Complete π-facial diastereoselectivity in Diels-Alder reactions of dissymmetric 2,4-cyclohexadienones

Article abstract of DOI:10.1021/ol020087o

(Matrix presented) R = CH₃ (b), CH=CH₂ (c), ortho,endo.syn CH₂CH=CH₂ (d), Ph (e) predominant/major The studies in the Diels-Alder reactions of 5-methoxy-masked o-benzoquinone (1a, R = OMe) and simple dissymmetri

Full text of DOI:10.1021/ol020087o

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2477-2480
Complete π-Facial Diastereoselectivity
in Diels−Alder Reactions of
Dissymmetric 2,4-Cyclohexadienones
Hui-Fang Hou, Rama Krishna Peddinti, and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu 300, Taiwan, Republic of China
ccliao@mx.nthu.edu.tw
Received April 23, 2002
ABSTRACT
The studies in the Diels−Alder reactions of 5-methoxy-masked o-benzoquinone (1a, R ) OMe) and simple dissymmetric 2,4-cyclohexadienones
1b−e with methyl vinyl ketone, styrene, and benzyl vinyl ether are described. The dienones 1b−e reacted with dienophiles to form syn adducts
(dienophile approach is syn to allylic methoxy group) exclusively.
The Diels-Alder reaction is one of the most versatile and
synthetically useful reactions in which four new contiguous
stereogenic centers can be generated in a one-step operation.1
The most recent stereochemical issue of this reaction is the
π-facial control that arises when two faces of the diene or
the dienophile are nonequivalent (dissymmetric).2 Both steric
and electronic factors contribute significantly toward π-face
selection. In recent years, several readily accessible plane-
nonsymmetric cyclopentadienes have been extensively probed
for the diastereoselection. Considerable attention has also
been focused on unsymmetrical cage-annulated 1,3-cyclo-
hexadienes in which conformational ambiguities are mini-
mized.3 However, the potential of simple dissymmetric
conjugated cyclohexadienones has not been explored pre-
sumably due to their high propensity toward dimerization
and conformational flexibility.4-7 In this paper, we report
our preliminary results on π-facial selectivity in the Diels-
Alder reactions of simple dissymmetric 2,4-cyclohexa-
dienones.
Masked o-benzoquinones (MOBs) and their orthoquinol
variants belong to a class of conjugated cyclohexadienones
and have been used to synthesize various structurally diverse
organic compounds via the Diels-Alder protocol8 (Figure
1). However, the synthetic utility of these building blocks is
(1) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: Oxford, 1990. (b) Fringuelli, F.; Taticchi, A. Dienes in the
Diels-Alder Reaction; Wiley: New York, 1990.
(2) (a) Li, H.; le Noble, W. J. Recl. TraV. Chim. Pays-Bas 1992, 111,
199. (b) Fallis, A. G.; Lu, Y.-F. In AdVances in Cycloaddition; Curran, D.
P., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 3, Chapter 1. (c) Ohwada,
T. Chem. ReV. 1999, 99, 1337-1375.
Figure 1. Masked o-benzoquinones and orthoquinol variants.
(3) (a) Coxon, J. M.; Froese, R. D. J.; Ganguly, B.; Marchand, A. P.;
Morokuma, K. Synlett 1999, 1681-1703. (b) Mehta, G.; Uma, R. Acc.
Chem. Res. 2000, 33, 278-286. (c) Marchand, A. P.; Chong, H. S.; Ganguly,
B.; Coxon, J. M. Croat. Chem. Acta 2000, 73, 1027-1038.
limited due to their high propensity toward dimerization.
Recently, we have deduced a general trend for the stability
and dimerization of MOBs.9 Now it is clearly established
10.1021/ol020087o CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/29/2002

