FULL PAPER

DOI: 10.1002/ejoc.201500207

Morita–Baylis–Hillman Reactions with Nitroalkenes: A Case Study

Vincent Barbier,[a] François Couty,[a] and Olivier R. P. David*[a]

Keywords: Organocatalysis / Lewis bases / Kinetics / Nucleophilic addition / Polymerization

We report on the use of a highly reactive super-DMAP cat-alyst in Morita–Baylis–Hillman (MBH) reactions of nitroalk-enes with ethyl glyoxylate, which result in excellent conver-sions and short reaction times with, importantly, very low cat-alyst loading. An extensive study of this particular reaction ispresented, which examines all mechanistic and experimentaldetails. Several critical points were hence uncovered that in-clude the correlation between reaction efficiency and Lewisbasicity of the catalyst; the double role played by the pro-

Introduction

Electron-deficient alkenes are versatile synthons em-ployed either as Michael acceptors, or as precursors of sta-bilized anions able to attack an electrophile, which is a con-dition epitomized in Morita–Baylis–Hillman (MBH) reac-tions.[1] Electrophilicity at the β-carbon atom and nucleo-philicity at the α-carbon atom can also be combined,through dipolar behavior, which is the basis of multiplecomplex transformations reported in modern organocat-alysis.[2] Although these reactions are amply described withacrylates and derivatives, nitroalkenes[3] are much less em-ployed as Michael acceptors or as two-carbon dipoles,[4]

and illustrations of their pro-nucleophile properties are rela-tively rarely reported in the literature (Scheme 1).

Scheme 1. Three reaction pathways possible with β-nitroalkenes.

Namboothiri’s group[5] extensively explored the reactivityof nitroalkenes activated with a Lewis base and their subse-

[a] Laboratoire Synthèse & Réactivité, Institut Lavoisier,UMR8180, Université de Versailles SQY45 Av. des Etats-Unis, 78035 Versailles, FranceE-mail: olivier.david@uvsq.frhttp://www.ilv.uvsq.fr/Supporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201500207.

Eur. J. Org. Chem. 2015, 3679–3688 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3679

moter, primarily as a nucleophilic activator towards the nitro-alkene, and as a Brønsted base that triggers glyoxylate de-polymerisation. More generally, the limitations in the choiceof electrophiles that can engage efficiently in MBH-typetransformations are rationalized by the competition betweena productive pathway and a nitroalkene polymerization pro-cess. Other aspects of this transformation, used as a casestudy, are presented in the light of physical organic chemis-try.

quent reactions with various electrophiles. Other groupsalso contributed to demonstrate the utility of nitroalkenesas pro-nucleophiles in MBH[6] or aza-MBH[7] reactions thatinvolved activated aldehydes or imines as the electrophilicpartner, Mannich[8] reactions with iminium ions, andRauhut–Currier[9] heterocouplings with a second Michaelacceptor. An enantioselective and intramolecular version ofthis last reaction has been reported by Gu and Xiao.[10] Fi-nally, hydrazination reactions[11] of nitroalkenes can be per-formed when azodicarboxylates are involved. Althoughgood conversions and stereoselectivities are typically ob-served in these transformations, several drawbacks canhamper their synthetic relevance. High substrate depen-dence on the level of conversion is a common pitfall, afeature that narrows the scope of the transformation. Inaddition, high catalyst loadings (ca. 100 mol-% in somecases) combined with protracted reaction times are oftennecessary to achieve full conversion.

With an array of highly nucleophilic/Lewis-basic pyr-idine catalysts[12] with known reactivity profiles in hand,[13]

we decided to take MBH reactions that involved nitroalk-enes as a case study, with the idea that these powerful toolscould help identify important gears in the complex MBHmachinery. Here, we present catalyst optimization toachieve high conversions in short reaction times and withlow catalyst loadings. Then, exploratory experiments arediscussed, and crucial parameters at play in MBH reactionsthat involve nitroalkenes and activated aldehydes are high-lighted.

Results and Discussion

The addition of β-substituted nitroethylene to ethylglyoxylate upon nucleophilic activation with a catalyst was

V. Barbier, F. Couty, O. R. P. DavidFULL PAPERselected as a model MBH reaction [Scheme 2 with β-nitro-styrene (1)]. This transformation was initially described byNamboothiri[6] and co-workers by using ethyl gyloxylate (2)(4 equiv.) in the presence of either 4-(dimethylamino)pyr-idine (DMAP, 3) in acetonitrile, or imidazole (ImH, 4) inchloroform, which led to desired MBH adduct 5 in 33 and31% isolated yields after 30 min and 5 h, respectively.

Scheme 2. Previous results of MBH reactions with DMAP andImH.

The same reaction with various nitrogen-based catalysts,with contrasting reactivity profiles in terms of nucleophil-icity and Lewis basicity, were investigated because of theinitial disappointing results (Figure 1).

