Bicyclic Piperazine Mimetics of the Peptide β-Turn ... - ACS Publications

Apr 27, 2018 - The latter are not only well-established mimetics of peptide β-turn but also ... Selenium Dioxide As an Alternative Reagent for the Di...
0 downloads 0 Views 2MB Size
Download PDF
Note Cite This: J. Org. Chem. 2018, 83, 5859−5868

pubs.acs.org/joc

Bicyclic Piperazine Mimetics of the Peptide β‑Turn Assembled via the Castagnoli−Cushman Reaction Liliia Usmanova,† Dmitry Dar’in,† Mikhail S. Novikov,† Maxim Gureev,‡ and Mikhail Krasavin*,† †

Saint Petersburg State University, Saint Petersburg 199034, Russian Federation Saint Petersburg State Institute of Technology (Technical University), Saint Petersburg 190013, Russian Federation

‡

S Supporting Information *

ABSTRACT: 5-Oxopiperazine-2-carboxamides and respective carboxylic acids (obtained by the Castagnoli−Cushman reaction of protected iminodiacetic anhydride) were converted into cis- and trans-configured bicyclic piperazines containing two stereogenic centers. The latter are not only well-established mimetics of peptide β-turn but also attractive, high-Fsp3 cores for drug design in general. The methodology was applied to the preparation of ring-expanded version of bicyclic piperazines not described in the literature.

eptide β-turn is one of the most important elements of protein secondary structure.1 It has a special significance not only in maintaining native conformation of the protein molecule but also as a principal recognition element for binding between a protein biological target and its ligands (small molecules, bioactive peptides, or proteins).2 Peptide β-turns structure (characterized by a hydrogen-bound ten-membered cyclic motif 1) can, in principle, be reproduced by a cyclic synthetic peptide.3 However, the use of peptides as therapeutic agents is limited by their poor absorption and hydrolytic stability.4 A lot more promising approach involves the mimicry of the peptide β-turn by a cyclic nonpeptide small molecule scaffold.5 In this context, bicyclic scaffold 2 (IUPAC name tetrahydro-1H-pyrazino[1,2-a]pyrazine-1,4,7-trione) gained prominence6 as a workable, conformationally constrained and hydrolytically stable replacement for the ten-membered cyclic motif featured in the β-turn. Although the synthetic routes reported for the construction of the bicyclic core 2 typically involve linear multistep sequences,6a−c the advantages of harnessing the power of multicomponent chemistry in their synthesis (in particular, the Ugi reaction6d) have also been showcased. Recently, it came to our attention that a specific substitution pattern around bicyclic core 2 (namely, 2,8,9-trisubstituted tetrahydro-1H-pyrazino[1,2-a]pyrazine-1,4,7-trione 3) has not been described in the literature while it certainly can be exploited as a novel chemotype for peptidomimetic drug design. Moreover, highly saturated (so-called high-Fsp3) template 3 containing two stereogenic centers is attractive from the standpoint of drug design in any biological target area as high degree of heterocycle saturation and stereochemical definition are associated7 with better physicochemical profile of such compounds, better solubility and, in general, better “developability” of such

P

© 2018 American Chemical Society

compounds as pharmaceuticals.8 Hence, we set off to develop a practical synthetic route to 3. Simple retrosynthetic disconnection of 3 (bearing a cycleforming acylation/alkylation with chloroacetyl chloride in mind) led us to 5-oxopiperazine-2-carboxamide 4. The latter was seen as obtainable by amidation/N-deprotection of carboxylic acid 5 which represents a product of the Castagnoli−Cushman reaction (CCR) between an imine and N-protected iminodiacetic anhydride 6. Recently, we reported such a dicarboxylic anhydride (as well as its O- and S-including congeners) as valid partners for the CCR,9 which essentially enabled potential realization of the above approach to construction of bicycles 3 (Figure 1). Herein, we report our findings in this regard. Similarly to our previously published work,9 we selected iminodiacetic anhydride 6a protected at the nitrogen atom with o-nitrophenylsulfonyl (ONPS or o-Ns) group. The CCR generally requires heating in high-boiling nonpolar aromatic hydrocarbon solvents. After testing toluene, xylenes, and chlorobenzene (typical solvents for this reaction10) at reflux or near-reflux temperatures, we found heating to 120 °C in chlorobenzene to provide the best results in terms of the yield of carboxylic acids 5a−l. In accordance with the well-established greater thermodynamic stability of the trans-configured CCR adducts like 5,10−12 compounds 5a−l were obtained in good to excellent yields solely as trans-isomers. This was unequivocally established by the singlecrystal X-ray analysis of a representative compound (5g, see Supporting Information). Conversion of 5-oxopiperazine-2carboxylic acids 5 into bis-nucleophilic substrates 4 suitable for establishment of the second piperazine-2,5-dione cycle required Received: March 30, 2018 Published: April 27, 2018 5859

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868

Note

The Journal of Organic Chemistry

amine. The ONPS protecting group was removed on treatment with potassium thiophenolate generated in acetonitrile to give compounds 4a−m in good yields over two steps (Scheme 1, Table 1). The stereochemical configuration of amides 4a−m did not alter, compared to carboxylic acids 5a−l, as confirmed by the single-crystal X-ray analysis of a representative compound (4c, see Supporting Information). Having synthesized 5-oxopiperazine-2-carboxamides 4, we proceeded to complete the envisioned route to bicyclic peptidomimetic compounds 3. N-Acylation of 4 with chloroacetyl chloride (presumably, toward 7) was achieved smoothly at 0 °C in acetonitrile in the presence of DIPEA as HCl scavenger. The SN2′ cyclization of anilide-type intermediates 7 was achieved with Cs2CO3 as a base; N-alkyl amides 7 required the use of sodium hydride (Scheme 2). The reaction turned out to be distinctly sensitive to the steric bulk around the secondary amide moiety: N-cyclopropyl group in 2h retarded the cyclization of 7h, and only 18% yield of 3h was isolated. At the same time, 7f (obtained by N-chloroacetylation of 2f) completely failed to cyclize, thereby demonstrating that even an isopropyl group was bulky enough to shut off the formation of the bicyclic product (Figure 2). However, the most notable feature associated with the formation of compounds 3 is their stereochemical identity. All compounds 3 were obtained as a single diastereomer (according to 1 H NMR analysis of the crude reaction mixtures). While the vicinal (3J) coupling constants between the methyne protons did not significantly change compared to the monocyclic starting α-amino amides 2, single-crystal X-ray analysis obtained for three representative bicyclic products (3a−c, see Supporting Information) confirmed their being cis-configured. This could only be a consequence of the cis-configured bicyclic core being more thermodynamically stable than its trans-configured counterpart, which provides a driving force for the observed isomerization under basic conditions. Using density functional theory approach, we calculated the energies of cis- and trans-isomers for the most stable boat conformer of the piperazin-2-one ring in tetrahydrofuran at 298.15K by B3LYP/6-31G(d) method (see Supporting Information for details). It was established that the cis-isomer of compound 3e is greater than 4 kcal/mol more stable than transisomer with the same conformation of bicyclic core (Figure S8), thus preliminarily justifying the observed trans → cis isomerization accompanying 2 → 3 conversion. At this point, we became curious if trans-configured (presumably, less thermodynamically stable) bicyclic compounds 3 could, in principle, be accessed using an alternative approach. To verify that, we converted CCR product 5e into N-deprotected methyl ester 8e (with retention of trans-configuration as confirmed by single-crystal X-ray analysis, see Supporting Information). The latter was coupled with Boc-protected sarcosine; the Boc group was removed on treatment with TFA, and the piperazine2,5-dione ring was formed on neutralization of the amide coupling product to give the trans-isomer of bicyclic compound

Figure 1. Structure of peptide β-turn (1), its bicyclic piperazine mimetics (2 and 3), and retrosynthetic disconnection of the latter based on the Castagnoli−Cushman reaction.

two sequential chemical operations but only one purification. Carboxylic acid functionality was activated by oxalyl chloride and converted to secondary amide on addition of a primary Scheme 1. General Approach to 5-Oxopiperazine-2carboxamides 4a−m

Table 1. Yields of Compounds 5a−l and 4a−m Prepared in This Work

Scheme 2. Synthesis of Bicyclic Piperazines 3a−m

5860

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868

Note

The Journal of Organic Chemistry

Figure 2. cis-Tetrahydro-1H-pyrazino[1,2-a]pyrazine-1,4,7-triones 3a−m synthesized in this work. Complex reaction mixture was obtained in which the target product was detected in low concentration by 1H NMR and HRMS, but all efforts to isolate pure bis-lactam were unsuccessful.

overlay of these compounds with a generalized structure of β-turn (Figure 3 shows such an overlay for representative

3e in 66% yield. Interestingly, the latter displayed the vicinal (3J) coupling constant between the methyne protons, which was nearly identical to that of cis-3e. However, the chemical shift values of these characteristic signals were clearly different (see Supporting Information). To our delight, when treated with sodium hydride over 12 h, trans-3e steadily converted to cis-3e, as observed by 1H NMR, although the full conversion was not achieved (Scheme 3). This observation additionally Scheme 3. Synthesis of trans-3e and Its Conversion into cis-3e

Figure 3. Spatial overlay of cis-configured compounds 3a, 3d, and 3k (gray) with peptide β-turn (purple).

compounds). We reasoned that the alternative synthetic approach to trans-configured bicyclic piperazine peptidomimetics depicted in Scheme 3 could, in principle, be applied to construction of ring-expanded bicyclic piperazine compounds by simply employing homologous 3-aminopropionic acid building block. To verify this possibility, we converted compounds 5a, 5b, 5h, and 5k into methyl esters 8a−d (Figure 4) using the same methylation/

Figure 4. CCR-derived methyl esters 8a−d synthesized in this work.

confirmed the higher thermodynamic stability of the cis-configured bicyclic piperazine series 3 predicted by DFT calculations (vide supra). cis-Configured compounds 3a−m are capable of effectively mimicking peptide β-turn as we demonstrated by examining an

deprotection reaction sequence as depicted in Scheme 3. However, the sequence of chemical operations that was successfully applied to the conversion of 8e into trans-3e did not convert 5861

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868

Note

The Journal of Organic Chemistry Scheme 4. Attempted Synthesis of Tetrahydropyrazino[1,2-a][1,4]diazepine-3,6,10-trione 9a

Scheme 5. Synthesis of Tetrahydropyrazino[1,2-a][1,4]diazepine-3,6,10-triones 9a−d

isomerization. DFT calculations using B3LYP/6-31G(d) method confirmed that in contrast to compounds 3, their ring-expanded versions 9 have lower energy in trans-configuration compared to its diastereomer (Figure S9). Finally, we were curious to see if the methodology applied to the preparation of seven-membered bicyclic compounds 9 could be followed to access the eight-membered versions by employing Boc-protected 4-aminobutyric acid. To our delight, this turned out to be true, and compound 8e was successfully (albeit in a greatly reduced yield) converted into tetrahydro-1H-pyrazino[1,2-a][1,4]diazocine-3,6,11-trione 11 via four sequential chemical operations followed by only one purification (Scheme 6).

compound 8a into tetrahydropyrazino[1,2-a][1,4]diazepine-3,6,10trione 9a on reaction with Boc-protected β-alanine. Apparently, the seven-membered ring formation via intramolecular nucleophilic addition−elimination was not energetically favored in this case, and the process stalled at uncyclized intermediate 10a (Scheme 4). We reasoned that if methyl ester 10a was obtained as respective free carboxylic acid, the latter could be activated for intramolecular amide coupling, and the desired seven-membered lactam would be formed. This vision was successfully realized by the sequence of steps shown in Scheme 5, and respective tetrahydropyrazino[1,2-a][1,4]diazepine-3,6,10-triones 9a−d were obtained in satisfactory yields following only one purification (Figure 5).

