Electrochemical synthesis of dimerizing and nondimerizing orthoquinone monoketals

Article abstract of DOI:10.1021/jo048677i

Anodic oxidation of appropriately substituted 2-methoxyphenols or α-(2-methoxyphenoxy)-2-methylpropionic acids in the presence of methanol furnishes stable orthoquinone monoketals, and thus constitutes a valuable alternative to the use of chemical oxidants that are often based on toxic metallic species. The propionic acid derivatives are initially converted into O-spirolactonic quinone bisketals that are then selectively hydrolyzed into the desired monoketal compounds. In the absence of blocking substituents, orthoquinone monoketals spontaneously undergo Diels-Alder dimerizations into tricyclododecadienedienones with extraordinary site selectivity, regioselectivity, and stereoselectivity. Suggestions are made to open up a new track for a long awaited rationalization of these controls on the basis of the intramolecular [2 + 2] reactivity of these orthoquinone monoketal-derived cyclodimers.

Full text of DOI:10.1021/jo048677i

Electrochemical Synthesis of Dimerizing and Nondimerizing
Orthoquinone Monoketals
Denis Deffieux,†,‡ Isabelle Fabre,†,‡ Alexander Titz,†,‡ Jean-Michel Le´ger,§ and
Ste´phane Quideau*,†,‡
Laboratoire de Chimie des Substances Ve´ge´tales, Centre de Recherche en Chimie Mole´culaire,
Universite´ Bordeaux 1, 351 cours de la Libe´ration, F-33405 Talence Cedex, Institut Europe´en de Chimie
et Biologie, Poˆle Chimie Organique et Bioorganique, 2 rue Robert Escarpit, F-33607 Pessac Cedex, and
Laboratoire de Chimie Physique et Cristallographie, UFR de Chimie, Universite´ Bordeaux 2,
146 rue Le´o Saignat, F-33076 Bordeaux Cedex
s.quideau@iecb.u-bordeaux.fr
Received July 30, 2004
Anodic oxidation of appropriately substituted 2-methoxyphenols or R-(2-methoxyphenoxy)-2-
methylpropionic acids in the presence of methanol furnishes stable orthoquinone monoketals, and
thus constitutes a valuable alternative to the use of chemical oxidants that are often based on
toxic metallic species. The propionic acid derivatives are initially converted into O-spirolactonic
quinone bisketals that are then selectively hydrolyzed into the desired monoketal compounds. In
the absence of blocking substituents, orthoquinone monoketals spontaneously undergo Diels-Alder
dimerizations into tricyclododecadienedienones with extraordinary site selectivity, regioselectivity,
and stereoselectivity. Suggestions are made to open up a new track for a long awaited rationalization
of these controls on the basis of the intramolecular [2 + 2] reactivity of these orthoquinone
monoketal-derived cyclodimers.
SCHEME 1
Introduction
Orthoquinone monoketals and their orthoquinol vari-
ants (i.e., 4, Scheme 1) are synthetically useful cyclohexa-
2,4-dienone derivatives that can serve in the rapid
elaboration of complex structural motifs of tremendous
value for natural products synthesis.1 The most direct
and efficient methods used to generate these synthons
rely on the oxidative dearomatization of 2-alkoxyphenols
(e.g., 1, Scheme 1).1,2 The two-electron oxidants lead
tetraacetate (LTA)3,4 and λ3-iodane (diacetoxy)iodoben-
zene (DIB)5,6 are the two chemical reagents most com-
monly used nowadays to perform such a task. Single-
† Universite´ Bordeaux 1.
‡ Institut Europe´en de Chimie et Biologie.
§ Universite´ Bordeaux 2.
(1) For reviews on this topic, see: (a) Quideau, S. In Modern Arene
Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002; pp 539-573.
(b) Quideau, S.; Pouyse´gu, L. Org. Prep. Proced. Int. 1999, 31, 617-
680. (c) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004,
104, 1383-1429. (d) Waring, A. J. In Adances in Alicyclic Chemistry;
Hart, H., Karabatsos, G. J., Eds.; Academic Press: New York and
London, 1966; Vol. 1, pp 129-256.
(2) (a) Quideau, S.; Pouyse´gu, L.; Deffieux, D. Curr. Org. Chem.
2004, 8, 113-148. (b) Eickhoff, H.; Jung, G.; Rieker, A. Tetrahedron
2001, 57, 353-364 and references therein. (c) Rieker, A.; Beisswenger,
R.; Regier, K. Tetrahedron 1991, 47, 645-654.
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4502. (b) Wessely, F.; Sinwel, F. Monatsh. Chem. 1950, 81, 1055-1070.
(4) For recent synthetic applications of LTA-generated orthoquinol
acetates, see: (a) Barnes-Seeman, D.; Corey, E. J. Org. Lett. 1999, 1,
1503-1504. (b) Nicolaou, K. C.; Simonsen, K. B.; Vassilikogiannakis,
G.; Baran, P. S.; Vidali, V. P.; Pitsinos, E. N.; Couladouros, E. A. Angew.
Chem., Int. Ed. 1999, 38, 3555-3559. (c) Nicolaou, K. C.; Vassiliko-
giannakis, G.; Simonsen, K. B.; Baran, P. S.; Zhong, Y.-L.; Vidali, V.
