Sustainable pathways to bio-based amines via the 'hydrogen borrowing' strategy Afanasenko, Anastasiia
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10.33612/diss.135979053
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Afanasenko, A. (2020). Sustainable pathways to bio-based amines via the 'hydrogen borrowing' strategy. University of Groningen. https://doi.org/10.33612/diss.135979053
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Chapter 5
Modular synthetic strategies from lignin-derived
platform chemicals to valuable nitrogen-containing
products
In this chapter, an advanced reaction network for the conversion of lignin-derived platform chemicals to a range of high-value aromatics, including amines, was established. Employing powerful catalytic methodologies such as ‘cross-coupling’ and ‘hydrogen borrowing’, our developed efficient protocols provided access to the valuable aniline products and the libraries of amino alkyl-phenol derivatives, respectively. Fully sustainable protocol for the construction of seven-membered N-heterocycles in two steps from lignin-derived monomer was for the first time described applying environmentally-friendly and benign deep eutectic solvents. Several molecules in these libraries have shown promising antibacterial or anticancer activity, emphasizing the advantage of this modular synthetic strategy and the potential for drug discovery.
This chapter was published as:
S. Elangovan, A. Afanasenko, J. Haupenthal, Z. Sun, Y. Liu, A. K. H. Hirsch, K. Barta, ACS
5.1 Introduction
The establishment of entirely new, energy-efficient, and waste-free pathways for the production of high-value chemicals from abundant and renewable resources is an utmost important subject to intensive research. Lignocellulose, being a promising renewable raw material, the main constituent of agricultural and forestry waste, harbours the great potential for the sustainable production of chemicals and fuels.1,2 However, in order to fully derive substantial value from its main constituents (cellulose, hemicellulose, and lignin) and benefit from its inherent structural complexity3, the development of novel catalytic methods4 and biorefinery approaches are highly desired.
Lignin, the largest natural feedstock of biorenewable aromatics, offers marvellous opportunities for the construction of valuable bioaromatic products.5 Mild lignin depolymerization has
attracted significant attention in recent years.6 Elegant strategies have emerged, which provide access to well-defined aromatic platform chemicals in near-theoretical yields.3,6–10 The next grand challenge in lignin refining is the diversification of these newly emerging building blocks to access industrially relevant products and concrete applications.2 While much research has focused on bulk chemicals (e.g. phenol, catechol, or BTX)6,7, surprisingly, only one example11
and no waste-free methods have been reported for the transformation of these aromatics to fine chemicals or pharmaceutical building blocks. Amines, being the key scaffolds of a wide variety of pharmaceutically active compounds, polymers, and surfactants12,13, is a prominent target to be achieved from lignin via chemo-catalytic approaches, which have, to the best of knowledge, not yet been realised. Production of such high-value products would be an important addition to the lignin-derived product portfolio as they significantly enhance the investment return and thus the overall economic feasibility of a biorefinery.
In this context, herein we elaborated on possibilities of upgrading lignocellulose derived chemicals towards the set of valuable products through C-N coupling reactions. The first part of this chapter (Figure 5.1) is disclosed the reaction network for the conversion of lignin-derived platform chemicals, namely dihydroconiferyl alcohol (1G) and dihydrosinapyl alcohol (1S) obtained from lignocellulose by means of our previously developed “LignoFlex”14process, to a variety of useful products, including amines, applying ‘cross-coupling’ and ‘hydrogen-borrowing’ strategies. The second part is described the highly selective catalytic amination of lignin-derived platform chemicals (1G and 1S) via the ‘hydrogen borrowing’ approach furnishing the formation of the amino alkyl-phenols followed by the subsequent cyclization to seven-membered N-heterocycles using deep eutectic solvents (DES)15 that consist solely of natural components.16,17 The former step takes place in the nontoxic solvent CPME and allows for obtaining valuable N-alkyl-amine derivatives directly from 1G (and 1S), contained in crude lignin-first depolymerization mixtures, by a new reactive separation strategy. The latter step uses benign, biodegradable, and recyclable alternative reaction media acting both as a catalyst and a solvent, leading to improved activity and selectivity, milder reaction conditions, and rendering strong acids or any other additives obsolete. The presented approach opens access to a library of tetrahydro-2-benzazepines, exhibiting antibacterial and anticancer activities.
Figure 5.1: Conversion of lignin-derived platform molecules to value-added chemicals
applying ‘cross-coupling’ and ‘hydrogen borrowing’ methodologies.
5.2 Results and discussion
Recently, we have developed the flexible use of copper-doped porous metal oxides (Cu20-PMO) for the full conversion of lignocellulose to valuable aromatics and fuels (LignoFlex).14,18 The reductive catalytic fractionation step of this method resulted in aromatic monomers, predominantly dihydroconiferyl alcohol 1G (>90% selectivity from pine) as well as smaller amounts of 4-ethylguaiacol (2G) and 4-propylguaiacol (3G). Taking advantage of the inherent phenylpropanoid moiety of lignin-derived 1G, which comprises both aliphatic and aromatic alcohol scaffolds, we primarily focused on its (de)functionalization into a set of value-added products via various catalytic and stoichiometric pathways (Chapter 5.2.1). Given the fact that primary and secondary amine scaffolds are at the core of fine and bulk chemical industry, we were sought to develop the catalytic methodologies that enable to incorporate the nitrogen on the phenolic and/or aliphatic end of the lignin-derived monomer via the ‘cross-coupling’ and the ‘hydrogen borrowing’ strategies, respectively (Chapter 5.2.1 and 5.2.2).
5.2.1 Establishment of reaction network towards the value-added chemicals
Initially, we planned on the establishment of the catalytic pathways for the direct conversion of1G to aniline derivatives; however, such transformation might be complicated due to the
presence of an aliphatic alcohol scaffold in the 1G structure. The latter may coordinate to transition metal species or interfere with the strong base, critical for these catalytic methods. Therefore, we started our investigations employing 3G, which was previously obtained through reductive defunctionalisation of 1G over a commercially available Ni/SiO2-Al2O3 catalyst.
Figure 5.2: The conversion of lignin-derived platform chemicals 1G and 1S to a range of
value-added compounds, including aromatic and aliphatic amines; (A) Homogeneous Ni-catalysed cross-coupling of 8G/8S with various amines and defunctionalisation pathway; (B) High-yield phenol to aniline transformation using 1G; Numbers in parentheses show yields calculated from GC-FID.
Applying established by Chatani and co-workers homogeneous nickel-catalysed cross-coupling19,20 methodology, pseudohalogenide 8G underwent cross-coupling with a number of
primary and secondary amines to yield the corresponding aromatic products 9aG–9eG (Figure
5.2A) that are structural moieties in synthetic Arctigenin derivatives that show anti-tumor
properties.21 Nonetheless, the inherent structure of lignin-derived 3G also posed limitations to the methodology applied, since in many cases, employing aliphatic, heteroaromatic amines as coupling partners, no reactivity was observed or there were competing side reactions, namely deprotection or deoxygenation.
Earlier, Chatani’s and Martin’s groups independently reported the Ni(0)/PCy3 system that
facilitates cross-coupling with hydrosilane22 or hydrosiloxane23, resulting in the substitution of an alkoxy group by a hydrogen atom. In this reductive cleavage reaction HSiMe2(OMe)2 or
(HSiMe2)2O are used as an effective hydride donor due to its relatively high Lewis acidity.
Employing carbamoyl-protected 4-propylguaiacol (8G) in such transformation, 3-ethylanisole (10G) was obtained in quantitative isolated yield, which cannot be obtained by electrophilic aromatic substitution of anisole, presenting a distinct advantage of using a lignin-derived substrate.
Aiming to directly obtained aniline products from 1G and 3G, we attempted the challenging nickel-catalysed ammonia monoarylations employing various pseudohalogenide electrophiles; however, such an approach did not work out due to the expected competing pathways, such as
deprotection and deoxygenation. Therefore, we turned our attention to alternative stoichiometric pathways, more specifically, to the one-pot synthesis of aniline products using an ipso-oxidative aromatic substitution (iS
OAr) process24. This adapted metal-free
phenol-to-aniline transformation (Figure 5.2B) was carried out through oxidation of 1G to the corresponding benzoquinone ketal 11G and a subsequent reaction with glycine methyl ester hydrochloride to provide the desired aniline, 12aG. The inherent structure of 1G was largely beneficial for obtaining excellent yields of 12aG, since the 3-hydroxy moiety was ideally positioned to obtain 11G, a stable spirocompound25. The corresponding one-pot procedure was applied to 3G as well, yielding aniline derivative 12bG, which can be used as intermediate in the synthesis of naturally occurring carbazole alkaloids (Figure 5.2A)26, for example, carbazole Murrayafoline-A27 and analogues, according to novel reported procedures28,29. The synthesis of the latter is in particularly relevant and has attracted significant attention due to its strong fungicidal activity against Cladosporium cucumerinum and growth inhibitory activity on human fibrosarcoma HT-1080 cells.30
Notably, regarding the pathways from 1G to 3G and the follow up steps from 3G, these transformations were initially performed with commercially available 1G and 3G. Subsequently, it was shown that the whole sequence till 9cG (1G→3G→8G→9cG) can be integrated starting from 1G isolated directly from lignocellulose and following the same procedure with a very negligible variation of product yields (Figure 5.3).