Scheme 6. Preparation of Tetrahydro-1H-pyrazino[1,2a][1,4]diazocine-3,6,11-trione 11

While “6/6” bicyclic piperazinones 3 are relatively wellrepresented in the synthetic organic and medicinal chemistry literature, tetrahydropyrazino[1,2-a][1,4]diazepine-3,6,10-trione core (featured in 9a−d) is completely novel. Likewise, its “6/8” version represented by 11 has not been described in the literature. Besides being attractive new cores for drug design in general, these two scaffolds could be viewed as hitherto undescribed peptidomimetic structures that can mimic peptide β-turns similarly to compounds 3 (vide supra). The overlay of compounds 9a and 11 with peptide β-turn structure convincingly supports the latter consideration (Figure 6). In summary, we described a novel approach to the wellestablished peptidomimetic bicyclic piperazines, tetrahydro-1Hpyrazino[1,2-a]pyrazine-1,4,7-triones, which were obtained either in cis- (more stable) or trans-configuration by two alternative synthetic routes involving the Castagnoli−Cushman reaction of protected iminodiacetic anhydride. The same Castagnoli− Cushman reaction-derived pyrazine template was employed in the synthesis of hitherto undescribed ring-expanded bicyclic templates featuring pyrazine-fused seven- and eight-membered rings. These novel scaffolds hold a potential for drug design in

Figure 5. Tetrahydropyrazino[1,2-a][1,4]diazepine-3,6,10-triones 9a−d synthesized in this work.

Compounds 9a−d were obtained in trans-configuration as was confirmed by single-crystal X-ray analysis of a representative compound (9a, see Supporting Information). Drawing an analogy with tetrahydro-1H-pyrazino[1,2-a]pyrazine-1,4,7-trione 3e, which was also obtained as a trans-isomer in the absence of a strong base (Scheme 3), we reasoned that if cis-configuration is also energetically more favored for compounds 9, then treatment of the latter obtained in trans-configuration with a strong base would trigger its conversion to the cis-counterpart. However, exposure of 9a to sodium hydride did not cause the expected 5862

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868

Note

The Journal of Organic Chemistry

7.21 (dd, J = 8.7, 5.3 Hz, 2H), 7.01 (t, J = 8.8 Hz, 2H), 5.21 (d, J = 1.8 Hz, 1H), 4.71 (d, J = 2.1 Hz, 1H), 4.30 (d, J = 16.8 Hz, 1H), 4.15 (d, J = 16.8 Hz, 1H), 3.71 (ddd, J = 13.4, 8.1, 7.4 Hz, 1H), 2.55−2.45 (m, 1H), 1.51−1.28 (m, 2H), 0.74 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.2, 163.2, 161.7 (d, J = 244.4 Hz), 146.8, 134.5, 133.3 (d, J = 2.9 Hz), 132.3, 130.3 (d, J = 8.7 Hz), 128.5, 128.4, 123.9, 115.3 (d, J = 21.6 Hz), 60.8, 60.2, 46.9, 46.1, 19.9, 10.9. HRMS (ESI) m/z calcd for C20H20FN3NaO7S+ [M + Na]+ 488.0898, found 488.0921. trans-3,4-Bis(4-fluorophenyl)-1-((2-nitrophenyl)sulfonyl)-5-oxopiperazine-2-carboxylic Acid (5c). Yield 480 mg, 93%; white powder; mp 225−226 °C. 1H NMR (400 MHz, DMSO-d6) δ 14.18 (br.s, 1H), 7.95−7.80 (m, 3H), 7.69 (t, J = 7.7 Hz, 1H), 7.41 (dd, J = 8.5, 5.1 Hz, 2H), 7.21 (t, J = 8.7 Hz, 2H), 7.14 (dd, J = 8.8, 5.1 Hz, 2H), 7.01 (t, J = 8.5 Hz, 2H), 5.54 (d, J = 1.9 Hz, 1H), 4.89 (d, J = 2.5 Hz, 1H), 4.57 (d, J = 17.1 Hz, 1H), 4.24 (d, J = 17.2 Hz, 1H). 13 C{1H} NMR (101 MHz, DMSO-d6) δ 169.2, 163.4, 161.71 (d, J = 244.8 Hz), 160.69 (d, J = 244.7 Hz), 146.9, 136.7 (d, J = 3.0 Hz), 134.7, 132.8 (d, J = 2.9 Hz), 132.3, 130.4, 130.3, 128.8 (d, J = 8.5 Hz), 128.6 (d, J = 8.9 Hz), 124.0, 116.1 (d, J = 22.9 Hz), 115.4 (d, J = 21.7 Hz), 64.5, 61.5, 46.6. HRMS (ESI) m/z calcd for C23H18F2N3O7S+ [M + H]+ 518.0828, found 518.0837. tra ns -3-(4-Chlorop henyl)-4-(4-methoxybenzyl)-1 -((2 nitrophenyl)sulfonyl)-5-oxopiperazine-2-carboxylic Acid (5d). Yield 498 mg, 89%; white powder, mp 205−206 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.72 (br.s, 1H), 7.86−7.77 (m, 2H), 7.67−7.59 (m, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 5.06 (d, J = 14.7 Hz, 1H), 5.01 (d, J = 1.8 Hz, 1H), 4.63 (d, J = 2.0 Hz, 1H), 4.40 (d, J = 16.9 Hz, 1H), 4.25 (d, J = 16.9 Hz, 1H), 3.71 (s, 3H), 3.54 (d, J = 14.7 Hz, 1H). 13 C{1H} NMR (101 MHz, DMSO-d6) δ 169.3, 164.0, 159.1, 147.2, 136.3, 135.0, 133.3, 132.8, 130.8, 130.7, 129.9, 129.0, 128.7, 128.1, 124.4, 114.3, 61.0, 60.4, 55.5, 48.1, 46.7. HRMS (ESI) m/z calcd for C25H22ClN3NaO8S+ [M + Na]+ 582.0708, found 582.0709. trans-4-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4-dimethoxyphenyl)-1-((2nitrophenyl)sulfonyl)-5-oxopiperazine-2-carboxylic Acid (5e). Yield 392 mg, 67%; pale yellow powder; mp 224−225 °C. 1H NMR (400 MHz, DMSO-d6) δ 14.10 (br.s, 1H), 7.86−7.72 (m, 3H), 7.62−7.55 (m, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.85−6.76 (m, 2H), 6.66 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 6.56 (dd, J = 8.3, 2.1 Hz, 1H), 6.02 (d, J = 1.0 Hz, 1H), 5.99 (d, J = 1.0 Hz, 1H), 5.36 (d, J = 2.3 Hz, 1H), 4.92 (d, J = 2.3 Hz, 1H), 4.52 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 3.71 (s, 3H), 3.68 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.5, 163.5, 148.5, 148.3, 147.3, 146.7, 146.3, 134.6, 134.4, 132.1, 130.5, 130.1, 128.6, 123.7, 119.6, 118.3, 111.0, 109.9, 108.2, 107.8, 101.7, 65.2, 61.6, 55.3, 55.2, 46.7. HRMS (ESI) m/z calcd for C26H23N3NaO11S+ [M + Na]+ 608.0946, found 608.0937. trans-4-Methyl-3-(3-nitrophenyl)-1-((2-nitrophenyl)sulfonyl)-5oxopiperazine-2-carboxylic Acid (5f). Yield 302 mg, 65%; beige solid; mp 263−264 °C (decomp.). 1H NMR (400 MHz, DMSO-d6) δ 13.99 (br.s, 1H), 8.02 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 7.96 (t, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.0, 1.1 Hz, 1H), 7.81−7.70 (m, 2H), 7.63 (dd, J = 6.9, 1.0 Hz, 1H), 7.59 (ddd, J = 8.1, 7.1, 1.8 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 5.42 (d, J = 1.9 Hz, 1H), 4.87 (d, J = 1.9 Hz, 1H), 4.35 (d, J = 17.0 Hz, 1H), 4.16 (d, J = 17.0 Hz, 1H), 2.82 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 168.8, 163.4, 147.6, 146.5, 139.3, 134.7, 133.1, 132.3, 130.4, 130.2, 130.2, 123.9, 123.2, 121.2, 62.2, 60.2, 46.1, 33.6. HRMS (ESI) m/z calcd for C18H16N4NaO9S+ [M + Na]+ 487.0530, found 487.0553. trans-3-(2-Methoxyphenyl)-4-methyl-1-((2-nitrophenyl)sulfonyl)5-oxopiperazine-2-carboxylic Acid (5g). Yield 274 mg, 61%; light yellow solid; mp 219−220 °C (decomp.). 1H NMR (400 MHz, DMSO-d6) δ 13.73 (br.s, 1H), 7.83−7.72 (m, 3H), 7.70−7.63 (m, 1H), 7.20 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 6.96 (dd, J = 8.3, 0.9 Hz, 1H), 6.78 (td, J = 7.5, 0.9 Hz, 1H), 6.72 (dd, J = 7.7, 1.6 Hz, 1H), 5.29 (d, J = 2.0 Hz, 1H), 4.77 (d, J = 2.0 Hz, 1H), 4.24 (d, J = 16.7 Hz, 1H), 4.10 (d, J = 16.7 Hz, 1H), 3.86 (s, 3H), 2.79 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.5, 163.9, 156.0, 146.8, 134.6, 132.4, 130.2, 129.9, 129.6, 125.5, 124.0, 123.7, 120.4, 111.1, 59.0, 57.9, 55.7,

Figure 6. Spatial overlay of trans-configured compounds 9a and 11 (gray) with peptide β-turn (purple).

general and peptidomimetic bioactive molecule design in particular. Investigation of medicinal chemistry utility of compounds described is currently underway in our laboratories; the results will be reported in due course.

