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HomeChemistryTransition-metal-free synthesis of pyrimidines from lignin β-O-4 segments by way of a...

Transition-metal-free synthesis of pyrimidines from lignin β-O-4 segments by way of a one-pot multi-component response

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Improvement of the response

Lignin β-O-4 linkages characterize a predominant portion of all linkages between the first models. Profitable breaking β-O-4 models in mannequin compounds ought to supply steerage for the depolymerization of reasonable lignin. Thus, a typical lignin β-O-4 mannequin compound 1a, accompanied by benzamidine hydrochloride (2a) and benzyl alcohol (3a) has been initially employed to synthesize 2,4,6-triphenylpyrimidine 4a (Fig. 2, entry 1, and Supplementary Desk 1). We discovered that the presence of a base performed an important function on this response. Within the absence of base, the response didn’t happen (Supplementary Desk 1, entry 1). Whereas NaOH was discovered to be probably the most environment friendly base in stark distinction to KOH, sodium tert-butoxide (t-BuOK), Cs2CO3, and CH3CH2ONa (Supplementary Desk 1, entries 2–6). After screening the response parameters together with solvents, base loading, response temperature, and time (Supplementary Tables 13 and Supplementary Fig. 3), the optimized situation was recognized, resulting in 95% gasoline chromatograph (GC) yield (93% remoted yield) of 4a primarily based on the quantity of 2a, together with 99% GC yield (95% remoted yield) of guaiacol 5a (Fig. 2, entry 1). On this case, 40.4 wt% of 1a is integrated in 4a formation (for an in depth calculation course of, see Supplementary Fig. 2). After the response, the solvent tert-amyl alcohol could be simply distilled from the response combination for recycling as a result of the boiling level of tert-amyl alcohol (101.8 °C) is far decrease than that of all of the reactants (e.g., 1a: 398 °C; 2a: 208 °C; 3a: 205 °C) and the merchandise (4a: 330 °C; 5a: 205 °C). Furthermore, the response could be proceeded at a better substrate focus (Supplementary Desk 1, entry 16) however the yields of the focused merchandise decreased on account of severer aspect reactions. Therefore, our technique not solely offers entry to a pyrimidine product in excessive remoted yield, but additionally achieves co-production of remoted guaiacol in glorious yield, which markedly will increase the atom economics.

Fig. 2: Conversion of various lignin β-O-4 mannequin compounds to pyrimidines.
figure 2

Situations: 1 (0.4 mmol), 2a (0.2 mmol), 3a (0.4 mmol), NaOH (1.6 mmol), and tert-amyl alcohol (abbreviation: t-AmOH, 4.0 mL) have been blended within the air at 110 °C, response time (t) = 20 h; until in any other case specified, the yields of 4 and 5 have been calculated primarily based on the quantity of 2a and 1, respectively. aRemoted molar yield; bGC molar yield was decided by GC-FID utilizing mesitylene as an inner customary.

To look at the generality of this protocol, the exercise of assorted lignin β-O-4 mannequin substrates was explored. Substrates with completely different useful teams on the aryl ring (Fig. 2) are discovered as fragments in several lignins1. Beneath optimized situation, all β-O-4 mannequin compounds have been fully consumed to afford the corresponding pyrimidines and monophenols. 2a and 3a reacting with β-O-4 mannequin compounds 1a–1f bearing methoxy teams on each aryl rings afforded reasonable to glorious remoted yields of pyrimidine merchandise 4a (74–93%) or 4b (64–90%) together with phenol derivatives 5a5c (68–99%) (Fig. 2, entries 1–6), indicating that the formation of pyrimidine heterocycles occurred related to selective C-O bond cleavage and C-C/C-N bonds building in a one-pot vogue. One methoxyl group on the O-terminal aryl ring exhibited a constructive affect on the response effectivity (90–93%) (Fig. 2, entries 1 and 4) in comparison with that bearing no useful group (64–75%) (Fig. 2, entries 2 and 5) and a couple of,5-dimethoxy substituents (74%) (Fig. 2, entries 3 and 6), whereas methoxyl substitution on the C-terminus aryl ring had little impression on the product yield. Particularly, the extremely substituted β-O-4 mannequin compound 1g containing γ-OH performance was additionally tolerated, easily offering the goal product 4c in 38% yield (Fig. 2, entry 7) regardless of it has a extra sophisticated construction and incorporates increased steric hindrance in comparison with 1a1f. Primarily based on the above-described outcomes, it may be concluded that this protocol results in the profitable cleavage of assorted β-O-4 mannequin compounds and to the synthesis of pyrimidines with good to glorious yields in a one-pot vogue, which thus offers a possibility for the utilization of lignin to provide value-added N-heterocyclic compounds.

