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Published in final edited form as: J Am Chem Soc. 2020 Mar 11;142(12):5627–5635. doi: 10.1021/jacs.9b12457

A Selenourea-Thiourea Brønsted Acid Catalyst Facilitates Asymmetric Conjugate Additions of Amines to α,β-Unsaturated Esters

Yingfu Lin 1, William J Hirschi 2, Anuj Kunadia 3, Anirudra Paul 4, Ion Ghiviriga 5, Khalil A Abboud 6, Rachael W Karugu 7, Mathew J Vetticatt 8, Jennifer S Hirschi 9, Daniel Seidel 10
PMCID: PMC7533150  NIHMSID: NIHMS1632676  PMID: 32118419

Abstract

β-Amino esters are obtained with high levels of enantioselectivity via the conjugate addition of cyclic amines to unactivated α,β-unsaturated esters. A related strategy enables the kinetic resolution of racemic cyclic 2-arylamines, using benzyl acrylate as the resolving agent. Reactions are facilitated by an unprecedented selenourea-thiourea organocatalyst. As elucidated by DFT calculations and 13C kinetic isotope effect studies, the rate-limiting and enantiodetermining step of the reaction is the protonation of a zwitterionic intermediate by the catalyst. This represents a rare case in which a thiourea compound functions as an asymmetric Brønsted acid catalyst.

Graphical Abstract

graphic file with name nihms-1632676-f0001.jpg

The prevalence of β-amino acids in nature and the utility of this structural motif in drug discovery have inspired the development of numerous synthetic methods.1 Particularly desirable are approaches that facilitate access to β-amino acid derivatives in a catalytic enantioselective fashion.1 An attractive way in which this can be accomplished is via the well-known conjugate addition of amines to α,β-unsaturated carboxylic acid derivatives.2 Indeed, a range of methods have been reported that facilitate catalytic enantioselective additions of nitrogen-centered nucleophiles to conjugate acceptors (Figure 1).3,4 Examples of such reactions include chiral Lewis-acid-catalyzed conjugate additions of O-alkylhydroxylamine to α,β-unsaturated acylpyrazoles, acylpyrroles, and ketones,5 hydrazoic acid to α,β-unsaturated imides,6 and amines to α,β-unsaturated nitriles,7 α,β-unsaturated imides,8 and maleimides.9 Asymmetric organocatalytic variants include the addition of TMS azide to α,β-unsaturated imides,10 N-silyloxycarbamates,11 and N-heterocycles12 to α,β-unsaturated aldehydes, O-benzylhydroxylamine to α,β-unsaturated acylpyrazoles13 and α,β-unsaturated acids,14 amines to nitroalkenes,15 benzyloxycarbamates to 4,4,4-trifluorocrotonates,16 indolines to α,β-unsaturated ketones,17 and hydroxamic acids to quinone imine ketals.18,19 Intramolecular versions are also known, albeit not with basic amine nucleophiles.20 Organocatalytic enantioselective additions to unactivated α,β-unsaturated esters are rare with any nucleophile,21 likely a consequence of their low electrophilicity.22 There appears to be only a single example of a catalytic enantioselective addition of a challenging basic amine to an α,β-unsaturated ester.23 Specifically, a polymeric Lewis acidic aluminum complex was reported to catalyze the addition of benzylamine to ethylcinnamate, with the corresponding product being obtained in 82% ee.23 Here we report the first examples of catalytic enantioselective conjugate additions of basic, cyclic amines to unactivated α,β-unsaturated esters.

Figure 1.

Figure 1.

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Examples of catalytic enantioselective additions of N-nucleophiles to conjugate acceptors and concept for bifunctional catalysis with α,β-unsaturated ester substrates.

