Selective Michael additions to alkylidenemalonates using thiourea-based bifunctional organocatalysts

Bifunctional thiourea catalysts have been found to be excellent promoters of the challenging Michael addition to alkylidenemalonates giving high yields of up to 99%. Substrate structure was important for enantiodiscrimination, with aryl alkylidenemalonate acceptors furnishing products with ee values of up to 73%.


Introduction
The development of simple and efficient asymmetric C-C bond forming reactions is a major challenge for the synthetic chemist. 1,24][5][6][7] Enamine and iminium ion generating organocatalysts have been successfully applied to the asymmetric Michael addition of aldehydes and ketones to a number of electron-deficient olefins, e.g.9][20][21][22] There have been considerably fewer publications reporting the use of bifunctional organocatalysts in the asymmetric Michael addition to the challenging alkylidenemalonates.Alkylidenemalonates are particularly difficult acceptors due to their reduced electrophilicity.4][25] Our interest in the Michael addition of pronucleophiles with a relatively acidic hydrogen to alkylidenemalonates is due to the potential synthetic utility of the functional group-rich chiral conjugate addition products (Scheme 1).Scheme 1. Michael addition of pronucleophiles to alkylidenemalonates yielding highly functionalized chiral products.
The group of Barbas reported the conjugate addition of ketones to alkylidenemalonates via a pyrrolidine-derived catalyst in 2001. 26In fact the majority of reports to date detailing organocatalytic Michael reactions involving alkylidenemalonate acceptors have employed covalent catalysts to promote the reaction. 3,27To the best of our knowledge, Zhao and co-workers reported the first H-bonding bifunctional organocatalysed Michael addition to an alkylidenemalonate in 2008.Zhao's report outlines a tandem Michael-Knoevenagel reaction employing aromatic thiols as the pronucleophile in the synthesis of substituted thiochromanes. 27There have been only two subsequent publications describing Michael type additions to alkylidenemalonates using Hbonding organocatalysts.In 2012 Yang et al. published an excellent paper discussing the use of novel guanidine derived organocatalysts in the addition of an α,β-unsaturated γ-butyrolactam to alkylidenemalonates. 28 Yang generated an impressively high yielding and highly selective reaction.Recently, Quintavalla and co-workers reported the enantioselective conjugate addition of nitroalkanes to alkylidenemalonates using cinchona derived bifunctional organocatalysts. 29It is this publication by Quintavalla that has prompted us to report our initial findings.
In this present study we have employed thiourea-based bifunctional organocatalysts in the enantioselective addition of β-diketones, malononitrile and nitromethane to alkyl and aryl alkylidenemalonates.Thiourea-based bifunctional organocatalysts have emerged as a viable catalytic design for many asymmetric transformations. 30Typically, a thiourea-based bifunctional catalyst consists of a thiourea hydrogen bond donor moiety, for electrophile activation, and a basic amine functionality, for nucleophile activation, Figure 1. 18,21We expected that a thiourea-based amine organocatalyst, due to its dual modes of activation, would offer the best opportunity for the generation of selective Michael type addition to alkylidenemalonates.As a result, we focused our initial catalyst screen on the three thioureabased organocatalysts depicted in Figure 1.Organocatalyst 1 has been a highly stereoselective promoter of Michael additions using activated olefins, 18 as have cinchona alkaloid-derived catalysts 2 and 3. 21