Figure 5.3: The upgrading of the obtained directly from pine lignocellulose platform chemical 1G.
Beside the network established with guaiacol-type monomers, we have also successfully performed selected transformations involving syringol-type monomers, summarized in Figure
5.2.
Next, we turned our attention to the functionalisation of aliphatic alcohol moiety of 1G (Figure
5.4). An N-mesyl derivative 13G, was prepared from 1G by direct amination of the aliphatic
alcohol moiety through a ‘hydrogen borrowing’ strategy, employing Ru(p-cymene)Cl2]2 with
the bidentate phosphine DPEphos as a catalyst31. Subsequently, 13G was converted to the aliphatic–aromatic diamine 12cG. Notably, the obtained building blocks 12aG-cG, 13G can potentially serve as precursors for new polyesters or polyamides as sole components or by
Figure 5.4: Functionalization of 1G using both ‘hydrogen borrowing’ and stoichiometric
approaches.
5.2.2 Highly efficient amination of lignin-derived alcohols via ‘hydrogen
borrowing’ approach
Inspired by our initial promising results in the synthesis of secondary amines employing ‘hydrogen-borrowing’ methodology33,34 (Figure 5.4, compound 13G) and given the fact that
this approach has been only scarcely14 applied to lignin-derived aromatics comprising a free phenol moiety, we were further interested in the establishment of a novel robust catalytic system for the synthesis of amino alkyl-phenols.
In Chapters 3 and 4 we have already demonstrated that Shvo’s catalyst (C1) is active in decarboxylative N-alkylation of α-amino acids35 and in amination of β-hydroxyl acid esters36 with alcohols. Furthermore, our group earlier reported the unprecedented catalytic activity of the Shvo’s catalyst in the base-free N-alkylation of potentially strongly coordinating unprotected amino acids with alcohols.37 Therefore C1 was evaluated in the catalytic amination
of 1G with aniline (Table 5.1). The desired secondary amine 5Ga was obtained in perfect selectivity (99%) and good isolated yield (75%) using the non-toxic solvent CPME and 1 mol%
C1 without any additives (Table 5.1, entry 1). Appropriate blank reactions showed no product
formation and a mercury poisoning experiment confirmed the homogeneous nature of the catalytic system. An even better, 97% isolated yield of 5Gb was obtained using 4-chloroaniline
4b as coupling partner (Table 5.1, entry 7). This reaction could also be upscaled using 1.3 g 1G to deliver a 94% isolated yield of 5Gb (Table 5.1, entry 8).
Remarkably, this ruthenium-catalyzed highly selective amination protocol, involving the aliphatic alcohol moiety of 1G (and 1S), tolerates the multicomponent crude depolymerization mixture, which commonly contains besides 1G, 2G and 3G, residual sugars and lignin oligomers, and is selective enough to allow for good separation while maintaining a high enough renewable carbon balance. The isolation and purification of single aromatic compounds from lignin or “lignin-first” depolymerization mixtures are a common challenge in the field, however, our newly-developed methodology allowed to accomplish the reactive separation of
1G by its one-step conversion to valuable amines – that have not yet been accessed from lignin
- directly in crude product mixtures obtained from reductive depolymerization of pine and poplar lignocellulose.
Table 5.1: Establishing the highly selective catalytic amination of dihydroconiferyl alcohol 1G.
Entrya Changes Yield (%)b
1 as above >99 (75) 2 C1 (0.5 mol%) 33 3 100 oC 42 4 1 equiv. 1G 93 5 8 h 52 6 no C1 - 7c 4-chloroaniline (4b) instead of aniline >99 (97) 8d 4b >99 (94)
aAll the reactions were run with 4a (0.25 mmol) and 1G (0.3 mmol). bYield was determined by GC-FID (Isolated yield). c4b (0.4 mmol), 1G (0.48 mmol), CPME (2 mL). d4b (5.95 mmol), 1G (7.14 mmol), CPME (20 mL).
In order to provide straightforward access to a library of novel lignin-based amino alkyl- and aryl-guaiacols, the modular coupling of 1G with (hetero)aromatic and aliphatic primary amines as well as secondary amines was successfully carried out using the developed Ru-catalyzed methodology (Table 5.2). Anilines 4b-4i carrying electron-withdrawing and donating groups were selectively mono-alkylated to form the corresponding secondary amine products 5Gb–
5Gi in good to outstanding isolated yields. Interestingly, excellent functional group tolerance
was observed with the sulfur-containing 4h as well as with anilines containing reducible functional groups –NO2, -CN, -COOCH3, COCH3 and an alkene. Among the obtained products,
5Gj containing a p-nitroaniline moiety may potentially serve as NO donor similarly to already
described phenolic analogues.38 Interestingly, anilines 4o and 4p gave 61% 5Go and 81% 5Gp, respectively. Previously, several bis- and tris-dihydroxyaryl analogues have shown valuable in the treatment of Alzheimer’s disease, type II diabetes, and Parkinson’s disease.39 Moreover,
5Gp could serve as a novel sustainable bisphenol for the synthesis of bio-based polymers.40
Furthermore, 5Gq, 5Gr and 5Gs were isolated in good to moderate yields (81%, 53% and 55% respectively). When secondary amines 4t, 4u and 4v were used as coupling partner, the corresponding tertiary amines 5Gt, 5Gu and 5Gv were obtained in good yields. These may serve as starting materials for the synthesis of pharmaceutically active compounds, primarily upon quaternarization.41,42 Primary amine, 3-aminopropyl guaiacol (5Gw) was considered as an important target that can be subjected to further derivatization. Despite several attempts, we were unable to obtain 5Gw from ammonia and 1G using the studied Ru-catalyzed coupling. Therefore, a novel methodology was developed that uses commercially available Raney nickel
Table 5.2: Selective Ru-catalysed amination of dihydroconiferyl alcohol 1G with various
amines.
General reaction conditions: 4b-y (0.4 mmol), 1G (0.48 mmol), C1 (1 mol%), CPME (2 mL), 130 °C, 20 h. Isolated yields are shown. a3 equiv. of secondary amine was used and the yield based on 1G. b3 mol% C1. cRaney Ni (200 mg), NH4OH (0.4 mL), t-amyl alcohol (3 mL), 180 oC, 24 h. Isolated as HCl salt. dCF3CH2OH was used as a solvent. *Compound was synthesized by Dr. Saravanakumar Elangovan. Gratifyingly, employing various aminophenols (4p1-4p3) as coupling partners and increasing the 1G: amine ratio to 2.5:1, the corresponding tertiary amines (Table 5.3, 5Gp1S1-5Gp3S1) were obtained in good to excellent isolated yields (65-81%). These partially lignin-derived polyphenols could be used as precursors to epoxy thermosets43,44; the development of such renewable materials has recently emerged highly important due to its potential to replace or supplement petroleum-based materials45–47.
Table 5.3: Synthesis of tertiary amines – potential polymer building blocks.
General reaction conditions: 4p1-4p3 (0.5 mmol), 1G (1.25 mmol), C1 (1 mol%), CPME (2 mL), 120 °C, 20 h. Isolated yields are shown.
In some cases, using aliphatic amines, such as benzylamine (4a^), furfuryl amine (4b^) and nonyl amine (4c^), the formation of tertiary amine through the coupling of 1G with two molecules of starting amine as a major product (Table 5.4, 5Ga^-5Gc^) was detected besides the N-dialkylated by-product (5Ga^S1-5Gc^S1) and 5a^-5c^ side-product formed due to the self-alkylation of aliphatic amines.48
Table 5.4: Untypical Ru-catalysed amination of dihydroconiferyl alcohol 1G with various
aliphatic amines.
General reaction conditions: 4a^-c^ (0.4 mmol), 1G (0.48 mmol), C1 (1 mol%), CPME (2mL), 130 °C, 20 h. Isolated yields are shown.