We reasoned that the challenging substrate combination of an unactivated α,β-unsaturated ester and a basic amine nucleophile might be successfully realized through bifunctional organocatalysis (Figure 1).24 Specifically, an organocatalyst featuring an electron-deficient thiourea functionality was envisioned to activate the α,β-unsaturated ester substrate via hydrogen bonding (HB) to the carbonyl oxygen. Such interactions have been observed in X-ray crystal structures25 and are implicated in prior work.21 A Brønsted basic/HB acceptor site on the catalyst could serve to simultaneously activate the amine nucleophile. The absolute stereochemistry of the resulting product would thus be controlled by a network of HB interactions.

This concept was evaluated with piperidine and benzyl crotonate as summarized in Table 1. Relatively high substrate concentrations in toluene solvent (2 M in piperidine) were initially employed. Under these conditions, in the absence of any catalyst at room temperature, approximately 50% conversion of piperidine was noted after 24 h (entry 1). Well-known bifunctional catalysts 1a,26 1b,27 1c,28 and 1d29 all modestly accelerated the reaction, albeit with low or no enantioinduction (entries 2–5). Significant rate acceleration was observed with the Nagasawa bisthiourea catalyst 1e.30 Encouragingly, product 2a was obtained with 43% ee (entry 6). Amide-thiourea 1f provided inferior results (entry 7),31 suggesting an important role for the second thiourea functionality and prompting the evaluation of several catalysts containing an electron-rich thiourea moiety in addition to an electron-poor one (entries 8–13).32 Catalysts 1g–l all outperformed 1e, with 1l providing the best results (entry 13). The analogous urea-thiourea 1m was found to be significantly less reactive and provided 2a in lower ee (entry 14). However, the corresponding selenourea-thiourea 1n achieved significantly improved ee while providing further rate acceleration (entry 15). Catalyst 1o containing an additional bromine substituent to further increase the electron-with-drawing character of the aryl substituent proved better still, despite not being fully soluble (entry 16). A reduction in piperidine concentration proved beneficial in regard to product ee with 0.2 M being optimal (entry 18). Under these conditions, there was no detectable background reactivity within 24 h (entry 19). Further evaluation of reaction parameters and additional catalysts resulted in the identification of catalyst 1q, which, at a 10 mol % loading at −10 °C, provided product 2a in 90% yield and 93% ee (entry 27).

Table 1.

Optimization of the Reaction Conditions

graphic file with name nihms-1632676-t0002.jpg
entry catalyst solvent (M) time [h] yield (%) ee (%)
1 - PhMe (2) 24 50 -
2 1a PhMe (2) 23 86 0
3 1b PhMe (2) 22 94 0
4 1c PhMe (2) 20 87 11
5 1d PhMe (2) 20 90 −28
6 1e PhMe (2) 4 93 43
7 1f PhMe (2) 7 91 34
8 1g PhMe (2) 5 93 46
9 1h PhMe (2) 4 93 58
10 1i PhMe (2) 4 92 55
11 1j PhMe (2) 5 95 50
12 1k PhMe (2) 4 94 58
13 1l PhMe (2) 4 92 59
14 1m PhMe (2) 18 92 53
15 1n PhMe (2) 3 93 71
16a 1o PhMe (2) 3 93 76
17 1o PhMe (0.5) 16 91 84
18 1o PhMe (0.2) 20 89 86
19 - PhMe (0.2) 24 trace -
20 1o TBME (0.2) 24 86 85
21 1o CHCl3 (0.2) 24 92 75
22a 1o PhCF3 (0.2) 24 92 79
23 1o PhH (0.2) 24 92 84
24 1p PhMe (0.2) 22 92 85
25 1q PhMe (0.2) 24 92 88
26b 1q PhMe (0.2) 34 89 88
27b,c 1q PhMe (0.2) 72 90 93
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a

Reaction mixture was partially heterogeneous.

b

Reaction was performed with 10 mol % catalyst.

c

Reaction was performed at −10 °C.

