Reactive dienes: Intramolecular aromatic oxidation of 3-(2-hydroxyphenyl)-propionic acids

Article abstract of DOI:10.1021/ol0169776

(formula presented) Treatment of 3-(2-hydroxyphenyl)-propionic acids with a hypervalent iodine reagent in the presence of a dienophile initiates a tandem intramolecular aromatic oxidation/Diels-Alder reaction. Herein we report (1) investigations on the scope and limitations of this novel reaction combination and (2) preliminary diastereoselectivity studies using α- and β-substituted acids.

Full text of DOI:10.1021/ol0169776

ORGANIC
LETTERS
2002
Vol. 4, No. 4
493-496
Reactive Dienes: Intramolecular
Aromatic Oxidation of
3-(2-Hydroxyphenyl)-propionic Acids
Ioana Drutu, Jo´n T. Njardarson, and John L. Wood*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity,
New HaVen, Connecticut 06520-8107
john.wood@yale.edu
Received October 30, 2001
ABSTRACT
Treatment of 3-(2-hydroxyphenyl)-propionic acids with a hypervalent iodine reagent in the presence of a dienophile initiates a tandem
intramolecular aromatic oxidation/Diels−Alder reaction. Herein we report (1) investigations on the scope and limitations of this novel reaction
combination and (2) preliminary diastereoselectivity studies using r- and â-substituted acids.
Masked o-benzoquinones (1) or o-benzoquinoid structures
(2) and their Diels-Alder adducts have provided elegant
approaches to a variety of structurally diverse organic
compounds.1,2 However, their high propensity toward dimer-
ization via cycloaddition reactions makes them more difficult
to handle than the corresponding p-benzoquinones, limiting
their general applicability as synthetic building blocks.
Since Wessely’s first reports in the 1950s,3 aromatic
oxidation reactions of phenols have become one of the
preferred methods for generating o-benzoquinones, and
considerable effort has been directed toward improving and
expanding the original procedure.2 However, to our knowl-
edge, the only example of intramolecular acid trapping of
the oxidation intermediate is the one reported by Danishefsky
in the synthesis of the tricyclic core of lactonamycin.4 In
the aforementioned example the authors used Pb(OAc)4 to
generate a naphthoquinone that was relatively stable against
Diels-Alder dimerization, as a result of extended conjugation
between the diene and the adjacent aromatic ring.
Scheme 1
We describe herein the development of a tandem Wessely-
type oxidation/Diels-Alder reaction of unfused phenols
bearing a carboxylic acid moiety suitably tethered for
intramolecular trapping.
In the course of our efforts toward the synthesis of CP-
263,1145 we discovered that 3-(2-hydroxyphenyl)-propionic
acid (3) undergoes a very facile aromatic oxidation in the
presence of bis(trifluoroacetoxy)-iodobenzene (BTIB) to
furnish spirolactonedienone 4 (observed by NMR), which
dimerizes at room temperature to produce 5.6 Performing
the reaction in the presence of excess methylvinyl ketone
(1) (a) Yates, P.; Bhamare, N. K.; Granger, T.; Macas, T. S. Can. J.
Chem. 1993, 71, 995. (b) Hwang, J. T.; Liao, C. C. Tetrahedron Lett. 1991,
32, 6583. (c) Singh, V.; Thomas, B. J. Org. Chem. 1997, 62, 5310. (d)
Hsu, P. Y.; Lee, Y. C.; Liao, C. C. Tetrahedron Lett. 1998 39, 659. (e)
Liu, W. C.; Liao, C. C. J. Chem. Soc., Chem. Commun. 1999, 117.
(2) For a review on the chemistry of orthoquinone monoketals and their
orthoquinol analogues, see: Quideau, S.; Pouysegu, L. Org. Prep. Proced.
Int. 1999, 31, 617.
(3) (a) Wessely, F.; Lauterbach-Keil, G.; Sinwel, F. Monatsh. Chem.
1950, 81, 811. (b) Metlesics, M.; Schinzel, E.; Vilsek, H.; Weselly, F.
Monatsh. Chem. 1957, 88, 1069.
(5) Njardarson, J. T.; McDonald, I. M.; Spiegel, D. A.; Inoue, M.; Wood,
(4) Cox, C.; Danishefsky, S. J. Org. Lett. 2000, 2, 3493.
J. L. Org. Lett. 2001, 3, 2435.
10.1021/ol0169776 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/31/2002

