Regioselective single and double conjugate additions to substituted cyclohexa-2,5-dienone monoacetals

Article abstract of DOI:10.1021/ol050715c

(Chemical Equation Presented) A series of quinone monoacetals bearing electron-withdrawing groups was treated with diethyl malonate and other bifunctional nucleophiles in the presence of KO-t-Bu in THF. Reactions of ethyl 3-nitropropionate or diethyl malo

Full text of DOI:10.1021/ol050715c

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3167-3170
Regioselective Single and Double
Conjugate Additions to Substituted
Cyclohexa-2,5-dienone Monoacetals
Scott Grecian, Aaron D. Wrobleski, and Jeffrey Aube´*
Department of Medicinal Chemistry, 1251 Wescoe Hall DriVe, Room 4070,
Malott Hall, UniVersity of Kansas, Lawrence, Kansas 66045-7582
jaube@ku.edu
Received April 4, 2005
ABSTRACT
A series of quinone monoacetals bearing electron-withdrawing groups was treated with diethyl malonate and other bifunctional nucleophiles
in the presence of KO-t-Bu in THF. Reactions of ethyl 3-nitropropionate or diethyl malonate resulted in single conjugate addition adducts.
When ethyl acetoacetate was used as a nucleophile, bridged bicyclic products were obtained in good yields. The regiochemistry of conjugate
addition was dependent on the quinone monoacetal substitution.
Cyclohexa-2,5-dienone monoacetals or masked para-ben-
zoquinone acetals have often been used as precursors to
structurally complex target molecules.1 Among the various
reaction types demonstrated with these systems, conjugate
additions are common and have been performed with a
variety of nucleophiles. The placement of alkyl- or hetero-
atom-containing substituents about the quinone monacetals
allows regioselective conjugate additions through adjustment
of the steric or electronic characteristics of these systems.2
On the other hand, we have been unable to find examples
of conjugate additions to quinone monoacetals bearing
electron-withdrawing substituents.3 The use of a quinone
monoacetal instead of its parent quinone is very useful in
complex synthesis because it permits an additional level of
regiochemical control and allows differentiation of the two
carbonyl groups in subsequent steps. In this letter, we report
a series of conjugate additions with a variety of bifunctional
nucleophiles that allow the rapid development of polyfunc-
tionalized mono- and bicyclic ring systems.
We were interested in both determining the regiochemistry
of conjugate addition within a series of substituted quinone
monoacetals as well as exploring the possibility of directed
tandem conjugate additions. Previously, it had been dem-
onstrated that nucleophiles add preferentially to the more
electrophilic double bond of 1,4-benzoquinones.4 In addition,
double conjugate additions to simple quinone monoacetals
have been reported.5 We hypothesized that the first-formed
(i.e., most stable) anion of a bifunctional nucleophile would
add to the more electrophilic double bond first. Upon proton
(1) The terms “quinone monoacetal” and “quinone monoketal” may be
used interchangeably. For a review of quinone monoacetal chemistry, see:
Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV. 2004, 104, 1383-
1430.
(2) For examples of conjugate additions to quinone monoacetals, see
ref 1 and the following specific examples. (a) Chenard, B. L.; Anderson,
D. K.; Swenton, J. S. J. Chem. Soc., Chem. Commun. 1980, 19, 932-933.
(b) Stern, A. J.; Swenton, J. S. J. Chem. Soc., Chem. Commun. 1988, 18,
1255-1256. (c) Parker, K. A.; Casteel, D. A. J. Org. Chem. 1988, 53,
2847-2850. (d) Stern, A. J.; Rohde, J. J.; Swenton, J. S. J. Org. Chem.
1989, 54, 4413-4419. (e) Ciufolini, M. A.; Dong, Q.; Yates, M. H.; Schunk,
S. Tetrahedron Lett. 1996, 37, 2881-2884. (f) Ho¨genauer, K.; Baumann,
K.; Mulzer, J. Tetrahedron Lett. 2000, 41, 9229-9232.
(3) For examples of conjugate additions to quinones containing electron-
withdrawing groups, see: (a) Valderrama, J. A.; Cortes, M.; Pessoa-Mahana,
D.; Preite, M.; Benites, J. Tetrahedron Lett. 2000, 41, 3563-3566. (b)
Valderrama, J. A.; Pessoa-Mahana, D.; Tapia, R. A.; Rojas de Arias, A.;
Nakayama, H.; Torres, S.; Miret, J.; Ferreira, M. E. Tetrahedron 2001, 57,
8653-8658. (c) Brimble, M. A.; Halim, R.; Petersson, M. Tetrahedron Lett.
2002, 43, 4777-5758. (d) Brimble, M. A.; Burgess, C.; Halim, R.;
Petersson, M.; Ray, J. Tetrahedron 2004, 60, 5751-5758.
10.1021/ol050715c CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/24/2005