The scope of the reaction is summarized in Scheme 1. A range of cyclic amines participated in the title reaction to provide products 2 with good to excellent levels of enantioselectivity. p-Methoxybenzylamine, a representative primary amine, provided products with slightly reduced ee. Surprisingly, a significant drop in reactivity was noted with benzyl 2-pentenoate, an observation that could be partially rationalized by our computational model (vide infra).33 Acyclic secondary amines such as diethylamine and N-benzylmethylamine provided poor conversions, even in reactions conducted at rt for a period of several days (not shown). α-Branched primary amines such as benzhydrylamine failed to undergo conjugate additions even at a temperature of 40 °C (not shown).

Scheme 1. Substrate Scope.

Scheme 1.

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aReaction mixture was partially heterogeneous. bReaction was performed at room temperature. cReaction was performed at a 0.025 M concentration of amine.

We recently reported a simple one-step method to access cyclic 2-arylamines in racemic form34 and wondered whether such substrates could be resolved via a conjugate addition strategy. With few exceptions,35 small-molecule-based catalytic strategies for the kinetic resolution of basic amine substrates typically rely on acylation and are limited to primary amines.36 There are few solutions to the kinetic resolution of cyclic amines,37 and no general strategies exist to resolve cyclic 2-arylamines. Following an extensive screen of readily available conjugate acceptors, using 2-phenylpiperidine as the model substrate,38 commercial benzyl acrylate was identified as a suitable resolving agent. As summarized in Scheme 2, catalyst 1q facilitated the kinetic resolution of a number of 2-arylpiperidines and related substrates with good to excellent selectivities.39 In situ Boc protection of the unreacted starting material was performed to facilitate product isolation and s-factor analysis.

Scheme 2.

Scheme 2.

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Kinetic Resolution of Cyclic 2-Arylamines

Our next efforts were directed toward understanding the mechanism and origin of enantioselectivity of this novel bifunctional selenourea-thiourea organocatalyzed reaction. The proposed catalytic cycle for the addition of secondary amines to α,β-unsaturated esters involves: [1] initial activation of the ester through H-bonding to the selenourea-thiourea catalyst; [2] conjugate addition of the amine to the activated complex, in the key C–N bond-forming (stereogenic-center-forming) step; and either [3a] direct C-protonation of the zwitterionic enolate intermediate (2azwit) to form the N-protonated β-amino ester (2aprot), which is subsequently deprotonated to deliver product 2a and regenerate catalyst 1q (red pathway, Figure 2), or [3b] the zwitterionic enolate intermediate (2azwit) undergoes an intramolecular proton transfer to form 2aenol followed by tautomerization to give 2a and regenerate 1q (blue pathway, Figure 2).

Figure 2.

Figure 2.

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Proposed catalytic cycle for the addition of amines to α,β-unsaturated esters catalyzed by a selenourea-thiourea catalyst. The stereogenic center is formed during C–N bond formation. Subsequent proton transfers may follow an intramolecular proton transfer path (shown in blue) or direct C-protonation (shown in red).

In order to understand the origin of enantioselectivity, we decided to model the stereogenic-center-forming step in the reaction of piperidine and benzyl crotonate catalyzed by 1q using density functional theory (DFT) calculations. Transition structures (TSs) for the C–N bond-forming step leading to formation of the R- and S-enantiomers of the β-amino ester (2azwit) were computed using the B3LYP method40 with a split 6–31G* (C,H,O,N,F)/6–31+G** (S, Se) basis set as implemented in Gaussian ‘09.41 Single-point energy calculations were performed using B3LYP-D3(BJ)42/6–311++G** with a PCM solvent model43 for toluene. Relative energies presented herein are the extrapolated Gibbs free energy obtained by adding the free energy correction to the high-level single-point energy computed for each structure. The free energies were corrected using Grimme’s quasi rigid rotor-harmonic oscillator (qRRHO) approach, which raises vibrational frequencies that are below 100 cm−1.44 This approach is routinely utilized to evaluate reactivity and selectivity in similar catalytic systems.45