The reactivity of 1S that can be obtained from poplar lignocellulose in larger quantities was found to be very similar to that of 1G, thus a library of amino alkyl-syringols was created smoothly with excellent functional group tolerance observed (Table 5.5).
Table 5.5: Selective catalytic amination of dihydrosinapyl alcohol 1S with various amines.
General reaction conditions: 4a-t (0.4 mmol), 1S (0.48 mmol), C1 (1 mol%), CPME (2 mL), 20 h, 130 °C. Isolated yields are shown.
5.2.3 Construction of seven-membered N-heterocycles in deep eutectic
solvents
Benzazepine derivatives are a prominent class of compounds in the pharmaceutical industry (e.g. Diazepam49).50 In particular, tetrahydro-2-benzazepines have shown promising biological activities.51–53 This scaffold is present in important naturally occurring alkaloids54 including
galanthamine55, a very effective drug for the treatment of Alzheimer’s disease. Furthermore, capsazepine and its derivatives have been widely investigated as selective antagonists of vanilloid type-1 receptors.56 Due to these valuable pharmacological properties, the synthesis of tetrahydro-2-benzazepines has been extensively studied.57–59 Taking advantage of the inherent phenylpropanoid moiety of lignin-derived 1G, our aim was to develop a new sustainable method that would represent a significant improvement over conventional synthetic routes. Given the importance of the Pictet–Spengler reaction in the synthesis of alkaloid scaffolds,60 and in particular, it’s use for the cyclization of 3-arylpropylsulfonamides with formaldehyde to construct N-sulfonyl-2-benzazepines,61 we attempted to realize the green synthesis of novel 7-membered-N-heterocycles via this method, starting from the library of amines obtained before (Table 5.2 and 5.5).
First, we started to adapt conventional protocols developed on imines of 2-phenethylamine derivatives as closest analogues to our substrates,62 and performed cyclization using 5Gb as model substrate and paraformaldehyde in various organic solvents screening Brønsted and Lewis acid catalyst (in collaboration with Dr. Saravanakumar Elangovan). This led to only
moderate success due to competing methylation of the alkyl-amine substrates that prevented efficient cyclization.
In order to markedly improve selectivity and efficiency, we have turned our attention to the use of deep eutectic solvents (DES) for the first time for the formation of tetrahydro-2-benzazepines. Due to their favorable properties such as excellent solvent power, negligible vapor pressure and good recyclability, DES have demonstrated enormous potential as sustainable and benign replacement of common organic solvents in various applications, including organic synthesis.15,17,63,64 The highly ionic nature and strong hydrogen-bond donor
properties of several DES have already shown beneficial for facilitating classical organic transformations (e.g., those involving activation of a carbonyl compound). One example of a Pictet–Spengler cyclization using the specific substrate tryptamine, has been reported in a choline chloride (ChCl):urea DES.65 However, the same DES turned out to be unsuitable for the formation of the desired tetrahydroisoquinoline using 3,4-dimethoxy-phenyl ethylamine, only leading to the corresponding imine intermediate. Inspired by this system, we reasoned that beside the excellent hydrogen-bond acceptor, choline chloride (ChCl), an organic acid component (lactic acid (LA) or oxalic acid (OA)) would be highly suitable for facilitating the required carbonyl-activation and proton-transfer events involved in the iminium formation and subsequent Mannich-type cyclization steps.17,65 Advantageously, such DES comprises solely
natural components, which are non-toxic, biodegradable and are potentially bio-derived.16 To our delight the combination ChCl/OA showed full conversion of 5Gb and very good selectivity (95% GC-MS yield) of the desired cyclization product 6Gb under mild reaction conditions (70
oC) without the need of any strong acids or other additives. Notably, good results were achieved
even at temperatures as low as 50 °C and 8 h reaction time (76% and 66% GC-MS yield,
respectively). Next, we explored the desired cyclizations with several alkyl amines in hand under optimized reaction conditions (Table 5.6). The 7-membered N-heterocyclic products were obtained in outstanding selectivity and good to excellent isolated yields.
Table 5.6: Construction of lignin-derived tetrahydro-2-benzazepines in deep eutectic solvent
comprising choline chloride/oxalic acid.
General reaction conditions: 5G or 5S (0.150-0.366 mmol), ChCl/OA (1 g), 70-80 °C, 20-48 h. Isolated yields are shown. We carried out all the cyclisation experiments under non-inert conditions during which all starting materials and solvents were handled under air. *These compounds were synthesized by Dr. Saravanakumar Elangovan.
5.2.4 Evaluation of biological activity of lignin-derived
tetrahydro-2-benzazepines
The evaluation of biological activity was carried out in collaboration with Prof. Dr. Anna K. H. Hirsch and Dr. Jörg Haupenthal, Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) – Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany. In order to identify possible biological effects of our compounds, we evaluated their potential anti-infective activity toward representative Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria. In parallel, we determined their effects on a human hepatoma cell line (Hep G2) as an early indication of anticancer activity.
While the compounds were inactive against E. coli K12, promising activities were observed against S. aureus (Figure 5.5), where the best compounds reached MIC (Minimum Inhibitory Concentration) values between 40 and 50 µM. If these values are compared with erythromycin, an antibiotic which is therapeutically used to treat this pathogen and utilized in this study as a reference compound, we observe an about tenfold higher MIC for the best lignin-derived inhibitor 6Ge. Since our compounds have not yet been optimized in this respect, this difference seems to be acceptable. Interestingly, as the activities of four selected compounds were much more pronounced in the efflux-pump-deficient E. coli TolC strain, the lack of activity against E. coli K12 might be due to compound efflux. Besides, also in E. coli TolC the MIC of 6Ge was only slightly (~5.5-fold) higher than that of the reference compound chloramphenicol. Furthermore, 14 out of the 41 tested compounds inhibited the viability of HepG2 cells by >85 % at 100 µM (Figure 5.5) with IC50 (half maximal inhibitory concentration) values ranging
from 30 to 50 µM for the best inhibitors. In detail, the IC50 value of the best inhibitor 5Gt (30.4
± 0.4 µM) was worse than that of the reference compound doxorubicin, but also here, the activity gap (44-fold) should be overcome during medicinal-chemistry optimization. Taken together, these moderate but promising activities of the novel lignin-derived scaffolds reported here will pave the way for the further optimization and development of the most promising inhibitors toward anticancer drugs and anti-infectives. A viable modification strategy would be to optimize and grow the fragments identified by introducing appropriate substituents, preferably by straightforward catalytic modification of reactive functional groups present in the obtained tetrahydro-2-benzazepines.
Analysis of the structure–activity relationships of each of the four classes of compounds revealed interesting common trends. Weakly electron-withdrawing substituents such as the halogens led to the highest cytotoxicities (e.g., 5Gb–e; 5Sb, 5Sc, 5Se; 6Gb, 6Gc, 6Ge; 6Sb,
6Se), whereas strongly deactivating substituents such as p-NO2 (e.g., 5Gj) caused a decreased
cytotoxicity. This decrease may also be ascribed to the increased steric demand of the substituents in question. When considering classes 5G and 5S, N-alkylation appears to be favourable for cytotoxicity (e.g., 5Gt or 5St) for the N-ethylated derivative. Replacement of the N-phenyl substituent by a heterocycle (5Gs) or o-substitution with a pyrrole heterocycle (5Gr) also lead to high cytotoxicity. The most promising antibacterial activities against S. aureus were observed for 6G and 6S compounds, in particular for the p-brominated derivatives (6Gc, 6Ge,
6Sc) as well as for the p-chlorinated analogue 6Sb. For class 5, the antibacterial activity against
S. aureus was weaker than for class 6. In class 5S, compounds 5Sb and 5Sc stood out, featuring p-halogen substituents. The pyrene-derivative 5Gq is the only representative of class 5G that showed significant antibacterial activity.
Figure 5.5: Inhibitory effects of compounds on bacterial growth (E. coli K12, S. aureus) and
on the viability of HepG2 cells. Bacteria and cells were treated with 100 µM of the indicated compounds. Percent (%) inhibition values are given. Standard deviations from at least two independent experiments are indicated by error bars. *: treatment of bacteria with only 50 µM. The presented evaluation of biological activities of these compounds was carried out at Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) – Helmholtz Centre for Infection Research (HZI) by Prof. Dr. Anna K. H. Hirsch and Dr. Jörg Haupenthal.