Figure 1. Nitrogen-based catalysts employed in this study.

An equimolar mixture of β-nitrostyrene (1) and ethylglyoxylate (2, EtG) in CDCl3 was placed in an NMR tube,the catalyst was added, and conversion was then measuredat three different times: 30 min, 1 h, and 2 h. Experimentswere repeated with decreasing amounts of catalysts, whichranged from 10 to 2 mol-%; see results in Figure 2.

As can be seen, all catalysts, except quinuclidine, pro-mote the MBH reaction with conversions above 70% after30 min with 10 mol-% loading; with protracted reactiontimes leading only to moderate increases in conversion. Thecritical loading necessary to promote this transformation isof more interest. If all pyridines are still active with 5 mol-% loading, a drastic drop in performance is observed when2 mol-% is used, except for s-DMAP (see structure in Fig-ure 1), which still promotes 85% conversion under theseconditions. With s-DMAP identified as the most potent cat-alyst in this series, various solvents were screened to selectthe best reaction medium. The choice of usable solvents wasactually quite small as a result of poor solubility of nitro-alkenes in nonpolar solvents. Among the solvents tested[tetrahydrofuran (THF), chloroform, acetonitrile, and di-methyl sulfoxide (DMSO)], acetonitrile proved optimal(Figure 3), as already observed by Namboothiri[6c,6d] forDMAP. The study included DMAP and s-DMAP as pro-moters. DMAP and s-DMAP behave quite differently inchloroform and acetonitrile. Although very basic s-DMAP

www.eurjoc.org © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2015, 3679–36883680

Figure 2. MBH reactions with catalysts 3 and 6–9 in CDCl3 withvarious loadings. Conversions were measured at 30, 60, and120 min.

performs well in both solvents, the use of chloroform inconjunction with DMAP results in a steep conversion de-crease relative to the same catalyst in acetonitrile.

Figure 3. Conversion in MBH reactions by varying the catalyst(2 mol-%) and solvent employed ([D8]THF, [D6]DMSO, CDCl3,CD3CN).

Under these conditions, we tested a small library ofchemically diverse nitroalkenes 1 and 10–18, as shown inTable 1. Attention was paid to the critical loading requiredfor each substrate, by testing 1 mol-% catalytic charge whengood results were obtained with 2 mol-%.

Morita–Baylis–Hillman Reactions with Nitroalkenes

Table 1. Conversions and isolated yields for MBH reaction withnitroalkenes 1 and 10–19 with various catalysts loadings of s-DMAP (9).

[a] Reaction performed in CD3CN with ethyl glyoxylate (1 equiv.)and s-DMAP (5, 2, or 1 mol-%). Conversion measured after 30 minby NMR spectroscopy. [b] Numbers in parentheses are isolatedyields after flash column chromatography.

Eur. J. Org. Chem. 2015, 3679–3688 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 3681

The same trends already observed in previous stud-ies[6c,6d] can be delineated: electron-poor aromatic alkenesproved less efficient in this reaction, whereas alkyl-substi-tuted nitroalkenes are superior substrates. In a typicalMBH reaction with β-nitrostyrene (1) these improved con-ditions result in a turnover frequency (TOF) of 83 h–1,whereas previous protocols perform at a TOF of 1.6 h–1.Finally, to illustrate the synthetic relevance of this method-ology with low catalyst loading of s-DMAP, a gram-scaleexperiment with methoxy-substituted nitrostyrene 11 wasperformed (Scheme 3).

Scheme 3. MBH reaction on a gram scale; preparation of 19.

After this optimization study, we were interested in scru-tinizing the mechanism of MBH reactions that involvednitroalkenes as substrates, and the results obtained are pre-sented below. It is important to bear in mind the three im-portant elementary steps of this transformation that arepresented in Scheme 4 as forward reactions for clarity.

Scheme 4. MBH reaction catalytic cycle.

The reaction is initiated by 1,4-nucleophilic addition ofthe Lewis basic catalyst onto the Michael acceptor, whichleads to zwitterionic intermediate 20. The producednitronate then reacts with the aldehyde that leads to a newC–C bond, and resulting alkoxide 21 undergoes a formal C� O proton shift to give 5 with departure of the Lewisbase, thus regenerating the catalyst. We will now considerthese three steps separately and present results that bringelements of comprehension for each of them in which nitro-alkenes are involved in an MBH reaction.

Step A is reversible, and physical organic chemistry pro-vides quantitative parameters for both reactants, such asthe electrophilicity of nitrostyrenes[14,15] and the nucleo-philicity of numerous Lewis bases.[16] It is therefore interest-ing to examine predictions that can be made about the ki-netics of this initial nucleophilic addition by employing

V. Barbier, F. Couty, O. R. P. DavidFULL PAPERMayr’s comprehensive nucleophilicity scale[17] in accord-ance with the linear free energy relationship [Equation (1);N = nucleophilicity, E = electrophilicity].

log k2 (20 °C) = sN (N + E) (1)

These data estimate that step A should be �2000 timesfaster with quinuclidine relative to DMAP. However, whenthe conversion at an intermediary time[18] was plottedagainst the nucleophilicity of the catalyst, as presented inFigure 4, no correlation was found between these param-eters (Table 2).