Following a thorough conformational search conducted via systematic variation of catalyst and reactant geometries,46 we identified the lowest energy C–N bond-forming transition structures leading to both enantiomers of 2azwit—R-TSC–N and S-TSC–N (Figure 3). Both TSs involve β-attack of piperidine on the s-cis conformation of benzyl crotonate, which is more favored than the corresponding s-trans conformation.47 In both of these TSs, the thiourea NHs activate the ester carbonyl by dual H-bonding (1.84 Å/1.97 Å R-TSC–N and 1.81 Å/1.90 Å S-TSC–N), while the selenourea directs the attack of piperidine via an H-bonding interaction between the selenium and the amine proton of piperidine (2.54 Å R-TSC–N and 2.56 Å S-TSC–N). This catalyst conformation is the most favored since it is stabilized by an intramolecular H-bonding interaction between the two arms of the catalyst, i.e., between the thiourea sulfur and the NH of the selenourea moiety. A careful analysis of R-TSC–N and S-TSC–N reveals that the key C–N bond-forming distances (1.87 Å R-TSC–N and 1.83 Å S-TSC–N) and all H-bonding interactions primarily responsible for transition state stabilization (vide supra) are almost identical for both TSs. Slightly stronger dual H-bonding interactions in S-TSC–N make it lower in energy than R-TSC–N, resulting in a predicted ee of 55% (S) at −10 °C. This is inconsistent with the experimental ee of 93% (R).

Figure 3.

Figure 3.

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Lowest energy transition structures for C–N bond formation leading to (R)- and (S)-enantiomers of 2azwit.

Since the extensive transition state search for C–N bond formation structures results in an incorrect prediction of enantioselectivity, we contemplated that the rate- and enantiodetermining step occurs after the stereogenic-center-forming step. To test this hypothesis, we measured 13C kinetic isotope effects (KIEs) for benzyl crotonate using Singleton’s 13C NMR methodology for starting materials at natural abundance.48 Two independent reactions of benzyl crotonate and piperidine were taken as 75 ± 2% and 79 ± 2% conversion with respect to the ester. Unreacted benzyl crotonate was reisolated, and the 13C isotopic composition was compared to samples of benzyl crotonate not subjected to reaction conditions. From the changes in relative isotopic composition and the fractional conversion, 13C KIEs were determined in a standard way.38

The key results are the unity KIE observed at the β-carbon and the normal KIE of ~1.5% on the α-carbon (Figure 4). If C–N bond formation is the first irreversible step in the catalytic cycle for benzyl crotonate, a normal KIE on the β-carbon is expected; however, the observed unity KIE is qualitatively consistent with reversible C–N bond formation. Second, an observed normal KIE of ~1.5% on the α-carbon suggests that α-protonation is likely the first irreversible step in the catalytic cycle. The results qualitatively validate our hypothesis that the C–N bond-forming step is reversible and that the rate- and enantiodetermining step occurs after this stereogenic-center-forming step—a finding that has important consequences for our future efforts in expanding the scope of this reaction.

Figure 4.

Figure 4.

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Experimental 13C KIEs for benzyl crotonate (numbers in parentheses represent the standard deviation in the last digit as determined from six independent measurements).

Experimental 13C KIEs suggest that the origin of enantioselectivity is best understood by analysis of the enantiomeric transition states for the α-carbon protonation step. In the absence of a more acidic proton on the catalyst or an external Brønsted acid in the system, we considered that one of the thiourea NHs is most likely involved in the α-protonation event (Figure 5). Based on this assumption, two possibilities emerge that are qualitatively consistent with a normal 13C KIE on the α-carbon-catalyst-mediated tautomerization (Figure 5, bottom panel) or catalyst-mediated direct C-protonation (Figure 5, top panel).49

Figure 5.

Figure 5.