■

EXPERIMENTAL SECTION

General. NMR spectroscopic data were recorded with a 400 spectrometer (400.13 MHz for 1H and 100.61 MHz for 13C) in DMSO-d6 or in CDCl3 or in acetone-d6 and were referenced to residual solvent proton signals (δH = 2.50, 7.26, and 2.05 ppm, respectively) and solvent carbon signals (δC = 39.52, 77.00, and 206.26 ppm, respectively). Mass spectra were recorded with a HRMS-ESI-qTOF spectrometer (ESI ionization). Melting points were determined with an automated heat block instrument and are uncorrected. Single crystal X-ray data were obtained using an Agilent Technologies SuperNova Atlas and an Agilent Technologies Xcalibur Eos diffractometers at a temperature of 100 K. Column chromatography was carried out with silica gel grade 60 (0.040−0.063 mm) 230−400 mesh. Chlorobenzene, dichloromethane, and MeCN were distilled over P2O5 and stored over 3 Å molecular sieves. THF and 1,4-dioxane were distilled after refluxing with sodium-benzophenone and stored over 3 Å molecular sieves. 4-((2-Nitrophenyl)sulfonyl)morpholine-2,6-dione (6a). The preparation of this compound has been described previously.9 General Procedure for the Preparation of Castagnoli− Cushman Acids 5a−l. Anhydride 6a (1.0 mmol) and corresponding imine (1.0 mmol) were suspended in dry chlorobenzene (∼1.5 mL/ 1 mmol) in a thick-walled glass tube with a screw cap. The tube was placed in a preheated (120 °C) oil bath and kept at this temperature for 1.5 h. After cooling to ambient temperature, the acids 5 were isolated by one of the following methods. Method A: The crude products were obtained by filtration of a precipitate (after addition 1.5 mL of CCl4) and purified by refluxing/recrystallization in the mixture of solvents (CH2Cl2:CCl4:MeCN, 5:1:0.3, 10−15 mL) to afford acid 5a−g and 5k−l as pure trans-isomer. Method B: The crude products were obtained by removing the solvent (C6H5Cl) in vacuo and purified by a acid/base extraction to give the acids 5h−j. A residue was diluted with 10 mL of CH2Cl2 and 10 mL of saturated aqueous NaHCO3. The organic layer was separated and thoroughly washed with saturated aqueous NaHCO3 (2 × 5 mL). The combined aqueous extracts were acidified with HClconc to pH 1−2. The crystalline solid formed was filtered off and air-dried. The pure trans-isomer was acquired by recrystallization from a small amount of CH2Cl2:EtOH:nhexane (5:1:1). trans-1-((2-Nitrophenyl)sulfonyl)-5-oxo-3,4-diphenylpiperazine2-carboxylic Acid (5a). Yield 389 mg, 81%; white powder; mp 240− 241 °C. 1H NMR (400 MHz, DMSO-d6) δ 14.11 (br.s, 1H), 7.88− 7.79 (m, 3H), 7.70−7.65 (m, 1H), 7.39−7.33 (m, 4H), 7.28−7.18 (m, 4H), 7.14−7.10 (m, 2H), 5.53 (d, J = 2.3 Hz, 1H), 4.89 (d, J = 2.3 Hz, 1H), 4.53 (d, J = 16.9 Hz, 1H), 4.24 (d, J = 17.0 Hz, 1H). 13 C{1H} NMR (101 MHz, DMSO-d6) δ 169.4, 163.3, 146.9, 140.7, 136.8, 134.7, 132.4, 130.2, 130.2, 129.1, 128.6, 128.2, 127.4, 126.4, 126.3, 123.9, 65.1, 61.6, 46.8. HRMS (ESI) m/z calcd for C23H19N3NaO7S+ [M + Na]+ 504.0836, found 504.0856. trans-3-(4-Fluorophenyl)-1-((2-nitrophenyl)sulfonyl)-5-oxo-4propylpiperazine-2-carboxylic Acid (5b). Yield 424 mg, 91%; white powder; mp 174−175 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.89 (br.s, 1H), 7.86−7.78 (m, 3H), 7.66 (ddd, J = 8.8, 4.5, 0.8 Hz, 1H), 5863

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868

Note

The Journal of Organic Chemistry 45.9, 33.8. HRMS (ESI) m/z calcd for C19H19N3NaO8S+ [M + Na]+ 472.0785, found 472.0807. trans-4-(3-(Methoxycarbonyl)phenyl)-3-(4-nitrophenyl)-1-((2nitrophenyl)sulfonyl)-5-oxopiperazine-2-carboxylic Acid (5h). Yield 257 mg, 44%; light beige solid; mp 201−202 °C (decomp.). 1H NMR (400 MHz, DMSO-d6) δ 14.33 (br.s, 1H), 7.99 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 7.9 Hz, 1H), 7.87−7.75 (m, 4H), 7.73 (d, J = 8.9 Hz, 2H), 7.66 (t, J = 8.1 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 5.84 (d, J = 1.5 Hz, 1H), 5.01 (d, J = 1.9 Hz, 1H), 4.65 (d, J = 17.3 Hz, 1H), 4.29 (d, J = 17.3 Hz, 1H), 3.83 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 168.8, 165.3, 163.6, 147.2, 146.8, 144.1, 140.5, 134.6, 132.3, 131.3, 130.8, 130.4, 130.3, 129.9, 128.3, 128.2, 127.2, 123.9, 123.4, 64.2, 61.1, 52.4, 46.9. HRMS (ESI) m/z calcd for C25H20N4NaO11S+ [M + Na]+ 607.0741, found 607.0769. trans-4-(tert-Butyl)-1-((2-nitrophenyl)sulfonyl)-5-oxo-3-phenylpiperazine-2-carboxylic Acid (5i). Yield 337 mg, 73%; light beige solid; mp 248−249 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.87 (br.s, 1H), 7.83−7.74 (m, 2H), 7.68 (dd, J = 8.1, 0.9 Hz, 1H), 7.62 (ddd, J = 7.1, 4.2, 1.3 Hz, 1H), 7.27−7.23 (m, 4H), 7.23−7.15 (m, 1H), 5.49 (d, J = 2.7 Hz, 1H), 4.71 (d, J = 2.6 Hz, 1H), 4.17 (d, J = 16.3 Hz, 1H), 4.03 (d, J = 16.3 Hz, 1H), 1.28 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.3, 164.0, 146.9, 138.9, 134.5, 132.3, 130.3, 129.9, 128.5, 127.9, 126.0, 123.9, 62.6, 58.9, 58.5, 47.5, 27.5. HRMS (ESI) m/z calcd for C21H23N3NaO7S+ [M + Na]+ 484.1149, found 484.1163. trans-4-(2-Methoxy-2-oxoethyl)-3-(4-methoxyphenyl)-1-((2nitrophenyl)sulfonyl)-5-oxopiperazine-2-carboxylic Acid (5j). Yield 244 mg, 48%; light beige solid; mp 258−259 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.76 (br.s, 1H), 7.87−7.76 (m, 3H), 7.67−7.61 (m, 1H), 7.09 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 5.20 (d, J = 1.6 Hz, 1H), 4.58 (d, J = 1.8 Hz, 1H), 4.36 (d, J = 16.6 Hz, 1H), 4.32 (d, J = 16.9 Hz, 1H), 4.25 (d, J = 16.9 Hz, 1H), 3.70 (s, 3H), 3.58 (s, 3H), 3.53 (d, J = 17.0 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 168.9, 168.2, 163.8, 158.9, 146.8, 134.6, 132.3, 130.3, 130.2, 128.6, 127.6, 124.0, 113.8, 62.0, 60.7, 55.0, 51.8, 47.4, 46.0. HRMS (ESI) m/z calcd for C21H21N3NaO10S+ [M + Na]+ 530.0840, found 530.0867. trans-1-((2-Nitrophenyl)sulfonyl)-5-oxo-3-(thiophen-3-yl)-4-(ptolyl)piperazine-2-carboxylic Acid (5k). Yield 406 mg, 81%; light beige solid; mp 231−232 °C. 1H NMR (400 MHz, DMSO-d6) δ 14.04 (br.s, 1H), 7.94−7.80 (m, 3H), 7.78−7.70 (m, 1H), 7.59−7.56 (m, 1H), 7.40 (dd, J = 5.0, 2.9 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.10 (dd, J = 5.0, 1.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 5.53 (d, J = 2.1 Hz, 1H), 4.94 (d, J = 2.4 Hz, 1H), 4.45 (d, J = 16.7 Hz, 1H), 4.19 (d, J = 16.7 Hz, 1H), 2.25 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.4, 162.9, 147.1, 138.5, 138.1, 136.8, 134.7, 132.4, 130.2, 130.2, 129.5, 127.2, 126.1, 126.0, 124.0, 123.6, 62.0, 61.1, 46.6, 20.5. HRMS (ESI) m/z calcd for C22H19N3NaO7S2+ [M + Na]+ 524.0557, found 524.0566. trans-4-(4-Methoxyphenyl)-1-((2-nitrophenyl)sulfonyl)-5-oxo-3(4-(trifluoromethyl)phenyl)piperazine-2-carboxylic Acid (5l). Yield 498 mg, 86%; white powder; mp 197−198 °C. 1H NMR (400 MHz, DMSO-d6) δ 14.13 (br.s, 1H), 7.89−7.78 (m, 3H), 7.76 (d, J = 8.4 Hz, 2H), 7.69−7.63 (m, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 5.59 (d, J = 2.0 Hz, 1H), 4.91 (d, J = 2.3 Hz, 1H), 4.58 (d, J = 17.1 Hz, 1H), 4.29 (d, J = 17.1 Hz, 1H), 3.70 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.3, 163.6, 158.9, 146.9, 144.1, 134.6, 132.3, 130.3, 130.3, 128.2, 127.6, 127.5 (q, J = 32.3 Hz), 126.9, 126.3 (q, J = 3.9 Hz), 123.9, 123.8 (q, J = 272.2 Hz), 113.9, 64.2, 61.6, 55.0, 46.8. HRMS (ESI) m/z calcd for C25H20F3N3NaO8S+ [M + Na]+ 602.0815, found 602.0843. General Procedure for the Preparation of Compounds 4a−m. A suspension of carboxylic acid 5 (0.6 mmol) in dry CH2Cl2 (10 mL) was treated with oxalyl chloride (91 mg, 0.72 mmol, 1.2 equiv) and a few drops of DMF. The resulting solution was refluxed for 1 h. After cooling to room temperature, the obtained solution was slowly added at 0 °C to the mixture of an amine (0.63 mmol, 1.05 equiv) and DIPEA (194 mg, 1.5 mmol, 2.5 equiv) in dry CH2Cl2 (5 mL). After being stirred at room temperature for 1 h, the reaction mixture was washed with 5% aqueous citric acid and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The crude product was fractionated

