Prototropic Tautomerism and C3 Bond Formation in 4-Hydroxycoumarin: Anion Delocalization and Acid–Base Behavior
Prototropic Tautomerism and C3 Bond Formation in 4-Hydroxycoumarin: Anion Delocalization and Acid–Base Behavior
Overview
4-Hydroxycoumarin is a derivative formed by introducing a hydroxyl group at C4 of the α-pyrone ring of coumarin. Its systematic name is 4-hydroxy-2H-chromen-2-one. Its C4 hydroxyl group differs from an ordinary phenolic hydroxyl group on the benzene ring. In the predominant 4-hydroxy-2H-chromen-2-one form, C4-OH is an enolic hydroxyl group conjugated with the C2 carbonyl. The position of C4-OH couples proton transfer, π-electron delocalization, and the C3 carbon center, thereby giving rise to pronounced tautomeric behavior, stronger acidity than that of benzene-ring hydroxycoumarins, and nucleophilic reactivity at C3.[1]
This structural difference can be observed directly from experimental acidity. In the same measurement system used by Nowak et al., the experimental pKₐ values of 4-hydroxycoumarin and 7-hydroxycoumarin were 4.06 and 7.54, respectively. Although the two compounds differ only in the position of hydroxyl substitution, they exhibit a pronounced difference in acidity.[5] This difference arises from electron delocalization in the anion after deprotonation, solvation, and the degree of coupling between hydroxyl groups at different positions and the carbonyl system.
1. Conjugation between the C4 Hydroxyl Group and the C2 Carbonyl Group
1.1 Structural Differences between C4-OH and an Ordinary Phenolic Hydroxyl Group on the Benzene Ring
In the coumarin scaffold, C2 is the lactone carbonyl carbon, and C3 and C4 form a double bond. Introduction of a hydroxyl group at C4 of 4-hydroxycoumarin creates the following continuous electronic unit:
C4–OH — C4=C3 — C2=O
The oxygen lone pair of C4-OH can undergo continuous electron delocalization with the C3=C4 double bond and the C2 carbonyl, giving this structure the characteristics of an enolized 1,3-dicarbonyl system. The literature refers to the electronic effect transmitted between 4-OH and the C2 carbonyl through a conjugated double bond as vinylogy.[1,7]
In 7-hydroxycoumarin, the OH group is located on the benzene ring, and deprotonation mainly produces a phenoxide-type resonance system. In contrast, 4-hydroxycoumarin can delocalize the negative charge toward the carbonyl through the C4—C3—C2 system. Although the two hydroxyl groups have the same elemental composition, they reside in different electronic environments.[5]
1.2 Delocalization of Negative Charge after Deprotonation
After 4-hydroxycoumarin (4-HC) loses the proton of C4-OH, it forms its conjugate base (4-HC⁻):
4-HC ⇌ 4-HC⁻ + H⁺
The negative charge of this anion can be delocalized along the C4—C3—C2 conjugated system. Its principal resonance contributors can be represented in simplified form as follows:
C4–O⁻ form ↔ C3 carbanion form ↔ C2 carbonyl O⁻ form
These forms are not three independently isolable chemical species, but different resonance contributors of the same delocalized anion. Negative-charge delocalization helps stabilize the conjugate base of 4-hydroxycoumarin and imparts carbon nucleophilicity to C3.[1,5]
2. Tautomerism of 4-Hydroxycoumarin
2.1 Three Formally Possible Prototropic Tautomeric Structures
The 4-hydroxycoumarin system generally includes three classes of prototropic tautomers:[1,3,4]
Tautomeric form | Principal structural feature | State of C3 | Oxygen-containing groups at C2/C4 |
4-Hydroxy-2H-chromen-2-one form | Retains 4-OH and the C2 lactone carbonyl | Part of the C3=C4 double bond | C2=O, C4-OH |
2,4-Chromandione form | C4 is converted into a carbonyl group | C3 tends toward a saturated CH₂ structure | C2=O, C4=O |
2-Hydroxy-4H-chromen-4-one form | The carbonyl position shifts to C4 | C2=C3 conjugation | C2-OH, C4=O |