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Possible transition states consistent with experimental KIEs.

Accordingly, we investigated both pathways for α-protonation using DFT calculations (vide supra). While intramolecular proton transfer from N to O of 2azwit to 2aenol is facile (not shown, ΔG‡ = 18.1 kcal/mol for proton transfer from R-2azwit), the ensuing catalyst-mediated tautomerization of 2aenol to 2a is prohibitively high in energy (Figure 5, ΔG‡ = 48.6 kcal/mol).45 On the other hand, the catalyst-mediated C-protonation is energetically accessible (Figure 5, ΔG‡ = 18.2 kcal/mol). Inaccessibility of the intramolecular proton transfer/tautomerization pathway led us to turn our explorations to the catalyst-mediated C-protonation as the rate- and enantioselectivity-determining step. Involvement of the thiourea catalyst directly as a Brønsted acid in the mechanism has only been reported in two instances in the literature,50 thus representing a new mode of catalysis, which should be considered in the development of future systems.51

In the lowest energy transition structure for direct protonation of R-2azwit (Figure 6, R-TSC-prot), the enolate adopts a geometry with strong intramolecular H-bonding interactions between the protonated piperidine and the enolate oxygen (1.81 Å). One of the thiourea NHs is loosely bound to the enolate oxygen (2.35 Å), while the other (more acidic) thiourea NH is transferred to the α-carbon of the ester. Selenium is engaged in a weak nonconventional CH⋯Se interaction with one of the α-CHs of the piperidine moiety (2.76 Å). A significantly altered arrangement is observed for the lowest energy transition structure for direct protonation of S-2azwit (Figure 6, S-TSC-prot). The enolate oxygen is bound via a strong H-bonding interaction with one of the thiourea NHs (1.94 Å) during the protonation event. Protonated piperidine NH is engaged in an H-bonding interaction with selenium (2.49 Å) (unlike R-TSC-prot, where the same NH is engaged in a stronger intramolecular H-bond with the enolate oxygen). Another key difference between the two TSs is the extent of proton transfer from the thiourea NH to the α-carbon of the enolate (1.35 and 1.26 Å for the breaking thiourea N–H bond in R-TSC-prot and S-TSC-prot, respectively). These differences in stabilizing interactions at the enantiomeric transition states for catalyst-mediated direct α-C-protonation result in R-TSC-prot being 1.9 kcal/mol lower in free energy than S-TSC-prot; this corresponds to a predicted 95% ee (R) at −10 °C, which is in excellent agreement with the 93% ee (R) observed experimentally. Additional support for direct α-C-protonation as the rate- and enantioselectivity-determining step was obtained by modeling the two transition structures by replacing the selenium atom with sulfur. With this sulfur analogue of catalyst 1q, we predicted a 59% ee which is in good agreement with the experimental ee of 62%.38 Finally, we also probed the effect of varying the β-substituent of the ester from methyl to ethyl by modeling the R-TSC-prot and S-TSC-prot for the β-ethyl-substituted benzyl ester. These analogous transition structures gave a drop in the predicted ee to 80%, which is a slight overestimation (0.7 kcal/mol) of the experimental ee of 47%. However, these calculations qualitatively predict the drop in ee experimentally observed with the bulkier β-ethyl substituent.38

Figure 6.

Figure 6.

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Lowest energy transition structures for catalyst-mediated direct C-protonation of (R)- and (S)-enantiomers of 2azwit.

As a key step in the quantitative interpretation of our experimental KIEs, we predict 13C KIEs from the scaled vibrational frequencies using the program ISOEFF98 for both R-TSC–N and R-TSC-prot, then applying a Wigner tunneling correction to all predicted KIEs.52–54 The large 13C KIE of 1.035 predicted for the β-carbon in R-TSC–N (Figure 7, red numbers) quantitatively eliminates C–N bond formation as the rate-determining step. On the other hand, the predicted KIEs for R-TSC-prot (Figure 7, green numbers) are in excellent agreement with experimental KIEs for all carbons, lending further support for rate-determining catalyst-mediated direct α-C-protonation.

