Synergistic catalysis of anthrone Dels-Ader reactions

Article abstract of DOI:10.1021/ol025760o

Matrix presented The combination of an amine base and Lewis acid (Li⁺) leads to synergistic catalysis of the Diels-Alder reaction of anthrone with methyl crotonate and some other less reactive dienophiles. These cycloadditions either do not occ

Full text of DOI:10.1021/ol025760o

ORGANIC
LETTERS
†
2002
Vol. 4, No. 10
Synergistic Catalysis of Anthrone
1
711-1713
Diels−Alder Reactions
Roy Harrison and Bruce Rickborn*
Department of Chemistry & Biochemistry, UniVersity of California Santa Barbara,
Santa Barbara, California 93106
rickborn@chem.ucsb.edu
Received February 21, 2002
ABSTRACT
+
The combination of an amine base and Lewis acid (Li ) leads to synergistic catalysis of the Diels−Alder reaction of anthrone with methyl
crotonate and some other less reactive dienophiles. These cycloadditions either do not occur with the individual catalysts used separately or
they are greatly accelerated by the combined catalysts. DMSO solvent allows the use of LiCl as the Lewis acid source and can provide greater
control of subsequent conversion to Michael adduct.
Bridgehead hydroxyl cycloadducts such as 3 have been
shown to undergo facile base-induced retro-Diels-Alder
reaction at or below room temperature (Figure 1). This
The adducts used to date in multistep syntheses have been
formed by Diels-Alder reaction of O-protected anthracenols,
1
1
with subsequent removal of the protecting group. The
modest diene reactivity of 9-RO-anthracenes limits the use
of this approach to cycloadditions with very reactive dieno-
philes.
The possibility of forming bridgehead-OH adducts di-
rectly from anthrone (1) was recognized as early as 1934,
although the attempted reaction with maleic anhydride (MA)
at 188 °C led only to Michael adduct and to the incorrect
conclusion that such Diels-Alder adducts could not be
3
isolated. Several years later it was shown that the Michael
Figure 1. Generalized base-induced retro-Diels-Alder reaction.
isomer is more stable than the Diels-Alder cycloadduct, but
either isomer can be made to dominate by controlling the
4
reaction time in refluxing HOAc (118 °C). The choice of
synthetically useful procedure is driven by the formation of
the phenoxide, and it benefits kinetically by accessing the
oxyanion energy surface.2
HOAc as solvent was intended to facilitate keto-enol
tautomerism, but we find that the reaction of 1 with MA
also affords, in nearly quantitative yields, Diels-Alder adduct
4
(2.0 h, refluxing toluene, 111 °C) or Michael adduct 5
†
Synergy ) working together; we have no evidence that bears on the
(3.5 h, refluxing m-xylene, 139 °C) as shown in Figure 2.
possibility that the combined effect may be greater than the sum of the
individual contributions of the two catalysts (an alternative definition).
These observations support the view that the cycloaddition
step, rather than tautomerism, is rate-determining. It was also
(
1) (a) Knapp, S.; Ornaf, R. M.; Rodriques, K. E. J. Am. Chem. Soc.
983, 105, 5494. (b) Nicolaou, K. C.; Bunnage, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1110.
2) (a) Rickborn, B. Org. React. 1998, 52, 1 (The Retro-Diels-Alder
Reaction: Part I. C-C Dienophiles). (b) Wilson, S. R. Org. React. 1993,
3, 94 (Anion-Assisted Sigmatropic Rearrangements).
1
(
(3) Barnett, E. d. B.; Goodway, N. F.; Higgins, A. G.; Lawrence, C. A.
J. Chem. Soc. 1934, 1224.
4
(4) Cohen, D.; Millar, I. T.; Richards, K. E. J. Chem. Soc. C 1968, 793.
1
0.1021/ol025760o CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/24/2002