The fact that these forms can be drawn as valence-bond structures does not mean that they coexist stably in comparable proportions in all media. The actual tautomeric composition is affected by the solvent, substituents, intramolecular/intermolecular hydrogen bonding, and crystal packing in the solid state.[2–4]
2.2 Identification of the Predominant Tautomeric Form by Infrared and Nuclear Magnetic Resonance Spectroscopy
After conducting an infrared spectroscopic study of eight 4-hydroxycoumarins, Farmer found that their spectra in dioxane solution generally supported a coumarin-type 4-hydroxy-2H-chromen-2-one structure.[2] Okumura and Kotera subsequently investigated the tautomeric relationship between 4-hydroxycoumarin and 2-hydroxychromone and likewise found that 4-hydroxycoumarin derivatives predominantly exhibited a coumarin-type structure in dioxane solution; associated solid-state forms, however, could exhibit different hydrogen-bonding and tautomeric characteristics.[3]
In the NMR spectra of 4-hydroxycoumarin, 4,5-dihydroxycoumarin, and 4,7-dihydroxycoumarin, the researchers directly observed only the predominant 4-hydroxy-2H-chromen-2-one structure. However, all three compounds underwent hydrogen–deuterium exchange (H–D exchange) at C3. On this basis, the researchers proposed that dynamic interconversion between 4-hydroxy-2H-chromen-2-one and 2,4-chromandione might participate in the C3 hydrogen-exchange process.[4]
2.3 Regulation of Tautomeric Equilibria by Substituents and Hydrogen Bonding
Tautomeric equilibria are highly sensitive to the position of substitution. When Traven et al. compared 4-hydroxycoumarin, 4,5-dihydroxycoumarin, and 4,7-dihydroxycoumarin, they found that the rate of C3 hydrogen–deuterium exchange was higher for 4,5-dihydroxycoumarin. The researchers related this observation to the ability of C5-OH to form an intramolecular hydrogen bond with the C4 carbonyl in a keto tautomeric structure: this hydrogen bond can relatively stabilize the 2,4-diketone form involved in the exchange process.[4]
Substitution at C3 itself can also redistribute tautomer stability. Stefanou et al. performed single-crystal X-ray diffraction and density functional theory (DFT) calculations on 3-methoxycarbonyl-4-hydroxycoumarin. Among the three calculated structures, the 4-hydroxycoumarin-type configuration consistent with the single-crystal structure had the lowest energy, whereas the other two configurations were approximately 14.21 and 14.92 kcal/mol higher in energy.[10] This result applies to the 3-methoxycarbonyl derivative and indicates that carbonyl substitution at C3 and intramolecular interactions can strongly select a tautomeric configuration; these energy differences do not apply to unsubstituted 4-hydroxycoumarin.
DFT-Optimized Structures of Different Tautomeric Configurations of 3-Methoxycarbonyl-4-hydroxycoumarin
In the figure, a, b, and c are three tautomeric configurations of 3-methoxycarbonyl-4-hydroxycoumarin. Configuration a retains the 4-hydroxycoumarin-type C2 carbonyl—C3—C4-OH system and is relatively consistent with the predominant structure determined by single-crystal X-ray diffraction. Configurations b and c involve redistribution of the proton position and the C2/C4 carbonyl forms and are approximately 14.21 and 14.92 kcal/mol higher in energy, respectively.[10]
This figure shows that C4-OH, the C2 carbonyl, and the C3 substituent jointly determine the relative stability of each tautomeric configuration after proton transfer. After a methoxycarbonyl group is introduced at C3, local conjugation, hydrogen bonding, and spatial arrangement all change, and the tautomeric equilibrium changes accordingly.
Figure source: Stefanou V, Matiadis D, Melagraki G, et al. Molecules, 2011, 16:384–402, Figure 6 in the original article.[10] Licensed under Creative Commons Attribution 3.0 (CC BY 3.0).