P.; Pitsinos, E. N.; Couladouros, E. A. J. Am. Chem. Soc. 2000, 122,
3071-3079.
electron transfer sequences can also be exploited to
perform similar dearomatization events using either
2-alkoxyphenols 1 or 2-alkoxyphenyl alkyl ethers 2 as
(5) (a) Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Ko, S.; Song,
L.-D.; Shia, H.-C. J. Org. Chem. 1999, 64, 4102-4110. (b) Pelter, A.;
Ward, R. S. Tetrahedron 2001, 57, 273-282. (c) Pelter, A.; Elgendy,
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10.1021/jo048677i CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/06/2004
J. Org. Chem. 2004, 69, 8731-8738
8731

Deffieux et al.
starting materials. Initiating these one-electron oxidation
reactions under appropriate electrochemical conditions
constitutes an attractive alternative to the use of chemi-
cal reagents, notably because of the possibility of per-
forming selective oxidation under environmentally friendly
conditions. Inspired by the work of Swenton, Thomas,
and co-workers on the electrochemical generation of
paraquinone ketals,7 we recently reported for the first
time similar anodic oxidations of 2-alkoxyphenyl alkyl
ethers of type 2 for the preparation of orthoquinone
bisketals 3 and monoketals 4 by using either methanol
or water, respectively, as a reaction cosolvent in aceto-
nitrile (i.e., 2 f III f IV f V f 3/4, Scheme 1).8a
Bisketals 3 are easily transformed into their correspond-
ing monoketals 4 by selective monohydrolysis.8a Monoket-
als can also be directly generated via anodic oxidation of
2-alkoxyphenols in methanol (i.e., 1 f I f II f 4,
Scheme 1). This approach was judiciously exploited by
Yamamura and co-workers for the synthesis of asatone
and other propenylphenol-derived asatone-type neolign-
ans,9 which were obtained by simply letting anodically
generated orthoquinone dimethyl monoketals undergo
Diels-Alder dimerizations upon standing at room tem-
perature (vide infra). To the best of our knowledge, the
only two examples of this electrochemical approach that
led to nondimerizing orthoquinone monoketals are the
ones reported by Swenton and co-workers and us.8b,c
Indeed, orthoquinone monoketals of type 4 are gener-
ally not very stable, and they rapidly succumb to Diels-
Alder dimerization processes, leading to bicyclo[2.2.2]-
octenones, because of the capability of their 2,4-dienone
unit to behave both as a diene and as a dienophile. The
lack of control over this cycloaddition chemistry is
undoubtedly one of the main reasons why the use of such
potentially useful building blocks has not yet been
generalized in organic synthesis. It is nevertheless pos-
sible to harness the reactivity of these 6,6-dioxocyclohexa-
2,4-dienone systems by choosing an appropriate substi-
tution pattern.1a,b The presence of a single substituent
on their ring system can drastically influence their
stability. For example, a bromine or an iodine substituent
at the 4-position of 6,6-dimethoxycyclohexa-2,4-dienones
(i.e., 4, R ) R′ ) Me)8b,10 or a small electron-releasing
group such as an alkyl or an alkoxy group at their
5-position10b,11 are particularly efficient at retarding
Diels-Alder dimerization. The presence of a bulky
carbon-based substituent at their 4-position also stabi-
lizes these orthoquinone monoketals.8c,11b,c,12a It has fur-
thermore been observed that their 6-acetoxy derivatives
or orthoquinol acetates (i.e., 4, R ) Me, R′ ) Ac) are much
less prone to undergo dimerization than their 6,6-
dimethoxy analogues.6,13
With this knowledge on dimerizing and nondimerizing
orthoquinone monoketals and related orthoquinols in
mind, we decided to further examine the scope of their
preparation by anodic oxidation of both 2-alkoxyphenols
of type 1 and 2-alkoxyphenyl alkyl ethers of type 2.
Herein we describe our results obtained with a series of
differently substituted 2-methoxyphenols 1a-g and a
series of spirolactonizable R-(2-methoxyphenoxy)-2-me-
thylpropionic acids 2b-f. Suggestions are also made to
explain the extremely high regioselectivity of the Diels-
Alder dimerization of orthoquinone monoketals on the
basis of the intramolecular [2 + 2] reactivity of their
dimers.
Results and Discussion
(6) For examples of synthetic applications of nondimerizing ortho-
quinol acetates from our own work, see: (a) Quideau, S.; Pouyse´gu, L.;
Oxoby, M.; Looney, M. Tetrahedron 2001, 57, 319-329. (b) Quideau,
S.; Pouyse´gu, L.; Looney, M. A. J. Org. Chem. 1998, 63, 9597-9600.
(c) Quideau, S.; Looney, M. A.; Pouyse´gu, L.; Ham, S.; Birney, D. M.
Tetrahedron Lett. 1999, 40, 615-618. (d) Quideau, S.; Pouyse´gu, L.;
Avellan, A.-V.; Whelligan, D. K.; Looney, M. A. Tetrahedron Lett. 2001,
42, 7393-7396. (e) Pouyse´gu, L.; Avellan, A.-V.; Quideau, S. J. Org.
Chem. 2002, 67, 3425-3436.
(7) (a) Swenton, J. S. In The Chemistry of Quinonoid Compounds;
Patai, S., Rappoport, Z., Eds.; John Wiley: New York, 1988; Vol. 2,
Part 2, pp 899-962. (b) Thomas, H. G.; Schwager, H.-W. Tetrahedron
Lett. 1984, 25, 4471-4474.
(8) (a) Deffieux, D.; Fabre, I.; Courseille, C.; Quideau, S. J. Org.
Chem 2002, 67, 4458-4465. For two examples of anodic oxidation of
2-methoxyphenols into stable orthoquinone dimethyl ketals, see: (b)
Quideau, S.; Pouyse´gu, L.; Deffieux, D.; Ozanne, A.; Gagnepain, J.;
Fabre, I.; Oxoby, M. Arkivoc 2003, 6, 106-119. (c) Swenton, J. S.;
Callinan, A.; Chen, Y.; Rohde, J. J.; Kerns, M. L.; Morrow, G. W. J.
Org. Chem. 1996, 61, 1267-1274.