5.3 Conclusion
In this chapter, we have shown a variety of efficient synthetic methodologies that enable the conversion of lignin-derived monomers to high-value chemicals including amines. In the first part of this chapter, we have demonstrated that dihydroconiferyl alcohol (1G) and dihydrosinapyl alcohol (1S), isolated as a single component directly from lignocellulose,
comprising both aliphatic and aromatic alcohol moieties, could be efficiently converted via ‘cross-coupling’ and ‘hydrogen borrowing’ methodologies to a variety of high-value products, increasing the available pool of sustainable platform chemicals. Remarkably, the obtained functionalized aromatics could be potentially used as polymer precursors and for the synthesis of pharmaceutically relevant compounds. In the second part of this chapter, we have developed a highly selective ruthenium-catalysed methodology which affords an access to amino alkyl-phenols through the direct amination of the lignin-derived platform chemicals 1G and 1S in a crude “lignin-first” depolymerization mixtures. We have reported the efficient protocol that for the first time provides access to 7-membered N-heterocycles using fully sustainable deep eutectic solvents (DES) without the formation of any by-products besides water. The present catalytic strategy uniquely incorporates all the intrinsic functional groups of the lignin-derived building blocks 1G and 1S into pharmaceutically relevant compounds. The viability of this greatly modular protocol has been demonstrated by the discovery of biologically active structures in the obtained compound library.
5.4 Experimental section
5.4.1 General methods
Column chromatography was performed using Merck silica gel type 9385 230-400 mesh and typically pentane and ethyl acetate as eluent.
Thin layer chromatography (TLC): Merck silica gel 60, 0.25 mm. The components were visualized by UV or KMnO4 staining.
Gas Chromatography (GC) was used for product identification as well as determination of conversion and selectivity values. Product identification was performed by GC-MS (Shimadzu QP2010 Ultra) with an HP-1MS column, and helium as carrier gas. GC-MS method: The temperature program started at 50 °C for 5 min, heated by 30 °C/minute to 250 °C and held for 15 min. Conversions and product selectivity were determined by GC-FID (Agilent Technologies 6890) with an HP-5MS column using nitrogen as carrier gas. GC-FID analysis method: The temperature program started at 50 °C for 5 min, heated by 30 °C/min to 320 °C and held for 15 min.
Mass spectrometry: Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or an LTQ Orbitrap XL (ESI+).
Gel Permeation Chromatography (GPC): GPC was performed on a Hewlett Packard 1100 system equipped with three PL-gel 3 µm MIXED-E columns in series. The columns were operated at 40 °C with a flow rate of 1 mL/min of THF. Detection was accomplished at 40 °C
respectively) and Bruker Avance NEO 600 (600 and 151 MHz, respectively) using CDCl3,
CD3OD and DMSO-d6 as a solvent. 1H and 13C NMR spectra were recorded at room
temperature. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C; CD3OD: 3.31 for 1H, 49.00 for 13C;
DMSO-d6: 2.50 for 1H, 39.52 for 13C). Data are reported as follows: chemical shifts, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, br. = broad, m = multiplet), coupling constants (Hz), and integration.
Standard techniques under inert atmosphere: Amination of alcohols was carried out under an argon atmosphere using oven (120 °C) dried glassware and standard Schlenk techniques as follows. The solid materials were weighed into a Schlenk tube under air and the Schlenk tube was subsequently connected to an argon line and vacuum-argon exchange was performed three times. Liquid starting materials and the solvent were charged under an argon stream. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then it was placed into a pre-heated oil bath to carry out the reaction at the indicated temperature for an indicated time.
Reagents and solvents: 1-Hydroxytetraphenylcyclopentadienyl-(tetraphenyl-2,4-cyclopentadi-en-1-one)-μ-hydrotetracarbonyldiruthenium(II) (Shvo’s catalyst) and bis(1,5-cyclooctadiene)-nickel(0) were purchased from Strem chemicals; dichloro(p-cymene)-ruthenium(II) dimer and Ni/Al2O3-SiO2 catalyst were purchased from Sigma-Aldrich; Cyclopentyl methyl ether (CPME,
99.9%, anhydrous) was purchased from Sigma-Aldrich without further purification. All other reagents were purchased from Sigma-Aldrich, Acros and TCI in reagent or higher grade and were used as received without further purification. Deep Eutectic Solvents (DES) were prepared by the reported procedures.66,67 Pine lignocellulose was purchased from Bemap Houtmeel B.V., and poplar lignocellulose was purchased from Morrow Oregon.
Evaluation of antibacterial effects: Antibacterial activities of compounds were determined in E. coli K12 (DSM 18039), E. coli TolC and Staphylococcus aureus subsp. aureus (Newman strain). As a bacteria start OD600, we used 0.03 (optical density of the bacteria at 600 nm) in a
total volume of 200 µL in lysogeny broth (LB) medium containing the compounds predissolved in DMSO (maximal DMSO concentration: 1%). Final compound concentrations prepared from serial dilutions ranged from 0.02 to 50 or 100 µM, depending on their solubility. The ODs at 600 nm were determined directly after addition of the compounds and again after incubation at 37 °C for 16 hours and 50 rpm in 96 well plates (Sarstedt, Nümbrecht, Germany) using a FLUOstar Omega microplate reader (BMG labtech). Percent inhibition values at defined compound concentrations could be determined by relating the ODs hereof to those of DMSO controls. Given minimal inhibitory concentrations (MIC) values are means of at least two independent determinations and are defined as the lowest concentration of compounds that reduced OD600 by ≥ 95%.
Cytotoxicity assay: Hep G2 (hepatocellular carcinoma) cells (2×105 cells per well) were seeded in 24-well, flat-bottomed plates. Culturing of cells, incubations and OD measurements were performed as described previously68 with small modifications. Twenty-four hours after seeding the cells, the incubation was started by the addition of compounds in a final DMSO
concentration of 1%. The living cell mass was determined after 48 hours in a PHERAstar microplate reader (BMG labtech, Ortenberg, Germany). At least two independent measurements were performed for each compound. The calculation of IC50 values was
performed by plotting the percent inhibition vs the concentration of inhibitor on a semi-log plot. From this, the molar concentration causing 50% inhibition was calculated.
5.4.2 Representative procedures
Synthesis of 4-ethyl-2-methoxyphenyl diethylcarbamate (8G)
To a solution of 3G (10 mmol, 1.52 g) in acetonitrile (30 mL) were subsequently added potassium carbonate (11 mmol, 1.52 g) and diethylcarbamoyl chloride (11 mmol, 1.49 g). The mixture was heated under reflux for 14 h, then cooled down to room temperature. The solid was filtered and the solvent was removed by evaporation, the oily residue was dissolved in diethyl ether and washed with a 20 wt% solution of KOH. The organic phase was dried over magnesium sulphate and the solvent was evaporated. A pure product could be obtained after column chromatography on silica gel, using pentane: ethyl acetate (5:1) as eluent to provide 2.10 g of 8G (84% yield).
Nickel-catalysed amination of aryl carbamates
Compounds 9aG-9eG were obtained by following the procedure developed by Mamoru Tobisu and Naoto Chatani.20
In a nitrogen-filled glovebox, Ni(COD)2 (0.04 mmol, 10 mg), iPrNHC (0.08 mmol, 32 mg) and
NaOtBu (0.5 mmol, 48 mg) were placed in a Schlenk tube equipped with a magnetic bar. The Schlenk was taken out of the glovebox and the nitrogen atmosphere was replaced with argon. Degassed toluene (2 mL) was added to the solids and the suspension was stirred for 5 min while the color turned from yellow to red-brown, then the substrate (0.25 mmol) and the N-nucleophile (0.35 mmol) were sequentially added. The mixture was stirred at 120 °C for 21 h; the suspension was filtered over silica using ethyl acetate as eluent and analyzed by GC-MS. The pure product 9aG-9eG was obtained by column chromatography on silica gel, using pentane: ethyl acetate (9:1) as eluent.
Nickel-catalysed reductive cleavage of aryl carbamates
Compound 10G was obtained by following the procedure developed by Paula Alvarez-Bercedo and Ruben Martin.23
In a nitrogen-filled glovebox, a mixture of [Ni(COD)2] (0.02 mmol) and PCy3 (0.04 mmol) was
The oxidative spiroannulation of 1G
This procedure was adapted from the work of Guy L. Plourde.25
To a pre-cooled solution (0 °C) of 1G (1 mmol, 182 mg) in MeOH (1.5 mL) was added dropwise a solution of Iodobenzene diacetate (PIDA) (1.05 equiv., 338 mg) in the same solvent (1 mL). The color immediately turned into bright yellow and the homogeneous solution was stirred for 15 min at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using hexane: ethyl acetate (2:1) as eluent to provide 0.133 g of 11G (78% yield).