by column chromatography on silica gel using CH2Cl2:EtOAc = 5:1 to 1:1 (amides from acids 5a−f, h, j, l) and CH2Cl2:nhexane = 5:1 to 10:1 (amides from acids 5g, i, k) as eluent. The fractions containing the desired amides (as confirmed by 1H NMR) were combined; the solvent was evaporated, and the residue was dissolved in dry MeCN (5 mL). K2CO3 (182 mg, 1.32 mmol, 2.2 equiv) and thiophenol (73 mg, 0.66 mmol, 1.1 equiv) were added. The resulting suspension was vigorously stirred for 3 h at room temperature. After the solvent was removed in vacuo, the reaction mixture was diluted with CH2Cl2 (30 mL) and water (50 mL). The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to column chromatography eluting with CHCl3:MeOH = 50:1 to 15:1 to afford pure compound 4. trans-N-(4-Methoxyphenyl)-5-oxo-3,4-diphenylpiperazine-2-carboxamide (4a). Yield 176 mg, 73%; white powder; mp 209−210 °C. 1 H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 7.51 (d, J = 9.0 Hz, 2H), 7.46−7.40 (m, 2H), 7.38−7.26 (m, 7H), 7.23−7.17 (m, 1H), 6.91 (d, J = 9.0 Hz, 2H), 5.89 (d, J = 1.5 Hz, 1H), 3.82 (br.s, 2H), 3.81 (s, 3H), 3.75 (d, J = 1.3 Hz, 1H), 2.56 (br.s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 166.8, 156.9, 141.5, 139.7, 130.5, 129.4, 129.2, 128.3, 127.4, 127.0, 126.5, 121.7, 114.4, 63.2, 62.0, 55.6, 45.8. HRMS (ESI) m/z calcd for C24H24N3O3+ [M + H]+ 402.1812, found 402.1809. trans-3-(4-Fluorophenyl)-N-(4-methoxyphenyl)-5-oxo-4-propylpiperazine-2-carboxamide (4b). Yield 171 mg, 85%; pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.45 (d, J = 9.0 Hz, 2H), 7.22 (dd, J = 8.7, 5.2 Hz, 2H), 7.12 (t, J = 8.5 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 5.50 (d, J = 1.0 Hz, 1H), 3.95 (ddd, J = 13.4, 9.4, 6.9 Hz, 1H), 3.79 (s, 3H), 3.64 (d, J = 1.1 Hz, 1H), 3.62 (d, J = 15.5 Hz, 1H), 3.58 (d, J = 15.6 Hz, 1H), 2.50 (ddd, J = 13.5, 9.4, 5.2 Hz, 1H), 2.37 (br.s, 1H), 1.68−1.49 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (101 MHz, CDCl3) δ 167.0, 166.4, 162.6 (d, J = 247.5 Hz), 156.8, 135.8 (d, J = 3.1 Hz), 130.5, 128.1 (d, J = 8.2 Hz), 121.6, 116.4 (d, J = 21.7 Hz), 114.4, 61.8, 58.2, 55.6, 48.1, 45.3, 20.3, 11.4. HRMS (ESI) m/z calcd for C21H25FN3O3+ [M + H]+ 386.1874, found 386.1889. trans-3,4-Bis(4-fluorophenyl)-N-(4-methoxyphenyl)-5-oxopiperazine-2-carboxamide (4c). Yield 176 mg, 67%; white powder; mp 190−191 °C. 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.49 (d, J = 9.0 Hz, 2H), 7.33−7.24 (m, 4H), 7.12 (t, J = 8.6 Hz, 2H), 6.98 (t, J = 8.7 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 5.82 (d, J = 1.0 Hz, 1H), 3.82 (br.s, 1H), 3.81 (s, 3H), 3.80 (br.s, 1H), 3.71 (dd, J = 5.4, 1.9 Hz, 1H), 2.59−2.51 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 166.6, 162.63 (d, J = 248.1 Hz), 161.57 (d, J = 247.0 Hz), 157.0, 137.3 (d, J = 3.2 Hz), 135.2 (d, J = 3.2 Hz), 130.4, 128.9 (d, J = 8.6 Hz), 128.1 (d, J = 8.2 Hz), 121.7, 116.5 (d, J = 21.7 Hz), 116.2 (d, J = 22.7 Hz), 114.5, 62.9, 61.9, 55.6, 45.7. HRMS (ESI) m/z calcd for C24H22F2N3O3+ [M + H]+ 438.1624, found 438.1645. trans-3-(4-Chlorophenyl)-N,4-bis(4-methoxybenzyl)-5-oxopiperazine-2-carboxamide (4d). Yield 186 mg, 63%; orange oil. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.5 Hz, 2H), 7.16−7.05 (m, 7H), 6.86 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 5.25 (d, J = 3.0 Hz, 1H), 5.14 (d, J = 14.5 Hz, 1H), 4.36 (d, J = 5.8 Hz, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.74 (d, J = 14.5 Hz, 1H), 3.63 (d, J = 18.7 Hz, 1H), 3.57 (d, J = 18.6 Hz, 1H), 3.44 (d, J = 3.0 Hz, 1H), 2.24 (br.s, 1H). 13 C{1H} NMR (101 MHz, CDCl3) δ 168.1, 167.6, 159.2 (2C), 138.2, 134.1, 130.2, 130.0, 129.4, 129.1, 128.1, 127.8, 114.3, 113.9, 61.9, 59.1, 55.4, 55.3, 48.5, 46.1, 43.2. HRMS (ESI) m/z calcd for C27H29ClN3O4+ [M + H]+ 494.1841, found 494.1865. trans-4-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4-dimethoxyphenyl)-Nmethyl-5-oxopiperazine-2-carboxamide (4e). Yield 167 mg, 68%; light yellow solid; mp 115−116 °C. 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 7.19 (q, J = 4.1 Hz, 1H), 6.92−6.86 (m, 2H), 6.79−6.74 (m, 2H), 6.73−6.68 (m, 2H), 5.91 (d, J = 1.4 Hz, 1H), 5.89 (d, J = 1.4 Hz, 1H), 5.67 (d, J = 1.7 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.74 (d, J = 19.5 Hz, 1H), 3.69 (d, J = 19.5 Hz, 1H), 3.54 (d, J = 1.6 Hz, 1H), 2.93 (d, J = 4.9 Hz, 3H), 2.41 (s, 1H). 13 C{1H} NMR (101 MHz, CDCl3) δ 169.5, 167.5, 149.9, 149.0, 147.9, 146.8, 135.5, 132.1, 120.5, 118.3, 111.7, 109.8, 108.7, 108.4, 101.6, 63.7, 61.7, 56.2, 56.2, 45.9, 26.6. HRMS (ESI) m/z calcd for C21H24N3O6+ [M + H]+ 414.1660, found 414.1677. 5864

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868

Note

The Journal of Organic Chemistry

mp 177−178 °C. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 5.8 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.38−7.26 (m, 5H), 7.22 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.81 (d, J = 2.0 Hz, 1H), 4.55 (d, J = 5.9 Hz, 2H), 3.80 (s, 3H), 3.76 (d, J = 19.9 Hz, 1H), 3.70 (d, J = 19.1 Hz, 1H), 3.66 (d, J = 2.0 Hz, 1H), 2.41 (br.s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.8, 167.3, 159.7, 144.6, 137.9, 130.9, 129.2 (q, J = 32.6 Hz), 129.0, 127.9, 127.9, 127.5, 127.2, 126.3 (q, J = 3.7 Hz), 124.0 (q, J = 272.1 Hz), 114.9, 62.9, 61.8, 55.5, 46.0, 44.0. HRMS (ESI) m/z calcd for C26H25 F3N3O3+ [M + H]+ 484.1843, found 484.1833. trans-3-(4-Fluorophenyl)-N-isobutyl-5-oxo-4-propylpiperazine-2carboxamide (4m). Yield 149 mg, 74%; glassy colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 6.1 Hz, 1H), 7.11 (dd, J = 8.4, 5.3 Hz, 2H), 6.98 (t, J = 8.4 Hz, 2H), 5.29 (br.s, 1H), 3.83−3.72 (m, 1H), 3.47 (d, J = 18.7 Hz, 1H), 3.41 (d, J = 18.7 Hz, 1H), 3.37 (d, J = 1.9 Hz, 1H), 3.10−2.92 (m, 2H), 2.43−2.30 (m, 2H), 1.74− 1.60 (m, 1H), 1.54−1.33 (m, 2H), 0.80 (d, J = 3.2 Hz, 3H), 0.78 (d, J = 3.2 Hz, 3H), 0.71 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.4, 167.3, 161.5 (d, J = 243.2 Hz), 136.0 (d, J = 2.9 Hz), 129.2 (d, J = 8.3 Hz), 115.2 (d, J = 21.4 Hz), 61.3, 60.0, 46.5, 46.0, 45.9, 27.9, 20.0, 19.9, 19.6, 11.1. HRMS (ESI) m/z calcd for C18H27FN3O2+ [M + H]+ 336.2082, found 336.2094. General Procedure for the Preparation of Bis-Lactams 3a−m. To a stirred solution of compound 4 (0.28 mmol) and DIPEA (72 mg, 0.56 mmol, 2.0 equiv) in dry MeCN (3 mL) was added a solution of chloroacetyl chloride (38 mg, 0.336 mmol, 1.2 equiv) in dry CH2Cl2 (1.5 mL) under cooling with ice water. After stirring the reaction mixture at room temperature for 30 min, the solvent was removed in vacuo. A residue was diluted with 20 mL of CH2Cl2 and 30 mL of water. The reaction mixture was extracted with CH2Cl2 (3 × 10 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was fractionated by flash chromatography on silica gel (CHCl3:EtOAc = 5:1 to 1:1), and the fractions containing N-acylation product 7 (as confirmed by 1H NMR) were combined and concentrated in vacuo. The residue was used directly in the next step, which was carried out by one of the following methods. Method A. Chloroacetamide (0.28 mmol, 1.0 equiv) and Cs2CO3 (137 mg, 0.42 mmol, 1.5 equiv) were combined in dry MeCN (5 mL). The reaction mixture was stirred overnight at room temperature, concentrated, and washed with water (3 × 10 mL) and brine. The organic layer was dried (anhydrous Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CHCl3:EtOAc = 50:1 to 15:1) to afford bis-lactams 3a−c, g, i−k. Method B. To a stirred solution of chloroacetamide (0.28 mmol, 1.0 equiv) in dry THF (5 mL) was added NaH (60% dispersion in mineral oil, 17 mg, 0.42 mmol, 1.5 equiv) in one portion at 0 °C. The resulting mixture was allowed to warm to room temperature, stirred for 2 h, and concentrated in vacuo. The residue was taken up in CH2Cl2 (10 mL), washed with water, brine, dried over Na2SO4, and concentrated to give a crude product, which was purified by column chromatography on silica gel (CHCl3:EtOAc = 50:1 to 5:1) to give bis-lactams 3d, e, h, l, m. cis-2-(4-Methoxyphenyl)-8,9-diphenyltetrahydro-1H-pyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3a). Yield 89 mg, 71%; white solid; mp 260−261 °C. 1H NMR (400 MHz, CDCl3) δ 7.52−7.42 (m, 3H), 7.34−7.27 (m, 4H), 7.26−7.22 (m, 1H), 7.16 (d, J = 7.2 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 5.47 (d, J = 18.7 Hz, 1H), 5.40 (d, J = 3.4 Hz, 1H), 5.07 (d, J = 3.4 Hz, 1H), 4.03 (d, J = 18.7 Hz, 1H), 3.79 (d, J = 17.6 Hz, 1H), 3.78 (s, 3H), 3.01 (d, J = 17.7 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.3, 161.9, 161.5, 159.2, 140.6, 134.5, 131.7, 129.8, 129.5, 129.3, 128.2, 128.1, 127.0, 126.7, 115.0, 66.4, 61.3, 55.6, 52.0, 45.5. HRMS (ESI) m/z calcd for C26H24N3O4+ [M + H]+ 442.1761, found 442.1783. cis-9-(4-Fluorophenyl)-2-(4-methoxyphenyl)-8-propyltetrahydro1H-pyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3b). Yield 99 mg, 83%; white solid; mp 227−228 °C. 1H NMR (400 MHz, CDCl3) δ 7.24−7.11 (m, 4H), 6.88 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 5.23 (d, J = 18.6 Hz, 1H), 5.03 (d, J = 3.5 Hz, 1H), 4.78 (d, J = 3.5 Hz, 1H), 3.88 (d, J = 18.4 Hz, 1H), 3.81 (d, J = 17.7 Hz, 1H),

