Bifunctional thiourea-catalyzed asymmetric addition of anthrones to maleimides

Article abstract of DOI:10.1002/adsc.201000031

For the first time, the addition of anthrones to maleimides catalyzed by bifunctional thiourea catalysts is reported. The thiourea moiety is able to activate the maleimide and the tertiary amine deprotonates the anthrone, furnishing the final DielsAlder o

Full text of DOI:10.1002/adsc.201000031

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DOI: 10.1002/adsc.201000031
Bifunctional Thiourea-Catalyzed Asymmetric Addition of
Anthrones to Maleimides
Alex Zea,a Guillem Valero,a Andrea-Nekane R. Alba,a Albert Moyano,a,*
and Ramon Riosa,b,*
a
Departament de Quꢀmica Orgꢁnica, Universitat de Barcelona, Martꢀ i Franquꢂs 1, 08028 Barcelona, Spain
Fax : (+34)-9-3339-7878; phone: +(34)-9-3402-1245; e-mail: amoyano@ub.edu or rios.ramon@icrea.cat
ICREA Researcher at UB; ICREA, Pg. Lluis Companya 23, 08019 Barcelona, Spain
b
Received: January 14, 2010; Revised: April 3, 2010; Published online: April 28, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000031.
Abstract: For the first time, the addition of anthro-
nes to maleimides catalyzed by bifunctional thiour-
ea catalysts is reported. The thiourea moiety is able
to activate the maleimide and the tertiary amine de-
protonates the anthrone, furnishing the final Diels–
Alder or Michael adducts in excellent yields and
enantioselectivities.
Anthrone has been used as the diene component in
Diels–Alder cycloadditions with a variety of dieno-
philes.[7,8] Kinetic studies performed by Koerner and
Rickborn[8] on the reaction between anthrone and N-
methylmaleimide showed that a substantial accelera-
tion took place in basic solvents such as DMF, pyri-
dine or triethylamine, or upon the addition of a small
quantity of triethylamine to a chloroform or THF so-
lution of the reactants.[8] These results were interpret-
ed by a catalytic oxyanion acceleration of the process,
probably via the anthrone enolate (Scheme 1).
Keywords: anthrones; Diels–Alder cycloaddition;
enantioselective; maleimides; Michael addition; or-
ganocatalysis
Building upon these results, Riant and Kagan inves-
tigated the effect of chiral bases in the same reac-
tion,[9] finding that quinidine and prolinol were the
most enantioselective catalysts (up to 61% ee was
Anthrones are important compounds in natural prod- achieved with a 10 mol% loading of quinidine in
ucts and in medicinal chemistry.[1] They are isolated, chloroform at À508C). Later on, Yamamoto and co-
either in the free form or as O- or C-glycosides, from workers[10] described the asymmetric cycloaddition of
a wide variety of natural sources (plants, shrubs), such anthrone and maleimides catalyzed by C2-chiral 2,5-
as rhubarb, Cassia, and “Cꢀscara sagrada” bark, bis(hydroxymethyl)pyrrolidines, obtaining good enan-
among others.[2] From the chemical standpoint, an- tioselectivities in some instances (up to 87% ee). The
thrones and their enol tautomers, the 9-anthrols, play enantioselective Diels–Alder cycloaddition of substi-
a central role in the chemistry of anthracenes, because tuted anthrones with maleimides catalyzed by chiral
by oxidation of the central ring they afford 9,10-an- bicyclic guanidines, which takes place with excellent
thraquinones, extremely valuable compounds as pig- yields and enantioselectivities (85–99% ee) when run
ments or anticancer agents.[3] On the other hand, the in dichloromethane solution at À208C, was reported
reduction of anthrones provides anthracenes, useful in in 2006 by Tan and co-workers.[11] This reaction
the preparation of dyestuffs and of optoelectronic ma- showed, however, a very strong temperature depend-
terials.[4]
ence, and the enantiomeric purity of the Diels–Alder
The parent anthrone, namely 9ACHTUNGTENR(NUNG 10H)-anthracenone, adduct was much lower when performed at room
has been classically used as a reagent for the analyti- temperature. In 2008, Gçbel and co-workers devel-
cal determination of sugars and many of its deriva- oped an addition of anthrones to maleimides cata-
tives have interesting biological properties: antimicro- lyzed by metal-free bis(oxazolines), with moderate
bial, laxative, antipsoriatic or as telomerase inhibi- enantioselectivities (39–70% ee).[12]
tors.[5] Recently, it has been found that some anthrone
In our research group, we have lately been focusing
derivatives may display potent and selective antitu- on the development of new asymmetric methodolo-
mour activity.[6]
gies based on organocatalysis.[13] As fruits of our re-
search, very recently we developed a highly enantio-
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Bifunctional Thiourea-Catalyzed Asymmetric Addition of Anthrones to Maleimides
Scheme 1. Catalytic oxyanion acceleration of the anthrone-maleimide Diels–Alder cycloaddition.