This response system has confirmed to be efficient not just for a wide range of amidine hydrochlorides, but additionally for a broad vary of main alcohols. As proven in Fig. 3, eight amidine hydrochlorides 2 have been efficiently employed within the transformation, and the yields of corresponding pyrimidine merchandise (4d4h, 80–94%) from aryl amidine hydrochlorides (Fig. 3, entries 1–5) have been comparatively increased than that from aliphatic amidine hydrochloride (Fig. 3, entry 7, 4j yield 64%). The low yield of pyrimidine 4j might be on account of a unfavourable digital impact of the ethylamine spine. Notably, guanidine hydrochloride additionally exhibited a excessive reactivity below customary circumstances, giving 4i in 83% yield (Fig. 3, entry 6). As well as, entries 1–5 in Fig. 3 present that the substituents on the aryl rings of aryl amidine hydrochlorides don’t clearly have an effect on the response effectivity, whatever the presence of electron-donating substituents (-CH3, -OCH3) or electron-withdrawing substituents (-Cl, -F). A broad vary of main alcohols 3 has additionally been examined (entries 8–12 in Fig. 3). All of the reactions proceeded pretty properly and yielded 71–92% of pyrimidines 4k4o. Notably, two heteroaryl main alcohols underwent the identical reactions to generate excessive yields of 4n (80%) and 4o (71%), respectively (entries 11–12). Due to this fact, the above outcomes counsel that such an unique protocol for bio-pyrimidines synthesis from lignin β-O-4 phase exhibits nice versatility for all three response elements. Numerous lignin mannequin compounds, amidine hydrochlorides, and first alcohols containing completely different useful teams are efficient within the transformation, representing an fascinating breakthrough for the functionalization of lignin merchandise.

Fig. 3: Scope of amidine hydrochlorides and first alcohols.
figure 3

Situations: 1a (0.4 mmol), 2 (0.2 mmol), 3 (0.4 mmol), NaOH (1.6 mmol), tert-amyl alcohol (abbreviation: t-AmOH, 4.0 mL) have been blended within the air at 110 °C, t = 20 h; the yields of 4 and 5a have been calculated primarily based on the quantity of 2 and 1a, respectively. aRemoted molar yield; bGC molar yield was decided by GC-FID utilizing mesitylene as an inner customary.

To additional decide the compatibility of the response system, a β-O-4 polymer mimicking pure lignin was ready and was used as a substrate for the synthesis of pyrimidine spinoff. Although the one-pot, direct conversion of the β-O-4 polymer to pyrimidine was not achieved by purpose that the reactive OH group on the para-position of β-O-4 polymer simply reacted with NaOH to provide the sodium phenolate salt below the bottom surroundings, an alternate three-step course of composed of our key response was developed, which achieved 66% total yield of pyrimidine spinoff 4p primarily based on β-O-4 polymer (Supplementary Fig. 1). First, binuclear rhodium complex-catalyzed delicate depolymerization of β-O-4 polymer led to 4-hydroxyacetophenone (compound I) in 75% remoted yield, then 4-hydroxyacetophenone reacted with benzyl bromide within the presence of Ok2CO3 to afford 1-(4-(benzyloxy)phenyl)ethan-1-one (compound II) in 95% remoted yield, which subsequently reacted with benzamidine hydrochloride and benzyl alcohol, efficiently offering pyrimidine spinoff 4p in 92% remoted yield (66 wt% yield primarily based on polymer).

Mechanistic research

To realize perception into the response mechanism, a number of management experiments have been carried out to determine attainable response intermediates. First, remedy of 1a alone below in any other case similar circumstances yielded 71% of acetophenone 6 and 82% of guaiacol 5a inside 1 h (response 1 in Fig. 4a), indicating that base-catalyzed C-O cleavage of 1a is likely to be the preliminary response step35. This assumption was confirmed by the three-component response utilizing compounds 6, 2a, and 3a as substrates (response 2 in Fig. 4a), which afforded the same yield of 4a (99%) to that in Fig. 2, entry 1. Therefore, in the entire response course of, NaOH facilitates the cleavage of β-O-4 mannequin compounds to launch 6 as an essential intermediate for subsequent reactions. Furthermore, when benzyl alcohol 3a (Fig. 2, entry 1) was changed by benzaldehyde 7 as a substrate, the respective response (response 3 in Fig. 4a) additionally afforded 4a in 82% yield, suggesting that dehydrogenation of 3a into the corresponding aldehyde 7 is one other prerequisite step below base situation for the transformation36. A further experiment utilizing 6, 2a, and 7 because the substrates (response 4 in Fig. 4a) offers a direct proof by exhibiting that the specified product 4a is obtained in a excessive yield of 99%. It’s well-known {that a} cross-aldol condensation readily happens between aldehyde and ketone below primary circumstances37. We subsequently assumed that aldol condensation between 6 and 7 would happen to generate chalcone (compound 8 in Fig. 4a) as an intermediate, which might additional react with 2a to kind the goal product 2,4,6-triphenylpyrimidine 4a. This assumption was supported by one other response utilizing 8 and 2a because the substrates, which afforded 4a in 59% yield (response 5 in Fig. 4a). On the idea of the above outcomes, a tentative multi-step consecutive pathway could be proposed: the transformation begins with cleavage of the C-O bond within the lignin β-O-4 mannequin compound 1a to launch 6, accompanied by the dehydrogenation of 3a to 7. Then 6 and 7 endure a cross-aldol condensation response to yield intermediate 8, which subsequently reacts with 2a to kind the six-membered ring intermediate 9 by way of cyclization response. Lastly, 9 undergoes an intramolecular dehydrogenative aromatization to furnish 4a (Fig. 4b). It’s value noting that NaOH performs an essential function in every step, viz. selective C-O bond cleavage, cross-aldol condensation, dehydrogenation, and dehydrogenative aromatization, of the entire transformation, and no different catalyst is required, as additional supported by the DFT calculation described beneath.