Anodic oxidation of 2-alkoxyphenols 1 in the presence
of a nucleophilic entity is the most direct method of
electrochemically generating orthoquinone monoketals 4
(Scheme 1), if these reactive species can withstand the
reaction conditions used. The first series of compounds
we submitted to anodic oxidation comprised the 2-meth-
oxyphenols 1a-g. Reactions were conducted in a single
cell at a constant current in methanol containing lithium
perchlorate as a supporting electrolyte (Table 1). Metha-
nol played both the role of reaction solvent and of the
nucleophilic entities necessary to trap cation intermedi-
ates of type II into 6,6-dimethoxycyclohexa-2,4-dienones
4 (i.e., R ) R′ ) Me). We were pleased to isolate such
(9) (a) Yamamura, S.; Nishiyama, S. Synlett 2002, 533-543. (b)
Yamamura, S.; Shizuri, Y.; Shigemori, H.; Okuno, Y.; Ohkubo, M.
Tetrahedron 1991, 47, 635-644. (c) Nishiyama, A.; Eto, H.; Terada,
Y.; Iguchi, M.; Yamamura, S. Chem. Pharm. Bull. 1983, 31, 2820-
2833. (d) Nishiyama, A.; Eto, H.; Terada, Y.; Iguchi, M.; Yamamura,
S. Chem. Pharm. Bull. 1983, 31, 2834-2844. (e) Nishiyama, A.; Eto,
H.; Terada, Y.; Iguchi, M.; Yamamura, S. Chem. Pharm. Bull. 1983,
31, 2845-2852. (f) Iguchi, M.; Nishiyama, A.; Eto, H.; Yamamura, S.
Chem. Lett. 1981, 939-942. (g) Iguchi, M.; Nishiyama, A.; Eto, H.;
Terada, Y.; Yamamura, S. Chem. Lett. 1979, 1397-1400. (h) Iguchi,
M.; Nishiyama, A.; Hara, M.; Terada, Y.; Yamamura, S. Chem. Lett.
1978, 1015-1018. (i) Iguchi, M.; Nishiyama, A.; Terada, Y.; Yamamura,
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Y.; Yamamura, S. Tetrahedron Lett. 1977, 4511-4514. (k) Chen, Y.-
P.; Hong, M.; Hsu, H.-Y.; Yamamura, S.; Hirata, Y. Tetrahedron Lett.
1972, 1607-1610. (l) Sasaki, K.; Hirata, Y.; Yamamura, S. Tetrahedron
Lett. 1973, 4881-4884. (m) Yamamura, S.; Sasaki, K.; Hirata, Y.; Chen,
Y.-P.; Hsu, H.-Y. Tetrahedron Lett. 1973, 4877-4880. (n) Yamamura,
S.; Terada, Y.; Chen, Y.-P.; Hsu, H.-Y.; Hirata, Y. Tetrahedron Lett.
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(10) (a) Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Rao, K.; Liao, C.-C. J.
Org. Chem. 2002, 67, 6493-6502. (b) Yen, C.-F.; Peddinti, R. K.; Liao,
C.-C. Org. Lett. 2000, 2, 2909-2912. (c) Lai, C.-H.; Shen, Y.-L.; Liao,
C.-C. Synlett 1997, 1351-1352. (d) Liu, W.-C.; Liao, C.-C. Synlett 1998,
912-914. (e) Lin, K.-C.; Shen, Y.-L.; Rao, N. S.; Liao, C.-C. J. Org.
Chem. 2002, 67, 8157-8165. (f) Andersson, G.; Berntsson, P. Acta
Chem. Scand. 1975, B 29, 948-952.
(11) (a) Hou, H.-F.; Peddinti, R. K.; Liao, C.-C. Org. Lett. 2002, 4,
2477-2480. (b) Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Ko, S.;
Song, L.-D.; Shia, H.-C. J. Org. Chem. 1999, 64, 4102-4110. (c)
Andersson, G. Acta Chem. Scand. 1976, B 30, 64-70. (d) Andersson,
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(12) (a) Mitchell, A. S.; Russell, R. A. Tetrahedron Lett. 1993, 34,
545-548. (b) Mitchell, A. S.; Russell, R. A. Tetrahedron 1997, 53,
4387-4410.
(13) (a) Quideau, S.; Looney, M. A.; Pouyse´gu, L.; Ham, S.; Birney,
D. M. Tetrahedron Lett. 1999, 40, 615-618. (b) Adler, E.; Dahlen, J.;
Westin, G. Acta Chem. Scand. 1960, 14, 1580-1596. (c) Holmberg, K.
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W. Monatsch. Chem. 1957, 88, 108-117.
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Dimerizing and Nondimerizing Orthoquinone Monoketals
TABLE 1. Anodic Oxidation of a Series of
2-Methoxyphenols
SCHEME 2
tions on the stability of chemically generated ortho-
quinone monoketals bearing a relatively large group at
their 4-position.8c,11b,c,12a The 2-methoxyphenol 1f, which
is equipped with a methoxy group at its 3-position, also
furnished the stable orthoquinone monoketal 4f (entry
6)11a,c in quantitative yield, thus confirming the stabiliz-
ing effect of a small electron-releasing group at the
corresponding cyclohexa-2,4-dienone 5-position (vide in-
fra).11 The anodic oxidation of 2,6-dimethoxyphenol (4g,
not shown) under the same conditions in MeOH was
totally inefficient at producing an orthoquinone monoket-
al or its corresponding dimer, and the only isolated
product was 2,6-dimethoxy-1,4-quinone in a moderated
30% yield. The most likely course of events leading to
the formation of this paraquinone is the anodic genera-
tion of a stable 2,6-dimethoxycyclohexa-2,5-dienonyl
cation intermediate of type II, which is trapped by
methanol to furnish 2,4,6-trimethoxyphenol, followed by
further oxidative methoxylation into 2,4,4,6-tetramethox-
ycyclohexa-2,5-dienone, and dimethyl ketal hydrolysis
during the aqueous workup.