that the 5-substituted MOBs are nondimerizing 2,4-cyclo-
hexadienones.10 Thus, an opportunity has arisen to identify
the stable MOBs, and it was soon realized that these MOBs
could be precursors for orthoquinol variants. To study the
effect of perturbation arising from the dissymmetrization of
MOBs on the chemical reactivities, in particular the facial
selectivities, we have synthesized several 2,4-cyclohexa-
dienones 1b-e from 5-methoxy-MOB (1a) and studied their
Diels-Alder reactions with different dienophiles.
group of the dienone) is major.12,13 Then the reaction
conditions were extended to dissymmetric cyclohexadienones
1b-e. Two regioisomers 4 and 5 were formed in each case,
and the combined yields were good in almost all cases.
Remarkably, all the dienones displayed complete syn prefer-
ence (MVK approaches toward methoxy face). The results
are summarized in Table 1. In the case of allyl-substituted
The commercially available 2,3-dimethoxyphenol (2),
when subjected to diacetoxyiodobenzene (DAIB) oxidation9b,10b
in methanol, furnished the corresponding MOB 1a in nearly
quantitative yield. 1,2-Addition on the dienone 1a with
several Grignard reagents provided tertiary alcohols 3b-e,
which were transformed into the requisite cyclohexadienones
1b-e by Lewis acid mediated rearrangement11 (Scheme 1).
Table 1. Diels-Alder Reactions of Cyclohexadienones 1a-e
with Methyl Vinyl Ketonea
Scheme 1a
yieldb (%)
time
dienone
R
T (°C)
(days)
4
5
1a
1b
1c
1d
1e
OMe
Me
CHdCH2
CH2CHdCH2
Ph
100
100
100
100
100
1
1
1
3
3
4a /60
4b/30
4c/39
4d /14
4e/57
5a /29
5b/17c
5c/25
5d /14
5e/16
a Key: (i) DAIB, MeOH; (ii) RMgBr, THF, 0 °C, 77-98%; (iii)
EtAlCl2, CH2Cl2, 40-98%; R ) Me (b), CHdCH2 (c), CH2CHdCH2
(d), Ph (e).
a All the reactions were carried out with 0.5 mmol of dienone and 10
mmol of MVK. b Pure and isolated products. c meta,endo,syn-5b and its
exo-isomer could not be separated by chromatography and 15% of unreacted
1b was recovered.
At the outset of our study, we examined the Diels-Alder
reaction of MOB 1a with electron-deficient dienophile
methyl vinyl ketone (MVK). As expected, the cycloaddition
of this 5-substituted MOB is very slow at room temperature.
However, when the reaction was performed under neat
conditions with 20 equiv of MVK in a sealed tube at 100
°C, a 2:1 mixture of two regioisomers 4a and 5a was
produced in which the ortho adduct (with respect to carbonyl
dienone 1d, phenols 6 (20%) and 7 (20%) formed via [3,3]
sigmatropic rearrangement were also isolated (Figure 2).
(4) For the Diels-Alder reactions with orthoquinol acetates, see: (a)
Metlesics, W.; Wessely, F.; Budzikiewiez, H. Monatsch. Chem. 1958, 89,
102-109. (b) Holmberg, K.; Kirudd, H.; Westin, G. Acta Chim. Scand. B
1974, 28, 913-921. (c) Auksi, H.; Yates, P. Can. J. Chem. 1981, 59, 2510-
2517. (d) Carman, R. M.; Owsia, S.; Dongen, J. M. A. M. V. Aust. J. Chem.
1987, 40, 333-340. (e) Snider, B. B.; Chen, Z. Org. Prep. Proc. Int. 1999,
31, 537-541.
Figure 2.
(5) For the Diels-Alder reactions with spiroepoxycyclohexadienones,
see: (a) Singh, V. K.; Deota, P. T.; Bedekar, A. V. J. Chem. Soc., Perkin
Trans. 1 1992, 903-912. (b) Bonnarme, V.; Bachmann, C.; Cousson, A.;
Mondon, M.; Gesson, J.-P. Tetrahedron 1999, 55, 433-448.
(6) For the Diels-Alder reactions with a spirolactone-cyclohexadienone,
see: Drutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett. 2002, 4, 493-496.
(7) For the Diels-Alder reactions with 2,6-dimethoxy-6-methylthio-
methylcyclohexadienone, see: Katayama, S.; Hiramatsu, H.; Aoe, K.;
Yamauchi, M. J. Chem. Soc., Perkin Trans. 1 1997, 561-576.
(8) (a) Liao, C.-C. In Modern Methodology in Organic Synthesis, Kyoto;
Sheno, T., Ed.; Kodansha: Tokyo, 1992; pp 409-424. (b) Quideau, S.;
Pouysegu, L. Org. Prep. Proc. Int. 1999, 31, 617-680. (c) Singh, V. Acc.
Chem. Res. 1999, 32, 324-333. (d) Liao, C.-C.; Peddinti, R. K. Acc. Chem.
Res., in press.
(9) (a) Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Ko, S.; Song,
L.-D.; Shiao, H.-C. J. Org. Chem. 1999, 64, 4102-4110. (b) Yen, C.-F.;
Peddinti, R. K.; Liao, C.-C. Manuscript in preparation.
(10) (a) Andersson, G. Acta Chem. Scand. B 1976, 30, 403-406. (b)
Yen, C.-F.; Peddinti, R. K.; Liao, C.-C. Org. Lett. 2000, 2, 2909-2912.
(11) Bach, T.; Eilers, F. J. Org. Chem. 1999, 64, 8041-8044.
To assess the influence of the dienophile on the π-facial
selectivity, we have also employed styrene and benzyl vinyl
ether (BVE) as conjugative and electron-rich dienophiles,
respectively. The cycloaddition of 1a with styrene furnished
57% of ortho adduct 8a in addition to 15% of meta adduct.
(12) General Procedure for Diels-Alder Reactions of 1. A mixture
of 2,3-cyclohexadienone 1 (0.5 mmol) and a dienophile (10 mmol, 20 equiv)
was kept in a sealed tube at 100 or 150 °C for a period of time (see Tables
1-3). The reaction mixture was then cooled to room temperature and
subjected to column chromatography (silica gel, ethyl acetate/hexanes) to
afford pure cycloadducts.
(13) All the new compounds were satisfactorily characterized by IR, 1H
(600 MHz) and 13C NMR (100 or 150 MHz), DEPT, and low- and high-
resolution MS analyses.
2478
Org. Lett., Vol. 4, No. 15, 2002