3. Acid–Base Properties and Anion Stabilization
3.1 C4-OH Is Markedly More Acidic than an Ordinary Phenolic Hydroxyl Group on the Benzene Ring
Nowak et al. compared several hydroxycoumarins within a unified experimental system and obtained the following experimental pKₐ values:[5]
Compound | Experimental pKₐ | Principal structural difference |
3-Hydroxycoumarin | 6.81 | The hydroxyl group is located at C3, adjacent to the C2 carbonyl and within the conjugated α-pyrone fragment |
4-Hydroxycoumarin | 4.06 | C4-OH, C3=C4, and the C2 carbonyl form a continuous conjugated fragment |
6-Hydroxycoumarin | 8.98 | C6 bears a phenolic hydroxyl group on the benzene ring |
7-Hydroxycoumarin | 7.54 | C7 bears a phenolic hydroxyl group on the benzene ring |
4,7-Dihydroxycoumarin | 4.43 | Contains both a conjugated C4 hydroxyl group and a phenolic C7 hydroxyl group |
Coumatetralyl | 4.36 | Retains the conjugated C4-OH system, with a 1,2,3,4-tetrahydronaphthalen-1-yl group attached at C3 |
Warfarin | 4.87 | Retains the conjugated C4-OH system, with a 3-oxo-1-phenylbutyl side chain attached at C3 |
These data show that the hydroxyl position can produce differences of several pKₐ units.[5] The relatively strong acidity of 4-OH is associated with the delocalized anion formed after deprotonation; computational studies also indicate that solvent–solute interactions make an important contribution to acidity differences among hydroxycoumarins.
Note: The values above were obtained under the same study conditions and can therefore be used for lateral comparison. pKₐ values measured in different media or at different temperatures and ionic strengths should not be directly combined.[5]
3.2 Electron Delocalization and Solvation Jointly Stabilize the Anion
After dissociation of 4-OH generates a negative charge, the electrons can be delocalized over the O4—C4—C3—C2—carbonyl oxygen region. Compared with an anion in which the negative charge is highly localized, a larger range of delocalization can generally reduce the local charge density and enhance anion stability.
However, the acidity of 4-hydroxycoumarin cannot be assessed solely by counting resonance structures. The experimental and theoretical results of Nowak et al. show that both the extent of electron delocalization in the anion and solvent–solute interactions determine acidity. Bulky C3 substituents can also alter the stability of protonated structures through intramolecular noncovalent interactions such as OH···O and OH···π interactions, causing the pKₐ values of C3-substituted derivatives such as warfarin and coumatetralyl to differ from that of the parent 4-hydroxycoumarin.[5]
4. Electronic Activation at C3 and Carbon–Carbon Bond Formation
4.1 C3 Hydrogen–Deuterium Exchange Reveals Proton-Transfer Capability
C3 of unsubstituted 4-hydroxycoumarin bears a hydrogen atom. Traven et al. observed H–D exchange at this position, even though the predominant species observed by NMR remained the 4-hydroxy-2H-chromen-2-one form.[4]
This phenomenon shows that C3 is not a completely inert alkenic carbon. Dynamic proton transfer between C4-OH and the 2,4-dicarbonyl tautomer can alter the hybridization state of C3 and the environment of its C–H bond, allowing hydrogen exchange to occur.
The further increase in the exchange rate of 4,5-dihydroxycoumarin indicates that neighboring substituents can further regulate proton-transfer behavior at C3 by stabilizing relevant transition structures or low-abundance tautomers through intramolecular hydrogen bonding.[4]
4.2 C3 Nucleophilicity of the 4-Hydroxycoumarin Anion
Under basic conditions, deprotonation of 4-OH produces a delocalized anion. Resonance contributors can transmit increased electron density to C3, causing C3 to behave as a carbon-centered nucleophile:
Deprotonation of 4-OH
→ Formation of a delocalized anion over the O4—C4—C3—C2 system
→ Appearance of a C3 carbanion-type resonance contributor
→ Attack by C3 on an appropriate electrophilic carbon center
→ Formation of a new C3—C bond.
This is also the electronic-structural basis for the formation of numerous 3-substituted 4-hydroxycoumarins through C3 functionalization.[1]
Michael addition provides a clear experimental example. 4-Hydroxycoumarin can undergo conjugate addition to activated alkenes to form a C3—C bond. The classical warfarin framework can likewise be obtained through C3 carbon–carbon bond formation between 4-hydroxycoumarin and an α,β-unsaturated carbonyl system. In a 2023 study, Goka and Klumpp further exploited the C3 nucleophilicity of 4-hydroxycoumarin in Michael-type conjugate additions to alkenyl heterocycles and proposed a reaction process involving electrophilic activation of the alkenyl group and nucleophilic attack at C3.[9]
Note: The “C3 nucleophilicity” described here arises from electron delocalization throughout the entire 4-OH—C4—C3—C2=O system, rather than from a free C3 carbanion that exists independently for an extended period.