Figure 4. Plot of the conversion at 30 min against the nucleophilic-ity value N of the employed catalyst.

Table 2. Calculations of rate constants for step A.

Therefore, the reversibility of step A must be taken intoaccount, in other words, the thermodynamic stability of theproduced zwitterion 20, and conversely its instantaneousconcentration, is more relevant to the conversion than itsrate of formation. Knowledge of the equilibrium constant K(Scheme 5) would thus be highly informative. Very recently,Mayr’s group introduced a new scale of Lewis basicities to-ward C-centered Lewis acids, based on Equation (2), inwhich LA and LB are quantitative parameters defined asLewis acidity and Lewis basicity, respectively.[19]

log K = LA + LB (2)

Scheme 5. Equilibrated formation of zwitterion 20.

Lewis basicity values are accessible for DMAP and s-DMAP in acetonitrile, but the Lewis acidity values fornitroalkenes are not yet known. We can, however, get

www.eurjoc.org © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2015, 3679–36883682

around this lack of information by calculating the ratio ofequilibrium constants for s-DMAP and DMAP (Ks-DMAP/KDMAP) with Equation (3).

(3)

Although imprecise, this ratio clearly indicates that theequilibrium of step A is more than four times displaced to-ward the formation of the zwitterion by using s-DMAP asa catalyst relative to DMAP. This ratio says that the s-DMAP-derived zwitterion is four times more stable than itsDMAP-derived congener. This stability can also be evalu-ated by using the “methyl cation affinity” (MCA), athermodynamic parameter that is easily and accurately cal-culated,[20] which represents the energy necessary to stripoff a methyl cation from the corresponding methylammo-nium species. This parameter quantifies the affinity of aLewis base for a carbon-centered electrophile (Table 3).

Table 3. MCA values for the tested catalysts.[23]

Catalyst QN DMAP PPY Azajul s-DMAP

MCA [kJmol–1] 576.0 581.2 590.1 602.7 636.8

A plot of conversion at an intermediary time againstMCA of the tested catalysts showed a general trend (Fig-ure 5).

Figure 5. Plot of conversion at 30 min against MCA values of theemployed catalysts.

Clearly, in this transformation the Lewis-basic characterof the catalyst is a key parameter to achieve good conver-sions. Incidentally, following this trend, phosphines shouldexhibit interesting catalytic activities, because tributyl-phosphine, for example, has an MCA value of639.6 kJmol–1. However, with these compounds, only mar-ginal conversions are observed, probably owing to the im-portant steric crowding around the phosphorus atom. Thisis not the case for the pyridine nitrogen atom, which is read-ily accessible for attack on the Michael acceptor. In anycase, within the DMAP/PPY/Azajul/s-DMAP series, inwhich steric crowding is identical, the superior basicity ofthe latter induces a superior concentration of active zwitter-

Morita–Baylis–Hillman Reactions with Nitroalkenes

ion 20 by limiting the reverse reaction, and results in higherconversions at equal times. It should be added that al-though zwitterion 20 derived from s-DMAP, is more stablethan its congener derived from DMAP, its instantaneousconcentration is very low, and 20 could not be detected byNMR spectroscopy.

This optimal reactivity profile observed for s-DMAP inMBH reactions with nitroalkenes is in stark contrast withthe behavior displayed by the catalysts that performed bestin other reactions. As proven by Zipse and co-workers,[13,16]

aza-MBH reactions perform best with phosphines, whereasazajulolidine (8) is by far the most efficient catalyst foralcohol acylation reactions. This enlightens the subtle bal-ance in catalyst reactivity profiles (nucleophilicity/nucleo-fugality/Lewis basicity) required for each type of transfor-mation.

The final investigation of step A was conducted by per-forming the MBH reaction in the presence of a thioureaadditive. Enhancement of the electrophilicity of nitroalk-enes by twofold H-bonding[21] is well established in organo-catalysis, so the influence of Schreiner’s catalyst 22 on theyield and rate of our benchmark transformation was exam-ined.

As can be seen in Figure 6, the use of DMAP in chloro-form rendered the catalytic system sensitive to the presenceof thiourea 22, and an almost twofold increase in conver-sion was observed after 1 h (33–56%), which suggests thisadditive is beneficial. As depicted in Scheme 6, the thiourealigand is capable of enhancing the electrophilicity of thenitroalkene and also stabilizing the zwitterionic adduct.However, in more polar acetonitrile only marginal changeswere observed upon addition of thiourea, either in the pres-ence of DMAP or s-DMAP. The solvent dipolar stabiliza-tion of the zwitterion in acetonitrile surpasses the effect ofthiourea.

