting Information Available: Detailed experimental
procedures and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(21) All attempts to react 5-(1-arylethylidene) Meldrum’s acids for the
formation of tetrahydrofluorenones bearing an all-carbon benzylic quaternary
center failed.
(22) Hoey, M. D.; Dittmer, D. C. J. Org. Chem. 1991, 56, 1947-1948.
JO0618876
9902 J. Org. Chem., Vol. 71, No. 26, 2006