Bifunctional Primary Amine-thiourea Research Articles

Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions

The preparation of a new class of six bifunctional thiourea organocatalysts having a D-fructose scaffold and a primary amino group was demonstrated. In the present study, the novel organocatalysts exhibited excellent enantio- and moderate diastereoselectivities in the asymmetric Michael addition of aliphatic ketones and 1,3-diketone to substituted nitroolefins at room temperature. In addition, the direct asymmetric aldol reaction between cyclic aliphatic ketone and aromatic aldehydes was also studied in the presence of the saccharide-thiourea organocatalysts giving excellent yield with moderate enantioselectivity.

Asymmetric Alkylation of Cyclic Ketones with Dehydroalanine via H-Bond-Directing Enamine Catalysis: Straightforward Access to Enantiopure Unnatural α-Amino Acids.

The growing importance of structurally diverse and functionalized enantiomerically pure unnatural amino acids in the design of drugs, including peptides, has stimulated the development of new synthetic methods. This study reports the challenging direct asymmetric alkylation of cyclic ketones with dehydroalanine derivatives via a conjugate addition reaction for the synthesis of enantiopure ketone-based α-unnatural amino acids. The key to success was the design of a bifunctional primary amine-thiourea catalyst that combines H-bond-directing activation and enamine catalysis. The simultaneous dual activation of the two relatively unreactive partners, confirmed by mass spectrometry studies, results in high reactivity while securing high levels of stereocontrol. A broad substrate scope is accompanied by versatile downstream chemical modifications. The mild reaction conditions and consistently excellent enantioselectivities (>95 % ee in most cases) render this protocol highly practical for the rapid construction of valuable noncanonical enantiopure α-amino-acid building blocks.

Concentration Effect in the Asymmetric Michael Addition of Acetone to β-Nitrostyrenes Catalyzed by Primary Amine Thioureas

Bifunctional primary amine thiourea (PAT) organocatalysts show remarkable improvement in enantioselectivity and catalytic activity (turnover frequency) in the asymmetric Michael addition of acetone to β-nitrostyrenes upon dilution. Mechanistic investigations indicate that this behavior corresponds to the inhibition of off-cycle catalyst deactivation at low concentration, rather than to the operation of aggregation phenomena at high concentration. Reaction at low concentration (≤0.2 M in β-nitrostyrene) leads to the minimization of catalyst deactivation and, thus, to the optimization of yield and ee of the Michael­ addition products.

Construction of Furan Derivatives with a Trifluoromethyl Stereogenic Center: Enantioselective Friedel-Crafts Alkylations via Formal Trienamine Catalysis.

An asymmetric Friedel-Crafts alkylation reaction of 2-furfuryl ketones with β-trifluoromethyl enones has been developed via formal trienamine catalysis of a bifunctional primary amine-thiourea substance derived from L-tert-leucine, delivering the furan derivatives incorporating a stereogenic trifluoromethyl (CF3) group in good to high yields with excellent enantioselectivity.

ChemInform Abstract: Enantioselective Direct Bisvinylogous 1,6‐Additions of β‐Allyl‐2‐cyclohexenone to α,α‐Dicyanodienes Through Trienamine Catalysis.

An asymmetric direct ϵ-regioselective bisvinylogous 1,6-addition reaction of β-allyl-2-cyclohexenone to β-substituted α,α-dicyanodienes was developed through trienamine catalysis of a bifunctional primary amine–thiourea compound. Excellent enantioselectivity (up to 97 % ee) was obtained even through such a remote reaction mode. In addition, more complex cyclic frameworks could be efficiently constructed with high stereoselectivity.

Enantioselective Direct Bisvinylogous 1,6‐Additions of β‐Allyl‐2‐cyclohexenone to α,α‐Dicyanodienes through Trienamine Catalysis

AbstractAn asymmetric direct ϵ‐regioselective bisvinylogous 1,6‐addition reaction of β‐allyl‐2‐cyclohexenone to β‐substituted α,α‐dicyanodienes was developed through trienamine catalysis of a bifunctional primary amine–thiourea compound. Excellent enantioselectivity (up to 97 % ee) was obtained even through such a remote reaction mode. In addition, more complex cyclic frameworks could be efficiently constructed with high stereoselectivity.