Figure 6. Results of MBH reactions between β-nitrostyrene andethyl glyoxylate (1 equiv.) in the presence of Lewis base (DMAP ors-DMAP; 2 mol-%) and with or without the addition of Schreiner’scatalyst (4 mol-%) in CDCl3 or CD3CN.

Eur. J. Org. Chem. 2015, 3679–3688 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 3683

Scheme 6. Double H-bonding of β-nitrostyrene (1) with Schreiner’scatalyst 22.

Therefore, there is substantial enhancement of the nitro-alkene electrophilicity upon complexation with an H-bonddonor in chloroform, and subsequently an increase of thezwitterion stability and thus in its concentration. However,this effect is surpassed in acetonitrile by the solvent dipolarstabilization of the zwitterion. It is also worth noting that inchloroform conversion stops at ca. 60 % even after extendedreaction times.

Step B in the catalytic process is associated with themajor problem of parasite polymerization that is encoun-tered in MBH reactions with nitroalkenes. This side-reac-tion is mentioned in several reports that deal with nucleo-philic activation of nitrostyrenes, but no particular atten-tion was given to understand and avoid it. During experi-ments aimed at characterizing pyridinium–nitronate zwit-terions by treating nitrostyrenes with equimolar quantitiesof Lewis bases, we observed a rapid decrease in the totalconcentration in the medium, and eventually complete dis-appearance of the reactants. Polymerization was evident,and these mixtures became turbid, and eventually precipi-tation of the organic material occurred. Polymerization ofnitroalkenes is documented in the literature with anionicinitiators.[22] This event occurs at step B and involves thezwitterion that results from step A, which can either attackthe second electrophile and evolve to the desired product,or alternatively attack a second nitrostyrene molecule andform oligomers as shown in Scheme 7.

Scheme 7. Concurrent pathways in step B: nitronate addition to anelectrophile or to the starting nitroalkene.

The relative rates of these two reactions determine theratio between oligomerization and the productive route.Here again, prediction of this ratio is quite straightforwardby using Mayr’s approach. Although the nucleophilicityvalues are not known for the nitronate intermediates, rateratios can be estimated by using Equation (4). If a value of1 is assumed for the sensitivity factor (sN), the ratio kadd/

V. Barbier, F. Couty, O. R. P. DavidFULL PAPERkpolym is simply calculated from the difference in electro-philicities of the considered electrophile and that of thenitrostyrene (Table 4). The electrophilicity scale in Figure 7presents a selection of carbonyl derivatives and Michaelacceptors that are classical partners in MBH reactions.

(4)

Table 4. Relative rates of addition/polymerization for various elec-trophiles.[23–26]

Figure 7. Electrophilicity scale with various electrophiles relative toβ-nitrostyrene.

These calculations bring to light the limitations observedin MBH reactions that involve nitroalkenes and explain whyaromatic and aliphatic aldehydes are not suitable partners.In these cases polymerization is overwhelmingly more rapidthan productive step B. Only carbonyl functions with ad-

www.eurjoc.org © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2015, 3679–36883684

ditional strongly withdrawing groups are reactive enough.The electrophilicities of activated aldehydes and ketoneslike glyoxylates, pyruvaldehydes, or pyruvates have not yetbeen measured, but their successful implication in MBHreactions with nitrostyrenes should be related to their E val-ues, which should logically be superior, or at least close,to those of nitrostyrenes. This table also explains why onlysulfonyl-substituted imines are efficient partners, becauseless activated ones (carbamyl, phosphoryl, ...) fall below thereactivity line of –13.8 and therefore cannot compete withthe polymerization process.[7] Other successful transforma-tions that involve azodicarboxylates in hydrazination[9] re-actions and disulfonylethylenes in Rauhut-Currier[11] reac-tions follow the same reasoning.

Examination of the relative reaction rates clarifies andallows the prediction of the occurrence of parasitic poly-merizations, but we wanted to gain more information onthe polymerization reaction itself, in particular, the reactionrate. Does this unwanted phenomenon occur in minutes,hours, or days? Polymerization experiments were performedin NMR spectroscopy tubes, by using the concentrationand catalyst loading conditions employed for MBH reac-tions (2 mol-% of DMAP), and with three different β-nitro-styrenes with contrasting electronic profiles (Figure 8).

Figure 8. Remaining β-nitrostyrenes 1, 11, and 12 plotted againsttime under polymerization conditions in the presence of DMAP(2 mol-%) in acetonitrile.

The fast rate of oligomerization, even with DMAP as theinitiator, is clear, because after 2 min �20 % of the substrateis already polymerized and 30 min is sufficient to drive halfof the nitrostyrene into its polymeric form. These experi-ments could not be reproduced with s-DMAP as initiator,because the reactions were too rapid for standard measure-ments. For a more precise quantification of this polymeriza-tion we hypothesized a classical scheme of propagation forliving anionic polymerization, considering [Zw] as the con-centration of propagative ends under the form of polymericzwitterions. An important approximation is that all the pyr-idine initiator present gives rise to a nitronate reactive end.