raised from 100 to 150 °C in the case of 1e, the yield was
increased dramatically from 20% to 76%.
Table 2. The Diels-Alder Reactions of Cyclohexadienones
1a-e with Styrenea
The stereochemical assignments given to the adducts were
1
deduced from H-1H decoupling experiments and NOE
studies and by correlating chemical shifts and coupling
1
constants of their H NMR spectral data. Furthermore, the
structure of ortho,endo,syn-4e was confirmed by its single-
crystal X-ray structure (Figure 3).
dienone
R
T (°C)
time (days)
yieldb (%)
1a
1b
1c
1d
1e
1e
OMe
Me
CHdCH2
CH2CHdCH2
Ph
Ph
100
100
100
100
100
150
3
3
3
3
3
1
8a /57c
8b/6d
8c/49
8d /0e
8e/11f
8e/32g
a All the reactions were carried out with 0.5 mmol of dienone and 10
mmol of styrene. b Pure and isolated products. c 15% of meta adduct was
also isolated. d 60% of 1b was recovered. e 1d rearranged to phenols 6 and
7. f 74% of 1e was recovered. g 24% of 1e was recovered.
The dienones 1c,e produced the single isomers 8c,e, albeit
in moderate yields (Table 2). The Diels-Alder adducts 8c,e
were formed with the dienophilic attack exclusively from
the methoxy (syn) face. The dienone 1b showed poor
reactivity toward styrene and provided 6% of syn adduct 8b.
The reaction of allyl-substituted dienone 1d with styrene
could not yield any cycloadduct; instead, the rearranged
phenols 6 and 7 were obtained in 10% yield each.
BVE exhibited better reactivity than styrene in the Diels-
Alder reactions with dienones 1a-c,e, and the results are
shown in Table 3. A single adduct was obtained in each
successful case, and the adducts 9b,c,e were formed via
exclusive syn addition with BVE. When the temperature was
Figure 3. ORTEP plot for X-ray crystal structure of compound
4e (numbering is orbitrary).
It is clear, by comparison of the reaction conditions and
yields of these cycloadditions, that the Diels-Alder reactivity
of MOB 1a is better than the corresponding MOB variants
1b-e with a given dienophile. It is quite remarkable that
these cyclohexadienones participated in the Diels-Alder
cycloadditions with three types of dienophiles, viz. electron-
deficient, conjugative, and electron-rich dienophiles. It may
be noted that 1a, being 5-substituted MOB, is less reactive
than the MOBs lacking 5-substitution, where the latter
smoothly undergo cycloadditions usually at 0 °C/room
temperature.8d,9a
The formation of regioisomers in the above-described
cycloaddition reactions may be attributed mainly to electronic
effects. By virtue of the structure of the 2,4-cyclohexadienone
1, the carbonyl and methoxy groups are present on its C-2
and C-5 positions, respectively, which exert opposite elec-
tronic effects on the incoming electron-deficient (MVK) and
conjugative (styrene) dienophiles during the cycloaddition
(Figure 4). As a result, the formation of both ortho and meta
adducts is expected.14 Nevertheless, due to the dominant
regioselective directing influence of the carbonyl group of
Table 3. Diels-Alder Reactions of Cyclohexadienones 1a-e
with Benzyl Vinyl Ethera
dienone
R
T (°C)
time (days)
yieldb (%)
1a
1b
1c
1d
1e
1e
OMe
Me
CHdCH2
CH2CHdCH2
Ph
Ph
100
100
100
100
100
150
3
3
3
2
3
3
9a /95
9b/42c
9c/35d
9d /0e
9e/20f
9e/76
a All the reactions were carried out with 0.5 mmol of dienone and 10
mmol of BVE. b Pure and isolated products. c 39% of 1b was recovered.
d 57% of 1c was recovered. e 1d rearranged to phenols 6 and 7. f 61% of
1e was recovered.
Figure 4. The two electronically differed groups at the termini of
the diene moiety of 2,4-cyclohexadienones.
Org. Lett., Vol. 4, No. 15, 2002
2479

