4-Acetoxy- and 4-triflyloxy-2,6,6-trimethyl-2,4-cyclohexadienones as non-dimerizing alternatives to 2,6,6-trimethyl-2,4-cyclohexadienone. Efficient synthesis of several bicyclo[2.2.2]octenone derivatives

Article abstract of DOI:10.1055/s-1999-2581

4-Acetoxy- and 4-triflyloxy-2,6,6-trimethyl-2,4-cyclo-hexadienones were employed as non-dimerizing alternatives to 2,6,6-trimethyl-2,4- cyclohexadienone in Diels-Alder reactions with substituted acetylenes which facilitated the synthesis of substituted bi

Full text of DOI:10.1055/s-1999-2581

LETTER
225
4-Acetoxy- and 4-Triflyloxy-2,6,6-trimethyl-2,4-cyclohexadienones as Non-
dimerizing Alternatives to 2,6,6-Trimethyl-2,4-cyclohexadienone. Efficient
Synthesis of Several Bicyclo[2.2.2]octenone Derivatives
Ming-Shyong Yang, Shi-Yi Chang, Shyue-Sheng Lu, Polisetti Dharma Rao and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300
Fax + 886-3-5711082, E-mail: ccliao@faculty.nthu.edu.tw
Received 2 December 1998
this approach.3 It is pertinent to mention that despite the
difficulties involved in the preparation and handling of 4,
it has been used in the total synthesis of natural products
on a number of occassions.4
Abstract: 4-Acetoxy- and 4-triflyloxy-2,6,6-trimethyl-2,4-cyclo-
hexadienones were employed as non-dimerizing alternatives to
2,6,6-trimethyl-2,4-cyclohexadienone in Diels-Alder reactions with
substituted acetylenes which facilitated the synthesis of substituted
bicyclo[2.2.2]octen-2,5-diones, bicyclo[2.2.2]octadienones and 5-
methylenebicyclo[2.2.2]octen-2-ones.
During the search for an alternative to 4, 4-acetoxy-2,6,6-
trimethyl-2,4-cyclohexadienone (5) prepared by Soukup
et al.,5 attracted our attention. Interestingly, although 5 is
quite stable and accessible in large quantities its Diels-
Alder chemistry has not been studied.6,7 We herein report
the first use of 4-acetoxy-2,6,6-trimethyl-2,4-cyclohexa-
dienone (5) and 4-triflyloxy-2,6,6-trimethyl-2,4-cyclo-
hexadienone (6) as attractive alternatives to 4 in Diels-Al-
der reactions with substituted acetylenes and a novel
approach to title compounds 1-3 starting from readily
available 4-ketoisophorone (7) (Schemes 1-3).
Key words: 2,4-cyclohexadienones, Diels-Alder reactions, vinyl
triflates, bicyclo[2.2.2]octendiones, bicyclo[2.2.2]octadienones
During our studies on competitive photochemical rear-
rangements of bicyclo[2.2.2]octenone derivatives, a need
for the synthesis of substituted bicyclo[2.2.2]octen-2,6-
diones 1, bicyclo[2.2.2]octadienones 2 and 5-methyl-
enebicyclo[2.2.2]oct-7-en-2-ones 3 (Figure 1) has arisen.