The conjugate base of 4-hydroxycoumarin is an O/C ambident nucleophile. Although C3 bond formation is a major pathway in many reactions, competing reactions such as O-alkylation may vary with the base, counterion, solvent, and nature of the electrophile. Its reactions with electrophiles therefore cannot all be understood as exhibiting exclusive C3 selectivity.[1]
4.3 C3 Substitution in Turn Alters the Tautomeric System
After a new carbon–carbon bond is formed at C3, the tautomeric behavior of 4-hydroxycoumarin may continue to change.
The C3 side chain of warfarin contains a carbonyl group that can undergo intramolecular cyclization with the 4-hydroxycoumarin moiety to generate a cyclic hemiketal structure. Through combined computational and NMR studies, Guasch et al. found that warfarin in aqueous solution consists predominantly of cyclic hemiketal diastereomers, whereas the open-chain 4-hydroxycoumarin-type structure is a minor component.[11]
C3 functionalization not only introduces a side chain outside the core scaffold, but may also reorganize intramolecular hydrogen bonding, proton transfer, and ring–chain equilibria. When the side chain contains functional groups such as carbonyl or hydroxyl groups, the original tautomeric system may become even more complex.
5. Hydrogen Bonding, Ionization, and Partitioning Properties
5.1 C4-OH and the Carbonyl Groups Form a Strong Hydrogen-Bonding System
4-Hydroxycoumarin contains both a C4-OH hydrogen-bond donor and multiple oxygen-containing acceptors. Farmer’s infrared study showed that several solid-state 4-hydroxycoumarins unsubstituted at C3 exhibited band characteristics resembling those of strongly hydrogen-bonded carboxylic acid associates: a broadened O–H stretching absorption occurred at approximately 3000 cm⁻¹, and the carbonyl absorption occurred at approximately 1700 cm⁻¹. After alkyl substitution at C3, the hydrogen-bonding environments and carbonyl vibrations of some compounds changed markedly.[2]
Subsequent infrared studies using C2-specific ¹³C isotopic labeling further confirmed that the carbonyl stretching vibrations of 3-substituted 4-hydroxycoumarins can vary over the range of approximately 1664–1718 cm⁻¹; strong intramolecular or intermolecular hydrogen bonding can substantially lower the carbonyl stretching frequency.[6]
This indicates that the C=O absorption position cannot be treated simply as a fixed “characteristic peak of 4-hydroxycoumarin.” C3 substitution, solid-state hydrogen bonding, and intramolecular interactions can all alter carbonyl bond order and vibrational frequency.
5.2 pH Alters the Proportions of Neutral Molecules and Anions
When the environmental pH approaches or exceeds the pKₐ of 4-OH, the proportion of the anion increases. Neutral molecules and anions differ in charge, hydrogen bonding, solvation, and their ability to partition into an organic phase. The apparent hydrophobicity of 4-hydroxycoumarin derivatives is therefore not a fixed value.
Van der Giesen and Janssen investigated the octanol–water partitioning of six C3-substituted 4-hydroxycoumarins over the pH range of 1–11 and observed that the apparent partition coefficient varied markedly with ionization state. At high pH, counterions and ion-pair formation further affected partitioning into the organic phase.[8]
When Ilijaš et al. compared 32 4-hydroxycoumarin analogues, they likewise found that their chromatographic behavior exhibited the typical characteristics of weakly acidic compounds, with systematic differences in partition-related parameters at pH 2.8 and 7.0.[7]
This change arises from the following sequence:
Change in pH
→ Change in the extent of 4-OH dissociation
→ Change in the neutral molecule/anion ratio
→ Changes in hydration, ion pairing, and hydrophobic interactions
→ Corresponding changes in partitioning and chromatographic retention.
Specific partitioning behavior is also affected by factors including the hydrophobic surface area of the C3 side chain, the number of aromatic rings, intramolecular hydrogen bonding, and counterion concentration, and therefore cannot be predicted solely from pKₐ.