Fig. 4: Mechanistic research of pyrimidine formation from lignin β-O-4 mannequin compound.
figure 4

a Management experiments and b the proposed pathway.

To acquire perception into the function of NaOH and additional disclose the underlying mechanism, DFT calculations have been carried out. Contemplating that polar solvent tert-amyl alcohol (t-AmOH) was used and sodium ions exist within the response answer, a response mediated by sodium hydroxide as a substitute of Zundel anion38 or hydroxide ion39 was proposed throughout DFT calculations (Fig. 5). In actual fact, sodium hydroxide can both deprotonate the Cα-H bond alongside path A or the O-H bond of CαH-OH moiety alongside path B to kind the corresponding intermediates A2 and B2, respectively, ranging from β-O-4 mannequin compound 1a (Fig. 5a). For Cα-H bond cleavage, A2 produces 5a and A4 by way of a proton switch step; within the different attainable pathway adopting O-H bond cleavage, B2 proceeds a cascade response of epoxidation, ring cleavage, and dehydration to kind A4 (B2B35a+B5B7A4), which additional tautomerizes into acetophenone 6 catalyzed by base. These calculation outcomes point out that the Cα-H bond and Cβ-O bond could be damaged concurrently by way of the transition state (TS) TSA1-2 activated by sodium hydroxide (Fig. 5b, path A). The free power barrier for this C-H/C-O activation step is calculated to be 25.2 kcal/mol. The sodium ion might polarize the β-O atom to result in a Cβ-O bond cleavage (paths E and F in Supplementary Fig. 22), additional illustrating {that a} sodium ion performs an important function on this response. Then the proton of the enol moiety of A2 is transferred to the phenol moiety by way of proton switch, with a free power barrier of three.7 kcal/mol. A3 releases phenol to provide A4. The proton from the water moiety of A4 is transferred to the enol ion once more by way of TSA4-5 to finish the keto-enol tautomerism with a free power barrier of 10.2 kcal/mol. Apparently, intermediate 6 could be simply generated alongside path A, and the C-H activation step is the rate-determining step within the course of from β-O-4 mannequin compound 1a to 6. In comparison with path A, the calculated power barrier of the epoxidation step from B2 to B3 in path B is 29.3 kcal/mol (Fig. 5c, path B), and that for the C-H activation step from B5 to enol A4 is 34.3 kcal/mol. Thus, path A is far more favorable for the Cβ-O bond cleavage of 1a (A1A25a+A4) than path B (B1B2B35a+B5B7A4).

Fig. 5: Computational evaluation of the C-O bond cleavage of compound 1a.
figure 5

a Proposed two pathways. b Computational evaluation of path A (unit: kcal/mol). c Computational evaluation of path B (unit: kcal/mol).

The success of this one-pot, multi-step response in the direction of pyrimidines synthesis is ruled by two dehydrogenation steps (Figs. 6 and 7): benzyl alcohol 3a dehydrogenation to benzaldehyde 7 and dehydrogenative aromatization of 9 to 4a.

Fig. 6: The Gibbs free power profiles for the dehydrogenation of benzyl alcohol 3a.
figure 6

Utilizing O2 within the air as hydrogen acceptor (path C), acetophenone 6 as hydrogen acceptor (path C-AP), and by way of hydrogen-acceptor-free pathway (path C-B) (unit: kcal/mol).

Fig. 7: The Gibbs free power profiles for the dehydrogenation of intermediate 9.
figure 7

Utilizing O2 within the air as a hydrogen acceptor (path D), acetophenone 6 as a hydrogen acceptor (path D-AP), and by way of hydrogen-acceptor-free pathway (path D-B) (unit: kcal/mol).