Morita–Baylis–Hillman Reactions with Nitroalkenes

After integration, the rate law was employed in the propa-gation model of living anionic polymerization and used tomeasure kp.

The plot in Figure 9 for methoxy-β-nitrostyrene is ap-proximately a straight line, which validates this model ofliving polymerization. However, the plots for nitrostyreneand the cyano-substituted monomer deviate significantlyfrom linearity, and such deviation by progressive decline ofthe curve is classically attributed to the disappearance ofreactive ends, so-called terminations, which can be ex-plained here by the precipitation of some living polymereven at early stages of the reaction. This holds particularlytrue for cyano-β-nitrostyrene, for which turbidity is ob-served within the first minutes of reaction and rapidly re-sulting in the complete precipitation of the active species. Inthis latter case conversion never exceeds 20%, as graphicallyobserved with a flat plateau. Quantification for the two for-mer substrates was performed by calculating the slope ofboth lines at short reaction times (ca. 5 min), for which noprecipitation was observed. This allows the determinationof kp constant rates, which are presented in Table 5.

Figure 9. Plot of the propagation model for living anionic poly-merizations, for the reaction of β-nitrostyrenes 1, 11, and 12 withDMAP (2 mol-%) in CD3CN at 20 °C.

Table 5. Propagation constant rates kp.

Logically, more electrophilic nitrostyrene 1 polymerizesthree times faster than the methoxy-substituted one. Thiscan explain the counter-intuitive fact that electron-richnitroalkenes are superior substrates in MBH reactions eventhough they are less electrophilic. With these less-activatedalkenes, polymerization is far less rapid and leaves moreroom for the desired reactive pathway to proceed. Addition-ally, and of practical relevance, the high rate of this poly-

Eur. J. Org. Chem. 2015, 3679–3688 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 3685

merization process stresses the importance of an appropri-ate reactant addition order. Good conversions can only beachieved by introducing the catalyst to the mixture of thetwo partners, whereas premixing catalyst with nitroalkenefollowed by aldehyde addition induces extensive polymeri-zation. Finally, these results outline the extreme rapidity ofthe MBH reaction, as effective examples proceed withyields higher than 85% and without any polymerization.

After having studied the parallel pathways to explain themodest conversions observed with certain reactants, we re-focused on ethyl glyoxylate. EtG is a very effective partnerin MBH reactions with nitroalkenes as a result of its supe-rior electrophilicity, but it is not ideal for studying its reac-tivity parameters. Being mostly polymeric in nature, accessto the usual kinetic and thermodynamic measurements ishampered by the absence of a precise knowledge of the con-centration of monomeric glyoxylate. It is well known thatin the presence of traces of water and under basic catalysismonomeric EtG quickly polymerizes to give linear poly-acetals (Scheme 8).[27] Commercial EtG solutions in tolueneare in the oligomeric forms at ca. 96%, and the NMR spec-trum reveals a small signal of aldehyde protons that equatesto ca. 4% of the mixture. However, the literature also clearlyshows that polyEtG can undergo facile depolymerisationunder basic conditions.[28]

Scheme 8. Equilibrium of oligomerization for ethyl glyoxylate.

A very simple experiment gave interesting and quantita-tive information on that point. Three NMR spectroscopictubes were prepared with three different concentrations ofcommercial EtG, which correspond to the reaction condi-tions of 1, 4, and 6 equiv., respectively, of EtG, (cf. condi-tions used in MBH reactions below; Figure 9). After 12 h,the three tubes revealed similar amounts of free monomericEtG, around 3.7% of the mixture. Then all three tubes werecharged with 2 mol-% of DMAP and were left to standagain for 12 h. The measured quantity of monomeric EtGwas now far higher and depended on the total concentra-tion of glyoxylate. The most dilute solution showed 37 % offree aldehyde, this amount decreased to 31 and then 26%as the total concentration increased (see Supporting Infor-mation for details). DMAP thus catalyzes the depolymeri-sation of commercial EtG and drives the solution to a ther-modynamically equilibrated state, conversely with more freealdehyde present in the reaction mixture. The role of thecatalyst is therefore twofold in this reaction, concomitantlyto activate the nitrostyrene partner as a Lewis base, andalso to depolymerize oligomeric EtG forms as a Brønstedbase.