3 2
Figure 3. Reaction of Et N with MA and H O.
Figure 2. Cycloadduct and Michael adduct of anthrone + MA.
surroundings to give triethylammonium maleate 7. The
details of the reaction steps remain unclear, but it appears
8
shown that the cycloadduct could serve as a precursor to
Michael product under both acidic and “neutral” conditions.
Previous work from this laboratory demonstrated that
anthrone in the presence of an amine can function as a very
reactive diene in Diels-Alder reactions. Cycloadducts of
dienophiles ranging in reactivity from N-methylmaleimide
that water is needed to generate color.
In principle, the isomerization of a cycloadduct to a
Michael product could occur as either an intra- or inter-
molecular process, the former being essentially a retro-aldol
reaction. The intermolecular possibility requires a retro-
Diels-Alder reaction, followed by a Michael reaction. The
latter pathway appears to be ruled out by the observation
that 4 is cleanly converted to 5 by prolonged amine-catalyzed
treatment. If free MA had been generated, it would have
been consumed by reaction with base.
(NMM) through maleonitrile, fumaronitrile, dimethyl fuma-
rate, methyl acrylate, to 2-butenolide at the least reactive
end were all formed, stereo- and regiospecifically, in room
5
temperature amine-catalyzed reactions. This greatly en-
hanced reactivity is again attributed to accessing the oxyanion
energy surface, with the notable difference that the weaker
amine base allows the cycloadduct to be favored thermody-
namically over the educts (compare Figure 1).
No reaction of any kind was observed in several attempts
to effect cycloaddition of anthrone with methyl crotonate
under basic conditions. However, when LiClO
4
in ether was
used in conjunction with Et N, both cycloadducts and
3
Several different cycloadducts were converted to the
corresponding Michael products under amine-catalyzed
conditions. With some substrates it proved difficult (or
impossible) to avoid formation of Michael adduct, and the
conversion of cycloadduct was especially facile in protic
solvents such as methanol. Additional evidence on the
mechanism of this isomerization was obtained in the present
study.
Michael adducts were formed. Neither catalyst was effective
separately; thus a synergistic effect is observed.
The use of Lewis acids including Li+ salts to catalyze
Diels-Alder reactions is well-known. We assume that this
4
is the fundamental role played by LiClO as a component
of the catalyst mixture, i.e., activation of the dienophile
through cation coordination, although other possibilities may
come into play including tethering of the reactants through
coordination to the metal ion.
While higher concentrations of the salt cause more rapid
reaction, the effect on rate is not directly proportional to
concentration. The salt is clearly catalytic, since less than 1
5
Conspicuously absent from the list of dienophiles that have
been successfully employed under the amine-catalyzed
conditions are MA and substituted acrylate analogues (e.g.,
crotonate). While the latter is rationalized simply on the basis
of diminished reactivity, the failure of MA to give cycload-
duct was initially puzzling. MA is very similar to (very
reactive) NMM in cycloaddition rates with a wide range of
3
equiv (per mole of either substrate or Et N) leads to one of
the better yields of cycloadduct 2, as shown in Table 1.
The catalyst mixture also enhances the conversion of
cycloadduct 2 to Michael product 8. This secondary reaction
can be largely avoided by the use of a lower concentration
6
dienes including anthracenes under neutral/acidic conditions.
The amine-catalyzed reaction of NMM with anthrone is rapid
and efficient, leading to cycloadduct in quantitative yield
within minutes. The failure of MA to give cycloadduct with
anthrone under these conditions proved to be due to a very
fast competing reaction of MA and the tertiary amine, which
consumes the base. This reaction has been reported previ-
ously, as marked by intense color changes (charge transfer)
of LiClO
DMSO as solvent has another advantage over Et
LiCl can be used in place of LiClO with no apparent loss
in reactivity. Although concentrations of LiClO in DMSO
4
in ether, or through the use of DMSO solvent.
2
O in that
4
4
reach a maximum near 3.5 M, concentrations of ap-
+
proximately 1.5 M Li in DMSO (and also in Et
2
O) appear
and presumed formation of the acylammonium zwitterion 6
to be optimal for synergistic catalysis, with no dramatic rate
7
(
Figure 3). We believe that 6 is indeed formed, but as a
very hygroscopic intermediate which absorbs water from the
(8) When sublimed MA and Et3N are mixed in anhydrous ether in a
closed system, color is not immediately observed. Upon exposure to (moist)
air, the solution rapidly darkens, passing through various stages of yellow
to intense brown as moisture diffuses through the solution. At higher
(
5) (a) Rickborn, B.; Koerner, M. J. Org. Chem. 1989, 54, 6. (b)
Rickborn, B.; Koerner, M. J. Org. Chem. 1990, 55, 2662. (c) Rickborn, B.;
Koerner, M. J. Org. Chem. 1991, 56, 1373.
1
concentrations, colorless 7 precipitates; this structure is supported by H
(
6) Harrison, R.; Tobia, D.; Philips, B.; White, T.; DiMare, M.; Rickborn,
B.J. Org. Chem. 1993, 58, 6701.
7) Mayahi, M. F.; El-Bermani, M. F. Can. J. Chem 1973, 51, 3539.
and 13C NMR spectra, which exhibit the symmetry expected of rapid OH
proton transfer, and by identity to material prepared by mixing maleic acid
and Et3N.
(
1712
Org. Lett., Vol. 4, No. 10, 2002