Synthesis of 3-(4-amino-3-methoxyphenyl)propan-1-ol (12aG)
Compound 11G (0.1 mmol, 18 mg) was dissolved in a 9:1 mixture of MeOH-H2O (1 mL) and
glycine methyl ester hydrochloride (0.7 mmol, 88 mg) and triethylamine (0.9 mmol, 0.125 mL) were subsequently added. The mixture was stirred at 40 °C for 3 h and the volatiles were removed. The pure compound was obtained by column chromatography on silica gel, using pentane: ethyl acetate (9:1) as eluent to provide 0.017 g of 12aG (95%).
ipso-Oxidative aromatic substitution of phenolic hydroxyl group of 3G
This procedure was adapted from the work of Alaniz and coworkers24.
Iodobenzene diacetate (PIDA) (0.354 g, 1.1 mmol) or phenyliodine bis(trifluoroacetate) (PIFA) (0.473 g, 1.1 mmol) was suspended in MeOH (5 mL) and cooled on an ice bath. The phenol
3G (1.0 mmol, 0.182 g) was dissolved in MeOH (5 mL) and added dropwise over 5 min. The
ice bath was removed and the reaction mixture was stirred for 30 min or until consumption of the starting material. The reagents Et3N (1.3 mL, 9 mmol, 9 equiv.), H2O (0.5 mL), and methyl
glycinate hydrochloride (0.883 g, 7 mmol, 7 equiv.) were added sequentially and the reaction mixture was stirred at 40 °C for overnight or until consumption of the quinone. The solvent was evaporated; DCM (50 mL) was added and extracted with HCl (aq) (1 M, 6 × 10 mL). The aqueous layers were combined, neutralized with saturated NaHCO3 (aq) (140 mL), and
extracted with DCM (3 × 50 mL). The organic layers were combined, dried over Na2SO4,
filtered, and the solvent removed under reduced pressure. The product was isolated by column chromatography on silica gel, using pentane: ethyl acetate (5:1) as eluent to provide 0.125 g of
12bG (83% yield).
Synthesis of N-(3-(4-amino-3-methoxyphenyl)propyl)methanesulfonamide (12cG)
This compound was obtained according to general procedure for the one-pot conversion of guaiacol derivatives to anilines (compound 3G to 12bG).24
PIDA (0.354 g, 1.1 mmol) was suspended in MeOH (5 mL) and cooled on an ice bath. The phenol 1G (1.0 mmol, 0.259 g) was dissolved in MeOH (5 mL) and added dropwise over 5 min. The ice bath was removed and then the reaction mixture was stirred for 30 min or until consumption of the starting material. The reagents Et3N (1.3 mL, 9 mmol, 9 equiv.), H2O (0.5
and the reaction mixture was stirred at 40 °C overnight or until consumption of the quinone. The solvent was evaporated; DCM (50 mL) was added and the organic layer was extracted with HCl (aq) (1 M, 6 × 10 mL). The aqueous layers were combined, neutralized with saturated NaHCO3 (aq) (140 mL), and extracted with DCM (3 × 50 mL). The organic layers were
combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The
product was isolated by column chromatography on silica gel, using pentane: ethyl acetate (4:1) as eluent to provide 0.198 g of 12cG (77% yield).
Ru-catalysed amination of 1G via ‘hydrogen borrowing’ approach
Compound 13G was obtained by modification of a reported procedure.31
A Schlenk tube was charged with compound 1G (90 mg, 0.5 mmol), MsNH2 (43 mg, 0.45
mmol), [Ru(p-cymene)Cl]2 (0.0125 mmol, 8 mg), DPEphos (0.025 mmol, 13 mg) and K2CO3
(0.05 mmol, 7 mg). After evacuating and filling the Schlenk with argon (3 times), degassed toluene (1 mL) was added under argon flow and the reaction mixture was heated at 130 °C for 24 h. After cooling down to room temperature, the solution was filtered through Celite and the toluene was evaporated. Pure 13G was obtained by column chromatography on silica gel, using pentane: ethyl acetate (9:1) as eluent to provide 0.060 g of 13G (52% yield).
General procedure (A) for the selective amination of 1G and 1S via ‘hydrogen borrowing’ approach catalysed by Shvo’s catalyst
An oven-dried 20 mL Schlenk tube, equipped with a stirring bar, was charged with amine (0.4 mmol, 1 equiv.), 1G or 1S (0.48 mmol, 1.2 equiv.), C1 (0.004 mmol, 1 mol%) and cyclopentyl methyl ether (CPME, 2 mL). Solid materials were weighed into the Schlenk tube under air. The Schlenk tube was subsequently connected to an argon line and vacuum–argon exchange was performed three times. Liquid starting materials and solvent were charged under an argon stream. The Schlenk tube was capped, and the mixture was rapidly stirred at room temperature for 1 min, placed into a pre-heated oil bath at 130 °C and stirred for 20 h. The reaction mixture was cooled down to room temperature and the crude mixture was filtered through silica gel, eluted with ethyl acetate (10 mL), and the solvent was removed in vacuo. The residue was purified by flash column chromatography using ethyl acetate/pentane as the eluent.
Representative procedure (B) for the synthesis of 4-(3-aminopropyl)-2-methoxyphenol (5Gw)
A 10 mL Swagelok stainless steel micro reactor equipped with a stirring bar was charged with substrate 1G (0.5 mmol), Raney Ni (200 mg), aqueous ammonia (0.4 mL, 25%) and t-amyl alcohol (3 mL). Then, the reactor was sealed and placed in a pre-heated aluminium heating block at 180 °C. After 24 h, the micro reactor was cooled down to room temperature using an
General procedure (C) for tetrahydro-2-benzazepine synthesis
An oven-dried vial equipped with a stirring bar, was charged with amino alkyl-phenol (0.150-0.366 mmol, 1 equiv.), paraformaldehyde (0.150-(0.150-0.366 mmol, 1 equiv.) and ChCl/C2H2O4.2H2O (1:1 molar ratio, 1 g) under air. Then the vial was capped and the mixture
was rapidly stirred at room temperature for 1 min, then was heated to 70-80 °C and stirred for 20-48 h. The reaction mixture was cooled down to room temperature, water (2 mL) and saturated solution of NaHCO3 (2 mL) were added and the reaction mixture was stirred for one
hour at room temperature. The crude mixture was extracted with ethyl acetate (3 × 10 mL) and and the solvent was removed in vacuo. The residue was purified by flash column chromatography using ethyl acetate/pentane as the eluent.
5.4.3 Spectral data of isolated compounds
4-ethyl-2-methoxyphenyl diethylcarbamate (8G)
3G affords 8G (2.10 g, 84% yield). The compound was purified by column chromatography
(SiO2, Pentane/EtOAc 5:1). 1H NMR (400 MHz, CDCl3): δ 6.98 (d, J = 8.0 Hz, 1H), 6.78-6.72
(m, 2H), 3.81 (s, 3H), 3.50-3.31 (m, 4H), 2.62 (q, J = 7.6 Hz, 2H), 1.32-1.12 (overlapping signals, m, 9H). 13C NMR (100 MHz, CDCl
3): δ 157.00, 154.03, 145.01, 141.18, 125.57,
122.42, 114.83, 58.52, 31.48, 18.32. HRMS (ESI+) Calculated for C14H22NO3 [M+H]+:
252.1600; found: 252.1592.
4-(4-ethyl-2-methoxyphenyl)morpholine (9aG)
8G affords 9aG (0.035 g, 64% yield). The compound was purified by column chromatography
(SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 6.86 (d, J = 8.0 Hz, 1H), 6.76
(d, J = 8.0 Hz, 1H), 6.72-6.70 (m, 1H), 3.90-3.86 (m, 7H), 3.04 (m, 4H), 2.61 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 154.80, 142.06, 141.51, 122.53,
120.50, 113.87, 69.89, 57.98, 54.00, 31.17, 18.24. HRMS (APCI+, m/z) calculated for C13H20NO2 [M+H]+: 222.14939; found: 222.14890.
4-ethyl-2-methoxy-N-phenylaniline (9bG)
8G affords 9bG (0.043 g, 75% yield). The compound was purified by column chromatography
(SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 7.30-7.25 (m, 3H), 7.13 (m, 2H),
6.92 (t, J = 7.6 Hz, 1H), 6.77-6.74 (m, 2H), 6.04 (br s, NH, 1H), 3.90 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl
3): δ 151.37, 146.08, 139.36,
132.98, 131.88, 123.17, 122.32, 120.40, 118.39, 113.17, 58.25, 31.31, 18.53. HRMS (APCI+, m/z) calculated for C15H18NO [M+H]+: 228.13883; found: 228.13829.
