Organocatalytic regioselective Michael additions of cyclic enones via asymmetric phase transfer catalysis

Article abstract of DOI:10.1039/b612606e

The regioselective Michael addition of 2-cyclohexenone and to other enones under the PTC-conditions was investigated. If no other Michael acceptors were present treatment of 2-cyclohexenone under PTC conditions afforded the dimerization product. The enant

Full text of DOI:10.1039/b612606e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Organocatalytic regioselective Michael additions of cyclic enones via
asymmetric phase transfer catalysis†
Roberto Ceccarelli, Susanna Insogna and Marco Bella*
Received 1st September 2006, Accepted 18th October 2006
First published as an Advance Article on the web 30th October 2006
DOI: 10.1039/b612606e
Cyclohexanone and cycloheptanone can be enantioselectively
functionalized in the 3-position with up to 92% ee and
87% ee, respectively, by the base-promoted dimerization
of the corresponding enones using 3,4,5-tribenzyloxybenzyl
cinchoninium bromide, as a new effective catalyst.
A simple filtration of the toluene phase of the reaction mixture
through a plug of silica gel and evaporation of the solvent afforded
nearly pure dimerization product. No byproducts or regioisomers
were observed.
We focus our efforts initially on controlling the stereochemistry
of the dimer 2. The enantiomers of 2 readily separated on a GC-
FID equipped with a chiral stationary phase column; we screened
most of the known Cinchona-derived PTC catalysts, and results
are summarized in Table 1. The asymmetric PTC dimerization
of linear phenyl activated enones has been recently described by
Corey and Zhang who employed the now commercially available
catalyst 3d developed in the Corey group.9
The formation of ketone enolates, one of the most fundamental
and thoroughly studied reactions in organic chemistry,1 proceeds
under PTC (phase transfer catalysis) conditions on activated
compounds such as the systems related to 2-aryl-indanone,2 b-
ketoesters3 and benzophenone imines of glycine.4 Recent advances
in the field of asymmetric PTC render this strategy very attractive.5
Here we show that 2-cyclohexenone 1, which is activated
towards deprotonation by a conjugate double bond, undergoes
a regioselective Michael addition to itself as well as to other
enones6 under the PTC-conditions. If no other Michael acceptors
were present, treatment of 1 under PTC conditions (KOHaq 50%,
toluene, 12.5% of catalysts 3a–q, rt) afforded the dimerization
product 2, as a result of vinylogous enolate formation and
electrophilic attack on the 2-position of a second molecule of 2-
cyclohexenone 1 (Scheme 1)7 and the reaction is greatly accelerated
by the addition of a PTC.
Simple N-benzyl cinchoninium chloride gave the dimerization
product in 47% (entry 1, Table 1). The benzyl substituent on the
nitrogen was necessary, methyl cinchoninium iodide 3b gave nearly
racemic products (entry 2) and any protection of the 9-OH of
the Cinchona alkaloids led to a drop in asymmetric induction
(entry 3). Employing Corey’s catalyst 3d (entry 4) we obtained a
moderate 75% ee (er = 7 : 1), confirming the benefit of the bulky 9-
methylanthracenyl substituent on the nitrogen with respect to the
simple benzyl group of catalyst 3a. The dimerization reaction of
2-cyclohexenone 1 is quite slow already at 0 ◦C therefore it was not
possible to achieve synthetically useful levels of conversion if the
transformation was run at lower temperatures. It is well known that
the asymmetric induction increases in most cases with an electron-
withdrawing group, such as fluorine, placed on the aryl moiety of
benzyl cinchoninium salts, and we actually observed an increase in
the ee, (entries 5 and 6) but more fluorine groups did not have the
beneficial synergic effect as reported by Jew et al. in the alkylation
of the benzophenone imine of glycine (entry 7).10 Introduction
of the bulky t-butyl group in the 4-position led to a modest
decrease in the asymmetric induction (entry 8). A methoxy-group
in the 3-positon of the aryl moiety slightly increased the ee (entry
9). The increase of the ee with the methoxy substituent on the
aromatic ring is quite uncommon in Cinchona alkaloid PTC, and
this prompted us to prepare a series of new catalysts based on
this motif.11 The effect of the alkoxy substituents is cooperative,
and it seems to be due to both ion-pair stabilizing12 electronic
and steric effects. More sterically hindered 3,4-dibenzyloxybenzyl
cinchoninium bromide 3l turned out to be a better catalyst of
3,5-dimethoxybenzyl cinchonidinium bromide 3k while less bulky
3,4-methylenedioxybenzyl cinchoninium bromide 3i gave lower
ee (entries 10, 11 and 12). The placement of a third methoxy
group on the catalyst as in 3m resulted in even higher ee (entry
13). Preparation of the 3,4,5-tribenzyloxybenzyl cinchoninium
bromide 3n, rewarded us with 88% ee (er = 15.5 : 1) at rt and 92%
(er = 24 : 1) ee at 0 ◦C (entries 14,15). However, lower temperatures
Scheme 1 Vinylogous deprotonation–addition of 2-cyclohexenone.