dienone 1, ortho adducts 4 were formed predominantly in
the case of MVK. The regioselective outcome is much better
in the reactions of 1 with styrene. In contrary to MVK and
styrene, the electron-donating dienophile BVE is expected
to produce ortho adducts based on ortho (C-2) directionality
of carbonyl group and meta (C-2) directionality of methoxy
group, which is in line with the experimental results.
In summary, in all cases shown in this work, the approach
of the dienophile was strictly syn to allylic methoxy group
(6-OMe) of the MOB variant. Only endo adducts were
obtained for stereoelectronic effects. The regiochemistry of
the cycloaddition was also well controlled in most cases,
since the ortho adduct was always the major Diels-Alder
product over the meta adduct, the carbonyl attached to C-2
having more influence than that of the methoxy group
attached to C-5. The overwhelming syn control experienced
in these reactions should be helpful to the organic chemists
as the bicyclo[2.2.2]octenones are valuable synthons. Theo-
retical calculations are underway to understand the experi-
mentally observed selectivities.
The Diels-Alder cycloadditions proceeded in a highly
stereoselective and facial selective manner under the reaction
conditions. The overwhelming diastereofacial selectivity
observed in these reactions is in consonance with that
observed in the Diels-Alder reactions of allylic oxygen atom
(OH/OAc/OMe/OCH2-) bearing cyclopentadienes2,15 and
cyclohexa-2,4-dienones.4-7 The results can be rationalized
in terms of (i) the Cieplak model,16 i.e., hyperconjugative
stabilization by σ bonds antiperiplanar to the incipient
bond15susing the Baker-Nathan ordering of σ-donar abil-
ity17 (σC-O < σC-C)swherein a preference should exist for
addition on the OMe face that is opposite to the better
donating σC-C bond or (ii) by invoking orbital mixing rule,18
i.e., a nonequivalent extension of the π HOMO by mixing
on the σ-orbitals of the carbon framework through interaction
with the n orbitals of oxygen atom of the C-6 methoxy group.
However, the importance of steric effects on the π-facial
selectivity cannot be ruled out in the present reactions.
Acknowledgment. Support has been provided by the
National Science Council of Republic of China. We thank
Dr. Chien-Hsun Lai for initial work. R.K.P. thanks NSC for
a postdoctoral fellowship.
1
Supporting Information Available: H NMR spectra and
1
tables of selected H NMR chemical shifts and coupling
constants. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL020087O
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