(MVK) afforded the corresponding adduct 6,6 albeit in low
yield (<40%), accompanied by dimer 5 and adduct 9. We
believe 9 arises from an initial Ritter-type attack of the
solvent at the activated 5-position of the aromatic ring,
followed by rearomatization and subsequent oxidation of the
substituted acid 8 (Scheme 2). The diastereoselectivity in
presence of various dienophiles all substituted acids 1010
produced the desired Diels-Alder adducts 11 in good yields
as single isomers (Table 1).11,12
Table 1. Oxidation of 5-Substituted
3-(2-Hydroxyphenyl)-propionic Acids in the Presence of
Electron-Deficient Dienes
Scheme 2
a Isolated yields after flash chromatography. b By performing the oxida-
tion in the absence of dienophile we were able to isolate the intermediate
spirolactonedienone in 98% yield. c Oxidation in the absence of dienophile
afforded upon concentration a mixture of spirolactonedieneone and dimer-
ization product.
the cycloaddition step is consistent with previous reports for
similar compounds,7 the attack occurring from the oxygen-
bearing face of the diene. The same facial selectivity applies
to the dienophile in the formation of dimer 5, whereas adduct
6 arises from the expected endo orientation of MVK. The
regioselectivity of the cycloaddition is consistent with
predictions based on frontier molecular orbital theory.8
To suppress the formation of undesired side products, we
sought to prepare and analyze a series of 3-(2-hydroxyphe-
nyl)-propionic acids bearing substituents with a range of
electronic properties. It is known that o-benzoquinoid
structures such as 2 are less prone to dimerization than the
corresponding o-benzoquinone monoacetals (1),9 and there-
fore we believed that minimal substitution of the aromatic
ring would prove sufficient for eliminating dimerization.
Substitution para to the phenolic oxygen seemed most
desirable for the purpose of avoiding unwanted para trapping
in the oxidation step (vide supra). Thus we initiated our
studies with a series of p-substituted substrates. We were
pleased to observe that when treated with BTIB in the
The yield and selectivity of the Diels-Alder step are
minimally influenced by the electronic profile of the diene,
making it a versatile diversity-building tool, especially
considering the capacity of vinyl iodides to act as valuable
handles for the introduction of a variety of functional groups.
The next step in testing the scope of the oxidation/Diels-
Alder reaction was the use of electron-deficient acetylenic
dienophiles to build systems such as 12, which possess a
variety of reactive sites that could be further manipulated
for synthetic purposes. In our hands these dienophiles proved
to be less reactive than their olefinic counterparts toward
the investigated dienones (elevated temperatures were re-
quired to promote the cycloaddition and the yields were
typically lower).13 We observed a correlation between the
electronic properties of the substrate and the yield of the
reaction, suggesting a direct electronic demand interaction
with electron-rich substrates giving better results than
electron-poor ones.
(10) Readily available from commercial starting materials. For experi-
mental details see Supporting Information.
(6) The structure was confirmed by preliminary single-crystal X-ray
analysis.
(11) General Procedure for Experiments in Table 1. The acid (0.25
mmol) and the dienophile (2.5 mmol, 10 equiv) were dissolved in 5 mL of
dry CH3CN. A solution of BTIB (0.3 mmol, 1.2 equiv) was added, and the
reaction mixture was allowed to stir overnight. The solvent was evaporated,
and the residue was purified by flash chromatography on silicagel. For
details, see Supporting Information.
(12) In a chemical correlation experiment, the Diels-Alder adduct 11
(R ) I, dienophile ) MVK) was reduced to the known structure 6, using
Bu3SnH, confirming that the regio- and stereochemistry of addition are not
affected by substitution.
(7) Auksi, H.; Yates, P. Can. J. Chem. 1981, 59, 2510.
(8) For a detailed discussion concerning the behavior of masked
o-benzoquinones in normal and inverse electronic demand Diels-Alder
reaction and possible FMO explanations, see: 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.
(9) (a) Holmberg, K. Acta Chem. Scand. 1974, B28, 857. (b) Metlesics,
W.; Wessely, F. Monatsh. Chem. 1957, 88, 108.
494
Org. Lett., Vol. 4, No. 4, 2002