Surprisingly, treatment of 1 with LDA (LDA, THF, −78 ◦C to
rt) does not give an appreciable amount of dimerization product 2.8
Dipartimento di Chimica and Istituto di Chimica Biomolecolare del CNR-
Sezione di Roma, Universita` “La Sapienza”, P.le Aldo Moro 5, 00185-Roma,
Italy. E-mail: Marco.Bella@uniroma1.it
† Electronic supplementary information (ESI) available: Physical data,
including copies of 1H and 13C NMR spectra, are given for new compounds.
See DOI: 10.1039/b612606e
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Table 1 Screening of the different catalysts for the dimerization reaction
of 2-cyclohexenenone 2a
Table 2 Effect of temperature, dilution, and alkaloid moiety on the ee of
2a
Entry
Alkaloid
T/◦C
Cat.
Eeb (%)
Y (%)
Entry
1
R
Rꢀ
H
X
Eeb(%)
47
Y (%)
1
2
3
4
5
6
7
8
9
Cinchonine
Cinchonine
Cinchonine
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonine
Cinchonine
Cinchonidine
Cinchonidine
rt
3m
3m
3m
3o
3o
3o
3n
3n
3p
3p
80
87
75
91
70
25
90
61
24
26
26
23
23
Cl
3a
96
0
−20
rt
−78c
−81c
−85c
92
2
3
H
I
3b
3c
rac.
35
85
96
0
−20
Allyl
Cl
0
−20
0
−20
87
−81c
4
H
Cl
3d
−75c,d
95
10
−88c
a Reactions were performed with 0.52 mmol of 1, 4 mL of toluene, 0.4 mL
of 50% KOHaq, and 0.065 mmol of catalyst 3; reaction time 24 h or 4 d in
entries 3 and 6–10. b Ees determined by CSP-GC. c Negative ee refers to
the formation of the opposite enantiomer.
5
6
7
H
H
H
Br
Br
Br
3e
3f
59
71
65
82
95
95
afford the reaction product in much longer reaction time and
in low conversion.13 Giving the numerous known applications of
asymmetric phase transfer catalysis we hope that these new alkoxy-
substituted catalysts 3a–n can also be successfully employed in
other new or known reactions. Next, we tested the effect of con-
centration and temperature on the level of asymmetric induction.
As expected, the ee increased from 70% (er = 5.5 : 1) to 80% (er
= 9 : 1) when performing the reaction at higher dilution (Table 2,
entry 1). Cinchona alkaloid enantiomers are not commercially
available, but it has been constantly observed that the “quasienan-
tiomers” cinchonidine and cinchonine induce comparable levels
of ee. Products of opposite absolute stereochemistry are formed
in most reactions.14 We expected the asymmetric induction to
increase on decreasing the temperature, since a “tighter” ion pair
is formed. However, the two “quasienantiomers” of the two N-
3,4,5-trimethoxybenzyl catalysts 3m,3o tested showed a singular
behavior: the diastereoisomers derived from the cinchonine series
lowered the level of asymmetric induction with the temperature
(entries 2 and 3); the highest ee is observed at 0 ◦C (87%) and
3g
8
H
Br
3h
42
92
9
H
H
Br
Br
3j
58
64
80
82
10
3k
11
12
H
H
Br
Br
3i
3l
38
70
86
80
13
14
15
H
H
H
Br
Br
Br
3m
3n
3n
70
88
92e
70
90
72
◦
it drops to 75% at −20 C. Further lowering of the temperature
was not tested because at −20 ◦C conversion after 4 days was
low. In contrast, the diastereoisomers derived from cinchonidine
always increased the level of enantioselection on decreasing the
temperature;15 similar behaviour was observed using the N-3,4◦,5-
tribenzyloxybenzyl pseudoenatiomeric catalysts 3n,3p at −20 C
and 0 ◦C (entry 7–10).16
The reaction was tested on different cyclic enones and results
are summarized in Table 3. 2-Cyclopentenone 4, (entry 1, Table 3)
does not give any product, because the double bond in the anion
can isomerize easily; the anion is more stabilized with respect to
the anion derived from 2-cyclohexenone 1 and consequently its
reactivity is reduced.17
a Reactions were performed with 0.52 mmol of 1, 4 mL of toluene, 0.4 mL of
50% KOHaq, and 0.065 mmol of catalyst 3. b Ees determined by CSP-GC.