Results and Discussion
The results from the catalyst screen are shown in Table 1.We employed the addition of 2,4pentanedione to dimethyl ethylidenemalonate as our initial test reaction, entries 1-4, Table 1.In addition to our work on extended Michael acceptors, 31 our group is interested in conjugate additions to activated olefins and previous work indicated that the most selective addition of βdiketones to -nitrostyrene using a thiourea-based organocatalyst occurred in toluene.As a result toluene was chosen as the solvent for this work. 32Reaction conditions: 0.028 mL (0.2 mmol) diethyl ethylidenemalonate, 0.4 mmol pronucleophile, 10 mol% catalyst, 0.8 mL toluene.a Enantiomeric excess determined by chiral HPLC analysis (Chiralpak IC).
All catalysts generated a high yielding reaction, 87-99%, with modest enantioselectivity.Of the three reactions employing 2,4-pentanedione as the Michael donor, catalyst 2 gave the highest selectivity, furnishing the product in 20% ee.Our group have previously applied the same catalysts in a highly enantioselective addition of β-diketones to -nitrostyrene. 32The reduced selectivity with dimethyl ethylidenemalonate, when compared to nitrostyrene, may result from the inferior Lewis basicity of the carbonyl group, in comparison to a nitro group, and hence a weaker catalyst-acceptor interaction. 3This weaker interaction with the Lewis acid catalyst may allow the competing and non-stereoselective background reaction to dominate.The Michael addition of 1,3-diphenylpropane-1,3-dione to dimethyl ethylidenemalonate also generated a high yielding reaction, 88-96%, but again only modest enantioselectivity was observed, entries 5-6, Table 1, although catalyst 2 gave a higher ee value (28%) with 1,3-diphenylpropane-1,3-dione.The presence of two carbonyl groups allows for convenient H-bonding with the thiourea moiety of the organocatalyst.Figure 2 shows the postulated transition state model, showing activation by the thiourea catalyst of the alkylidenemalonate acceptor and the 1,3-diketone pronucleophile.We also explored the reactivity of the simpler α,β-unsaturated ester, methyl crotonate 7, Table 2, reasoning that this substrate would yield useful product synthons in a more atomefficient manner.For this reaction the initial pronucleophile chosen was dimethyl malonate, a prominent Michael donor in conjugate addition reactions.Several base catalysts were screened in the addition of the 1,3-diester to methyl crotonate, Table 2. Triethylamine and DABCO were chosen as the first nitrogen-based achiral promoters of this reaction due to their low cost and ready availability.As no product was detected in these reactions we then tested quinuclidine (the basic unit in our organocatalysts) and the cinchona alkaloid quinine, reasoning that the presence of the H-bonding hydroxyl group in the latter catalyst would activate the Michael acceptor toward attack from the incipient carbanion.Although the amine bases are weak bases, pKa ≈ 9-10, we wondered if they would promote the conjugate addition via a general base catalyzed mechanism (pKa of dimethyl malonate ≈ 13).However, only reactions employing the stronger inorganic bases generated the desired product.We therefore propose that the reduced electrophilicity of methyl crotonate prevents the amine catalysts from promoting a General Base Catalysed reaction and that the Michael addition can only occur under Specific Base Catalysis with the stronger inorganic bases.Having established that a second activating ester group on the Michael acceptor is critical for reactivity we extended our substrate scope to non-carbonyl containing pronucleophiles.To do this we employed both nitromethane 10a and malononitrile 10b as pronucleophiles and report their use in the organocatalytic Michael type addition to dimethyl ethylidenemalonate for the first time (Table 3).Mayr's reactivity scales indicate that both nitromethane and malononitrile are excellent nucleophiles, with nucleophilicity values (N) of 20.71 and 19.36, respectively (in DMSO). 25We also found this to be the case, with nitromethane generating yields of up to 84%, entry 4, Table 3, and a much improved enantiomeric excess of 48%, entry 2, Table 3. Malononitrile also proved to be very reactive with yields of 75-89%.Unfortunately, the two product enantiomers could not be separated by chiral HPLC and hence the enantiomeric excess could not be determined.We also undertook a series of experiments aimed at expanding the scope of this methodology to arylalkylidenemalonates, namely dimethyl benzylidenemalonate 12a and dimethyl 2-(4nitrobenzylidene)malonate 12b.The Mayr reactivity scales predict that the addition of 2,4pentanedione (nucleophilicity value, N, of 17.64 in DMSO) 24 to diethyl benzylidenemalonate (electrophilicity value, E, of -20.55) would be quite slow.The same reactivity scales suggest that adding an electron withdrawing para-nitro group on the aryl ring of the alkyldiene malonate will improve electrophilicity, diethyl 2-(4-nitrobenzylidene)malonate has higher electrophilicity value © ARKAT-USA, Inc.
(E) of -17.67. 23We observed this improved reactivity in our work as dimethyl benzylidenemalonate 12a proved to be completely unreactive in our hands, entry 1, Table 4.The nitro-substituted dimethyl 2-(4-nitrobenzylidene)malonate 12b showed an improved reactivity with significant enantioselectivity (Entries 2-5, Table 4).As the acceptor 12a was too poor an electrophile to undergo the organocatalyzed Michael addition we did not explore even less electrophilic substrates containing electron-donating substitutions on the aryl moiety.As can be seen from Table 4, all three catalysts exhibited a greater degree of stereocontrol with arylalkylidenemalonate subsrates compared to the alkyl substituted acceptors.We postulate that the improved selectivity is a consequence of the lower reactivity of dimethyl (4nitrobenzylidene)malonate compared to dimethyl ethylidenemalonate.In the case of the β-alkylsubstituted acceptor, the β-carbon is sufficiently electrophilic to allow the non-stereoselective background reaction to occur.It is possible that the aromatic acceptor is too unreactive to allow this background reaction to occur and that it requires an interaction with the thiourea moiety to sufficiently activate it toward nucleophilic attack.The autocatalytic background Michael reaction is unable to proceed due to the lack of reactivity of the uncoordinated (and thus unactivated) electrophile.Thus the presence of the catalyst is essential for reactivity and a more stereoselective reaction ensues.© ARKAT-USA, Inc.

Conclusions
In conclusion, we have demonstrated that thiourea-based bifunctional organcatalysts are excellent promoters of conjugate additions to the challenging Michael acceptors, alkylidenemalonates.The structure of the Michael acceptor is very important for enantioselectivity, with the para-nitro-substituted aromatic substrate giving the highest selectivities (up to 73% ee).The β-alkyl-substituted acceptor, dimethyl ethylidenemalonate, furnished Michael products in high yields but lower enantiomeric excess.It is likely that this is due to the relatively weak interaction between the catalyst and the carbonyl group of the acceptor, which results in the autocatalytic racemic background reaction prevailing.

Supporting information available
NMR spectra and HPLC chromatograms are available free of charge via the Internet at http://www.arkat-usa.org.

Figure 1 .
Figure 1.Bifunctional thiourea-based organocatalysts.We expected that a thiourea-based amine organocatalyst, due to its dual modes of activation, would offer the best opportunity for the generation of selective Michael type addition to alkylidenemalonates.As a result, we focused our initial catalyst screen on the three thioureabased organocatalysts depicted in Figure1.Organocatalyst 1 has been a highly stereoselective promoter of Michael additions using activated olefins, 18 as have cinchona alkaloid-derived catalysts 2 and 3.21

Table 2 .
Michael addition of dimethyl malonate to methyl crotonate a No product detected.

Table 3 .
Michael addition of nitromethane and malononitrile to dimethyl ethylidenemalonate a Enantiomeric excess determined by chiral HPLC analysis (Chiralpak IB, IC).