Organocatalytic enantioselective Michael addition of β-diketones to β-nitrostyrene: The first Michael addition of dipivaloylmethane to an activated olefin

The addition of a family of β-diketones to β-nitrostyrene was explored using a library of cinchona organocatalysts. A thiourea organocatalyst, under improved reaction conditions, is shown to be much more efficient at catalyzing this reaction than previously reported giving excellent yields and enantioselectivites (up to 95% yield and 97% ee ). The same thiourea organocatalyst was employed in the first successful Michael addition of the sterically challenging dipivaloylmethane to β-nitrostyrene (99% ee ).


Introduction
The synthesis of enantiopure molecules in a simple and environmentally friendly manner is a major challenge for synthetic chemistry and the chemical industry.Organocatalysis has emerged as an exciting method of choice for the generation of such efficient asymmetric reactions.In this field, the asymmetric Michael addition of carbon-centred nucleophiles to electron deficient nitroolefins is an important and powerful tool. 1,2The resulting optically active nitroalkanes are versatile synthetic building blocks by virtue of the reactive nitro functional group, which can be easily transformed into a variety of groups. 1,22][3][4][5] There have been fewer reports of successful additions of diketones to nitroolefins.To the best of our knowledge, Brunner et al. described the first enantioselective addition of a -diketone to a nitroolefin in 1996 (ee < 30%) 6 with the first report of a highly enantioselective addition only appearing in 2005. 7Subsequent publications by Wang 8 and others, 9,10 have also described the selective addition of a -diketone to nitrostyrene using bifunctional organocatalysts.
Bifunctional organocatalysts consisting of urea/thiourea hydrogen-bond donors and a basic amine function has emerged as a viable organocatalyst design for many asymmetric transformations. 11In 2003 Takemoto and co-workers 12 reported the first bifunctional aminethiourea organocatalyst 1 and applied it in a highly enantioselective Michael addition of dimethyl malonate to nitroolefins.Takemoto's catalyst represented a logical extension of earlier work on thiourea H-bonding catalysts by Curran, Jacobsen and Schreiner. 13Since then significant advances have been made in catalyst design with Chen, Soós, Connon and Dixon independently reporting the design and application of new cinchona urea/thiourea catalysts in 2005. 5,11,14n this present study we have screened nine cinchona catalysts in the addition of β-diketones to β-nitrostyrene.Our study indicates that (a) under improved reaction conditions the cinchona thiourea catalyst 2 is much more effective (95% yield after only 1 hour) at catalyzing this reaction than previously reported (47% yield after 48 hours), 8 (b) the first Michael addition of the sterically challenging dipivaloylmethane to an activated olefin, β-nitrostyrene (99% ee), was achieved using catalyst 2 and (c) both a H-bonding motif and steric bulk is required at C9 to generate a high yielding and enantioselective reaction.

Results and Discussion
We anticipated that solvent choice would have a large effect on the catalytic activity of a bifunctional catalyst 4a and began our study by performing a solvent screen for the organocatalyzed Michael addition of 2,4-pentanedione to β-nitrostyrene.Quinine 3 was chosen as the model catalyst for the solvent screen as it is a bifunctional catalyst, inexpensive and commercially available (Figure 1).The results for the solvent screen are shown in Table 1.The stereochemistry of the major product was confirmed as (R) by comparing the specific rotation of 6a with literature values. 9Results were examined for any correlation between yield or enantioselectivity with polarity (ET30), H-bond donor ability (α values) and H-bond acceptor ability (β values).A good correlation was observed when enantioselectivity was plotted as a function of solvent polarity, ET30, (Table 1, Figure 2).The enantioselectivity directly depends on the solvent polarity with the less polar solvents giving superior enantioselectivity.A similar trend was observed in both aprotic solvents (Figure 2) and protic solvents (Figure 2, insert).No direct correlation was observed between enantioselectivity and H-bond donor, α, or H-bond acceptor, β, ability (Table 1), although the protic solvents did give poorer enantioselectivity when compared to the aprotic solvents.This was as expected as the achiral protic solvents and chiral catalyst were anticipated to competitively activate the reaction.4a,12 No direct correlation was observed in terms of reaction yield.Acetonitrile generated the highest yielding reaction, albeit with poor selectivity, with toluene emerging as the highest yielding of the selective non-polar solvents.All of the protic solvents gave high yields due to their ability to activate the Michael acceptor.Although acetonitrile generated a high yielding reaction it was not chosen for the subsequent catalyst screen due to its propensity to disrupt the hydrogen bonding action of bifunctional catalysts and hence lower the enantioselectivity (2% ee with quinine).The less polar solvent, toluene, gave a similar yield and an improved ee and was clearly more effective at promoting a selective reaction than the polar solvents.As such toluene was selected as the solvent of choice for the subsequent catalyst screen.The role and choice of catalyst was explored in a catalyst screen involving nine cinchona type organocatalysts 2, 3, 7-13 (Figure 3).The Michael addition of 2,4-pentanedione to β-nitrostyrene was employed as the model reaction, with toluene as the solvent of choice, (Table 2).