c N-Methylanthracenyl cinchonidinium bromide was used. d Negative ee
refers to the formation of the opposite enantiomer. e Reaction performed
at 0 ◦C. The absolute configuration was determined by comparison of
optical rotation with a known compound, see ESI.†
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2-Cycloheptenone 5 (entry 3) instead affords the dimerization
product showing a similar level of asymmetric induction as
cyclohexenone 1. If there are no a-hydrogens with respect to the
double bond, no product is observed (entry 5). Dimerization of
8 does occur in comparable ees but the reaction is much slower,
since a crowded quaternary stereocenter is formed (entry 6).
We were able also to isolate in nearly quantitative yields (94–
95%) the adducts of 2-cyclohexenone 1 to conjugate ketone 10
that cannot dimerize (Scheme 2); while with the aryl trimethoxy
catalyst 3m the level of asymmetric induction was comparable to
the cyclic enones (65% vs. 70% of the cyclic enones); our best
performing catalyst 3n gave only 47% ee.
We also tested esters as Michael acceptors, e.g. di-t-butyl
fumarate, but in this case yields and ees were poor (catalyst 3m: Y
= 20%, ee = 40%; catalyst 3n: Y = 32%, ee = 0%) but also here the
best catalysts were the N-3,4,5-trimethoxybenzyl substituted ones,
in contrast with what has been observed for the cyclic enones.
In summary, herein we present the development of a new class of
Cinchona alkaloid-based catalysts used in the asymmetric Michael
addition. Dimerization of 2-cyclohexenone 1 proceeds with up to
92% ee. Further work to define the scope of this reaction and to
extend it to other electrophiles, is underway in our group.
Acknowledgements
Authors are grateful to Prof. P. Kocˇovsky´ and Dr S. Brandes for
crucial observations during the preparation of this manuscript, to
Prof. L. Zoccolillo for a useful discussion about GC apparatus
but most of all to Prof. G. Piancatelli for constant scientific and
financial support without whom this work could no be done.
Notes and references
1 F. A. Carey and R. J. Sundberg, Advanced Organic Chemistry, Part B,
Plenum Press, New York, US, 4th edn, 2001, ch. 1 and 2.
2 U.-H. Dolling, P. Davis and E. J. J. Grabowski, J. Am. Chem. Soc.,
1984, 106, 446.
Table 3 Reaction of different enones catalyzed by 3na
Entry
1
Reactant
Product
None
Eeb (%)
—
Y (%)
3 (a) E. J. Park, M. H. Kim and D. Y. Kim, J. Org. Chem., 2004, 69, 6897;
(b) T. Ooi, T. Miki, M. Taniguchi, M. Shiraishi, M. Takeuchi and K.
Maruoka, Angew. Chem., Int. Ed., 2003, 42, 3796.
N. R.
4 Leading references: (a) M. J. O’Donnell, Acc. Chem. Res., 2004, 37,
506; (b) B. Lygo and B. I. Andrews, Acc. Chem. Res., 2004, 37, 518.
5 See also: (a) M. E. Halpern, Phase-Transfer Catalysis. Mechanism
and Synthesis, American Chemical Society, Washington, DC, 1997;
(b) Y. Sasson and R. Neumann, Handbook of Phase-Transfer Catalysis,
Blackie A & M, London, 1997. Reviews: (c) K. Kacprzak and J.
Gawronski, Synthesis, 2001, 961; (d) T. Ooi and K. Maruoka, Chem.
Rev., 2003, 103, 3013; (e) A. Berkessel and H. Gro¨ger, Asymmetric
Organocatalysis, Wiley-VCH, Weinheim, Germany, 2005, ch. 3 and 4.
6 Differently from 1, chiral non-racemic 2-phenyl cyclohexananones,
under solvent free liquid PTC conditions, are diastereoselectively
deprotonated on the unexpected 6-position: E. Diez-Barra, A. de la
Hoz, S. Merino and P. Sanchez-Verdu, Tetrahedron Lett., 1997, 38,
2359.