6. Relationships between Structural Variables and Physicochemical Properties
Structural variable | Change in electronic structure or intermolecular interactions | Principal physicochemical consequence | Representative structural evidence |
Transfer of OH from the benzene ring to C4 | C4-OH forms a continuous conjugated system with C3=C4 and C2=O | Greater stability of the deprotonated anion and markedly increased acidity | 4-HC pKₐ 4.06; 7-HC pKₐ 7.54 |
Proton transfer involving 4-OH | Redistribution of the C2/C4 carbonyl groups and the hybridization state of C3 | Possibility of 4-hydroxy, 2,4-diketone, and 2-hydroxychromone tautomers | IR, NMR, and H–D exchange |
Deprotonation of C4-OH | Negative charge is delocalized over O4—C4—C3—C2—carbonyl oxygen | C3 acquires a carbon-nucleophile-type resonance contribution | C3 Michael addition and functionalization |
Introduction of OH at C5 | An intramolecular hydrogen bond can form with the C4 keto tautomer | Increased stability of the relevant low-abundance diketone structure and accelerated C3 H–D exchange | 4,5-Dihydroxycoumarin |
Introduction of a carbonyl-containing substituent at C3 | Additional electronic effects, hydrogen bonding, and conformational constraints | Changes in tautomeric ratios and proton-transfer pathways | 3-Acetyl and 3-methoxycarbonyl derivatives |
Introduction of a long carbonyl-containing side chain at C3 | C4-OH can participate in new intramolecular interactions with the side chain | Ring–chain tautomerism may occur | Warfarin |
Increase in pH | Increased proportion of the 4-OH anion | Changes in hydration, partitioning, and chromatographic behavior | 4-HC and C3-substituted derivatives |
Strengthening of intramolecular/intermolecular hydrogen bonding | Changes in the bond orders and environments of C=O and O–H | Shifts and broadening of IR carbonyl and OH absorptions | Solid-state and 3-substituted 4-HC |
In summary, C4-OH, C3, and the C2 carbonyl form an interdependent structural unit that jointly determines the acid–base properties, tautomerism, and C3 bond-forming behavior of 4-hydroxycoumarin.
7. Classification of Representative 4-Hydroxycoumarin Chemicals
Table 1. 4-Hydroxycoumarin Core Scaffold and Benzene-Ring-Substituted Derivatives
Classification | CAS Number | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
4-Hydroxycoumarin core scaffold | 1076-38-6 | 4-Hydroxycoumarin | ≥98% | Parent compound containing the continuously conjugated C4-OH, C3, and C2 carbonyl system; suitable for studies of tautomerism, electron delocalization, acid–base equilibria, C3 hydrogen exchange, and carbon–carbon bond formation at C3. | |
Benzene-ring hydroxy-substituted 4-hydroxycoumarin | 1983-81-9 | 4,7-Dihydroxycoumarin | ≥98% | Contains both an enolic C4 hydroxyl group and a phenolic C7 hydroxyl group; suitable for comparing the ionization behavior of the two types of hydroxyl groups and for studying tautomerism, C3 hydrogen exchange, and the electronic effects of substitution position. | |
Benzene-ring methyl-substituted 4-hydroxycoumarin | 13252-83-0 | 4-Hydroxy-6-methylcoumarin | ≥98% | C6 methyl substitution retains the complete C4-OH—C3—C2 carbonyl system; suitable for investigating the effects of alkyl substitution on the aromatic ring on electron distribution, acid–base properties, hydrophobicity, and C3 reactivity. | |
Benzene-ring methyl-substituted 4-hydroxycoumarin | 18692-77-8 | 4-Hydroxy-7-methylcoumarin | ≥98% | C7-methyl positional isomer; suitable for comparison with the C6-methyl derivative to investigate how the position of the methyl group affects the electronic environment of the core scaffold, tautomeric equilibrium, intermolecular interactions, and C3 reactivity. | |
Benzene-ring methoxy-substituted 4-hydroxycoumarin | 17575-15-4 | 4-Hydroxy-7-methoxycoumarin | ≥98% | The C7 methoxy group exerts a resonance electronic effect without introducing ionization of a phenolic hydroxyl group; suitable for comparison with 4,7-dihydroxycoumarin to investigate the effects of O-methylation on electron delocalization, hydrogen bonding, acid–base properties, and C3 reactivity. |
Table 2. C3-Functionalized and C3-Bridged 4-Hydroxycoumarin Derivatives
Classification | CAS Number | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