Calixarene-based highly efficient primary amine–thiourea organocatalysts for asymmetric Michael addition of aldehydes to nitrostyrenes

The synthesis of calix[4]arene-based chiral bifunctional primary amine–thiourea catalysts has been described from p-tert-butylcalix[4]arene for the first time. The calix[4]arene-based catalysts were successfully applied to promote Michael addition of aldehydes with nitroalkenes affording preferentially the (R)- or (S)-adducts in high yields (up to 95%) and excellent enantioselectivities (up to 99% ees).

Bifunctional primary amine-thioureas in asymmetric organocatalysis

Research disclosed since the demonstration of the first examples of primary amine-thiourea organocatalysis in 2006 has shown that primary amine-based thioureas can successfully catalyze a diverse variety of highly enantioselective transformations providing a wide range of versatile organic compounds. Recent remarkable progress with these chiral catalysts is summarized in this review.

Asymmetric Vinylogous Aldol Reaction via H-Bond-Directing Dienamine Catalysis

The enantioselective direct vinylogous aldol reaction of 3-methyl 2-cyclohexen-1-one with α-keto esters has been developed. The key to success was the design of a bifunctional primary amine-thiourea catalyst that can combine H-bond-directing activation and dienamine catalysis. The simultaneous dual activation of the two reacting partners results in high reactivity while securing high levels of stereocontrol.

An Efficient Organocatalytic Method for Highly Enantioselective Michael Addition of Malonates to Enones Catalyzed by Readily Accessible Primary Amine-Thiourea

A practical and highly enantioselective Michael addition of malonates to enones catalyzed by simple and readily available bifunctional primary amine-thiourea derived from 1,2-diaminocyclohexane is reported. The addition of weak acids and elevated temperature (ca. 50 °C) improved the efficiency of the Michael reaction. This approach enables the efficient synthesis of 1,5-ketoesters with good yields, excellent enantioselectivities (up to 99% ee), and low loading (0.5-5 mol %) of simple chiral primary amine-thiourea catalysts, and is applicable in multigram scale synthesis.

ChemInform Abstract: Dioxindole in Asymmetric Catalytic Synthesis: Direct Access to 3‐Substituted 3‐Hydroxy‐2‐oxindoles via 1,4‐Additions to Nitroalkenes.

AbstractA bifunctional primary amine—thiourea catalyst for the asymmetric Michael addition of dioxindoles to β‐substituted nitroalkenes is presented.

Enantioselective Conjugate Addition of 4-Hydroxycoumarin to Enones Catalyzed by Binaphthyl-Modified Primary Amine Organocatalyst

The Michael addition reaction is widely recognized as one of the most general methods for formation of C-C bonds in organic synthesis, and the development of enantioselective catalytic conjugate addition reaction has been subject of intensive research. In addition to the great success catalyzed by metal complexes, the powerful and environmentally friendly organocatalyst-mediated asymmetric conjugate addition reaction has been explored intensively in recent years. Enantioselective organocatalytic conjugate addition reaction of β-ketoesters to α,β-unsaturated carbonyl compounds represents a direct and most appealing approach to chiral 1,5-dicarbonyl compounds that are versatile intermediates in organic synthesis. Particularly, the addition of 4-hydroxycoumarin to α,β-unsaturated ketones is a straightforward method to access warfarin which is an effective anticoagulants. Further investigation showed that (S)-warfarin had higher anticoagulant activity than the R enantiomer. As a result, achieving the optically pure R or S enantiomer of warfarin would be of great importance. Among the established strategies for the synthesis of chiral warfarin, chiral auxiliary strategy, hydrogenation, and hetero-Diels-Alder reaction have been intensively studied. Recently, several groups reported an enantioselective conjugate addition reaction of 4-hydroxycoumarin to enones, catalyzed by chiral secondary amines, primary amines, and bifunctional primaryamine thioureas. Although several efficient methods have been achieved by these systems, an effective method for the synthesis of warfarin is still a challenge. As part of the research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, we recently reported asymmetric conjugate addition reaction of active methylenes and methines. Herein, we wish to describe the enantioselective asymmetric conjugate addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by binaphthyl-modified primary amine organocatalyst. Validation of the feasibility of the proposed Michael addition process started by evaluating a model reaction between 4-hydroxycoumarin (1) with (E)-4-phenylbut-3-en-2-one (2a) in the presence of 20 mol % bifunctional catalysts (Fig. 1) and 40 mol % of TFA as additive at room temperature. As shown in Table 1, 9-amino-9-deoxyepicinchonidine (I) effectively promoted the reaction with high enantioselectivity (entry 1). While chiral primary amine organocatalysts (IIIV) bearing both central and axial chiral elements gave moderate to high enantioselectivity (entries 2-4). The best result has been obtained with binaphthyl-modified 1,2diphenylethylenediamine catalyst (III). We examined our