2
88
90
3
4
5
−73
87
75c,d
80d
7 Product 2 has been previously isolated in low yield from the treatment
of 1 with inorganic bases: see e.g. (a) N. J. Leonard and W. J. Musliner,
J. Org. Chem., 1966, 31, 639 and ref. 16. Electrochemical synthesis:
(b) M. Mubarak, M. Pagel, L. M. Marcus and D. G. Peters, J. Org.
Chem., 1998, 63, 1319. Using Morita–Baylis–Hilman reaction: (c) G.
Jenner, Tetrahedron Lett., 2000, 41, 3091, and; (d) J. R. Hwu, G. H.
Hakimelani and C.-T. Chou, Tetrahedron Lett., 1992, 33, 6469. See
also (formation of 2 mediated by t-buthoxide): (e) I. D. Reingold, A. M.
Butterfield, B. C. Daglen, R. S. Walters, Jr., K. Allen, S. Scheuring, K.
Kratz, M. Gembicky´ and P. Baran, Tetrahedron Lett., 2005, 46, 3835.
8 For deprotonation in the 4-position of 3-alkoxy-2-cyclohexeneonones
see e.g.: (a) E. R. Koft and A. B. Smith, J. Am. Chem. Soc., 1982, 104,
5568; (b) K. C. Nicolaou, T. Montagnon and G. Vassilikogiannakis,
Chem. Commun., 2002, 2478.
None
—
N. R.
6
85
15e
9 F.-Y. Zhang and E. J. Corey, Org. Lett., 2004, 6, 3397.
10 S.-S. Jew, M.-S. Yoo, B.-S. Jeong, I. Y. Park and H.-g. Park, Org. Lett.,
2002, 4, 4245.
11 Recently, Malkov and Kocˇovsky´ reported the benificial effect of a
trimethoxy aryl moiety in the organocatalytic allylation of aldehydes;
see: A. V. Malkov, M. Bell, F. Castelluzzo and P. Kocˇovsky´, Org. Lett.,
2005, 7, 3219.
a Reactions were performed with 0.52 mmol of reactant, 4 mL of toluene,
0.4 mL of 50% KOHaq, and 0.065 mmol of catalyst 3n, reaction time: 24 h.
b Ees determined by CSP-GC. c Catalyst 3o is used. d Reaction time: 2 d.
e Reaction time: 4 d.
Scheme 2 Cross vinylogous deprotonation–addition of 2-cyclohexenone.
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12 Asymmetric induction in Cinchona alkaloid-mediated PTC stems from
weak interactions arising in a thight ion pair; for a useful discussion on
the role of the 9-OH see ref. 5c and references cited therein.
13 Dendritic Cinchona alkaloids-derived PTC, in which benzyloxy groups
substituted on the aromatic moiety in several patterns, have been
prepared and employed in the alkylation of benzophenone imine glycine
esters: G. Gulliena, R. Kreiter, R. van de Coervering, R. J. M. Klein
Gebbink, G. van Koten, R. Chinchilla and C. Najera, Tetrahedron:
Asymmetry, 2003, 14, 3705; however the level of asymmetric induction
achieved is moderate, 50% ee, if compared with Corey’s catalyst, well
above 90% ee.
15 A similar finding was observed by Jørgensen and co-workers: S.
Brandes, M. Bella and K. A. Jørgensen, Angew. Chem., Int. Ed., 2006,
45, 1147. Only relatively few papers dealing with Cinchona alkaloids
mediated asymmetric PTC report high enantioselectivities with both
quasienantiomeric catalysts.
16 Racemic 2 has a synergic herbicidal effect if used with atrazine: H. A.
Kaufman and R. P. Napier, German Patent, DE 2016666, 1970, 1105.
17 (a) The charge delocalization of the 2-cyclopentenone anion can
account for the facile isomerization in basic conditions of prostaglandin
related systems: see e.g.: B. Y. Lee, J. W. Han, Y. K. Chung and S. W.
Lee, J. Organomet. Chem., 1999, 587, 181; (b) Y. Fujita and T. Nakai,
Synthesis, 1983, 12, 997; no analogous isomerization is reported for
6-membered rings or larger cyclic enones.
14 For the use of the term quasienantiomers see: Q. Zhang and D. P.
Curran, Chem.–Eur. J., 2005, 11, 4866.
4284 | Org. Biomol. Chem., 2006, 4, 4281–4284
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