transfer to the resulting enolate, intramolecular conjugate
addition of the other nucleophilic site to the remaining double
bond seemed possible. Such a reaction sequence would allow
the direct regioselective formation of functionalized bridged
ring systems from simply substituted quinone monoacetals
and common nucleophiles.
Table 1. KO-t-Bu-Catalyzed Reactions of Quinone Monoacetal
1 with Nucleophiles
To examine this, we synthesized quinone monoacetals 1-4
bearing electron-withdrawing groups from simple phenols
(Figure 1).6 Initially, we treated quinone monoacetal ester 1
Figure 1. Substituted quinone monacetals used in this study.
with 1.0 equiv of diethyl malonate in the presence of 0.15
equiv of KO-t-Bu in THF at room temperature for 10 h. Upon
workup and chromatography, phenol 5 was obtained as the
result of conjugate addition to C-3 followed by elimination
of ethanol. This step was accelerated by treatment of the
unstable addition adduct with a catalytic amount of p-TsOH
in refluxing benzene.2c
Three bisnucleophiles were investigated for their propen-
sity to undergo directed tandem conjugate additions (Table
1). Treatment of 3 with ethyl 3-nitropropionate7 in the
presence of KO-t-Bu provided the adduct 6 quantitatively
as a ca. 10:1 mixture of diastereomers (major diastereomer
shown). This adduct underwent extensive aromatization
during chromatography on silica gel. When ethyl acetoacetate
was used, the double conjugate addition adduct was obtained
with the anticipated regiochemistry in good yield. Compound
7 was the result of C-alkylation of the stabilized enolate,
followed by O-alkylation at the remaining double bond.
Likewise, treatment of quinone monoacetal ester 1 with
2-nitroacetone8 in the presence of base provided the double
conjugate addition adduct 8 in modest yield.
a Treatment with p-TsOH in refluxing benzene converted the unstable
adduct to the aromatized product. b Diastereomeric ratio determined by crude
NMR analysis. c Unstable adduct was converted to the corresponding phenol
for characterization. See Supporting Information for details.
X-ray crystallographic analysis of the major isomer of 6
showed that the nitro ester side chain was oriented pseudo-
axially (Figure 2). Thus, we wondered if the stabilized
enolate 9, the immediate result of conjugate addition with
ethyl 3-nitropropionate, was preventing a subsequent in-
(4) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992; Vol. 9, pp 1-8. (b) Aponick, A.; Buzdygon,
R. S.; Tomko, R. J., Jr.; Fazal, A. N.; Shughart, E. L.; McMaster, D. M.;
Myers, M. C.; Pitcock, W. H., Jr.; Wigal, C. T. J. Org. Chem. 2002, 67,
242-244. (c) Towers, M. D. K. N.; Woodgate, P. D.; Woodgate, P. D.;
Brimble, M. A. ARKIVOC 2003, 1, 43-55.
(5) (a) Parker, K. A.; Kang, S.-K. J. Org. Chem. 1980, 45, 1218-1224.
(b) Camps, P.; Gonzalez, A.; Munoz-Torrero, D.; Simon, M.; Zuniga, A.;
Martins, M. A.; Font-Bardia, M.; Solans, X. Tetrahedron 2000, 56, 8141-
8151. (c) Carreno, M. C.; Luzon, C. G.; Ribagorda, M. Chem. Eur. J. 2002,
8, 208-216.
(6) Quinone monoacetals 1-4 were generally made by oxidation of the
corresponding 4-alkoxy phenol. See Supporting Information for details.
(7) Silva, P. C.; Costa, J. S.; Pereira, V. L. P. Synth. Commun. 2001, 31,
595-600.
Figure 2. Ball-and-stick depiction of the X-ray crystallographic
analyses of 6 and 10.
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Org. Lett., Vol. 7, No. 15, 2005