Dioxindole in asymmetric catalytic synthesis: direct access to 3-substituted 3-hydroxy-2-oxindoles via 1,4-additions to nitroalkenes

The asymmetric Michael addition of dioxindoles to β-substituted nitroalkenes is reported. The bifunctional primary amine-thiourea A, by means of a non-covalent-based mode of catalysis, secures direct access to 3-substituted 3-hydroxyoxindole derivatives with high stereocontrol.

Bifunctional primary amine-thiourea–TfOH (BPAT·TfOH) as a chiral phase-transfer catalyst: the asymmetric synthesis of dihydropyrimidines

An enantioselective Biginelli reaction has been developed by using a bifunctional primary amine-thiourea-TfOH (BPAT·TfOH) as a chiral phase-transfer catalyst and t-BuNH(2)·TFA as an additive in saturated brine at room temperature. The corresponding dihydropyrimidines were obtained in moderate-to-good yields with up to 99% ee under mild conditions. A plausible transition state has been proposed to explain the origin of the activation and the asymmetric induction.

Asymmetric Michael Addition of Aromatic Ketones to Nitroolefins Catalyzed by Simple Chiral Bifunctional Primary Amine-Thioureas

Asymmetric Michael Addition of Aromatic Ketones to Nitroolefins Catalyzed by Simple Chiral Bifunctional Primary Amine-Thioureas

Enantioselective Michael Addition of Aromatic Ketones to Nitroolefins Catalyzed by Bifunctional Thioureas and Mechanistic Insight

AbstractA highly enantioselective Michael reaction of aromatic ketones with nitroolefins was accomplished in the presence of a chiral bifunctional primary amine–thiourea catalyst and 4‐nitrobenzoic acid as the co‐catalyst; the corresponding adducts were obtained in excellent enantioselectivities (up to 99 % ee) and yields (up to 98 %). The catalytic mechanism of the Michael reaction was confirmed through the ESI‐MS detection of proposed reaction intermediates and the 1H NMR detection of hydrogen bonding between thiourea and the nitroolefins. DFT calculations showed that chiral moieties of the thiourea impacted the yields and enantioselectivities of the adducts remarkably, which corresponds to the observed experimental results.

A highly efficient asymmetric Michael addition of α,α-disubstituted aldehydes to maleimides catalyzed by primary amine thiourea salt

The first highly efficient Michael addition of challenging α,α-disubstituted aldehydes to maleimides catalyzed by a simple bifunctional primary amine thiourea catalyst/benzoic acid system has been successfully developed to generate quaternary carbon centers in high yields (up to 99%) with excellent enantioselectivities (91-99%).

Editorial: Crystal‐Clear View of Chemistry

Editorial: Crystal‐Clear View of Chemistry

ChemInform Abstract: Highly Enantioselective Michael Addition of Acetone to Nitroolefins Catalyzed by Chiral Bifunctional Primary Amine—Thiourea Catalysts with Acetic Acid.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Asymmetric Iminium Ion Catalysis with a Novel Bifunctional Primary Amine Thiourea: Controlling Adjacent Quaternary and Tertiary Stereocenters

A chiral primary amine thiourea catalyzes the stereoselective addition of oxindoles to α,β-unsaturated aldehydes, generating valuable chiral scaffolds with contiguous quaternary and tertiary stereocenters (see scheme). For the first time, a chiral primary amine thiourea catalyst has been successfully applied for iminium-ion activation.