While there are no efficient general methods available for
the preparation of bicyclo[2.2.2]oct-7-en-2,5-diones1
which are immediate precursors of 5-methylenebicy-
clo[2.2.2]oct-7-en-2-ones, there exist reports on synthesis
of bicyclo[2.2.2]octadienones via Diels-Alder reactions
of 2,4-cyclohexadienones and acetylene derivatives.2 In
principle, it should be possible to prepare bicy-
clo[2.2.2]octadienones of the required type 2 via Diels-
Alder reactions of appropriate acetylene derivatives with
2,6,6-trimethyl-2,4-cyclohexadienone (4). However, the
tedious procedures involved in the preparation of 4 and its
high propensity to dimerize have deterred us from using
Scheme 1
Compound 5 was prepared from 7 following the proce-
dure developed by Soukup et al.5 The Diels-Alder reac-
tions of 5 with substituted acetylenes such as ethyl
propiolate (8a), dimethyl acetylenedicarboxylate (8b),
phenylacetylene (8c) and diphenylacetylene (8d) were
performed by heating 5 with two equivalents of an ace-
tylene derivative at an appropriate temperature to obtain
the adducts 9a-d in excellent yields (Scheme 1).8 The re-
gioselectivity observed in the reactions of 5 with 7a and
7c is noteworthy. Subsequent hydrolysis of 9a-d with po-
tassium carbonate in ethanol or methanol at 0 oC proceed-
ed
smoothly
to
furnish
the
desired
bicyclo[2.2.2]octendiones 1a-d in >93% yields.9 It should
be mentioned that compounds of type 1 were prepared by
others from hydroquinone and maleic anhydride in very
low yields (16%).1
Figure 1
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226
M.-S. Yang et al.
LETTER
After several unsuccessful attempts to convert 1a into 2a,
it was finally decided to adopt Cacchi’s procedure10 for the
conversion of enolizable ketones into olefins. According-
ly, 1a-d were converted into corresponding vinyl triflates
10a-d in >90% yield by treating 1a-d with LHMDS in
THF at -78 oC and then with N-phenyltriflimide. Vinyl tri-
flates 10a-d were then subjected to Cacchi’s conditions
(HCOOH, n-Bu3N, Pd(PPh3)2Cl2, DMF, 60-80 oC) to ob-
tain the desired bicyclo[2.2.2]octadienones 2a-d in good
overall yields (Scheme 2). However, a rethinking enlight-
ened us with the idea that instead of starting with 5, the cy-
clohexadienone 6 could be employed to obtain the
compounds 10a-d directly rather than in three steps. This
hypothesis was immediately examined. The cyclohexadi-
enone 6 was prepared from 4-ketoisophorone in >90%
yield using the conditions employed for the conversion of
1a-d into 10a-d. Diels-Alder reactions of 6 with ace-
tylenes 8a-d proceeded smoothly as expected to provide
the adducts 10a-d in excellent yield.8 However, in the
case of 8a, regioisomer 10e (12%) was also produced
along with 10a (73%).
Scheme 3
It is important to note that compounds 1a-d with an active
methylene group and two distinguishable keto groups
should allow further transformations characteristic to
these groups. Similarly, compounds 2a-d with a vinyl tri-
flate moiety should undergo facile Heck-type and Stille
coupling reactions. In fact this transformation forms the
corner stone of a common approach to quinane-based and
cedranoid natural products being developed in our labora-
tory. Nevertheless, compounds 1 and 2 clearly hold sub-
stantial potential.
In conclusion, the present studies unravelled two new sta-
ble 2,4-cyclohexadienones as well as attractive and stable
alternatives to highly useful but readily dimerizing and te-
dious to prepare 2,6,6-trimethyl-2,4-cyclohexadienone
(4). In fact, both 5 (200 mM) and 6 (50 mM) can be pre-
pared in large scale. The targeted compounds 1-3 were ob-
tained in good overall yields by the present procedures
and hence an efficient route for these types of compounds
has been developed. Studies on competetive di-π-methane
and oxa-di-π-methane rearrangements11 of compounds 1-
3 are in progress in our laboratory and the details will be
published in the near future.
Acknowledgement
Scheme 2
We thank the National Science Council (NSC) of the Republic of
China for financial support to our research. PDR thanks the NSC for
a post-doctoral fellowship.