selective anthrone addition to a,b-unsaturated alde- moiety would lead to higher enantioselectivities
hydes.[14,15] In this context, our attention was caught (Figure 1, b).
by the observation that, with the exception of guani-
In an initial screening of conditions, having selected
dine-catalyzed reactions, good enantioselectivities in the Diels–Alder cycloaddition between anthrone 1a
anthrone-maleimide cycloadditions were attained and N-phenylmaleimide 2a as the benchmark reac-
only when the chiral amine catalysts had hydroxy tion, we pleasingly found that Takemotoꢄs bifunction-
groups and the reaction was effected in aprotic sol- al amine thiourea (R,R)-I[17] catalyzed efficiently the
vents. This fact was interpreted, first by Kagan[9] and process, affording the expected cycloadduct 3a in opti-
subsequently by Yamamoto,[10] in terms of a transition cally active form. The reaction worked well in non-
state assembly such as that depicted in Figure 1, a, polar solvents such as toluene, CHCl3 or CH2Cl2 (en-
where the anthrone enolate is bound to the protonat- tries 1, 2 and 3 in Table 1), but when a more polar sol-
ed chiral amine, which is itself associated to the male- vent (DMSO) was used no reaction was observed
imide by hydrogen-bonding through the hydroxy (entry 4 in Table 1). As expected from our working
group. We anticipated that bifunctional thiourea cata- hypothesis, the best enantioselectivity (90% ee) was
lysts[16] would provide a similar activation mode for obtained in the less polar solvent (toluene). Next, we
the anthrone-maleimide cycloaddition, and that the decided to test other bifunctional catalysts such as the
stronger hydrogen-bonding ability of the thiourea Cinchona alkaloid-derived thioureas II (entry 5) and
III (entry 6), but they afforded lower enantioselectivi-
ties. When the reaction was run in the presence of
quinidine (entry 7 in Table 1), the (S,S)-adduct 3a
(34% ee) was obtained, as previously described by
Yamamoto.[10] This allowed us to assign an absolute
(R,R) configuration to the major enantiomer of 3a ob-
tained with thioureas (R,R)-I and II. The reaction was
generally complete (1H NMR monitoring) after stir-
ring overnight at room temperature, and no further
efforts were made to optimize the reaction time.
With these optimized reaction conditions (Takemo-
toꢄs thiourea catalyst I, toluene, room temperature)
we studied the scope of the addition of anthrone 1a
to different maleimides (Table 2). To our delight, we
found that with maleimides 2a–d the reaction gave
the desired cycloadducts 3a–d both with excellent
yields (90–92%) and enantioselectivities (85–97% ee).
Figure 1. Transition state models for the anthrone-male-
imide cycloaddition with chiral amino alcohol catalysts (1a)
and with chiral bifunctional thiourea catalysts (1b).
ACHTUNGTRENNUNG
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Table 1. Screening of conditions for the bifunctional thiour-
ea-catalyzed Diels–Alder cycloaddition of anthrone 1a with
maleimide 2a.[a]
Table 2. Substrate scope for reactions of 1a.[a]
[a]
Maleimide 2a–e (1 equiv.) was added to a mixture of 1a
(1.2 equiv.) and the catalyst (R,R)-I (10 mol%) in toluene
at room temperature.
Isolated yield after column chromatography.
Determined by chiral HPLC.
[b]
[c]
[d]
Michael adduct 3’e was isolated as the only product.
phatic N-substituents (e.g., benzydhryl, 1-phenylethyl)
were present in the maleimide both the reaction rate
and the stereoselectivities were drastically decreased.
We decided next to study the reaction with dithra-
nol [1,8-dihydroxy-9ACTHNUGRTENUNG(10H)-anthracenone, 1b; Table 3].