We performed calculations on molecular orbitals of
4a-f at both semiempirical PM3 and ab initio RHF/3-
21G levels with the aim of identifying some reasons that
might explain the dimerizing and nondimerizing behav-
iors of these orthoquinone monoketals on the basis of
HOMO-LUMO energy gaps and/or electronic effects due
to the presence or lack of substituents on the atomic
coefficients of their cyclohexa-2,4-dienone system. No
clear-cut explanation could be drawn from the results of
these calculations. In all cases, HOMO-LUMO energy
gaps are similar and the relative magnitudes of the C2,
C3, C4, and C5 coefficients of these FMOs are not affected
by substituent electronic effects in a way that could
a All reactions were carried out in methanol containing LiClO4
as a supporting electrolyte (see Experimental Section for details).
b Isolated yields are given in parentheses where applicable.
c OQMK ) orthoquinone monoketal. d DAD ) Diels-Alder dimer.
e Not observed.
orthoquinone dimethyl monoketals in good to excellent
yields in cases for which the substitution pattern of their
cyclohexa-2,4-dienone ring system was appropriate to
block the Diels-Alder dimerization process (Table 1). All
products were isolated, purified, and characterized by
standard chromatographic and spectroscopic techniques.
As expected, the anodic oxidation of the unsubstituted
2-methoxyphenol, guaiacol 1a (entry 1, Z ) H), furnished
the known Diels-Alder dimer 5a10f as the sole product.
Similar high-yielding dimerizations were obtained using
2-methoxyphenols bearing either a tert-butyldiphenylsi-
lyloxymethyl group (entry 2, 1b f 5b) or a bromine atom
(entry 3, 1c f 5c) at their 5-position. The presence of
the orthoquinone monoketal monomers 4a-c were not
even detected by NMR analysis of the crude products.
The regio- and stereochemistry of dimers 5b and 5c were
deduced from their NMR characterization data (see
Supporting Information) and by analogy with previously
established structures of related dimers. In all reported
cases,1a,b,d the cyclodimerization takes place via an endo-
selective “back-to-back” mutual approach of the two
cyclohexa-2,4-dienone monomers with the C4′-C5′ double
bond always acting as the dienophile (Scheme 2). In
contrast to 1b and 1c, the 2-methoxyphenols 1d and 1e
bearing the same substituents, but at their 4-position,
led to the desired orthoquinone monoketals 4d and 4e
in 100 and 64% yields, respectively (entries 4 and 5).
These results are in agreement with previous observa-
J. Org. Chem, Vol. 69, No. 25, 2004 8733

Deffieux et al.
TABLE 2. Anodic Oxidation of a Series of
support drastic changes in chemical reactivity (see Sup-
porting Information). Similar calculations have been
carried out by others at the same and higher levels11b,14
in order to rationalize the reactivity and high regiose-
lectivity observed in the case of reactions of differently
substituted orthoquinone monoketals with various ex-
ternal dienophiles. It was also concluded that calculations
based on such simple terms of FMO theory are not
enough to delineate any general trends in the reactivity/
selectivity profile of orthoquinone monoketals with elec-
tron-deficient dienophiles.11b,14 These reactions are analo-
gous to the dimerization reactions in the sense that the
C4′-C5′ double bond of the orthoquinone monoketal unit
acting as a dienophile is under the influence of the
electron-withdrawing effect of the 2-en-1-one unit of the
system (Scheme 2). Thus, the stabilizing effects observed
with a bromine atom or a tert-butyldiphenylsilyloxym-
ethyl group at the 4-position of the cyclohexa-2,4-dienone
system, as well as with a methoxy group at the 5-position,
are simply due to the size of the substituent rather than
to its electronic effect. Although the methoxy group does
not exhibit a large steric demand, its presence at the
5-position of the system such as in 4f can still block the
cyclodimerization by mutually interfering with the gemi-
nal groups at the sp3-hybridized C6 center of the other
unit, as first suggested by Waring for generic cyclohexa-
2,4-dienones (Scheme 2).1d The known blocking effect of
a methyl group at the same position,10b,11 as well as that
of a bulky group at the 4-position,8c,11b,c,12a is probably due
to the same type of steric impediment.1d
r-(2-Methoxyphenoxy)-2-methylpropionic Acids
This first series of reactions confirmed previous obser-
vations made by us and others on the critical and fine
influence exhibited by substituent positioning and size,
rather than electronic effect, on the stability of ortho-
quinone monoketals. A bulky substituent at their 4-posi-
tion blocked the Diels-Alder process, but the same
substituent at their 3-position did not (entries 4 and 5
vs entries 2 and 3), and a relatively small group at their
5-position is enough to furnish nondimerizing species
(entry 6). Three new examples are reported herein
(entries 2-4, Table 1). Most importantly, anodic oxidation
of 2-methoxyphenols in methanol appears as a valuable
alternative methodology for generating nondimerizing
orthoquinone monoketals.8b,c
a Reactions were carried out in CH3CN-MeOH (9:1) containing
LiClO4 as a supporting electrolyte. b Reactions were carried out
in CH3CN-H2O (9:0) containing LiClO4 as a supporting electro-
lyte. c Isolated yields are given in parentheses where applicable.
d OQMK ) orthoquinone monoketal. e OQBK ) orthoquinone
bisketal. f DAD ) Diels-Alder dimer. g Not observed. h See ref 8a.