4-ethyl-2-methoxy-N-(4-methoxyphenyl)aniline (9cG)
8G affords 9cG (0.052 g, 81% yield). The compound was purified by column chromatography
(SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 7.11 (dd, J = 8.8 Hz, J = 2.4 Hz,
2H), 7.01 (d, J = 8.0 Hz, 1H), 6.87 (dd, J = 8.8 Hz, J = 2.4 Hz, 2H), 6.71 (d, J = 1.6 Hz, 1H), 6.69 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 5.86 (br s, NH, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 157.54, 150.35,
138.81, 137.87, 135.13, 124.55, 122.37, 117.24, 116.00, 112.90, 58.24, 58.21, 31.22, 18.60.
HRMS (APCI+, m/z) calculated for C16H20NO2 [M+H]+: 258.14939; found: 258.14886.
N1-(4-ethyl-2-methoxyphenyl)benzene-1,4-diamine (9dG)
8G affords 9dG (0.036 g, 59% yield). The compound was purified by column chromatography
(SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 7.00 (d, J = 8.4 Hz, 2H), 6.92
(d, J = 8.0 Hz, 1H), 6.71-6.64 (m, 4H), 5.78 (br s, NH, 1H), 3.89 (s, 3H), 3.49 (br s, NH, 2H), 2.59 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl
3): δ 150.04,
144.24, 137.25, 136.96, 135.89, 125.65, 122.37, 118.81, 115.43, 112.78, 58.20, 31.18, 18.61.
HRMS (APCI+, m/z) calculated for C15H20N2O [M+H]+: 243.14973; found: 243.14930.
CDCl3): δ 149.33, 144.53, 140.86, 138.97, 136.86, 135.99, 131.05, 129.17, 128.41, 122.45,
113.75, 112.51, 58.32, 31.07, 27.31, 21.01, 18.45, 17.52. HRMS (APCI+, m/z) calculated for C18H24NO [M+H]+: 270.18577; found: 270.18543.
1-ethyl-3-methoxybenzene (10G)
8G affords 10G (0.026 g, 94% yield). The compound was purified by column chromatography
(SiO2, Pentane/EtOAc 95:5). 1H NMR (400 MHz, CDCl3): δ 7.23 (t, J = 7.9 Hz, 1H), 6.83 (d,
J = 7.7 Hz, 1H), 6.80-6.73 (m, 2H), 3.83 (s, 3H), 2.66 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl
3): δ 159.65, 145.92, 129.26, 120.29, 113.67, 110.83, 55.10,
28.94, 15.53. HRMS (ESI+) calculated for C9H13O [M+H]+: 137.0966; found: 137.0958.
7-methoxy-1-oxaspiro[4.5]deca-6,9-dien-8-one (11G)
1G affords 11G (0.133 g, 78% yield). The compound was purified by column chromatography
(SiO2, Pentane/EtOAc 2:1). 1H NMR (400 MHz, CDCl3): δ 6.81 (dd, J = 9.6 Hz, 2.4 Hz, 1H),
6.14 (d, J = 9.6 Hz, 1H), 5.71 (d, J = 2.4 Hz, 1H), 4.13-4.03 (m, 2H), 3.67 (s, 3H), 2.21-2.15 (m, 2H), 2.12-2.06 (m, 2H). 13C NMR (100 MHz, CDCl
3): δ 179.79, 175.58, 150.80, 146.17,
128.07, 113.08, 81.00, 55.24, 33.12, 28.27. HRMS (ESI-) calculated for C10H12O3 [M-H]-:
181.08592; found: 181.08580.
3-(4-amino-3-methoxyphenyl)propan-1-ol (12a)
11G affords 12aG (0.017 g, 95% yield). The compound was purified by column
chromatography (SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 6.66-6.60 (m,
3H), 3.83 (s, 3H), 3.66 (t, J = 6.5 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 1.89-1.82 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 147.40, 133.89, 132.22, 120.58, 115.08, 110.79, 62.39, 55.44,
34.56, 31.75. HRMS (ESI-) calculated for C10H14NO2 [M-H]-: 180.1025; found: 180.1031.
4-ethyl-2-methoxyaniline (12bG)
3G affords 12bG (0.125 g, 83% yield). The compound was purified by column chromatography
(SiO2, Pentane/EtOAc 5:1). 1H NMR (400 MHz, CDCl3): δ 6.67-6.62 (m, 3H), 3.85 (s, 3H),
2.56 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl
137.58, 136.25, 122.57, 117.71, 113.00, 58.10, 31.12, 18.65. HRMS (ESI-) calculated for C9H13NO [M-H]-:152.10699; found: 152.10704.
N-(3-(4-amino-3-methoxyphenyl)propyl)methanesulfonamide (12cG)
13G affords 12cG (0.198 g, 77% yield). The compound was purified by column
chromatography (SiO2, Pentane/EtOAc 4:1). 1H NMR (400 MHz, CDCl3): δ 6.65-6.57 (m, 3H),
4.37 (br s, NH, 1H), 3.84 (s, 3H), 3.16-3.11 (m, 2H), 2.93 (s, 3H), 2.60 (t, J = 7.5 Hz, 2H), 1.86 (q, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl
3): δ 150.11, 136.86, 133.68, 123.22, 117.74,
113.41, 58.14, 45.34, 42.89, 35.01, 34.54. HRMS (ESI+) calculated for C11H19N2O3S [M+H]+:
259.1116; found: 259.1110.
N-(3-(4-hydroxy-3-methoxyphenyl)propyl)methanesulfonamide (13G)
1G affords 13G (0.060 g, 52% yield). The compound was purified by column chromatography
(SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 6.82 (d, J = 8.0 Hz, 1H),
6.69-6.64 (m, 2H), 5.56 (s, OH, 1H), 4.54 (s, NH, 1H), 3.87 (s, 3H), 3.15-3.09 (m, 2H), 2.93 (s, 3H), 2.62 (t, J = 7.5 Hz, 2H), 1.86 (q, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl
3): δ 149.18,
146.59, 135.33, 123.53, 117.01, 113.71, 58.59, 45.26, 42.84, 34.98, 34.54. HRMS (ESI -)
calculated for C11H16NO4S [M-H]-: 258.0800; found: 258.0807.
2-methoxy-4-(3-(phenylamino)propyl)phenol (5Ga)
The compound was synthesized according to the General procedure (A). Aniline (37.2 mg, 0.4 mmol) affords 5Ga (77 mg, 75% yield). Pale yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30).1H NMR (400 MHz, CDCl3): δ 7.19 (t, J = 7.2
Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.74-6.71 (m, 3H), 6.61 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 3.16 (t, J = 6.8 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 1.94 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 151.02, 149.06, 146.44, 136.22, 131.88, 123.59, 119.87, 116.90, 115.41, 113.59,
58.51, 46.01, 35.72, 33.95. HRMS (APCI+, m/z) calculated for C16H20NO2[M+H]+: 258.1489;
found: 258.1488.
4-(3-((4-chlorophenyl)amino)propyl)-2-methoxyphenol (5Gb)
The compound was synthesized according to the General procedure (A). 4-Chloroaniline (50.8 mg, 0.4 mmol) affords 5Gb (113 mg, 97% yield). Brown solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ 7.11 (d, J = 8.8
Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.71-6.69 (m, 2H), 6.49 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.11 (t, J = 6.8 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 1.91 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 149.55, 149.13, 146.50, 136.06, 131.67, 124.35, 123.57, 116.98, 116.48, 113.60,
58.52, 46.13, 35.68, 33.74. HRMS (APCI+, m/z) calculated for C16H19ClNO2 [M+H]+:
292.1099; found: 292.1099.
4-(3-((4-bromophenyl)amino)propyl)-2-methoxyphenol (5Gc)
The compound was synthesized according to the General procedure (A). 4-Bromoaniline (69 mg, 0.4 mmol) affords 5Gc (129 mg, 96% yield). Off-white solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ 7.25 (d, J = 8.4
Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.71-6.70 (m, 2H), 6.45 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.10 (t, J = 6.8 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 1.92 (p, J = 7.2 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 149.98, 149.15, 146.50, 136.09, 134.54, 123.59, 117.03, 113.64, 111.34, 104.99,
58.55, 46.04, 35.68, 33.71. HRMS (APCI+, m/z) calculated for C16H19BrNO2 [M+H]+:
336.0594; found: 336.0594.