tramolecular conjugate addition with the carbon R to the ethyl
ester and the remaining double bond (Scheme 1). When
Table 2. KO-t-Bu-Catalyzed Reactions of Quinone
Monoacetals 2 and 3 with Nucleophilesa
Scheme 1. Conjugate Addition and Methylation of 9 and
Attempted Intramolecular Conjugate Addition of 10
quinone monoacetal 1 was treated with ethyl 3-nitropropi-
onate and MeI in the presence of 1.0 equiv of KO-t-Bu,
enone 10 was isolated in 45% yield as a diastereomeric
mixture. In this case, ca. 10:1 selectivity for the nitro center
relative to the adjacent methine was observed, while the
methyl group and hydrogen at the ring junctions were
exclusively trans. Resubmission of 10 to KO-t-Bu in THF
failed to provide the intramolecular conjugate addition
adduct. A brief survey of other base/solvent systems did not
afford bridged products, and in several cases starting quinone
monoacetal was isolated. So far, the formation of 6,6-bridged
ring systems from these double conjugate additions has been
facile, but we have not yet succeeded in accomplishing the
formation of 6,5-bridged ring systems using this strategy.
We suspect that the position R to the ethyl ester in 10 may
not be sufficiently acidic to permit double cylization to occur
in this and related examples.
a Reactions were performed with 1.0 equiv of quinone monoacetal, 1.0
equiv of nucleophile, and 0.15 equiv of KO-t-Bu in dry THF. b Treatment
with p-TsOH in refluxing benzene converted the unstable adduct to the
aromatized product. c tert-Butyl alcohol was used in the conjugate addition
step.
To extend our study to a variety of substituted quinone
monoacetals, we treated quinone monoacetal 2 with diethyl
malonate in the presence of KO-t-Bu in THF. Acidic
treatment of the unstable addition adduct provided the
aromatized condensation product, imide 11, in 77% yield
(Table 2). Similar treatment with ethyl 3-nitropropionate and
quinone monoacetal 2 gave phenol 12 in 57% yield following
acidic treatment. We isolated adduct 13, resulting from
double conjugate addition, when ethyl acetoacetate and
quinone monoacetal 2 were reacted. The regiochemistry and
mode of alkylation were in line with our results from the
reactions of 1,3-bisnucleophiles with the quinone monoacetal
ester 1.
When aryl quinone monoacetal 3 was treated with nu-
cleophiles, we observed a change in regiochemistry. When
diethyl malonate and this quinone monoacetal were reacted
under the usual reaction conditions (catalytic KO-t-Bu in
THF), adduct 14 was isolated, the result of addition to C-5,
para to the nitroaryl group. This adduct did not aromatize
upon treatment with p-TsOH but rather proved to be stable.
Similar treatment with ethyl 3-nitropropionate did not afford
conjugate addition adduct. Interestingly, treatment of the
starting aryl quinone monoacetal with ethyl acetoacetate gave
adduct 15 in 76% yield. In this case, the regiochemistry of
addition mirrors that for diethyl malonate with this aryl
quinone monoacetal. Moreover, this adduct was the result
of C-alkylation in both addition events, in contrast to our
previous findings. It is unclear at present which factors favor
C- or O-alkylation in this system, as the mode of addition
was unaffected by using additives such as hexamethyl
phosphoramide or 18-crown-6. Other solvents (t-BuOH and
ethanol) and bases (LiO-t-Bu, K2CO3, Cs2CO3) led to the
same products but often in lower yields.
To complete our survey of conjugate additions to substi-
tuted quinone monoacetals, we subjected 4, which has
opposing dipoles, to reactions with nucleophiles (Table
3).9 When treated with diethyl malonate in the presence of
(8) Jung, M. E.; Grove, D. D.; Khan, S. I. J. Org. Chem. 1987, 52, 4570-
4573.
(9) Danishefsky, S.; Schuda, P.; Kato, K. J. Org. Chem. 1976, 41, 1081-
1088.
Org. Lett., Vol. 7, No. 15, 2005
3169

addition adduct 17 in 69% yield. In this case, the C-alkylated
bridged system was obtained to the exclusion of the
O-alkylated product that was seen in most of the previous
examples. At this time, we do not have an explanation for
this phenomenon.
Table 3. KO-t-Bu-Catalyzed Reactions of Quinone Monoacetal
4 with Nucleophiles
We have demonstrated that the regiochemistry of conjugate
addition reactions to quinone monoacetals depends on both
the placement and the nature of the substituent. Furthermore,
double conjugate additions to quinone monoacetals with 1,3-
bisnucleophiles, in particular ethyl acetoacetate, are generally
useful. Further work will focus on the use of the highly
functionalized bridged products of these tandem conjugate
additions in total synthesis.
Acknowledgment. We thank the National Institutes of
Health (GM-49093) for funding this work. S.G. acknowl-
edges a Madison and Lila Self Graduate Fellowship, and
A.D.W. thanks the American Chemical Society and Abbott
Laboratories for an Organic Chemistry Division Fellowship.
We are also grateful to Doug Powell for X-ray crystal-
lographic data.
Supporting Information Available: Experimental pro-
cedures, characterization data for new compounds, and X-ray
crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
KO-t-Bu in THF, adduct 16 was isolated in 58% yield, which
resulted from exclusive addition to the enone rather than the
enamide. Although this reaction failed with ethyl 3-nitro-
propionate, ethyl acetoacetate again gave double conjugate
OL050715C
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Org. Lett., Vol. 7, No. 15, 2005