1
Alder reactions under very mild conditions, and amines can
cause rearrangement to Michael adducts, many standard
reaction conditions may prove difficult or impossible to
apply. This question takes on special significance since in
our experience the sterically hindered bridgehead hydroxyl
does not react with most common protecting group reagents.
We chose reduction of the ester function as a demanding
test of structural stability, using crotonate adduct 2 as the
substrate. The “acidic” reducing agent DIBAL cleanly
afforded the diol 11 (83%). More interestingly, the “basic”
Table 1. Reaction of Methyl Crotonate and Anthrone under
Synergistic Catalysis
4
reducing agent LiAlH worked equally well (85%), perhaps
reflecting the formation and covalent nature of OAl (as
opposed to OLi) bonds. Both reactions were carried out in
0.25 h at 0 °C, in ether. The ability to use these strong
reducing agents without cleaving the bicyclic structure is
encouraging (Figure 5).
[
LiX]b
[Et3N]
solvent
t (h)
% 2
% 8
0
1
.07a
.25
.4
.4
.2
1
Et2O
Et2O
Et2O
Et2O
acetone
DMSO
DMSO
45
16
0.5
0.5
0.5
16
62
38
15
15
12
71
80
trace
22
0
0
0
0.25
0.25
1
0.25
1
5
5
5
1
1
.53
.52c
0
0
1
18
a
b
[
crotonate]init. ) [anthrone]init. ) ca. 0.25. LiClO4 unless otherwise
c
noted. LiCl.
increases noted for higher concentrations. Additionally, both
4
LiClO and LiCl show appreciable solubility in DMSO as
hydrates, which maintain catalytic reactivity for cyclo-
addition.
Figure 5. Reduction of unprotected cycloadducts.
9
Synergistic catalysis also proved useful for methyl 2-
butynoate cycloaddition to form 9, a reaction that was
otherwise sluggish at best. The reaction was carried out in
In conclusion, the utility of the base-catalyzed Diels-Alder
reactions of anthrone has been extended to previously
unreactive dienophiles through the addition of lithium salt
cocatalysts. Since neither catalyst alone is effective with
methyl crotonate, the effect is synergistic. The use of DMSO
ether at high (5.1 M) LiClO
4
concentration and halted after
h; 9 was isolated in 55% yield.1 Hydrogenation of 9
0
3
quantitatively produced the formal (Z)-methyl 2-butenoate
cycloadduct 10, demonstrating a potentially useful approach
to such cis-substituted materials (Figure 4).
solvent and LiCl instead of LiClO is noteworthy. Some
further reactions of the cycloadducts illustrate a useful level
4
of structural stability. Attempts to apply the mixed catalyst
procedure to other substrates brought out limitations. Simple
enones (cyclopentenone, cyclohexenone) do not react when
either catalyst alone is employed but react rapidly under
synergistic catalysis to give Michael adduct without evidence
of cycloadduct intermediate. More highly substituted enones
and unsaturated esters gave no reaction under any of the
conditions explored. Substituted maleic anhydrides gave
other processes, likely related to the reaction of MA described
in this paper. No adducts could be isolated when quinones
were employed as prospective dienophiles.
Figure 4. Cycloaddition of methyl 2-butynoate and double bond
reduction.
Acknowledgment. This work was supported in part by
the UCSB Committee on Research.
The further utility of free bridgehead hydroxyl cycload-
ducts in multistep syntheses remains to be examined. Since
KH and also BuLi have been used to effect retro-Diels-
Supporting Information Available: Experimental pro-
1
13
cedures and characterizations. H NMR and C NMR for
1
2
, 8 (ethyl ester), 9, and 11 and H NMR compound 10.
HiRes-MS available for compounds 2, 9, and 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
9) LiCl is completely insoluble in Et2O; LiClO4 is soluble in Et2O only
when anhydrous.
10) Equimolar amounts of reagents and Et3N were used. The course of
(
the reaction was followed by NMR. It was stopped when bianthronyl (air
oxidation of anthrone) was detected.
OL025760O
Org. Lett., Vol. 4, No. 10, 2002
1713