trans-N-Isopropyl-4-methyl-3-(3-nitrophenyl)-5-oxopiperazine-2carboxamide (4f). Yield 129 mg, 67%; white solid; mp 95−96 °C. 1 H NMR (400 MHz, CDCl3) δ 8.17 (dt, J = 7.8, 1.5 Hz, 1H), 8.07 (t, J = 1.9 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.56 (dt, J = 7.8, 1.5 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 5.42 (d, J = 2.6 Hz, 1H), 4.16−3.99 (m, 1H), 3.58 (d, J = 19.3 Hz, 1H), 3.53 (d, J = 19.5 Hz, 1H), 3.47 (d, J = 2.4 Hz, 1H), 2.86 (s, 3H), 2.28 (br.s, 1H), 1.17 (d, J = 6.6 Hz, 3H), 1.12 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.6, 167.0, 149.1, 142.3, 132.6, 130.5, 123.3, 121.4, 61.6, 61.4, 45.5, 41.8, 34.2, 22.8, 22.7. HRMS (ESI) m/z calcd for C15H21N4O4+ [M + H]+ 321.1557, found 321.1570. trans-3-(2-Methoxyphenyl)-4-methyl-5-oxo-N-(p-tolyl)piperazine-2-carboxamide (4g). Yield 110 mg, 52%; white solid; mp 118−119 °C. 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.35 (ddd, J = 8.3, 7.0, 2.2 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.08−6.99 (m, 2H), 6.95 (d, J = 8.1 Hz, 1H), 5.72 (d, J = 1.6 Hz, 1H), 3.86 (s, 3H), 3.78 (br.s, 1H), 3.62 (d, J = 18.0 Hz, 1H), 3.54 (d, J = 18.2 Hz, 1H), 2.93 (s, 3H), 2.35 (br.s, 1H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.9, 167.1, 156.6, 135.1, 134.2, 129.7, 129.5, 126.9, 126.7, 121.1, 119.7, 111.0, 58.9, 56.8, 55.6, 45.2, 34.5, 21.0. HRMS (ESI) m/z calcd for C20H24N3O3+ [M + H]+ 354.1812, found 354.1810. trans-Methyl 3-(3-(cyclopropylcarbamoyl)-2-(4-nitrophenyl)-6oxopiperazin-1-yl)benzoate (4h). Yield 166 mg, 63%; beige solid; mp 148−149 °C. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.7 Hz, 2H), 7.91 (t, J = 1.8 Hz, 1H), 7.87 (dt, J = 7.8, 1.3 Hz, 1H), 7.56 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 3.4 Hz, 1H), 5.97 (d, J = 2.1 Hz, 1H), 3.85 (s, 3H), 3.78 (dd, J = 19.2, 6.5 Hz, 1H), 3.69 (dd, J = 19.0, 6.5 Hz, 1H), 3.62 (br.s, 1H), 2.86−2.78 (m, 1H), 2.48−2.38 (m, 1H), 0.93−0.78 (m, 2H), 0.62−0.49 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.5, 167.0, 166.2, 147.8, 145.0, 141.1, 131.4, 131.3, 129.7, 128.8, 128.2, 127.7, 124.5, 63.2, 61.3, 52.4, 45.9, 22.9, 6.8, 6.7. HRMS (ESI) m/z calcd for C22H23N4O6+ [M + H]+ 439.1612, found 439.1624. trans-4-(tert-Butyl)-N-(2-methoxyphenyl)-5-oxo-3-phenylpiperazine-2-carboxamide (4i). Yield 133 mg, 58%; light yellow solid; mp 159−160 °C. 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 8.37 (dd, J = 8.0, 1.7 Hz, 1H), 7.46−7.39 (m, 2H), 7.36−7.27 (m, 3H), 7.11−7.04 (m, 1H), 6.98 (td, J = 7.8, 1.4 Hz, 1H), 6.89 (dd, J = 8.1, 1.3 Hz, 1H), 5.83 (d, J = 1.9 Hz, 1H), 3.87 (s, 3H), 3.71 (dd, J = 18.5, 7.6 Hz, 1H), 3.67 (dd, J = 5.3, 2.1 Hz, 1H), 3.61 (dd, J = 18.5, 8.4 Hz, 1H), 2.28− 2.18 (m, 1H), 1.41 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.8, 167.3, 148.7, 141.9, 129.3, 127.8, 127.2, 126.3, 124.4, 121.1, 120.0, 110.3, 63.4, 59.3, 56.9, 55.9, 47.4, 28.2. HRMS (ESI) m/z calcd for C22H28N3O3+ [M + H]+ 382.2125, found 382.2134. trans-Methyl 2-(3-((4-fluorophenyl)carbamoyl)-2-(4-methoxyphenyl)-6-oxopiperazin-1-yl)acetate (4j). Yield 115 mg, 45%; yellow solid; mp 129−130 °C. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.53 (dd, J = 9.0, 4.8 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 5.24 (d, J = 3.3 Hz, 1H), 4.55 (d, J = 17.2 Hz, 1H), 3.81 (s, 3H), 3.72 (d, J = 11.9 Hz, 1H), 3.69 (s, 3H), 3.69 (d, J = 11.5 Hz, 1H), 3.65 (d, J = 3.4 Hz, 1H), 3.47 (d, J = 17.2 Hz, 1H), 2.32 (br.s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.5, 168.1, 167.4, 160.0, 159.7 (d, J = 244.0 Hz), 133.5 (d, J = 2.8 Hz), 130.4, 128.2, 121.9 (d, J = 7.9 Hz), 115.8 (d, J = 22.5 Hz), 114.8, 62.8, 61.0, 55.5, 52.5, 47.1, 46.3. HRMS (ESI) m/z calcd for C21H23FN3O5+ [M + H]+ 416.1616, found 416.1634. trans-N-(4-Chlorophenyl)-5-oxo-3-(thiophen-3-yl)-4-(p-tolyl)piperazine-2-carboxamide (4k). Yield 120 mg, 47%; white solid; mp 247−249 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.47 (dd, J = 5.0, 2.9 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.9 Hz, 2H), 7.14 (dd, J = 5.0, 1.3 Hz, 1H), 7.12− 7.04 (m, 4H), 5.49 (d, J = 3.8 Hz, 1H), 3.92 (dd, J = 6.6, 3.9 Hz, 1H), 3.67 (dd, J = 18.0, 7.3 Hz, 1H), 3.54 (dd, J = 18.0, 5.7 Hz, 1H), 3.46− 3.36 (m, 1H), 2.23 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 169.3, 167.0, 140.7, 139.0, 137.5, 135.8, 129.0, 128.6, 127.3, 127.0, 126.9, 126.5, 123.3, 121.4, 61.3, 60.7, 46.9, 20.5. HRMS (ESI) m/z calcd for C22H21ClN3O2S+ [M + H]+ 426.1038, found 426.1046. trans-N-Benzyl-4-(4-methoxyphenyl)-5-oxo-3-(4-(trifluoromethyl)phenyl)piperazine-2-carboxamid (4l). Yield 194 mg, 66%; white solid; 5865