Towards synthesis of 5-methylenebicyclo[2.2.2]oct-7-en-
2-ones 3a-d, compounds 1a-d were treated with triphe-
nylmethylenephosphorane in toluene at 60-80 C. While
o
References and Notes
1a, 1c and 1d underwent smooth and selective Wittig ole-
fination at the less hindered keto group, in the case of 1b
the ester group interfered and the major product was 11
(37%). The desired compound 3b was obtained only in
25% yield (Scheme 3). The structures of all the new com-
(1) (a) Weitemeyer, C.; de Meijere, A. Angew. Chem. Int. Ed.
Engl. 1976, 15, 686-687. (b) Hill, R. K.; Morton, G. H.; Peter-
son, J. R.; Walsh, J. A.; Paquette, L. A. J. Org. Chem. 1985,
50, 5528-5533. (c) Demuth, M.; Ritterskamp, P.; Weigt, E.;
Schaffner, K. J. Am. Chem. Soc. 1986, 108, 4149-4154.
(2) (a) Alder, K.; Flock, F. H.; Lessenich, H. Chem. Ber. 1957, 90,
1709-1720. (b) Becker, H.-D.; Ruge, B. J. Org. Chem. 1980,
45, 2189-2195.
1
pounds were unambiguously established by their IR, H
and 13C NMR, DEPT and low- and high-resolution mass
spectral data.
Synlett 1999, No. 2, 225–227 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of Several Bicyclo[2.2.2]octenone Derivatives
227
(3) (a) Brown, T. L., Curtin, D. Y.; Fraser, R. R. J. Am. Chem.
Soc. 1958, 80, 4339-4341. (b) Quinkert, G.; Durner, G.; Klein,
E.; Adam, F.; Haupt, E.; Leibfritz, R. Chem. Ber. 1980, 113,
2227-2248. (c) Bertrand, M.; Teisseire.; Pelerin, G. Tetrahe-
dron Lett. 1980, 21, 2055-2056. (d) Berge, J. M.; Rey, M.;
Dreiding, A. S. Helv. Chim. Acta 1982, 65, 2230-2241.
(4) (a) Naf, F.; Ohloff, G. Helv. Chim. Acta 1974, 57, 1868-1870.
(b) Naf, F.; Decorzant, R.; Giersch, W.; Ohloff, G. Helv.
Chim. Acta 1981, 64, 1387-1397. (c) Oppolzer, W.; Briner, P.
H.; Snoden, R. L.; Helv. Chim. Acta 1980, 63, 967-969.
(d) Bertrand, M.; Teisseire.; Pelerin, G. Tetrahedron Lett.
1980, 21, 2051-2054. (e) Magee, T. V.; Stork, G.; Fludzinski,
P. Tetrahedron Lett. 1995, 36, 7607-7610.
HRMS (EI): Calcd for C16H20O5 (M+) 292.1311, found
292.1310. Anal. Calcd. for C16H20O5: C, 65.74; H, 6.96.
Found: C, 65.84; H, 6.93.
Spectral data of compound 10a. IR (film): 2980, 1727, 1653
cm-1. 1H NMR (300 MHz, CDCl3): δ 7.44 (d, J = 6.6 Hz, 1H),
5.87 (d, J = 3.1 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.57 (dd, J
= 6.6, 3.1 Hz, 1H), 1.70 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.25
(s, 3H), 1.12 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 206.7,
163.5, 154.7, 144.9, 137.5, 119.8, 118.4, 61.0, 57.2, 51.9,
39.9, 27.5, 26.6, 15.0, 14.0. FABMS: m/z (relative intensity)
383 (M++1, 61), 337 (49), 267 (32), 159 (19), 137 (21), 91
(22), 70 (100). HRMS (FAB): Calcd for C15H18O6F3S (M++1)
383.0776, found 383.0775.
(5) Soukup, M.; Lukac, T.; Zell, R.; Roessler, F.; Steiner, K.;
Widmer, E. Helv. Chim. Acta 1989, 72, 365-369.