With the idea of determining the partial order relative tothe aldehyde reactant in the rate law, we performed severalMBH reactions with increasing amounts of EtG (1, 2, 4,and 6 equiv.) and monitored the rate of conversion againsttime in the presence of identical catalytic loadings of s-

V. Barbier, F. Couty, O. R. P. DavidFULL PAPERDMAP (Scheme 9). An increase in reaction rates wouldshow the intervention of EtG in the rate-determining step,whereas similar conversion profiles would denote a zeroorder for this reactant and suggest that step B is not rate-determining. However, the third possibility, which was actu-ally observed, was unexpected, in which increasing amountsof EtG produced a steep decrease in reaction rates. Thissurprising result was reproducible and did not depend onreactant batches. This inhibition phenomenon by EtG is ofsuch a magnitude that, in the presence of 6 equiv. of EtG,any reactivity is destroyed, as presented in Figure 10.

Scheme 9. Hypotheses for catalyst inhibition in the presence of highconcentrations of EtG, here presented with DMAP for simplicity.

Figure 10. MBH reactions of β-nitrostyrene with different numbersof equivalents of EtG in the presence of 2 mol-% s-DMAP, inCD3CN at 20 °C.

We first hypothesized a problem associated with tracesof acid that could partially protonate and ultimately fullyinactivate the pyridine catalyst when excess amounts wereused. Control experiments undertaken in the presence of0.5 equiv. of N,N-diisopropylethylamine (DIPEA), a non-nucleophilic base, under otherwise identical conditions.Conversion in the absence of DIPEA was measured at 33%after 30 min of reaction, and addition of DIPEA resultedin an identical conversion, 34 %, which eliminated protonicinhibition as a cause. Two hypotheses remain: a strong H-bond formed between the catalyst and the hemiacetalmoieties of EtG oligomers, or a concurrent nucleophilic ad-dition onto the activated EtG monomer, to trap the catalystin a dormant, zwitterionic, state.

www.eurjoc.org © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2015, 3679–36883686

It is important to realize that the use of reaction condi-tions that employ 2 mol-% pyridine catalyst in the presenceof 6 equiv. of EtG results from the catalyst’s “point of view”in quite high 300 equiv. To probe the nature of this detri-mental interaction we recorded 13C NMR spectra of a rea-sonable quantity of DMAP in the presence of an excess ofEtG and in the presence of methanol as a model compoundfor putative H-bond interactions. The results are displayedin Table 6.

Table 6. 13C NMR chemical shifts (δ [ppm]).

As shown by 13C NMR chemical shifts, the addition ofmethanol induces a clear, although moderate, perturbationon DMAP. However, addition of EtG leads to greatermodifications; in particular the C2 carbon atom, next to thenitrogen atom, experiences a shielding effect of ca. 10 ppm,which reveals an interaction between EtG and the pyridinecatalyst. However, these results do not give decisive proofto be able to draw definitive conclusions about the natureof the observed reactant-induced catalyst inhibition.

After studying details about step B, by evaluating thestate of each reactant, zwitterion and glyoxylate, and afterhaving elucidated the origin and extent of polymerizationside-reactions, we turned our attention towards the laststep C that features the final proton shift, concomitant withcatalyst release. This final step has been particularly investi-gated, because it is often the rate-determining step in MBHreactions. Acceleration of this proton shift is possible if anexternal O–H function serves as a proton conveyor within asix-membered ring, as shown by Aggarwal;[29] alternatively,intercalation of a second aldehyde substrate allows for anintermolecular elimination process that results in a hemia-cetal that decomposes into the MBH adduct, as hypothe-sized by McQuade[30] (Scheme 10). In 2009, Eberlin andCoelho[31] substantiated, by mass spectrometry measure-ments, the parallel occurrence of both mechanisms in aclassical MBH reaction.

It has been shown in aza-MBH reactions with quininederivatives that adjunction of phenol derivatives could ac-celerate the transformation,[32] by relaying the proton shift.To probe this point, we performed MBH reactions in thepresence of 2-naphthol. In this MBH transformation, how-ever, no detectable effect was measured upon addition oftwice the catalytic charge in 2-naphthol, regardless of thecatalyst/solvent combination (see Supporting Informationfor details). It may be possible that 2-naphthol is not ableto interact with the pyridinium alcoholate in this context,or more simply, that step C is not rate-determining underthese reaction conditions.

Morita–Baylis–Hillman Reactions with Nitroalkenes

Scheme 10. McQuade and Aggarwal mechanistic proposals for as-sisted proton abstraction in step C.

Conclusions

The use of highly nucleophilic pyridine catalysts like su-per-DMAP allowed a mechanistic dissection of the complexmachinery involved in MBH reactions between nitroalkenesand ethyl glyoxylate. Some crucial points were identified toachieve reaction efficacy, and intrinsic limitations were ra-tionalized. The Lewis basicity of the catalyst proved ofutmost importance to form substantial quantities of thezwitterionic intermediate by intrinsic stabilization. Studiesaimed at quantifying the competitive nitroalkene polymeri-zation explained the necessity for minimal contact betweenthe Michael acceptor and the catalyst in the absence of al-dehyde, with the oligomerization reactions being extremelyrapid. This parasitic pathway was identified as the reasonwhy this reaction is limited to highly electrophilic partners,because only reactants that display an electrophilicity supe-rior to that of the nitroalkene can be used. Studies centeredon EtG revealed the dual role played by the pyridine cata-lyst. Although primarily employed as a nucleophilic acti-vator for the nitroalkene partner, it also serves as a basicdepolymerisation catalyst for the oligomeric aldehyde reac-tant. Finally, this work highlights the high efficiency of s-DMAP in the catalysis of this reaction, which tolerates anunprecedentedly low catalyst loading (2 mol-%) for prepar-ative purposes.