created stereogenic centers by means of appropriate substitu-
tion of the propionic acid chain.
In preliminary studies, we prepared the R- and â-methyl
derivatives of 3-(2-hydroxy-5-methylphenyl)-propionic acid)
and we subjected these substrates to the standard oxidation
conditions in the presence of MVK (Scheme 3). Interestingly,
Table 2. Substituent Effects in Diels-Alder Reactions with
Acetylenic Dienophiles
Scheme 3
1
a Ratio determined by NMR. Structural assignment is based on 2D H
NMR experiments.
Taking into consideration the preference for the less
electron-deficient olefin in the dimerization reaction (a well
precedented behavior of quinoid dienes),8,14 we anticipated
that our spirodienones would be excellent substrates for
inverse electronic demand Diels-Alder reactions. We again
observed a marked substituent effect on the rate of the
reaction, with electron-deficient dienes giving excellent yields
and the 5-Me substrate reacting with great difficulty, as
expected.15 In all cases, however, single isomers of the
products were obtained.16
while the â-methylated derivative provided exclusively one
adduct, in the case of the R-methyl acid practically no
selectivity could be observed, the reaction yielding a 1:1
mixture of diastereomers (Scheme 3). Although somewhat
surprising, the results are in good agreement with the
proximity of the resident and newly formed stereogenic
centers.
These results led us to explore the construction of an
isotwistane skeleton, similar to that utilized in our approach
toward the synthesis of the phomoidrides.5
Table 3. Substituent Effects in Diels-Alder Reactions with
Electron-Rich Olefins
To our delight, treatment of the â-allyl substrate 18 with
BTIB under standard conditions furnished the desired isot-
wistane 19 in 55% unoptimized yield, as a single diastere-
omer.
(13) General Procedure for Experiments in Table 2. The acid (0.25
mmol) and the dienophile (2.5 mmol, 10 equiv) were dissolved in 5 mL of
dry CH3CN, and the reaction was heated to 60 °C. A solution of BTIB (0.3
mmol, 1.2 equiv) was added over 4 h (via syringe pump), and the reaction
mixture was allowed to stir overnight at 60 °C. The reaction was cooled to
room temperature, the solvent was evaporated under reduced pressure, and
the residue was purified by flash chromatography on silicagel. For details,
see Supporting Information.
(14) (a) Gao, S. Y.; Ko, S.; Lin, Y. L.; Peddinti, R. K.; Liao, C. C.
Tetrahedron 2001, 57, 297. (b) Arjona, O.; Mendel, R.; Plumet, J.
Tetrahedron Lett. 1999, 40, 8431.
a If the reaction mixture was maintained at room temperature for several
days, significant amounts (∼45% yield) of dimer could be isolated.
(15) General Procedure for Experiments in Table 3. The acid (0.25
mmol) was dissolved in 5 mL of dry CH3CN. A solution of BTIB (0.3
mmol, 1.2 equiv) was added, and the reaction mixture was allowed to stir
for 10 min. Solid K2CO3 (200 mg) was added, followed (after 5 min) by
the dienophile (2.5-12.5 mmol, 10-50 equiv), and the reaction was allowed
to stir overnight. The solvent was evaporated, and the residue was purified
by flash chromatography on silicagel. For details, see Supporting Informa-
tion.
Having demonstrated a potentially general oxidation/
Diels-Alder sequence with respect to both the aromatic
substrate and the dienophile, we sought next to exploit the
intramolecular character of the oxidation step and investigate
the possibility of inducing substrate control over all newly
(16) Structural assignments are based on 2D 1H NMR experiments and
previous reports on similar systems (see ref 14).
Org. Lett., Vol. 4, No. 4, 2002
495

In this case, the reversed facial selectivity is dictated by
the one-carbon tether, which prevents trapping from the
oxygenated face of the diene.
Acknowledgment. We acknowledge the support of this
work by Bristol-Myers Squibb, Eli Lilly, Glaxo-Wellcome,
Merck, Pfizer, Yamanouchi, and Zeneca through their
Faculty Awards Programs and the Camille and Henry
Dreyfus Foundation for a Teacher-Scholar Award.
In summary, we have begun to establish the broad scope
of a tandem intramolecular oxidation/Diels-Alder reaction
that is applicable to the construction of complex polycyclic
systems and proceeds with good substrate control. Investiga-
tions are currently being conducted for obtaining improved
diastereoselectivity for the R-substituted series, as well as
for the development of an enantioselective version of this
reaction.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0169776
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Org. Lett., Vol. 4, No. 4, 2002