(9) General procedure for hydrolysis of compounds 9a-d. A solu-
tion of an enol-actate 9 (2 mM) in 20 mL of ethanol (for 9a)
or methanol (for 9b-d) was cooled to 0 oC. Then K2CO3 (1
mM) was added and stirring was continued until the comple-
tion of hydrolysis as indicated by TLC analysis (75 min for 9a
and 10 min for 9b-d). Then the alcohol was removed under re-
duced pressure and the residue was diluted with ethyl acetate.
Washed the contents with water and dried the organic layer
over anhyd. Na2SO4. Removal of solvent followed by column
chromato-grapy of thus obtained residue on silica gel using
25% ethyl acetate in hexanes as eluent furnished the products
1a-d.
(6) Addition of sodium acetylide and double Michael addition re-
actions of corresponding trimethylsilyl ether were reported:
(a) Widmer, E.; Zell, R.; Grass, H.; Marbet, R. Helv. Chim.
Acta 1982, 65, 958-967. (b) Hagiwara, H.; Yamada, Y.; Sakai,
H.; Suzuki, T.; Ando, M. Tetrahedron 1998, 54, 10999-
11010.
(7) Asymmetric hydrogenation of compound 5 and related deriva-
tives of 4 was reported: Broger, E. A.; Yvo, C.; Schmid, R.;
Siegfried, T. Chem. Abst. 1996, 124:260450, 1215.
(8) General procedure for Diels-Alder reactions of 5 and 6 with
acetylene derivatives 8a-d. A mixture of 5/6 (5 mM) and 8 (10
mM) were heated for 24 h (at 80 oC for 8a,b and 120 oC for
8c,d). Removal of excess 8 under reduced pressure followed
by column chromatography of the crude adduct on silica gel
using 15% ethyl acetate in hexanes as eluent furnished the
desired adducts 9a-d and 10a-e.
Spectral data of compound 1a. IR (film): 2970, 1728, 1710,
1705, 1630 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.26 (d, J =
7.0 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.30 (d, J = 7.0 Hz, 1H),
2.36 (d, J = 19.2 Hz, 1H), 2.18 (d, J = 19.2 Hz, 1H), 1.51 (s,
3H), 1.30 (t, J = 7.2 Hz, 3H), 1.16 (s, 3H), 1.13 (s, 3H). 13
C
NMR (100 MHz, CDCl3): δ 211.7, 205.9, 163.5, 140.0, 136.9,
62.1, 61.1, 51.7, 42.3, 42.0, 26.2, 25.3, 15.7, 14.0. EIMS (70
eV): m/z (relative intensity) 250 (M+, 31), 205 (22), 181 (19),
121 (21), 109 (21), 107 (21), 91 (26) 70 (100). HRMS (EI):
Calcd for C14H18O4 (M+) 250.1205, found 250.1205.
(10) (a) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984,
25, 4821-4824. (b) Cacchi, S.; Morera, E.; Ortar, G. Org.
Synth. 1990, 68, 126-132.
Spectral data of compound 9a. IR (film): 3080, 2966, 1775,
1765, 1721, 1645 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.42
(d, J = 7.0 Hz, 1H), 5.70 (d, J = 2.8 Hz, 1H), 4.14 (q, J = 7.2
Hz, 2H), 3.38 (dd, J = 7.0, 2.8 Hz, 1H), 2.14 (s, 3H), 1.62 (s,
3H), 1.25 (t, J = 7.2 Hz, 3H), 1.16 (s, 3H), 1.03 (s, 3H). 13
C
NMR (100 MHz, CDCl3): δ 208.4, 167.8, 164.0, 156.0, 146.0,
137.4, 115.2, 60.6, 56.1, 52.0, 40.1, 27.5, 26.1, 21.0, 15.0,
14.0. EIMS (70 eV): m/z (relative intensity) 292 (M+, 1),
251(11), 223 (13), 180 (14), 177 (13), 135 (28), 70 (100).
(11) Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065-
3112.
Synlett 1999, No. 2, 225–227 ISSN 0936-5214 © Thieme Stuttgart · New York