2-methoxy-4-(3-((4-(trifluoromethyl)phenyl)amino)propyl)phenol (5Gd)
The compound was synthesized according to the General procedure (A). 4-(Trifluoromethyl)aniline (64 mg, 0.4 mmol) affords 5Gd (113 mg, 87% yield). Yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 80:20). 1H NMR (400 MHz,
CDCl3): δ 7.39 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H), 6.71-6.68 (m, 2H), 6.55 (d, J = 8.4
Hz, 2H), 5.51 (s, 1H), 3.85 (s, 3H), 3.17 (t, J = 6.8 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 1.94 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl
3): δ 153.36, 149.13, 146.54, 135.86, 129.21 (q, J C-F = 3.8 Hz), 127.67 (q, J C-F = 271.5 Hz), 123.55, 121.19 (q, J C-F = 32.7 Hz), 116.97, 114.37,
113.54, 58.49, 45.49, 35.61, 33.58. HRMS (APCI+, m/z) calculated for C17H19F3NO2 [M+H]+:
4-(3-((4-bromo-3-fluorophenyl)amino)propyl)-2-methoxyphenol (5Ge)
The compound was synthesized according to the General procedure (A). 4-Bromo-3-fluoroaniline (76 mg, 0.4 mmol) affords 5Ge (135 mg, 95% yield). Off-white solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ
7.23 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 2H), 6.32 (dd, J = 11.2 Hz, J = 2.4 Hz, 1H), 6.23 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 3.86 (s, 3H), 3.08 (t, J = 7.2 Hz, 2H), 2.66 (t, J = 7.2 Hz, 2H), 1.91 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl 3): δ 162.48 (d, JC-F = 244.6 Hz), 151.92 (d, JC-F = 10.1 Hz), 149.18, 146.53, 135.91, 123.57, 117.01, 113.60, 112.76 (d, JC-F = 2.5 Hz), 102.97 (d, JC-F = 26.1 Hz), 96.96 (d, JC-F = 21.5 Hz), 58.54, 45.95, 35.60,
33.49. HRMS (APCI+, m/z) calculated for C16H18BrFNO2 [M+H]+: 354.0499; found:
354.0500.
2-methoxy-4-(3-((4-methoxyphenyl)amino)propyl)phenol (5Gf)
The compound was synthesized according to the General procedure (A). 4-Methoxyaniline (49.2 mg, 0.4 mmol) affords 5Gf (93 mg, 81% yield). Pale brown solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ 6.84
(d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.70-6.69 (m, 2H), 6.57 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.75 (s, 3H), 3.10 (t, J = 6.8 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 1.91 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl
3): δ 154.79, 149.09, 146.44, 145.18, 136.27, 123.57, 117.56,
116.94, 116.91, 113.62, 58.50, 58.49, 47.16, 35.75, 34.02. HRMS (APCI+, m/z) calculated for C17H22NO3 [M+H]+: 288.1594; found: 288.1593.
2-methoxy-4-(3-((4-phenoxyphenyl)amino)propyl)phenol (5Gg)
The compound was synthesized according to the General procedure (A). 4-Phenoxyaniline (74 mg, 0.4 mmol) affords 5Gg (127 mg, 91% yield). Pale brown solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ 7.31 (t,
2-methoxy-4-(3-((4-(methylthio)phenyl)amino)propyl)phenol (5Gh)
The compound was synthesized according to the General procedure (A). 4-(Methylthio)aniline (56 mg, 0.4 mmol) affords 5Gh (101 mg, 83% yield). Light yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 80:20). 1H NMR (400 MHz,
CDCl3): δ 7.21 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 2H), 6.52 (d, J = 8.8
Hz, 2H), 3.85 (s, 3H), 3.12 (t, J = 6.8 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 2.40 (s, 3H), 1.91 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl
3): δ 149.79, 149.06, 146.46, 136.06, 134.24, 126.74,
123.56, 116.91, 116.04, 113.55, 58.51, 46.05, 35.67, 33.79, 21.91. HRMS (ESI+, m/z) calculated for C17H22NO2S [M+H]+: 304.13658; found: 304.13703.
2-methoxy-4-(3-(o-tolylamino)propyl)phenol (5Gi)
The compound was synthesized according to the General procedure (A). o-Toluidine (42.8 mg, 0.4 mmol) affords 5Gi (96 mg, 89% yield). White semi-solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ 7.18 (t, J = 8.0
Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.78-6.76 (m, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 3.25 (t, J = 7.2 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.16 (s, 3H), 2.04 (p, J = 7.2 Hz, 2H). 13C NMR (101 MHz, CDCl
3): δ 149.18, 148.91, 146.54,
136.28, 132.75, 129.83, 124.52, 123.65, 119.49, 117.04, 113.67, 112.39, 58.55, 46.10, 35.90, 33.92, 20.11. HRMS (APCI+, m/z) calculated for C17H22NO2 [M+H]+: 272.16451; found:
272.16459.
2-methoxy-4-(3-((4-nitrophenyl)amino)propyl)phenol (5Gj)
The compound was synthesized according to the General procedure (A). 4-Nitroaniline (55.2 mg, 0.4 mmol) affords 5Gj (112 mg, 93% yield). Yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 9.2
Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.69-6.67 (m, 2H), 6.47 (d, J = 9.2 Hz, 2H), 5.52 (br s, 1H), 3.85 (s, 3H), 3.22 (t, J = 6.8 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 1.96 (p, J = 7.2 Hz, 2H). 13C
NMR (101 MHz, CDCl3): δ 155.95, 149.20, 146.65, 140.51, 135.47, 129.07, 123.53, 117.04,
113.65, 113.51, 58.53, 45.44, 35.53, 33.33. HRMS (APCI+, m/z) calculated for C16H19N2O4
4-((3-(4-hydroxy-3-methoxyphenyl)propyl)amino)benzonitrile (5Gk)
The compound was synthesized according to the General procedure (A). 4-Aminobenzonitrile (47.2 mg, 0.4 mmol) affords 5Gk (99 mg, 88% yield). Pale yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, CDCl3): δ 7.38
(d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.68-6.67 (m, 2H), 6.49 (d, J = 8.8 Hz, 2H), 5.57 (br s, 1H), 4.24 (br s, 1H), 3.84 (s, 3H), 3.16 (t, J = 7.2 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 1.93 (p, J = 7.2 Hz, 2H). 13C NMR (101 MHz, CDCl
3): δ 154.03, 149.18, 146.59, 136.32, 135.67,
123.53, 123.23, 117.02, 114.75, 113.57, 100.95, 58.53, 45.20, 35.55, 33.39. HRMS (APCI+, m/z) calculated for C17H19N2O2 [M+H]+: 283.14410; found: 283.14410.
Methyl 4-((3-(4-hydroxy-3-methoxyphenyl)propyl)amino)benzoate (5Gl)
The compound was synthesized according to the General procedure (A). Methyl 4-aminobenzoate (60.5 mg, 0.4 mmol) affords 5Gl (76 mg, 60% yield). Light yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz,
CDCl3): δ 7.85 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.69-6.62 (m, 2H), 6.51 (d, J = 8.8
Hz, J = 2.0 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.18 (t, J = 6.8 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 1.93 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl
3): δ 169.99, 154.54, 149.15, 146.55,
135.80, 134.19, 123.54, 120.89, 116.99, 116.46, 114.14, 113.57, 58.51, 54.19, 45.44, 35.58, 33.56. HRMS (APCI+, m/z) calculated for C18H22NO4 [M+H]+: 316.15488; found: 316.15492.
1-(4-((3-(4-hydroxy-3-methoxyphenyl)propyl)amino)phenyl)ethan-1-one (5Gm)
The compound was synthesized according to the General procedure (A). 1-(4-Aminophenyl)ethan-1-one (54 mg, 0.4 mmol) affords 5Gm (98 mg, 82% yield). White solid was obtained after column chromatography (SiO2, Pentane/EtOAc 80:20). 1H NMR (400 MHz,
CDCl3): δ 7.81 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.70-6.63 (m, 2H), 6.51 (d, J = 8.8
Hz, 2H), 5.56 (s, 1H), 4.20 (s, 1H), 3.84 (s, 3H), 3.22-3.18 (m, 2H), 2.67 (t, J = 7.2 Hz, 2H),
2-methoxy-4-(3-((4-vinylphenyl)amino)propyl)phenol (5Gn)
The compound was synthesized according to the General procedure (A). 4-Vinylaniline (48 mg, 0.4 mmol) affords 5Gn (49 mg, 43% yield). Light yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 80:20). 1H NMR (400 MHz, CDCl3): δ 7.26 (d, J = 8.0
Hz, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.72-6.70 (m, 2H), 6.63 (dd, J = 17.6 Hz, J = 11.2 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 5.54 (d, J = 17.6 Hz, 1H), 5.03 (d, J = 10.8 Hz, 1H), 3.86 (s, 3H), 3.16 (t, J = 7.2 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.93 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 150.79, 149.11, 146.47, 139.32, 136.16, 130.01, 129.70, 123.59, 116.95, 115.27,
113.61, 111.93, 58.52, 45.95, 35.70, 33.88. HRMS (APCI+, m/z) calculated for C18H22NO2
[M+H]+: 284.16451; found: 284.18041.