Experimental SectionTo a stirred solution of (E)-1-methoxy-4-(2-nitrovinyl)benzene (11;1.185 g, 6.62 mmol), ethyl glyoxalate (2) (50% in toluene suppliedby Alfa Aesar; 1.3 mL, 6.56 mmol, 1 equiv.) in CH3CN (11 mL),was added super-DMAP (9) (47.3 mg, 0.13 mmol, 2 mol-%). After30 min, the solvent was removed under reduced pressure and theresidue purified by silica gel (60–120 mesh) column chromatog-raphy (petroleum ether/EtOAc, 8:2; Rf = 0.2) to afford MBH prod-uct 10 as a bright yellow solid (1.35 g, 4.8 mmol, 72.5%). Spectro-scopic data are identical to that reported.[6d]

Eur. J. Org. Chem. 2015, 3679–3688 © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 3687

Acknowledgments

This work was supported by the Université de Versailles SQY andthe Centre National de la Recherche Scientifique (CNRS), whichare gratefully acknowledged. V. C. is thankful to the French Minis-try of Research for a doctoral position.

[1] Y. Wie, M. Shi, Chem. Rev. 2013, 113, 6659–6690.[2] C. M. R. Volla, I. Atodiresei, M. Rueping, Chem. Rev. 2014,

114, 2390–2431.[3] C. Roux, Cyril Bressy, “Addition to Nitroolefins and Vinyl

Sulfones” in Comprehensive Enantioselective Organocatalysis,vol. 1 (Ed.: P. Dalko), Wiley-VCH, Weinheim, 2013, pp. 1013–1042.

[4] X.-Y. Chen, L.-H. Sun, S. Ye, Chem. Eur. J. 2013, 19, 4441–4445.

[5] Reviews: a) K. Kaur, I. N. N. Namboothiri, Chimia 2012, 66,913–920; b) J. Mansilla, J. M. Saá, Molecules 2010, 15, 709–734.

[6] a) M. Shiga, H. Kono, I. Motoyama, K. Hata, Bull. Chem.Soc. Jpn. 1969, 42, 798.801; b) N. Rastogi, I. N. N. Nam-boothiri, M. Cojocaru, Tetrahedron Lett. 2004, 45, 4745–4748;c) I. Deb, M. Dadwal, S. M. Mobin, I. N. N. Namboothiri,Org. Lett. 2006, 8, 1201–1204; d) I. Deb, P. Shanbhag, S. M.Mobin, I. N. N. Namboothiri, Eur. J. Org. Chem. 2009, 24,4091–4101; e) H.-H. Kuan, R. J. Reddy, K. Chen, Tetrahedron2010, 66, 9875–9879.

[7] a) N. Rastogi, R. Mohan, D. Panda, S. M. Mobin, I. Nam-boothiri, Org. Biomol. Chem. 2006, 4, 3211–3214; b) S. Takiz-awa, A. Horii, H. Sasai, Tetrahedron: Asymmetry 2010, 21,891–894; c) N. Lu, L. Meng, D. Chen, G. Zhang, RSC Adv.2011, 1, 1113–1118.

[8] K. Rajesh, P. Shanbhag, M. Raghavendra, P. Bhardwaj,I. N. N. Namboothiri, Tetrahedron Lett. 2010, 51, 846–849.

[9] a) M. Dadwal, R. Mohan, D. Panda, S. M. Mobin, I. N. N.Namboothiri, Chem. Commun. 2006, 3, 338–340; b) P.Shanbhag, P. R. Nareddy, M. Dadwal, S. M. Mobin, I. N. N.Namboothiri, Org. Biomol. Chem. 2010, 8, 4867–4873; c) R.Kumar, T. Kumar, S. M. Mobin, I. N. N. Namboothiri, J. Org.Chem. 2013, 78, 5073–5077.

[10] X.-F. Wang, L. Peng, J. An, C. Li, Q.-Q. Yang, L.-Q. Lu, F.-L. Gu, W.-J. Xiao, Chem. Eur. J. 2011, 17, 6484–6491.

[11] a) M. Dadwal, S. M. Mobin, I. N. N. Namboothiri, Org. Bio-mol. Chem. 2006, 4, 2525–2528; b) X.-Y. Chen, F. Xia, S. Ye,Org. Biomol. Chem. 2013, 11, 5722–5726.