We then applied similar anodic oxidation conditions
to a series of 2-alkoxyphenyl alkyl ethers of type 2. For
this, we used R-(2-methoxyphenoxy)-2-methylpropionic
acids 2b-f for which the first nucleophilic entities (i.e.,
R′OH) trapping the radical cation intermediate of type
III into a radical of type IV are tethered to one of the
alkoxy groups (Scheme 1). The incentive for this choice
was initially based on the fact that 6-acetoxy-6-meth-
oxycyclohexa-2,4-dienones (i.e., 4, R ) Me, R′ ) Ac,
Scheme 1) do not dimerize.6,13 The reasons for this
efficient blocking effect of a 6-acetoxy group are not
known. Liao and co-workers suggested that one methoxy
group in 6,6-dimethoxy derivatives participates in sec-
ondary orbital interactions (SOIs) through its oxygen lone
pair to enhance the propensity of these species to self-
dimerize (e.g., 4a f 5a, Scheme 2).11b A downward
modulation of this orbital control with an adequately
oriented acetoxy group in which the oxygen lone pair is
now conjugated with the adjacent carbonyl group cer-
tainly opens up a track for further theoretical investiga-
tions (Scheme 2). In any event, we thought that having
a cyclic version of the same ketal functionality would
allow the generation of nondimerizing O-spirolactone
cyclohexa-2,4-dienones (e.g., 4h, Scheme 2), with the
added advantage of introducing chiral centers next to the
carbonyl group for asymmetric induction in subsequent
transformations. Unfortunately, as we previously re-
ported,8a the conformational constraint brought about by
the cyclic structure counteracts any Diels-Alder blocking
effect of the lactonic acyloxy unit and cyclodimers are
readily produced (Scheme 2 and Table 2, entry 1).
Furthermore, only R-dialkylated carboxylic units undergo
the desired intramolecular spirocyclization thanks to the
(14) (a) Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856-
866. (b) Gao, S.-Y.; Ko, S.; Lin, Y.-L.; Peddinti, R. K.; Liao, C.-C.
Tetrahedron 2001, 57, 297-308. (c) Arjona, O.; Medel, R.; Plumet, J.;
Herrera, R.; Jime´nez-Va´zquez, H. A.; Tamariz, J. J. Org. Chem 2004,
69, 2348-2354.
8734 J. Org. Chem., Vol. 69, No. 25, 2004

Dimerizing and Nondimerizing Orthoquinone Monoketals
help of a gem-dialkyl Thorpe-Ingold effect, in contrast
to R-monomethylated carboxylic acids and acetic acid
derivatives that do not cyclize.8a Notwithstanding, we
here wanted to identify an appropriate substitution
pattern on R-(2-methoxyphenoxy)-2-methylpropionic ac-
ids that would permit the generation of stable O-
spirolactone cyclohexa-2,4-dienones.
by performing the anodic oxidation in the presence of
water (route b, Scheme 1 and Table 2). For this approach,
electrolyses of the R-(2-methoxyphenoxy)-2-methylpro-
pionic acids 2b-f were carried out at a constant current
in a CH3CN-H2O (9:1) solvent mixture, still containing
LiClO4 as a supporting electrolyte. Under these condi-
tions, the O-spirolactone quinone monoketals 4h/i and
4l/m behaved in a similar manner, but overall yields were
consistently lower than those obtained by the two-step
electrolysis-hydrolysis procedure (Table 2). All together,
these results validate the anodic oxidation approach as
an alternative to chemical means to transform either
2-alkoxyphenols of type 1 or 2-alkoxyphenyl alkyl ethers
of type 2 into orthoquinone monoketals, which can be
isolated as such if equipped with appropriate substituents
at appropriate positions to prevent their cyclohexa-2,4-
dienone unit from engaging in cyclodimerization. Fur-
thermore, it is worth noting that these electrooxidations
were carried out using a convenient single-cell system
with electrolytic media compatible with the reduction
events. In particular, no side-reduction of aryl bromides
was observed in these reactions.
The [4 + 2] cyclodimerization of orthoquinone monoket-
als and related orthoquinols has been extensively studied
over the last 50 years. Ample chemical evidence sup-
ported by a few crystallographic analyses has been
gathered early on, in particular by Adler and co-
workers,11d,13,15 to confirm the structures of such dimers,
but the extraordinary selectivity of this chemistry has
not yet been thoroughly rationalized. Indeed, this Diels-
Alder-type reaction exhibits extremely high site selectiv-
ity, regioselectivity, and stereoselectivity. The ortho-
quinone monoketal unit acting as a dienophile always
engages its C4′-C5′ double bond, never its C2′-C3′ double
bond, and the dimerization always furnishes dimers with
ortho regiochemistry and anti stereochemistry (i.e., the
C3′-C2′ double bond is adjacent and anti to the C1
carbonyl group, Scheme 2).14a The anti selectivity can be
classically explained as resulting from an endo transition
state that is preferred over the exo alternative because
it is stabilized by SOIs between the C2′-C3′ double bond
of the monomer acting as a dienophile and the olefinic
double bonds of the monomer acting as a diene. However,
the ortho regioselectivity of the process remains puzzling.
Again, calculations of atomic coefficients of both the
HOMO and LUMO we performed on the dimerizing
orthoquinone monoketals 4a and 4c do not provide any
clear-cut rationale (see Supporting Information). For the
HOMOs, coefficients at C2 and C5 are both the largest
ones but are nearly the same, with a somewhat larger
coefficient at C2, and for the LUMOs, the largest coef-
ficients are at C3′, so the observed regioselectivity cannot
be explained on this basis, since it would at best favor a
participation of the C2′-C3′ double bond as a dienophile.