4-(3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)propyl)-2-methoxyphenol (5Go)
The compound was synthesized according to the General procedure (A). 2,3-dihydrobenzo[b][1,4]dioxin-6-amine 5Go (60.5 mg, 0.4 mmol) affords (76 mg, 61% yield). Light yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H
NMR (400 MHz, CDCl3): δ 6.85-6.83 (m, 1H), 6.71-6.68 (m, 3H), 6.17-6.12 (m, 2H),
4.24-4.22 (m, 2H), 4.19-4.17 (m, 2H), 3.85 (s, 3H), 3.07 (t, J = 6.8 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 1.89 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl
3): δ 149.11, 146.68, 146.44, 146.09,
138.21, 136.27, 123.58, 120.26, 116.96, 113.63, 109.52, 104.20, 67.43, 66.86, 58.51, 46.90, 35.74, 33.97. HRMS (APCI+, m/z) calculated for C
18H22NO4 [M+H]+: 316.15488; found:
316.15484.
4,4'-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)azanediyl)bis(propane-3,1-diyl))bis(2-methoxyphenol) (5GoS1)
The compound was synthesized according to the General procedure (A). 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (60.5 mg, 0.4 mmol) affords 5GoS1 (46 mg, 24% yield). Light yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H
NMR (400 MHz, CDCl3): δ 6.85-6.82 (m, 2H), 6.73 (d, J = 8.8 Hz, 1H), 6.67-6.66 (m, 4H),
6.22-6.16 (m, 2H), 5.53 (br s, 2H), 4.25-4.23 (m, 2H), 4.20-4.18 (m, 2H), 3.85 (s, 6H), 3.18 (t, J = 7.6 Hz, 4H), 2.56 (t, J = 7.6 Hz, 4H), 1.84 (p, J = 7.6 Hz, 4H). 13C NMR (101 MHz, CDCl ):
δ 149.06, 146.56, 146.44, 146.35, 137.51, 136.38, 123.53, 120.09, 116.87, 113.51, 109.63, 104.86, 67.45, 66.92, 58.51, 53.77, 35.63, 31.56. HRMS (APCI+, m/z) calculated for C28H34NO6 [M+H]+: 480.23861; found: 480.23861.
4-(3-((4-hydroxyphenyl)amino)propyl)-2-methoxyphenol (5Gp)
The compound was synthesized according to the General procedure (A). 4-Aminophenol (43.6 mg, 0.4 mmol) affords 5Gp (88 mg, 81% yield). Pale brown solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, DMSO-d6): δ 8.62
(br s, 1H), 8.34 (br s, 1H), 6.74-6.73 (m, 1H), 6.67-6.65 (m, 1H), 6.58-6.51 (m, 3H), 6.42-6.38 (m, 2H), 4.78 (br s, 1H), 3.71 (s, 3H), 2.88 (t, J = 6.8 Hz, 2H), 2.54 (t, J = 7.6 Hz, 2H), 1.76 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, DMSO-d
6): δ 151.22, 150.47, 147.51, 145.13, 135.90,
123.44, 118.76, 118.38, 116.40, 115.59, 58.61, 46.61, 35.50, 34.09. HRMS (APCI+, m/z) calculated for C16H20NO3 [M+H]+: 274.14377; found: 274.14376.
2-methoxy-4-(3-(pyren-1-ylamino)propyl)phenol (5Gq)
The compound was synthesized according to the General procedure (A). Pyrene-1-amine (87 mg, 0.4 mmol) affords 5Gq (123 mg, 81% yield). Yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10). 1H NMR (600 MHz, CDCl3): δ 8.02-8.01 (m,
3H), 7.96 (d, J = 9.0 Hz, 1H), 7.91-7.83 (m, 3H), 7.76 (d, J = 8.4 Hz, 1H), 7.33 (br s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 1.8 Hz, 1H), 5.48 (br s, 1H), 3.77 (s, 3H), 3.50 (t, J = 6.6 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.18 (p, J = 7.2 Hz, 2H). 13C NMR (151 MHz, CDCl3): δ 146.53, 143.98, 133.33, 132.34, 131.62, 127.67, 126.26, 125.94, 125.61,
123.89, 123.30, 120.99, 119.31, 114.38, 110.98, 55.83, 44.15, 33.32, 30.93. HRMS (APCI+, m/z) calculated for C26H24NO2 [M+H]+: 382.18016; found: 382.18056.
4-(3-((2-(1H-pyrrol-1-yl)phenyl)amino)propyl)-2-methoxyphenol (5Gr)
The compound was synthesized according to the General procedure (A).
CDCl3): δ 149.10, 146.54, 146.48, 135.93, 131.60, 129.86, 129.76, 124.58, 123.60, 118.92,
116.99, 113.76, 113.58, 112.09, 58.54, 45.27, 35.41, 33.58. HRMS (ESI+, m/z) calculated for C20H23N2O2[M+H]+: 323.17540; found: 323.17588.
4-(3-(benzo[d]thiazol-2-ylamino)propyl)-2-methoxyphenol (5Gs)
The compound was synthesized according to the General procedure (A). Benzo[d]thiazol-2-amine (60 mg, 0.4 mmol) affords 5Gs (69 mg, 55% yield). White solid was obtained after column chromatography (SiO2, Pentane/EtOAc 70:30). 1H NMR (400 MHz, DMSO-d6): δ 8.64
(s, 1H), 8.01 (t, J = 5.2 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.18 (td, J = 7.2 Hz, J = 1.2 Hz, 1H), 6.98 (td, J = 6.8 Hz, J = 1.2 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.58 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 3.71 (s, 3H), 3.35-3.29 (m, 2H), 2.55 (t, J = 7.2 Hz, 2H), 1.83 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6): δ 192.81, 169.20, 155.78, 150.49, 147.61, 135.40, 133.30, 128.59, 123.96, 123.47, 121.00, 118.41, 115.64, 58.62, 46.57, 35.13, 33.82. HRMS (ESI+, m/z) calculated for C
17H19N2O2S [M+H]+: 315.11616;
found: 315.11688.
4-(3-(ethyl(phenyl)amino)propyl)-2-methoxyphenol (5Gt)
The compound was synthesized according to the General procedure (A). N-ethylaniline (48 mg, 0.4 mmol) affords 5Gt (97 mg, 85% yield). Light yellow oil was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10). 1H NMR (400 MHz, CDCl3): δ 7.21 (d, J = 7.6
Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.73-6.71 (m, 2H), 6.67-6.64(m, 3H), 5.50 (s, 1H), 3.88 (s, 3H), 3.37 (q, J = 7.2 Hz, 2H), 3.29 (t, J = 7.6 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.92 (p, J = 7.2 Hz, 2H), 1.15 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl
3): δ 150.61, 149.05, 146.38,
136.38, 131.88, 123.57, 118.12, 116.87, 114.63, 113.52, 58.54, 52.41, 47.60, 35.68, 31.82, 14.97. HRMS (ESI+, m/z) calculated for C18H24NO2 [M+H]+: 286.18016; found: 286.18062.
4-(3-(dimethylamino)propyl)-2-methoxyphenol (5Gu)
The compound was synthesized according to the General procedure (A). 4-(3-Hydroxypropyl)-2-methoxyphenol (91 mg, 0.5 mmol) affords 5Gu (55 mg, 53% yield). White semi-solid was obtained after column chromatography (SiO2, MeOH/EtOAc 50:50 to 100:0).
1H NMR (400 MHz, CD
3OD): δ 7.76 (d, J = 1.6 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.61 (dd, J
= 8.0 Hz, J = 2.0 Hz, 1H), 3.82 (s, 3H), 2.53 (t, J = 7.6 Hz, 2H), 2.35-2.31 (m, 2H), 2.23 (s, 6H), 1.77 (p, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CD