Figure 7.

Figure 7.

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Comparison of experimental and predicted KIEs for the C–N bond-forming transition structure R-TSC–N (shown in red) and the direct C-protonation transition structure R-TSC-prot (shown in green).

Finally, the computed reaction coordinate diagram summarizes the relevant energies from our theoretical investigation (Figure 8). Energies of all TSs and intermediates are computed relative to the free energy of separated catalyst and starting materials (Figure 8, catalyst + piperidine + benzyl crotonate). To the left of the starting materials is the reaction pathway leading to (S)-2a (minor product), and to the right is the corresponding pathway leading to (R)-2a (major product). As discussed earlier, the C–N bond-forming step is reversible, and the enantioselectivity is determined at the rate-determining direct C-protonation step.55

Figure 8.

Figure 8.

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Computed reaction coordinate diagram (qRRHO) depicting the proposed pathway leading to (R)- and (S)-enantiomers of 2a.

In summary, we have achieved highly enantioselective conjugate additions of cyclic amines to unactivated α,β-unsaturated esters. This strategy is applicable to the kinetic resolution of cyclic 2-arylamines. A novel bifunctional selenourea-thiourea was identified in the course of this study. Experimental and predicted KIEs, free energy estimates, and enantioselectivity predictions all lend strong support to a reaction mechanism that proceeds via reversible C–N bond formation to form a β-amino enolate. This is followed by rate- and enantioselectivity-determining protonation by one of the thiourea NHs, which functions as a Brønsted acid. The transition structure, in which a thiourea compound functions as an asymmetric Brønsted acid, should serve as a guide for further development of this new mode of catalysis by chiral thiourea organocatalysts.

Supplementary Material

SupportingInformation
CrystalStructure1
CrystalStructure2

ACKNOWLEDGMENTS

This material is based upon work supported by the National Science Foundation under CHE-1806747 and CHE-1856613 (grants to D.S.). M.J.V. and J.S.H. acknowledge support from NIGMS - R01 GM126283 and the XSEDE Science Gateways Program, which is supported by the National Science Foundation grant number ACI-1548562. We further acknowledge the National Science Foundation (grant# 1828064 to K.A.A.) and the University of Florida for funding the purchase of the X-ray equipment.

Footnotes

Supporting Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.9b12457.

Experimental procedures and characterization data, kinetic isotope effect studies, details of the theoretical studies along with coordinates, and energies of all calculated structures (PDF)

X-ray crystal structure of catalyst 1q (CIF)

X-ray crystal structure of product 2d (CIF)

The authors declare no competing financial interest.

Contributor Information

Yingfu Lin, Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States; Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.

William J. Hirschi, Department of Chemistry, Binghamton University, Binghamton, New York 13902, United States

Anuj Kunadia, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.

Anirudra Paul, Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States; Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.

Ion Ghiviriga, Center for NMR Spectroscopy, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States.

Khalil A. Abboud, Center for X-ray Crystallography, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States

Rachael W. Karugu, Department of Chemistry, Binghamton University, Binghamton, New York 13902, United States

Mathew J. Vetticatt, Department of Chemistry, Binghamton University, Binghamton, New York 13902, United States;.

Jennifer S. Hirschi, Department of Chemistry, Binghamton University, Binghamton, New York 13902, United States;

Daniel Seidel, Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States; Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States;.

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Associated Data

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Supplementary Materials

SupportingInformation
NIHMS1632676-supplement-SupportingInformation.pdf (17.4MB, pdf)
CrystalStructure1
NIHMS1632676-supplement-CrystalStructure1.cif (3.1MB, cif)
CrystalStructure2
NIHMS1632676-supplement-CrystalStructure2.cif (7.2MB, cif)

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