The two electrochemical tactics here available to us for
carrying out such a task are the anodic oxidation-
selective hydrolysis sequence to orthoquinone monoketals
of type 4 (route a, Scheme 1) and their in situ generation
by performing the anodic oxidation in the presence of
water (route b, Scheme 1). Both approaches were imple-
mented, and anodic oxidations of 2b-f were carried out
at a controlled potential in order to minimize the con-
comitant oxidation of water that would otherwise occur
during constant-current electrolysis. The anode potential
was set at 1.8 V vs Ag/AgCl. The electrolysis was stopped
after passage of 2.5 F/mol. The anodic oxidation-hy-
drolysis sequence was first applied by performing the
reaction in a CH3CN-MeOH (9:1) solvent mixture. The
O-spirolactone quinone bisketals 3b-f were all obtained
in yields ranging from 42 to 78% (Table 2). Selective
hydrolysis of these bisketals led to different results
depending on the nature and positioning of the substit-
uents on the cylohexadienone ring. Treatment of bisketal
3a with 10% aq HCl in acetone (1:1) for 30 min was
sufficient to selectively hydrolyze it into the monoketal
4h, which spontaneously dimerized into 5h in quantita-
tive yield. The structure of 5h has been unambiguously
determined by an X-ray analysis.8a Stronger acidic condi-
tions (i.e., 2 N aq H2SO4 in acetone at room temperature
for 30 min) had to be used to convert bisketal 3b into
the monoketal 4i, which again quickly dimerized to
furnish 5i in 78% yield, indicating that the presence of
the electron-releasing n-propyl group at the 3-position
of the lactonic monoketal 4i does not block the Diels-
Alder process (Table 2, entry 2). It is already known from
the work of Yamamura and co-workers that the presence
of secondary alkyl groups or alkenyl groups with similar
steric demand at the 4-position of orthoquinone monoket-
als does not prevent their dimerization.9 Bisketal 3e was
hydrolyzed under the same conditions as for 3a8a to
furnish the dimer 5l in 78% yield (Table 2, entry 5),
indicating that a bromine atom at the 3-position of the
lactonic monoketal 4l does not express any retarding
effect on the Diels-Alder dimerization process, as already
observed for 4c (Table 1, entry 3). However, monoketal
4m was isolated in a good yield of 71% after selective
hydrolysis of its bisketal parent 3f under the same
conditions (Table 2, entry 6), showing again the efficacy
of a bromine atom at the 4-position in stabilizing the
cyclohexadienone unit.
Direct evidence of this importance of the bromine atom
positioning in the control of the Diels-Alder dimerization
was obtained when a 1:1 mixture of the two regioisomers
3e and 3f was monohydrolyzed to cleanly furnish the
dimer 5l (46%) and the nondimerizing ketal 4m (41%),
respectively. Monohydrolysis attempts on bisketals 3c
and 3d bearing a tert-butyldiphenylsilyloxymethylenyl
group at their 4- and 5-positions, respectively, only led
to untractable mixtures (Table 2, entries 3 and 4). The
same disappointing observations were made when at-
tempting to generate directly their monoketal versions
(15) (a) Adler, E.; Andersson, G.; Edman, E. Acta Chem. Scand.
1975, B 29, 909-920. (b) Adler, E.; Holmberg, K.; Ryrfors, L.-O. Acta
Chem. Scand. 1974, B 28, 888-894. (c) Adler, E.; Holmberg, K. Acta
Chem. Scand. 1974, B 28, 465-472. (d) Adler, E.; Holmberg, K. Acta
Chem. Scand. 1974, B 28, 549-554. (e) Adler, E.; Holmberg, K. Acta
Chem. Scand. 1971, 25, 2775-2776. (f) Adler, E.; Brasen, S.; Miyake,
H. Acta Chem. Scand. 1971, 25, 2055-2069. (g) Adler, E.; Junghahn,
L.; Lindberg, U.; Berggren, B.; Westin, G. Acta Chem. Scand. 1960,
14, 1261-1273. (h) Metlesics, W.; Wessely, W. Monatsch. Chem. 1957,
88, 108-117. For X-ray analyses, see: (i) Karlsson, B.; Kierkegaard,
P.; Pilotti, A.-M.; Wiehager, A.-C.; Lindgren, B. O. Acta Chem. Scand.
1973, 27, 1428-1430.
J. Org. Chem, Vol. 69, No. 25, 2004 8735

Deffieux et al.
SCHEME 3
SCHEME 4
of 4-allyl-2,6-dimethoxyphenol (1h) in methanol contain-
ing LiClO4 as a supporting electrolyte to furnish the
orthoquinone monoketal 4n; this monoketal quantita-
tively dimerized into 5n upon standing overnight at room
temperature (Scheme 3).9c,19 With this precedent directly
related to our work in mind, we submitted 5i in a 3:1
n-hexanes-Et2O solution to irradiation at room temper-
ature using a medium-pressure mercury lamp with a
Pyrex filter. The bicyclo[2.2.2]octenone 5i was thus
cleanly converted to the pentacyclododecanedione 6i in
83% yield (Scheme 3).
If we compare the coefficients at C2 and C5 of the LUMO
of one orthoquinone monoketal acting as the diene
partner, the C5 coefficient is the largest one of the two,
but the slightly larger coefficient of the HOMO of the
other orthoquinone monoketal unit acting as the dieno-
phile is at C2′. It has already been reported that Diels-
Alder reactions of dienes and dienophiles terminally
substituted by electron-demanding groups cannot be
explained in terms of simple FMO theory when unper-
turbed reactants are considered but that other factors
such as SOIs at the transition state level may be
controlling these dimerization regioselectivities.11b,16
In the case of orthoquinone monoketal-derived [4 + 2]
cycloadducts, their inherent reactivity might actually
provide further insight into their remarkable regioselec-
tivity. In an attempt to confirm the structure of 5i (Table
2) by X-ray crystallography, we let a sample of this dimer
(i.e., 10 mg) in CH2Cl2 be exposed to light on the bench.
Crystallization did occur slowly, but the compound we
obtained was 6i (see the ORTEP diagram in Scheme 3),
resulting from an intramolecular [2 + 2] cyclobutanation.