As a result of the above dehydrogenations are base promoted40, it was unclear whether or not this course of employs a hydrogen acceptor or not. Due to this fact, a management experiment below argon environment was performed, which resulted in a a lot decrease 4a yield (68%, response 6 in Fig. 4a) in comparison with that within the air (99%, response 2 in Fig. 4a), illustrating that oxygen in air acted as a hydrogen acceptor within the response. It additionally ought to be famous that 1-phenylethanol was detected, indicating that intermediate 6 (acetophenone) acted as one other hydrogen acceptor. With the intention to confirm this hypothesis and higher perceive the dehydrogenation mechanism, additional DFT calculation was carried out. The outcomes, summarized in Fig. 6, present that benzyl alcohol 3a reacts with sodium hydroxide by way of TSC1-2 to generate C2 with an power barrier of 0.2 kcal/mol. In path C utilizing O2 because the hydrogen acceptor, C2 interacts with O2 to attain C3, adopted by the dehydrogenation of C3. The power barrier for the dehydrogenation step by way of TSC3-4 is 10.8 kcal/mol. And in path C-AP utilizing acetophenone 6 as a hydrogen acceptor, the power barrier of the dehydrogenation by way of TSC3-4-AP is 17.5 kcal/mol. That is in line with the experimental commentary in response 2 Fig. 4a. As well as, the acceptor-free dehydrogenation pathway was additionally calculated below the identical situation, giving two prospects. As proven in Fig. 6 and Supplementary Fig. 23, for acceptor-free dehydrogenation, the power barrier by way of TSC2-3-B1 could be 34.4 kcal/mol, which is increased than in path C. Furthermore, the experiment outcomes additional counsel that no hydrogen was detected throughout the response. Combining the DFT calculation and experimental outcomes, it may be concluded that acceptor-free dehydrogenation didn’t happen for the dehydrogenation of benzyl alcohol.

Equally, the dehydrogenation of intermediate 9 utilizing each O2 within the air (path D) and 6 (path D-AP) as hydrogen acceptors was additionally studied. For comparability, an acceptor-free dehydrogenation pathway (path D-B) was additionally investigated by DFT calculation. As proven in Fig. 7, 9 first reacts with sodium hydroxide by way of TSD1-2 to generate D2. Then D2 follows path D-B to generate pyrimidine 4a within the absence of a hydrogen acceptor with an power barrier of 30.1 kcal/mol. Alternatively, D2 goes via D3 and D4 to kind 4a within the presence of air with a a lot decrease power barrier of three.2 kcal/mol, which is decrease than that of path D-AP from D3-AP and D4-AP (13.0 kcal/mol), and H2 will not be detected throughout the response. Apparently, the pathway from 9 to 4a can also be not an acceptor-free dehydrogenation response. The DFT outcomes summarized in Figs. 6 and 7 illustrate that O2 within the air acts as a hydrogen acceptor for the dehydrogenation of benzyl alcohol 3a to 7 and 9 to 4a. As well as, the by-product NaOOH in path C and path D might oxidize 3a or 9 to launch two NaOH molecules (Supplementary Fig. 24).

Software in synthesis of meridianin derivatives

The potential utility of this protocol is additional highlighted by the preparation of pharmaceutical intermediates, specifically meridianin derivatives. Meridianin derivatives are an essential class of pure marine alkaloids that show distinctive bioactivities, resembling excessive antitumor exercise, and subsequently are extensively used within the pharmaceutical trade41,42. Sometimes, meridianin derivatives are synthesized both by a multi-step condensation of substituted indoles with guanidines42,43,44, or by a Suzuki coupling response between indolyl boronates and halopyrimidines over palladium catalysts45. Primarily based on the above-described route for bio-based pyrimidines, right here we established an fascinating protocol that permits meridianin spinoff manufacturing, ranging from a lignin β-O-4 mannequin compound via a two-step course of (Fig. 8). First, intermediate 10 was produced in 69% yield upon isolation by remedy of β-O-4 mannequin compound 1d, guanidine hydrochloride 2g with (1-benzyl-1H-indol-3-yl) methanol 3g. Subsequently, debenzylation of 10 with t-BuOK/DMSO below an oxygen environment efficiently afforded the meridianin analog 11 in 70% yield (21.5 wt% primarily based on lignin mannequin compound 1d, Supplementary Fig. 2). Such a easy methodology doesn’t require any transition-metal catalyst, thus offering an economical various to synthesize value-added meridianin derivatives.

Fig. 8: Synthesis of a meridianin spinoff from lignin β-O-4 mannequin compound.
figure 8

The 1st step:synthesis of compound 10 from a combination 1d, 2g and 3g by this protocol; step two: debenzylation of 10 within the presence of t-BuOK/DMSO below an oxygen environment to afford meridianin spinoff 11.

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