Figure 3. Screened organocatalysts.
There have been several reports of asymmetric C-C bond forming reactions employing the dimeric catalysts (DHQD)2PHAL 11, (DHQ)2AQN 12 and (DHQD)2PYR 13. 11a In our hands the dimeric catalysts proved ineffective giving either a poor yield or poor ee in each case.The reactions with (DHQ)2AQN 12 and (DHQD)2PYR 13, entries 9 and 10, were sluggish and gave only 6% and 7% of the Michael adduct respectively after 144 hours.On the other hand, (DHQD)2PHAL 11 proved more reactive giving a 77% yield after 144 hours but with no enantiocontrol.The monomeric C9-OR modified catalysts 8, 9 and 10 showed a slight improvement with yields of 32-52% and ee of 11-35% in 144 hours, entries 5, 6 and 7.The catalytic activity increased greatly with the monodentate hydrogen bond donor catalysts quinine 3 and DHQD 7, 89% and 87% yield respectively in just 24 hours.This is likely due to their ability to activate the nitroolefin through the C9-OH hydrogen bonding functionality. 4 This increase in catalytic activity was not mirrored by a corresponding increase in enantiocontrol and instead the enantioselectivity dropped to only 16% ee for quinine and 7% ee for DHQD.This reduction in selectivity may be due to the reduced steric bulk at C9 in quinine and DHQD when compared with the more selective C9-OR catalysts 8, 9 and 10.Reaction conditions: 60 mg (0.4 mmol) of trans-β-nitrostyrene, 0.8 ml (0.8 mmol) of 2,4pentanedione, 10 mol% catalyst, 2 ml of toluene, rt. a Isolated yields.b Enantiomeric excess (ee) determined by chiral HPLC analysis (Chiralpak IA).c As reported by W. Wang and coworkers using 10 mol% catalyst in THF. 8 The thiourea catalyst 2 showed an even larger and more dramatic enhancement in catalytic activity generating the Michael adduct in 95% yield and 97% ee (S = major product) after only 1 hour.Catalyst 2 has both a thiourea and a tertiary amino functionality on a chiral cinchona scaffold and introduces both a bidentate hydrogen bonding functionality and steric bulk at C9.The bifunctional nature of catalyst 2 allows it to activate both β-nitrostyrene and 2,4pentanedione simultaneously, Figure 3. 7 The excellent result in toluene is a marked improvement from that reported by Wang 8 in THF (95% yield, 97% ee in 1 hour versus 47% yield, 96% ee in 48 hours) and emphasizes the importance of solvent choice in bifunctional organocatalysis.The catalytic activity of the thiourea catalyst 2 is greatly enhanced in the less polar solvent toluene, generating a significantly higher yielding and faster reaction.This effect is most likely due to increased hydrogen bonding activation of β-nitrostyrene by 2 in the less polar solvent.The size of the R group on the β-diketones 4a-g had a significant effect on the yield of the reaction.The yield was similar for β-diketones with similarly sized R groups, e.g.R = Et or Ph, entries 3 and 7, (Table 3).In contrast, the more sterically bulky R groups, iPr and tBu, resulted in a substantial reduction in reactivity, entries 4 and 5, (Table 3).A plot comparing yield and Charton steric value clearly demonstrates the effect the R group has on reaction yield (Figure 5).The size of the R group had no real effect on the enantiomeric ratios with all reactions giving high enantioselectivities (92-99% ee), with the exception of 6f (70% ee).
The tBu substituted β-diketone, dipivaloylmethane, was expected to be too sterically hindered to undergo a Michael addition.To our delight catalyst 2 successfully generated a Michael addition of dipivaloylmethane to β-nitrostyrene, (99% ee), entry 5, (Table 3).To the best of our knowledge, the chiral or achiral Michael addition of dipivaloylmethane to an activated olefin has never been reported.Attempts to generate a racemic addition of dipivaloylmethane to β-nitrostyrene proved unsuccessful and indicate how challenging this transformation is.KOtBu, DABCO and NEt3 were employed as base but all returned unreacted β-nitrostyrene.NaOMe resulted in polymerization of the β-nitrostyrene with no sign of the desired Michael adduct.The fact that the addition only occurred when the cinchona thiourea catalysts were used demonstrates the exceptional activating ability of the thiourea motif and that a highly activating bifunctional catalyst is essential for this challenging Michael addition.The quinidine bifunctional catalyst 14 was used to obtained the opposite enantiomer of the dipivaloylmethane product 6d and hence allow accurate determination of the enantioselectivity.Reaction conditions: 37.5 mg (0.25 mmol) of trans-β-nitrostyrene, (0.5 mmol) of β-diketone, catalyst 2 (10 mol%), 1 ml toluene, rt. a Isolated yields.b Enantiomeric excess (ee) determined by chiral HPLC analysis (Chiralpak IA) c Reaction performed with catalyst 14 (10 mol%).d ee determined by chiral HPLC analysis (Chiralpak IB). e Diastereomeric ratio = 1:1.2(determined by 1 H NMR), ee of major isomer = 70%.The cyclohexyl derivative 4g proved to be completely unreactive in our hands, entry 6, Table 3. Toma and coworkers reported the same result for 4g in their ionic liquid-proline catalyzed addition to β-nitrostyrene.They suggested that the reduced reactivity was due to the geometry of 4f allowing the formation of a hydrogen bond-stabilized enol. 20Decreasing the ring size to the cyclopentyl derivative 4f resulted in a change in geometry and a high yielding Michael addition, entry 9, (Table 3).