This is a well-known process of cyclohexa-2,4-dienone
photochemistry,17,18 which has been, inter alia, judiciously
exploited by Yamamura and co-workers for the synthesis
of neolignan-type compounds.9c,g,i,j,l,n For example, isoa-
satone 6n was synthesized in 64% yield by irradiating
asatone 5n,9n which has been prepared in 36% yield by
electrolyzing at constant current (0.31 mA/cm2) a solution
Dimers 5a-c were then submitted to the same pho-
tochemical reaction conditions and again cleanly fur-
nished the corresponding [2 + 2] photodimers 6a-c
featuring two fused four-membered rings. Despite their
intrinsic strain energy, these cage compounds are quite
stable and they all exhibit very simple NMR signal
patterns, because their structure is characterized by a
2-fold axis of symmetry, all atoms and substituents
constituting equivalent pairs around this axis (see Sup-
porting Information).17,18 The structures of 6a-c are here
deduced by analogy with that of 6i, which has been
unambiguously determined by X-ray crystallography
(Schemes 3 and 4). Furthermore, the X-ray structure of
6i confirmed the structure of its [4 + 2] dimer parent,
and hence those of all the dimers described therein
(Tables 1 and 2) that all exhibit the same spectroscopic
criteria. Of particular note is the fact that the racemic
O-spirolactones 5h,8a 5i, and 5l exclusively result from
dimerization of 4h, 4i, and 4l, respectively, in which the
configuration at C6/C6′ is the same (S/S shown or R/R)
with the two less sterically demanding acyloxy units
pointing toward each other and the two gem-dimethyl
units pointing away from each other during the Diels-
Alder approach. No dimer resulting from the pairing of
two enantiomers of different configuration at C6/C6′ is
formed. This diastereoselectivity is further evidence of
the extraordinary manner with which these [4 + 2]
cyclodimerizations are controlled, but again, this stereo-
selectivity still demands to be further explained. How-
(16) (a) Houk, K. N. J. Am. Chem. Soc. 1973, 95, 4092-4094. (b)
Houk, K. N.; Domelsmith, L. N.; Strozier, R. W.; Patterson, R. T. J.
Am. Chem. Soc. 1978, 100, 6531-6533. (c) Alston, P. V.; Ottenbrite,
R. M.; Guner, O. F.; Shillady, D. D. Tetrahedron 1986, 42, 4403-4408.
(d) Alston, P. V.; Ottenbrite, R. M.; Shillady, D. D. J. Org. Chem. 1973,
38, 4075-4077. (e) Fleming, I.; Michael, J. P.; Overman, L. E.; Taylor,
G. F. Tetrahedron Lett. 1978, 15, 1313-1314. (f) Eisenstein, O.; Lefour,
J. M.; Anh, N. T.; Hudson, R. F. Tetrahedron 1977, 33, 523-531.
(17) (a) Hamada, T.; Iijima, H.; Yamamoto, T.; Numao, N.; Hirao,
K.-i.; Yonemitsu, O. J. Chem. Soc., Chem. Commun. 1980, 696-697.
(b) Iwakuma, T.; Hirao, K.-i.; Yonemitsu, O. J. Am. Chem. Soc. 1974,
96, 2570-2575. (c) Iwakuma, T.; Yonemitsu, O.; Kanamaru, N.;
Kimura, K.; Witkop, B. Angew. Chem., Int. Ed. 1973, 12, 72-73.
(18) (a) Becker, H.-D.; Konar, A. Tetrahedron Lett. 1972, 5177-5180.
(b) Antus, S.; Nogradi, M.; Baitz-gacs, E.; Radics, L.; Becker, H.-D.;
Karlsson, B.; Pilotti, A.-M. Tetrahedron 1978, 34, 2573-2577.
(19) For another synthesis of asatone 5n by oxidation of 1h using
(diacetoxy)iodobenzene, see: Ku¨rti, L.; Szilagyi, L.; Antus, S.; Nogradi,
M. Eur. J. Org. Chem. 1999, 2579-2581. These authors claimed an
improved synthesis of 5n, but the corresponding yield they reported
is only 22%.
8736 J. Org. Chem., Vol. 69, No. 25, 2004

Dimerizing and Nondimerizing Orthoquinone Monoketals
SCHEME 5
double bond would respectively connect with the C5 and
C2 sp2-centers of the other unit (Scheme 5) indicates that
the latter [4 + 2] approach does not permit the most
adequate sp2 orbitals’ alignment for extra stabilization
from SOIs and, hence, subsequent photocyclization dur-
ing which the same orbital interactions are involved in
the observed [2 + 2] bond-making events. In both cases,
the C2′-C3′ double bond remains conjugated with the C1′
carbonyl group that can hence behave as an effective
intramolecular triplet sensitizer in the process;20 how-
ever, the orbitals alignment differences are in favor of
the case resulting in product formation, that is, 5a
(Scheme 2) and not 5a′ (Scheme 5). The only other
explanation that has been put forward early on to
rationalize this remarkable regioselectivity in the [4 +
2] cycloaddition of cyclohexa-2,4-dienones relied on an
agreement to the principle of the lowest dipole moment
of the transition state: dimers of type 5a displaying a
lower dipole than dimers of type 5a′.21 Such an argument
is certainly valid, but our hypotheses deserve to be
examined with the help of computer-based molecular
modeling, as they constitute new premises for such
theoretical investigations.