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868

Note

The Journal of Organic Chemistry

Methyl 2-(cis-8-(4-Fluorophenyl)-1-(4-methoxyphenyl)-3,6,9-trioxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)acetate (3j). Yield 60 mg, 49%; white solid; mp 220−221 °C. 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.7 Hz, 2H), 7.04 (t, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.84 (dd, J = 9.0, 4.8 Hz, 2H), 5.30 (d, J = 18.6 Hz, 1H), 5.04 (d, J = 3.7 Hz, 1H), 4.97 (d, J = 3.7 Hz, 1H), 4.64 (d, J = 17.3 Hz, 1H), 3.92 (d, J = 18.6 Hz, 1H), 3.83 (s, 3H), 3.79 (d, J = 17.4 Hz, 1H), 3.74 (s, 3H), 3.37 (d, J = 17.4 Hz, 1H), 3.11 (d, J = 17.4 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.7, 164.8, 161.8 (d, J = 248.6 Hz), 161.7, 161.6, 161.1, 135.0 (d, J = 3.2 Hz), 129.5, 127.5 (d, J = 8.7 Hz), 125.1, 116.7 (d, J = 23.0 Hz), 114.7, 63.4, 60.7, 55.6, 52.6, 51.8, 47.3, 45.1. HRMS (ESI) m/z calcd for C23H22FN3NaO6+ [M + Na]+ 478.1385, found 478.1402. cis-2-(4-Chlorophenyl)-9-(thiophen-3-yl)-8-(p-tolyl)tetrahydro1H-pyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3k). Yield 88 mg, 68%; white solid; mp 253−254 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.52−7.47 (m, 3H), 7.42 (d, J = 8.9 Hz, 2H), 7.40−7.38 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.15−7.10 (m, 3H), 5.87 (d, J = 5.5 Hz, 1H), 5.15 (d, J = 5.5 Hz, 1H), 4.70 (d, J = 16.6 Hz, 1H), 4.63 (d, J = 16.5 Hz, 1H), 4.49 (d, J = 16.5 Hz, 1H), 3.89 (d, J = 16.6 Hz, 1H), 2.25 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 165.4, 164.2, 163.6, 139.2, 139.1, 137.6, 136.0, 131.0, 129.0, 128.8, 127.3, 127.2, 126.6, 126.5, 123.9, 60.2, 59.2, 52.5, 44.9, 20.5. HRMS (ESI) m/z calcd for C24H21ClN3O3S+ [M + H]+ 466.0987, found 466.0988. cis-2-Benzyl-8-(4-methoxyphenyl)-9-(4-(trifluoromethyl)phenyl)tetrahydro-1H-pyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3l). Yield 74 mg, 51%; pale yellow solid; mp 272−273 °C. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.5 Hz, 2H), 7.31−7.24 (m, 5H), 7.03 (d, J = 8.7 Hz, 2H), 6.98 (dd, J = 7.4, 1.8 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 5.36 (d, J = 19.1 Hz, 1H), 5.33 (d, J = 3.4 Hz, 1H), 4.96 (d, J = 3.2 Hz, 1H), 4.52 (d, J = 14.4 Hz, 1H), 4.19 (d, J = 14.4 Hz, 1H), 3.98 (d, J = 19.0 Hz, 1H), 3.76 (s, 3H), 3.54 (d, J = 17.7 Hz, 1H), 2.78 (d, J = 17.7 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.3, 161.9, 161.2, 160.7, 143.7 (q, J = 1.5 Hz), 133.9, 130.0 (q, J = 32.8 Hz), 129.5, 129.0, 129.0, 128.9, 128.4, 127.3, 126.6 (q, J = 3.8 Hz), 125.5, 123.8 (q, J = 272.4 Hz), 114.7, 65.7, 61.0, 55.4, 49.6, 48.1, 45.4. HRMS (ESI) m/z calcd for C28H25F3N3O4+ [M + H]+ 524.1792, found 524.1806. cis-9-(4-Fluorophenyl)-2-isobutyl-8-propyltetrahydro-1Hpyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3m). Yield 41 mg, 39%; pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.11 (dd, J = 8.7, 5.3 Hz, 2H), 7.05 (t, J = 8.5 Hz, 2H), 5.15 (d, J = 18.6 Hz, 1H), 4.97 (d, J = 3.5 Hz, 1H), 4.63 (d, J = 3.5 Hz, 1H), 3.82 (d, J = 18.9 Hz, 1H), 3.78−3.71 (m, 1H), 3.61 (d, J = 17.9 Hz, 1H), 3.01 (dd, J = 13.4, 8.3 Hz, 1H), 2.92 (d, J = 17.9 Hz, 1H), 2.82 (dd, J = 13.4, 6.9 Hz, 1H), 2.70−2.61 (m, 1H), 1.79−1.69 (m, 1H), 1.63−1.48 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H), 0.70 (d, J = 6.7 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.0, 163.5 (d, J = 249.8 Hz), 161.5, 161.4, 130.3 (d, J = 3.3 Hz), 129.8 (d, J = 8.3 Hz), 116.2 (d, J = 21.7 Hz), 61.9, 60.4, 53.7, 49.5, 48.2, 45.1, 26.0, 20.7, 20.0, 19.9, 11.4. HRMS (ESI) m/z calcd for C20H27FN3O3+ [M + H]+ 376.2031, found 376.2043. General Procedure for the Preparation of Compounds 8a−e. The Castagnoli−Cushman reaction product 5 (0.8 mmol) was dissolved in dry acetone (10 mL). Methyl iodide (284 mg, 2.0 mmol, 2.5 equiv) and K2CO3 (331 mg, 2.4 mmol, 3.0 equiv) were added to the solution, and the resulting suspension was stirred overnight at room temperature. The volatiles were removed in vacuo. The residue was taken up in CH2Cl2, washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give the crude methyl ester. The latter was fractionated by flash chromatography on silica gel. The fractions containing the product (as judged by 1H NMR) were collected; the solvent was evaporated, and the residue was dissolved in dry acetonitrile (5 mL). K2CO3 (243 mg, 1.76 mmol, 2.2 equiv) and thiophenol (97 mg, 0.88 mmol, 1.1 equiv) were added, and the resulting suspension was vigorously stirred for 3 h at room temperature. After removing the solvent in vacuo, the reaction mixture was diluted with CH2Cl2 (20 mL) and water (50 mL). The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography to afford compound 8 (eluent: CHCl3:MeOH = 50:1 to 30:1 for 8a, b;

3.78 (s, 3H), 3.78−3.74 (m, 1H), 3.14 (d, J = 17.8 Hz, 1H), 2.71 (ddd, J = 13.7, 9.2, 5.8 Hz, 1H), 1.66−1.49 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (101 MHz, CDCl3) δ 164.0, 163.6 (d, J = 250.3 Hz), 161.6, 161.5, 159.3, 131.6, 130.4 (d, J = 3.3 Hz), 130.0 (d, J = 8.3 Hz), 126.6, 116.3 (d, J = 21.6 Hz), 115.0, 62.0, 60.8, 55.6, 52.0, 48.3, 45.1, 20.7, 11.4. HRMS (ESI) m/z calcd for C23H25FN3O4+ [M + H]+ 426.1824, found 426.1842. cis-8,9-Bis(4-fluorophenyl)-2-(4-methoxyphenyl)tetrahydro-1Hpyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3c). Yield 72 mg, 56%; white solid; mp 237−238 °C. 1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J = 8.7, 5.1 Hz, 2H), 7.15 (t, J = 8.5 Hz, 2H), 7.10 (dd, J = 9.1, 4.8 Hz, 2H), 6.99 (t, J = 8.5 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 5.43 (d, J = 18.8 Hz, 1H), 5.34 (d, J = 3.5 Hz, 1H), 5.05 (d, J = 3.5 Hz, 1H), 4.02 (d, J = 18.8 Hz, 1H), 3.89 (d, J = 17.8 Hz, 1H), 3.78 (s, 3H), 3.21 (d, J = 17.8 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.8 (d, J = 250.6 Hz), 164.4, 161.9 (d, J = 248.5 Hz), 161.6, 161.3, 159.4, 136.3 (d, J = 3.3 Hz), 131.5, 130.2 (d, J = 3.3 Hz), 130.0 (d, J = 8.3 Hz), 128.9 (d, J = 8.7 Hz), 126.6, 116.7 (d, J = 22.8 Hz), 116.5 (d, J = 21.7 Hz), 115.1, 66.0, 61.0, 55.6, 52.1, 45.4. HRMS (ESI) m/z calcd for C26H21F2N3NaO4+ [M + Na]+ 500.1392, found 500.1409. cis-9-(4-Chlorophenyl)-2,8-bis(4-methoxybenzyl)tetrahydro-1Hpyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3d). Yield 81 mg, 54%; pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.88−6.77 (m, 6H), 5.33 (d, J = 14.5 Hz, 1H), 5.22 (d, J = 18.6 Hz, 1H), 4.84 (d, J = 3.7 Hz, 1H), 4.58 (d, J = 14.3 Hz, 1H), 4.53 (d, J = 3.7 Hz, 1H), 3.87 (d, J = 14.3 Hz, 1H), 3.84 (d, J = 18.7 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.50 (d, J = 17.8 Hz, 1H), 3.40 (d, J = 14.5 Hz, 1H), 2.83 (d, J = 17.8 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.1, 161.7, 160.8, 159.8, 159.7, 135.6, 132.4, 130.2, 130.2, 129.4, 129.4, 127.4, 125.9, 114.5, 114.3, 60.4, 60.1, 55.5, 55.4, 49.1, 48.1, 47.9, 45.0. HRMS (ESI) m/z calcd for C29H28ClN3NaO5+ [M + Na]+ 556.1610, found 556.1623. cis-8-(Benzo[d][1,3]dioxol-5-yl)-9-(3,4-dimethoxyphenyl)-2-methyltetrahydro-1H-pyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3e). Yield 66 mg, 52%; pale yellow solid; mp 236−237 °C (decomp.). 1 H NMR (400 MHz, CDCl3) δ 6.86 (d, J = 8.3 Hz, 1H), 6.75−6.73 (m, 1H), 6.73−6.71 (m, 1H), 6.62−6.58 (m, 3H), 5.94 (d, J = 1.4 Hz, 1H), 5.93 (d, J = 1.4 Hz, 1H), 5.39 (d, J = 18.8 Hz, 1H), 5.19 (d, J = 3.2 Hz, 1H), 4.84 (d, J = 3.2 Hz, 1H), 3.93 (d, J = 18.8 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.57 (d, J = 17.7 Hz, 1H), 2.71 (d, J = 17.4 Hz, 1H), 2.68 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.6, 161.7, 161.6, 149.9, 149.3, 148.2, 147.3, 134.4, 126.2, 120.4, 120.1, 111.2, 110.4, 108.6, 108.4, 101.8, 66.4, 61.0, 56.1, 56.0, 50.7, 45.3, 33.2. HRMS (ESI) m/z calcd for C23H24N3O7+ [M + H]+ 454.1609, found 454.1618. cis-9-(2-Methoxyphenyl)-8-methyl-2-(p-tolyl)tetrahydro-1Hpyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3g). Yield 73 mg, 62%; white solid; mp 237−238 °C. 1H NMR (400 MHz, CDCl3) δ 7.48− 7.40 (m, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.08 (dd, J = 7.6, 1.7 Hz, 1H), 7.01 (td, J = 7.5, 0.8 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 8.3 Hz, 2H), 5.30 (d, J = 2.4 Hz, 1H), 5.21 (d, J = 18.1 Hz, 1H), 4.85 (d, J = 3.6 Hz, 1H), 3.82 (d, J = 18.0 Hz, 1H), 3.76 (d, J = 17.4 Hz, 1H), 3.69 (s, 3H), 3.13 (d, J = 17.5 Hz, 1H), 2.91 (s, 3H), 2.31 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 161.9, 161.1, 158.3, 138.1, 136.8, 131.2, 130.2 (2C), 125.1, 121.7, 121.1, 111.3, 60.8 (2C), 55.8, 52.0, 51.9, 45.5, 33.8, 21.2. HRMS (ESI) m/z calcd for C22H24N3O4+ [M + H]+ 394.1761, found 394.1770. cis-8-(tert-Butyl)-2-(2-methoxyphenyl)-9-phenyltetrahydro-1Hpyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (3i). Yield 81 mg, 69%; beige solid; mp 234−235 °C. 1H NMR (400 MHz, CDCl3) δ 7.47− 7.39 (m, 2H), 7.39−7.30 (m, 4H), 7.21 (dd, J = 7.7, 1.6 Hz, 1H), 7.05−6.98 (m, 2H), 6.27 (s, 1H), 4.76 (d, J = 16.0 Hz, 1H), 4.66 (s, 1H), 4.49 (d, J = 16.4 Hz, 1H), 3.98 (d, J = 16.6 Hz, 1H), 3.84 (s, 3H), 3.57 (d, J = 16.0 Hz, 1H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.7, 166.3, 164.7, 154.4, 140.7, 130.0, 129.4, 128.6, 128.6, 128.0, 126.1, 121.2, 112.3, 63.3, 59.1, 55.8, 55.0, 53.8, 46.5, 28.3. HRMS (ESI) m/z calcd for C24H28N3O4+ [M + H]+ 422.2074, found 422.2091. 5866