As reported by Tan,[11] dithranol afforded exclusively
the Michael adducts, in high yields (91–94%) and
with excellent enantioselectivities (up to 99% ee;
entry 1).[18]
The absolute configuration of the Michael adducts
was ascertained by chemical correlation of product 4a
with that previously obtained by Tan.[11] When cata-
lyst (R,R)-I was used, the resulting Michael adduct
[a]
Maleimide 2a–e (1.2 equiv.) was added to a mixture of 1a
(1 equiv.) and the catalyst (10 mol%) in the solvent de-
scribed in the table at room temperature.
[b]
[c]
1
Determined by H NMR.
Determined by chiral HPLC.
On the other hand, anthrone 1a reacted with N-(4-tri- had an (S) configuration.
fluoromethylphenyl)maleimide 2e to afford exclusive-
In order to expand the scope of the reaction, we ex-
ly the Michael adduct 3’e in 94% yield and 97% ee plored the reaction of anthrones to nitrostyrene
(entry 5, Table 2). As previously discussed by Rick- (Scheme 2). As previously reported,[15] the reaction
born[8] and by Gçbel,[12] the thermodynamically more between 1a and nitrostyrene renders the desired Mi-
stable Michael adduct probably arises from base-cata- chael adduct 5a in excellent yield and enantioselectiv-
lyzed retro-aldol ring-opening of the kinetic Diels– ities. However, when dithranol was used the reaction
Alder product 3e, facilitated in this case by the elec- afforded the desired Michael adduct 6a in excellent
tron-defficient nature of the maleimide aryl substitu- yield but with poor enantioselectivity, probably due to
ent. It should be noticed that when a-branched ali- a retro-Michael reaction.
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Bifunctional Thiourea-Catalyzed Asymmetric Addition of Anthrones to Maleimides
Table 3. Substrate scope for reactions of 1b.[a]
Scheme 2. Reaction of anthrones with nitrosyrene.
by the bifunctional thiourea (R,R)-I can be easily ac-
counted for within the working mechanistic hypothe-
sis schematized in Figure 1b by the transition state
depicted in Figure 2a. Molecular modelling of the TS
(Figure 2b) suggest that p-stacking interactions be-
tween the N-arylmaleimide substituent and the (3,5-
bistrifluoromethyl)phenyl moiety of the catalyst plays
a key role on selecting the preferred orientation of
[a]
Maleimide 2a, b, d, f (1 equiv.) was added to a mixture of
1b (1.2 equiv.) and catalyst
at room temperature.
Isolated yield.
ACHTUNGTNER(NUNG R,R)-I (10 mol%) in toluene
[b]
[c]
Determined by chiral HPLC.
The stereochemical course of the anthrone-male- the maleimide. This is in accordance with the above
ACHTUNGTRENNUNGimide Diels–Alder cycloaddition (and that of the Mi- observation that N-(a-branched benzyl)maleimides
chael addition observed in some instances) catalyzed give very poor results.
Figure 2. (a) Proposed transition state for the reaction between 1a and 2a. (b) Ball and stick model for the proposed transi-
tion state.
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In summary, we have described for the first time
the use of bifunctional thiourea catalysts for the addi-
tion of anthrones to maleimides, affording the final
Diels–Alder or Michael adducts in excellent yields
and enantioselectivities. As anticipated, the dual acti-
vation dramatically enhances the enantioselectivity of
the reaction. This operationally simple methodology
is very attractive not only for its high levels of stereo-
selectivity, unprecedented at room temperature, but
also by the fact that both enantiomers of the catalyst
of choice (Takemotoꢄs thiourea I) are commercially
available.
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Typical Experimental Procedure for the Diels–Alder
Cycloaddition
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In a small flask, a mixture of anthrone 1a (0.25 mmol), mal-
eimide 2a (0.30 mmol, 1.2 equiv.), and catalyst (R,R)-I
(0.025 mmol, 0.1 equiv.) in toluene (1 mL) was stirred at
room temperature overnight. Next the crude reaction mix-
ture was directly submitted to chromatographic purification
(silica gel, hexane-ethyl acetate) to afford (R,R)-3a; yield:
83 mg (91%, 90% ee). Both the NMR and polarimetric data
for this compound were in accordance with those previously
reported in the literature.[10,11]
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Acknowledgements
We thank the Spanish Ministry of Science and Innovation
(MICINN) for financial support (Project AYA2009-13920-
C02-02). A.-N. R. Alba is also grateful to MICINN for a pre-
doctoral fellowship.
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