In conclusion, this work has demonstrated that anodic
oxidation of 2-methoxyphenols of type 1 and R-(2-meth-
oxyphenoxy)-2-methylpropionic acids of type 2 is a valu-
able alternative to the use of chemical oxidants to
generate orthoquinone monoketals, which are stable if
properly equipped with substituents to block their [4 +
2] cyclodimerization. When formed, the corresponding
dimers can be readily converted to C2-symmetric cage
photodimers. Suggestions were made on the basis of this
[2 + 2] reactivity to explain the extraordinary site
selectivity, regioselectivity, and stereoselectivity observed
in the [4 + 2] cyclodimerization of orthoquinone monoket-
als. Computational work is in progress with the aim of
providing a sound rationalization of this chemistry at the
theoretical level, and results will be reported in due
course.
ever, as alluded to above, an explanation can be proposed
for their ortho regioselectivity on the basis of the facility
with which orthoquinone monoketal-derived endo-dimers
can be photochemically converted into [2 + 2] pentacy-
clododecanediones. This facility may be a consequence
of the SOIs that can take place between their C2′, C3′,
C3, and C4 sp2-centers (Scheme 2, 2 × 4a f 5a). In other
words, these stabilizing SOIs could be the factor that
kinetically selects the transition state path leading not
only to the endo(anti) stereochemistry17,18 but also to the
ortho regiochemistry exclusively observed for these dimers.
Upon irradiation, these [4 + 2]-controlling SOIs are then
allowed to engage into the bond-making events of the [2
+ 2]-cyclization.
The presence of additional substituents on the dimer-
izing orthoquinone monoketals does not appear to have
any major deleterious effects on the facility with which
the [2 + 2] cycloaddition occurs, since dimers 5a-c and
5i were here all readily and cleanly converted to their
corresponding pentacyclododecanedione photodimers
(Schemes 3 and 4). For the sake of simplicity, only the
three alternative endo approaches of two orthoquinol
monoketal units 4a are depicted in Scheme 5, including
those for which the C2′-C3′ double bond acts as a
dienophile that would give rise to the meta/anti dimers
5a′′ and the ortho/anti dimer 5a′′′. These two possibilities
can be ruled out on the basis that the remaining C4′-C5′
double bond loses its conjugation with the electronic-
demanding C1′ carbonyl group in the process, thus
probably affecting the extent of any participation of this
double bond in SOIs with the C3 and C4 p-orbitals of the
other 4a unit (Scheme 5). Could this trivial hypothesis
constitute a premise for a theoretical rationalization of
the yet unexplained site-selectivity observed in these
orthoquinone monoketal Diels-Alder dimerizations? Turn-
ing our attention back to the ortho regioselectivity
observed in the participation of the C4′-C5′ double bond
as a dienophile, a simple comparative examination of
molecular models of the [4 + 2] cycloadducts resulting
from (1) the operational approach during which the C4′-
C5′ double bond of one unit respectively connects with
the C2 and C5 sp2-centers of the other unit (Scheme 2)
and (2) the alternative approach during which the same
Experimental Section
General Procedures for Electrochemical Oxidation.
Procedure A. Constant-current electrolyses were carried out
in a 100 mL, undivided, cylindrical cell, equipped with a
platinum-coated titanium grid (50 g Pt/m2, 40 × 60 mm) as
the anode and a copper wire (0.5 mm diameter) as the cathode.
Lithium perchlorate (LiClO4, 1.5 g, 14.0 mmol) was added as
a supporting electrolyte to anhydrous MeOH (50 mL). The
starting material was introduced ,and the electrolysis was then
performed at 50 or 100 mA using a regulated DC power supply
until the desired charge passed (ca. 2.5 F/mol). All reactions
were vigorously stirred. After electrolysis, the solution was
evaporated, and the residue was diluted in CH2Cl2 (50 mL)
and washed with H2O (3 × 30 mL). The layers were then
separated, and the aqueous layer was extracted with CH2Cl2
(3 × 30 mL). The combined organic extracts were dried over
Na2SO4, filtered, and evaporated to dryness. Procedure B.
Controlled-potential electrolyses were carried out in a 100 mL,
undivided, cylindrical cell, equipped with a platinum-coated
titanium grid (50 g Pt/m2, 40 × 60 mm) as the anode and a
copper wire (0.5 mm diameter) as the cathode. Lithium
perchlorate (LiClO4, 1.5 g, 14.0 mmol) was added as supporting
(20) de Mayo, P. Acc. Chem. Res. 1971, 4, 41.
(21) Brown, T. L.; Curtin, D. Y.; Fraser, R. R. J. Am. Chem. Soc.
1958, 80, 4339-4341.
J. Org. Chem, Vol. 69, No. 25, 2004 8737

Deffieux et al.
electrolyte to a 50 mL mixture of acetonitrile-methanol or
acetonitrile-water (9:1). The starting acid and the base (e.g.,
2,6-lutidine or pyridine, 2 equiv) were introduced, and the
electrolysis was then performed at constant potential on a
potentiostat using an Ag/AgCl reference electrode until the
current decayed smoothly to background. All reactions were
vigorously stirred. After electrolysis, the solution was evapo-
rated, and the residue was diluted in CH2Cl2 (50 mL) and
washed with H2O (3 × 30 mL). The layers were then separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 30 mL).
The combined organic extracts were dried over Na2SO4,
filtered, and evaporated to dryness.
assistantship and the European undergraduate student
exchange ERASMUS program for A.T.’s scholarship.
Supporting Information Available: Detailed descrip-
tions of experimental procedures, 1H and 13C NMR spectra of
compounds 1b-d,g, 2b-f, 3b-f, 4d-f,m, 5a-c,i,l, and 6a-
c,i, an ORTEP diagram and a CIF file (CCDC 245748) of the
X-ray structure of 6i, and HOMO/LUMO energies, atomic
coefficients, and computational data of compounds 4a,c,e,f.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. The authors wish to thank the
French Ministry of Research for I.F.’s graduate research
JO048677I
8738 J. Org. Chem., Vol. 69, No. 25, 2004