Conclusion
In conclusion, we have demonstrated that polarity has a significant effect on enantioselectivity in the quinine catalyzed Michael addition of acetylacetone to β-nitrostyrene, with less polar solvents giving a superior enantiomeric ratio.Furthermore, it was necessary to have both a good H-bonding motif and steric bulk at C9 of the cinchona catalyst to generate both a high yielding and enantioselective reaction.The thiourea bifunctional organocatalyst 2 was the most powerful catalyst tested and was shown to be much more effective at catalyzing the Michael addition of β-diketones to β-nitrostyrene than previously reported with a dramatic improvement in yield and reaction time (47% → 95%, 48 h → 1 h).The thiourea bifunctional organocatalyst 2 is such an effective catalyst for this transformation that it was able to promote the challenging Michael addition of dipivaloylmethane to β-nitrostyrene (99% ee), which is reported herein for the first time.

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

Experimental Section
General.Reagents were used as purchased from suppliers, unless otherwise indicated.Solvents were distilled and dried before use.Toluene and anhydrous DMF were used as purchased.Reactions requiring inert conditions were performed in dried glassware under a positive pressure of argon.Compounds 4a-g, 5 and catalysts 3,7-13 were purchased and used without further purification.Reactions were monitored by thin layer chromatography using SiO2 (silica gel 60 F254, Merck, coated aluminum plates), and visualizing by UV light or by aqueous KMnO4 or solutions.Flash chromatography was carried out on SiO2 (silica gel 60 F254, 230-400 mesh ASTM, Merck). 1 H and 13 C NMR spectra were recorded with a Bruker Avance 300 NMR spectrometer.Chemical shifts are reported in ppm relative to TMS internal standard (δ = 0.00) in CDCl3 for 1 H NMR spectra.For 13 C NMR spectra, solvent residual peaks (δ = 77.0ppm for CDCl3 were used as internal reference.Abbreviation of multiplicities is as follows: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), app s (apparent singlet), br s (broad singlet).High-resolution mass spectrometric data was recorded with an Agilent Technologies 6410 Time of Flight LC/MS at NUI Maynooth.IR spectra were recorded with Perkin Elmer System 2000 FT-IR instrument.Optical rotations were obtained with a Perkin-Elmer 343 polarimeter (λ = 589 nm) using a 0.5 dm cell.Chiral HPLC analysis was performed with a Perkin Elmer Series 200 HPLC.The exact conditions are reported in connection with each analyzed substance.HPLC analyses were performed before crystallization steps to exclude possible additional enantioenrichment.Melting points were recorded with Stuart SMP11 melting point apparatus in open capillary tubes.

General procedure for conjugate addition reactions
To a stirred solution of trans--nitrostyrene (37.5 mg, 0.25 mmol) and 1,3-dicarbonyl compound (2 equiv., 0.5 mmol) in solvent (1 mL) was added the chiral organocatalyst (10 mol%).Upon consumption of the nitrostyrene (monitored by TLC), the reaction mixture was concentrated under reduced pressure.The residue was purified by flash chromatography to afford the conjugate addition product.The corresponding racemic products were synthesized using KOtBu (5 mol%) in toluene.

Figure 4 .
Figure 4. Simultaneous activation of both the nitroolefin and nucleophile.