4-Hydroxycoumarin with a C3 aryl–carbonyl side chain | 152-72-7 | Acenocoumarol | Moligand™, ≥98% (HPLC) | C3 bears a side chain containing a nitro-substituted aromatic ring and a ketone carbonyl; suitable for studying how the electron-withdrawing group, carbonyl, and aryl group in the side chain affect the electron distribution, conformation, and acid–base properties of 4-hydroxycoumarin after C3 carbon–carbon bond formation. | |
4-Hydroxycoumarin with a C3 aryl–carbonyl side chain | 81-81-2 | Warfarin | Moligand™, ≥98% | C3 bears an aryl–ketone side chain; suitable for studies of C3 functionalization, intramolecular interactions involving the side-chain carbonyl, ring–chain structural equilibria, tautomerism, and chiral conformations. | |
C3-bridged bis(4-hydroxycoumarin) | 66-76-2 | Dicoumarol | Moligand™, ≥98% | Two 4-hydroxycoumarin units are connected through a methylene bridge at C3; suitable for studying carbon–carbon bond formation at C3, electronic interactions between the two core scaffolds, hydrogen bonding, and tautomeric behavior. | |
C3 aralkyl-substituted 4-hydroxycoumarin | 435-97-2 | Phenprocoumon | Moligand™, ≥97% | C3 bears a 1-phenylpropyl group, and the side chain contains no carbonyl; suitable for comparison with C3 derivatives bearing ketone-containing side chains to examine the effects of the side-chain carbonyl, aryl group, and hydrophobic hydrocarbon chain on tautomerism, acid–base properties, and conformation. | |
C3-nitro-4-hydroxycoumarin | 20261-31-8 | 4-Hydroxy-3-nitrocoumarin | ≥98% (HPLC) | A strongly electron-withdrawing nitro group is directly attached at C3, replacing the original C3-H; suitable for studying the effects of C3 electronic modulation on C4-OH—C3—C2 carbonyl conjugation, electron-density distribution, and tautomeric properties. | |
4-Hydroxycoumarin with a bulky polyaromatic C3 side chain | 90035-08-8 | Flocoumafen | ≥98% | C3 bears a bulky side chain containing a fused-ring system, aromatic rings, and a trifluoromethyl group; suitable for studying the effects of steric hindrance, hydrophobic surface area, and fluorinated aryl groups on 4-hydroxycoumarin conformation, partitioning properties, and the electronic properties of the core scaffold. | |
4-Hydroxycoumarin with a C3 haloaryl–carbonyl side chain | 81-82-3 | Coumachlor | ≥98% | C3 bears a side chain containing a para-chloroaryl group and a ketone carbonyl; suitable for comparison with warfarin and acenocoumarol to investigate how halogen or nitro substitution on the aromatic ring affects the electronic effects, hydrophobicity, conformation, and acid–base properties of the C3 side chain. | |
C3-acyl-4-hydroxycoumarin | 2555-37-5 | 3-Acetyl-4-hydroxy-2H-chromen-2-one | ≥95% | Direct introduction of an acetyl group at C3 adds a carbonyl acceptor near C3; suitable for studying the effects of C3 acylation on tautomerism, intramolecular hydrogen bonding, carbonyl conjugation, and NMR and infrared structural characteristics. |
Note: The products above are representative Aladdin products related to scientific research. Their specific uses should be determined with reference to the product specifications, batch-specific certificates of analysis (COAs), and the intended reaction or evaluation system. Additional product specifications, grades, and COA information can be retrieved from the Aladdin website using the product name, CAS number, or catalog number.
References
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[7] Ilijaš M, Malnar I, Gabelica Marković V, Stepanić V. Study of lipophilicity and membrane partition of 4-hydroxycoumarins by HPLC and PCA. Journal of Pharmaceutical and Biomedical Analysis, 2013, 76: 104–111. DOI: 10.1016/j.jpba.2012.11.043.
[8] van der Giesen W F, Janssen L H M. Influence of ionization and ion-pair formation on lipophilicity of some 4-hydroxycoumarin derivatives in the octanol-water system. International Journal of Pharmaceutics, 1982, 12(2–3): 231–249. DOI: 10.1016/0378-5173(82)90122-3.
[9] Goka B, Klumpp D A. Synthesis of warfarin analogs: conjugate addition reactions of alkenyl-substituted N-heterocycles with 4-hydroxycoumarin and related substrates. RSC Advances, 2023, 13: 4754–4756. DOI: 10.1039/D3RA00251A.
[10] Stefanou V, Matiadis D, Melagraki G, Afantitis A, Athanasellis G, Igglessi-Markopoulou O, McKee V, Markopoulos J. Functionalized 4-Hydroxy Coumarins: Novel Synthesis, Crystal Structure and DFT Calculations. Molecules, 2011, 16(1): 384–402. DOI: 10.3390/molecules16010384.
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