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868

Note

The Journal of Organic Chemistry

5.92 (d, J = 1.5 Hz, 1H), 5.91 (d, J = 1.5 Hz, 1H), 5.74 (d, J = 4.0 Hz, 1H), 5.08 (d, J = 16.8 Hz, 1H), 4.57 (d, J = 4.0 Hz, 1H), 4.15 (d, J = 17.3 Hz, 1H), 4.03 (d, J = 17.3 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.73 (d, J = 16.8 Hz, 1H), 3.06 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.8, 164.2, 163.4, 149.8, 149.2, 147.9, 146.7, 134.1, 130.8, 119.8, 118.7, 111.4, 109.9, 108.2, 108.2, 101.7, 63.2, 61.6, 56.2, 56.0, 52.4, 45.3, 34.5. HRMS (ESI) m/z calcd for C23H24N3O7+ [M + H]+ 454.1609, found 454.1625. General Procedure for the Preparation of Compounds 9a−d and 11. A solution of amine 8a−d (0.28 mmol, 1.0 equiv) or 8e (100 mg, 0.24 mmol), Boc-β-Ala-OH (58 mg, 0.308 mmol, 1.1 equiv) [or Boc-GABA−OH (53 mg, 0.26 mmol)], and HATU (138 mg, 0.364 mmol, 1.3 equiv) in DMF (5 mL) was treated with DIPEA (40 mg, 0.308 mmol, 1.1 equiv). The reaction mixture was stirred at 25 °C for 24 h, and the solvent was removed in vacuo. The residue was taken up in CH2Cl2 (10 mL), washed with water, 5% aq citric acid, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was fractionated by chromatography on silica gel [eluting with CHCl3:EtOAc (3:1)]. The fractions containing the amide coupling product (as judged by 1H NMR) were combined, concentrated in vacuo, and the residue was dissolved in 3:1 t-BuOH:H2O mixture (3 mL) and treated with anhydrous LiOH (13 mg, 0.56 mmol, 2.0 equiv) at 0 °C. After being stirred for 2 h at 0 °C, the reaction was acidified with 1 M HCl (5 mL, pH 2−3) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to afford the hydrolysis product, which was dissolved in dry 1,4-dioxane (2 mL). HCl (4 M) in 1,4-dioxane (3 mL) was added at room temperature. The resulting solution was stirred for 4 h and concentrated in vacuo. The residue was dissolved in 5:1 CH2Cl2:DMF mixture (3 mL) at 0 °C. EDCI (70 mg, 0.364 mmol, 1.3 equiv), DIPEA (54 mg, 0.42 mmol, 1.5 equiv), and HOAt (38 mg, 0.28 mmol, 1.0 equiv) were added, and the reaction mixture was allowed to warm to 25 °C and stirred at that temperature for 16 h. After the volatiles were removed in vacuo, the residue was taken up in CH2Cl2 (10 mL), washed with water, 5% aq citric acid, brine, dried over anhydrous Na2SO4, filtered, and evaporated. The obtained crude product was purified by column chromatography (silica gel) eluted with CH2Cl2:MeOH = 30:1 to 10:1 to afford the title compounds 9a−d or 11. trans-1-(4-Fluorophenyl)-2-propyltetrahydropyrazino[1,2-a][1,4]diazepine-3,6,10(2H,4H,7H)-trione (9a). Yield 52 mg, 56%; white powder; mp 256−257 °C. 1H NMR (400 MHz, CDCl3) δ 7.22 (dd, J = 8.3, 5.0 Hz, 2H), 7.11 (t, J = 8.3 Hz, 2H), 6.02 (br.s, 1H), 5.49 (s, 1H), 4.80 (s, 1H), 4.36 (d, J = 18.2 Hz, 1H), 3.98 (d, J = 18.3 Hz, 1H), 3.72 (ddd, J = 13.4, 10.1, 6.1 Hz, 1H), 3.59 (m, 2H), 3.25−3.09 (m, 2H), 2.68 (m, 2H), 1.79−1.66 (m, 1H), 1.65−1.54 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.2, 168.5, 165.5, 162.5 (d, J = 248.6 Hz), 134.0 (d, J = 3.2 Hz), 127.8 (d, J = 8.2 Hz), 116.4 (d, J = 21.8 Hz), 61.0, 58.2, 49.1, 46.1, 40.6, 33.6, 20.6, 11.4. HRMS (ESI) m/z calcd for C17H20FN3NaO3+ [M + Na]+ 356.1381, found 356.1399. trans-1,2-Diphenyltetrahydropyrazino[1,2-a][1,4]diazepine3,6,10(2H,4H,7H)-trione (9b). Yield 56 mg, 57%; white powder; mp 267−268 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (br.s, 1H), 7.49−7.29 (m, 9H), 7.23 (t, J = 7.3 Hz, 1H), 5.68 (d, J = 1.0 Hz, 1H), 5.33 (d, J = 1.8 Hz, 1H), 4.16 (d, J = 18.1 Hz, 1H), 3.98 (d, J = 18.1 Hz, 1H), 3.56−3.42 (m, 1H), 3.31−3.20 (m, 2H), 2.49−2.37 (m, 1H). 13 C{1H} NMR (101 MHz, DMSO-d6) δ 171.5, 169.2, 164.8, 141.3, 138.2, 128.9, 128.7, 127.9, 126.6, 126.6, 126.1, 61.5, 59.3, 46.2, 38.6, 33.4. HRMS (ESI) m/z calcd for C20H19N3NaO3+ [M + Na]+ 372.1319, found 372.1323. trans-1-(Thiophen-3-yl)-2-(p-tolyl)tetrahydropyrazino[1,2-a][1,4]diazepine-3,6,10(2H,4H,7H)-trione (9c). Yield 63 mg, 61%; white solid; mp 231−232 °C. 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 5.1, 3.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.22 (dt, J = 2.7, 1.1 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 6.96 (dd, J = 5.1, 1.4 Hz, 1H), 6.07 (br.s, 1H), 5.87 (s, 1H), 5.00 (s, 1H), 4.57 (d, J = 18.0 Hz, 1H), 4.02 (d, J = 18.0 Hz, 1H), 3.68−3.49 (m, 2H), 3.27−3.16 (m, 1H), 2.76− 2.68 (m, 1H), 2.33 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.9, 168.2, 166.5, 138.6, 137.9, 137.0, 132.5, 130.7, 126.0, 124.3, 124.2, 50.4, 48.0, 45.9, 35.7, 33.7, 21.3. HRMS (ESI) m/z calcd for C19H20N3O3S+ [M + H]+ 370.1220, found 370.1225.

CHCl3:MeOH = 100:1 to 95:5 for 8c; CH2Cl2:EtOAc = 1:1 to 1:4 for 8e, d). trans-Methyl 3-(4-Fluorophenyl)-5-oxo-4-propylpiperazine-2carboxylate (8a). Yield 160 mg, 68%; light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 8.8, 5.2 Hz, 2H), 7.00 (t, J = 8.6 Hz, 2H), 4.92 (d, J = 2.7 Hz, 1H), 3.84 (ddd, J = 13.5, 8.9, 7.1 Hz, 1H), 3.74 (d, J = 17.8 Hz, 1H), 3.72 (s, 3H), 3.62 (d, J = 2.7 Hz, 1H), 3.54 (d, J = 17.7 Hz, 1H), 2.41−2.31 (m, 1H), 2.27 (br.s, 1H), 1.56− 1.34 (m, 2H), 0.76 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.2, 167.2, 162.5 (d, J = 247.1 Hz), 134.8 (d, J = 3.2 Hz), 128.6 (d, J = 8.2 Hz), 115.7 (d, J = 21.7 Hz), 61.0, 60.3, 52.5, 46.8, 46.6, 20.0, 11.1. HRMS (ESI) m/z calcd for C15H20FN2O3+ [M + H]+ 295.1452, found 295.1459. trans-Methyl 5-Oxo-3,4-diphenylpiperazine-2-carboxylate (8b). Yield 166 mg, 67%; colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.41−7.25 (m, 7H), 7.23−7.11 (m, 3H), 5.40 (d, J = 2.4 Hz, 1H), 3.96 (d, J = 18.1 Hz, 1H), 3.86 (s, 3H), 3.84 (d, J = 18.2 Hz, 1H), 3.84 (d, J = 2.4 Hz, 1H), 2.25 (br.s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.5, 167.4, 141.2, 139.0, 129.1, 128.6, 128.3, 127.3, 127.1, 127.0, 65.2, 61.3, 52.8, 47.2. HRMS (ESI) m/z calcd for C18H19N2O3+ [M + H]+ 311.1390, found 311.1403. trans-Methyl 5-Oxo-3-(thiophen-3-yl)-4-(p-tolyl)piperazine-2carboxylate (8c). Yield 198 mg, 75%; pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.32 (dd, J = 5.0, 3.0 Hz, 1H), 7.21 (ddd, J = 3.0, 1.3, 0.6 Hz, 1H), 7.13−7.08 (m, 3H), 6.98 (d, J = 8.3 Hz, 2H), 5.41 (d, J = 2.6 Hz, 1H), 3.92 (d, J = 18.0 Hz, 1H), 3.89 (d, J = 2.6 Hz, 1H), 3.87 (s, 3H), 3.80 (d, J = 18.0 Hz, 1H), 2.33 (br.s, 1H), 2.29 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 167.2, 140.6, 138.6, 137.4, 129.9, 126.9, 126.8, 126.6, 123.3, 61.4, 60.7, 53.0, 47.2, 21.2. HRMS (ESI) m/z calcd for C17H19N2O3S+ [M + H]+ 331.1111, found 331.1108. trans-Methyl 4-(3-(Methoxycarbonyl)phenyl)-3-(4-nitrophenyl)5-oxopiperazine-2-carboxylate (8d). Yield 122 mg, 37%; white solid; mp 198−199 °C. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 7.5 Hz, 1H), 7.82 (t, J = 1.4 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.39−7.30 (m, 2H), 5.53 (d, J = 2.5 Hz, 1H), 3.94 (d, J = 18.2 Hz, 1H), 3.90 (s, 3H), 3.88 (d, J = 18.1 Hz, 3H), 3.86 (s, 3H),, 3.84 (d, J = 2.6 Hz, 1H), 2.29 (br.s, 1H). 113C{1H} NMR (101 MHz, CDCl3) δ 171.0, 167.0, 166.1, 148.0, 146.1, 140.8, 131.8, 131.6, 129.5, 128.9, 128.5, 128.2, 124.0, 64.4, 60.9, 53.2, 52.4, 47.4. HRMS (ESI) m/z calcd for C20H20N3O7+ [M + H]+ 414.1296, found 414.1298. trans-Methyl 4-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4-dimethoxyphenyl)-5-oxopiperazine-2-carboxylate (8e). Yield 202 mg, 61%; light yellow solid; mp 126−127 °C. 1H NMR (400 MHz, CDCl3) δ 6.88 (dd, J = 8.2, 2.0 Hz, 1H), 6.86−6.81 (m, 2H), 6.69 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.57 (dd, J = 8.2, 2.1 Hz, 1H), 5.92 (d, J = 1.4 Hz, 1H), 5.90 (d, J = 1.4 Hz, 1H), 5.22 (d, J = 2.6 Hz, 1H), 3.91 (d, J = 18.2 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.81 (d, J = 18.1 Hz, 1H), 3.80 (d, J = 2.7 Hz, 1H), 2.15 (br.s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 167.6, 149.3, 149.1, 148.0, 146.9, 135.1, 131.3, 120.6, 119.6, 111.2, 110.3, 108.7, 108.4, 101.6, 65.4, 61.4, 56.1, 56.0, 53.0, 47.3. HRMS (ESI) m/z calcd for C21H23N2O7+ [M + H]+ 415.1500, found 415.1516. trans-8-(Benzo[d][1,3]dioxol-5-yl)-9-(3,4-dimethoxyphenyl)-2methyltetrahydro-1H-pyrazino[1,2-a]pyrazine-1,4,7(6H,8H)-trione (trans-3e). A stirred solution of compound 8e (190 mg, 0.46 mmol), Boc-Sar-OH (130 mg, 1.5 equiv) and Py (54 mg, 1.5 equiv) in dry CH2Cl2 (8 mL) was treated with DCC (189 mg, 2.0 equiv) at 0 °C. The reaction mixture was stirred for 24 h, poured into ice-cold 1 M HCl (10 mL), and extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were washed with water and sat. aq. NaHCO3, dried over anhydrous Na2SO4, and concentrated in vacuo. A brief fractionation on silica gel (CH2Cl2:MeOH = 60:1 to 30:1) yielded the amide coupling product. To a solution of this material (183 mg, 0.31 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (2 mL), and the resulting mixture was stirred at RT for 3 h. The volatiles were removed under reduced pressure; the residue was neutralized by sat. aq NaHCO3 (5 mL) and stirred at ambient temperature for 1 h. The solid was collected by filtration and air-dried to give trans-3e. Yield 136 mg, 66%; white solid; mp 226−227 °C. 1H NMR (400 MHz, CDCl3) δ 6.85−6.78 (m, 2H), 6.75 (t, J = 1.2 Hz, 1H), 6.70−6.67 (m, 3H), 5867