[12] a) M. R. Heinrich, H. S. Klisa, H. Mayr, W. Steglich, H. Zipse,Angew. Chem. Int. Ed. 2003, 42, 4826–4828; Angew. Chem.2003, 115, 4975–4977; b) S. Singh, G. Das, O. V. Singh, H. Han,Org. Lett. 2007, 9, 401–404; c) N. De Rycke, G. Berionni, F.Couty, H. Mayr, R. Goumont, O. R. P. David, Org. Lett. 2011,13, 530–533.

[13] a) N. De Rycke, F. Couty, O. R. P. David, Chem. Eur. J. 2011,17, 12852–12871; b) C. Lindner, R. Tandon, Y. Liu, B. Marya-sin, H. Zipse, Org. Biomol. Chem. 2012, 10, 3210–3218; c) R.Tandon, T. Unzner, T. A. Nigst, N. De Rycke, P. Mayer, B.Wendt, O. R. P. David, H. Zipse, Chem. Eur. J. 2013, 19, 6435–6442.

[14] I. Zenz, H. Mayr, J. Org. Chem. 2011, 76, 9370–9378.[15] V. Rai, I. Namboothiri, Eur. J. Org. Chem. 2006, 1693–4703.[16] R. Tandon, T. Unzner, T. A. Nigst, N. De Rycke, P. Mayer, B.

Wendt, O. R. P. David, H. Zipse, Chem. Eur. J. 2013, 19, 6435–6442.

[17] H. Mayr, A. R. Ofial, J. Phys. Org. Chem. 2008, 21, 584–595.[18] For a strictly accurate correlation a plot of reaction half-time

(t1/2) against nucleophilicity is required, but the former value isnot accessible, because the calculation of t1/2 is for a clean reac-tion, running to completion in all experiments, which is not thecase here.

V. Barbier, F. Couty, O. R. P. DavidFULL PAPER[19] H. Mayr, J. Ammer, M. Baidya, B. Maji, T. A. Nigst, A. R.

Ofial, T. Singer, J. Am. Chem. Soc. 2015, 137, 2580–2599.[20] C. Lindner, R. Tandon, B. Maryasin, E. Larionov, H. Zipse,

Beilstein J. Org. Chem. 2012, 8, 1406–1442.[21] a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289–296; b) P. M.

Pihko in Hydrogen Bonding in Organic Synthesis Wiley-VCHVerlag GmbH & Co. KGaA, Weinheim, 2009.

[22] a) H. Wieland, E. Sakellarios, Ber. Dtsch. Chem. Ges. 1919, 52,898–904; b) A. T. Blomquist, W. J. Tapp, J. R. Johnson, J. Am.Chem. Soc. 1945, 67, 1519–1524; c) J. L. Nash Jr., Polymeriza-tion Studies of Unsaturated Derivatives of Beta-Nitrostyrene,PhD Thesis of the University of Florida, January, 1953; d)R. W. H. Berry, R. J. Mazza, Polymer 1973, 14, 172–174; e)R. W. H. Berry, R. J. Mazza, S. F. Sullivan, Makromol. Chem.1984, 185, 559–567.

[23] H. Asahara, H. Mayr, Chem. Asian J. 2012, 7, 1401–1407.[24] T. Kanzian, H. Mayr, Chem. Eur. J. 2010, 16, 11670–11677.[25] R. Appel, H. Mayr, J. Am. Chem. Soc. 2011, 133, 8240–8251.[26] D. S. Allgäuer, H. Mayr, Eur. J. Org. Chem. 2014, 14, 2956–

2963.

www.eurjoc.org © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2015, 3679–36883688

[27] F. Burel, L. Rossignol, P. Pontvianne, J. Hartman, N. Coues-non, C. Bunel, e-Polymers 2003, 3(1), 407–418.

[28] B. Fan, J. F. Trant, A. D. Wong, E. R. Gillies, J. Am. Chem.Soc. 2014, 136, 10116–10123.

[29] V. K. Aggarwal, S. Y. Fulford, G. C. Lloyd-Jones, Angew.Chem. Int. Ed. 2005, 44, 1706–1708; Angew. Chem. 2005, 117,1734–1736.

[30] a) K. E. Price, S. J. Broadwater, H. M. Jung, D. T. McQuade,Org. Lett. 2005, 7, 147–150; b) K. E. Price, S. J. Broadwater,B. J. Walker, D. T. McQuade, J. Org. Chem. 2005, 70, 3980–3987.

[31] G. W. Amarante, H. M. S. Milagre, B. G. Vaz, B. R. Vil-achã Ferreira, M. N. Eberlin, F. Coelho, J. Org. Chem. 2009,74, 3031–3037.

[32] N. Abermil, G. Masson, J. Zhu, J. Am. Chem. Soc. 2008, 130,12596–12597.

Received: February 12, 2015Published Online: May 6, 2015