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868

Note

The Journal of Organic Chemistry Methyl 3-(trans-1-(4-Nitrophenyl)-3,6,10-trioxooctahydropyrazino[1,2-a][1,4]diazepin-2(1H)-yl)benzoate (9d). Yield 54 mg, 43%; white solid; mp 269−270 °C. 1H NMR (400 MHz, Acetone-d6) δ 8.42 (dd, J = 8.4, 1.4 Hz, 1H), 8.30 (d, J = 8.8 Hz, 2H), 8.23 (t, J = 1.7 Hz, 1H), 7.93−7.88 (m, 3H), 7.82−7.78 (m, 1H), 7.09 (br.s, 1H), 6.04 (d, J = 1.0 Hz, 1H), 5.53 (d, J = 1.5 Hz, 1H), 4.34 (d, J = 18.4 Hz, 1H), 4.15 (d, J = 18.5 Hz, 1H), 3.89 (s, 3H), 3.78−3.62 (m, 1H), 3.61−3.47 (m, 1H), 3.44−3.33 (m, 1H), 2.63−2.47 (m, 1H). 13C{1H} NMR (101 MHz, Acetone-d6) δ 166.5, 165.0, 163.2, 162.85 149.4, 143.4, 142.3, 132.9, 132.2, 130.5, 130.2, 129.4, 129.1, 124.5, 66.6, 60.7, 52.5, 49.5, 46.0, 29.3. HRMS (ESI) m/z calcd for C22H20N4NaO7+ [M + Na]+ 475.1224, found 475.1233. trans-2-(Benzo[d][1,3]dioxol-5-yl)-1-(3,4-dimethoxyphenyl)tetrahydro-1H-pyrazino[1,2-a][1,4]diazocine-3,6,11(2H,4H,11aH)trione (11). Yield 36 mg, 32%; white solid; mp 211−212 °C. 1H NMR (400 MHz, CDCl3) δ 6.86 (d, J = 8.3 Hz, 1H), 6.79 (dd, J = 8.3, 2.1 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H), 6.64 (dd, J = 8.2, 2.0 Hz, 1H), 6.15 (t, J = 6.1 Hz, 1H), 5.93 (d, J = 1.4 Hz, 1H), 5.92 (d, J = 1.4 Hz, 1H), 4.89 (br.s, 1H), 4.84 (d, J = 19.4 Hz, 1H), 4.66 (s, 1H), 3.95 (d, J = 19.4 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.46−3.32 (m, 2H), 2.56 (ddd, J = 13.8, 6.8, 2.5 Hz, 1H), 2.39−2.29 (m, 1H), 2.03−1.93 (m, 1H), 1.88−1.75 (m, 1H). 13 C{1H} NMR (126 MHz, CDCl3) δ 172.9, 171.8, 164.8, 149.6, 149.5, 148.1, 147.3, 135.2, 131.6, 121.1, 119.2, 111.7, 109.5, 109.0, 108.5, 101.7, 63.9, 56.2 (2C), 56.1, 45.2, 43.8, 35.0, 27.6. HRMS (ESI) m/z calcd for C24H25N3NaO7+ [M + Na]+ 490.1585, found 490.1603.

■

(2) Hirschmann, R. F.; Nicolaou, K. C.; Angeles, A. R.; Chen, J. S.; Smith, A. B. The β-D- Glucose Scaffold as a β-Turn Mimetic. Acc. Chem. Res. 2009, 42, 1511−1520. (3) (a) Brust, A.; Wang, C.-I. A.; Daly, N. L.; Kennerly, J.; Sadeghi, M.; Christie, M. J.; Lewis, R. J.; Mobli, M.; Alewood, P. F. Vicinal Disulfide Constrained Cyclic Peptidomimetics: a Turn Mimetic Scaffold Targeting the Norepinephrine Transporter. Angew. Chem., Int. Ed. 2013, 52, 12020−12023. (b) Chouhan, G.; James, K. Efficient Construction of Proline-Containing β-Turn Mimetic Cyclic Tetrapeptides via CuAAC Macrocyclization. Org. Lett. 2013, 15, 1206−1209. (c) Arbor, S.; Kao, J.; Wu, Y.; Marshall, G. R. c[D-pro-Pro-D-pro-NMethyl-Ala] Adopts a Rigid Conformation That Serves As a Scaffold to Mimic Reverse-Turns. Biopolymers 2008, 90, 384−393. (d) Salvati, M.; Cordero, F. M.; Pisaneschi, F.; Cini, N.; Bottoncetti, A.; Brandi, A. New Cyclic Arg-Gly-Asp Pseudopentapeptide Containing the β-Turn Mimetic GPTM. Synlett 2006, 2006, 2067−2070. (4) Di, L. Strategic approaches to optimizing peptide ADME properties. AAPS J. 2015, 17, 134−143. (5) MacDonald, M.; Aube, J. Approaches to Cyclic Peptide β-Turn Mimics. Curr. Org. Chem. 2001, 5, 417−438. (6) (a) Belov, V. N.; Funke, C.; Labahn, T.; Es-Sayed, M.; de Meijere, A. An Easy Access to Bicyclic Peptides with an Octahydro[2H]pyrazino[1,2-a]pyrazine Skeleton. Eur. J. Org. Chem. 1999, 1999, 1345−1356. (b) Golebiowski, A.; Klopfenstein, S. R.; Shao, X.; Chen, J. J.; Colson, A.-O.; Grieb, A. L.; Russell, A. F. Solid-Supported Synthesis of a Peptide β-Turn Mimetic. Org. Lett. 2000, 2, 2615−2617. (c) Kim, H.-O.; Nakanishi, H.; Lee, M. S.; Kahn, M. Design and Synthesis of Novel Conformationally Restricted Peptide Secondary Structure Mimetics. Org. Lett. 2000, 2, 301−302. (d) Golebiowski, A.; Jozwik, J.; Klopfenstein, S. R.; Colson, A.-O.; Grieb, A. L.; Russell, A. F.; Rastogi, V. L.; Diven, C. F.; Portlock, D. E.; Chen, J. J. SolidSupported Synthesis of Putative Peptide β-Turn Mimetics via Ugi Reaction for Diketopiperazine Formation. J. Comb. Chem. 2002, 4, 584−590. (7) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752−6756. (8) Ritchie, T. J.; Macdonald, S. J. F. The impact of aromatic ring count on compound developability − are too many aromatic rings a liability in drug design? Drug Discovery Today 2009, 14, 1011−1020. (9) Dar’in, D.; Bakulina, O.; Chizhova, M.; Krasavin, M. New Heterocyclic Product Space for the Castagnoli−Cushman ThreeComponent Reaction. Org. Lett. 2015, 17, 3930−3933. (10) Gonzalez-Lopez, M.; Shaw, J. T. Cyclic Anhydrides in Formal Cycloadditions and Multicomponent Reactions. Chem. Rev. 2009, 109, 164−189. (11) Dar’in, D.; Bakulina, O.; Nikolskaya, S.; Gluzdikov, I.; Krasavin, M. The rare cis-configured trisubstituted lactam products obtained by the Castagnoli−Cushman reaction in N,N-dimethylformamide. RSC Adv. 2016, 6, 49411−49415. (12) Lepikhina, A.; Bakulina, O.; Dar’in, D.; Krasavin, M. The first solvent-free synthesis of privileged γ- and δ-lactams via the Castagnoli−Cushman reaction. RSC Adv. 2016, 6, 83808−83813.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00811. Crystallographic information for 8e (CIF) Crystallographic information for 5g (CIF) Crystallographic information for 4c (CIF) Crystallographic information for 3b (CIF) Crystallographic information for 3c (CIF) Crystallographic information for 3a (CIF) Crystallographic information for 9a (CIF) Details of DFT calculations and copies of 1H and 13C NMR spectra(PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Mikhail S. Novikov: 0000-0001-5106-4723 Mikhail Krasavin: 0000-0002-0200-4772 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This research was supported by the Russian Scientific Foundation (Project Grant 14-50-00069). NMR, mass spectrometry, X-ray diffraction studies, and DFT calculations were performed at the Research Center for Magnetic Resonance, the Center for Chemical Analysis and Materials Research, the Center for X-ray Diffraction Methods, and the Computing Center of Research Park of Saint Petersburg State University.

■

REFERENCES

(1) Marcelino, A. M.; Gierasch, L. M. Roles of β-Turns in Protein Folding: From Peptide Models to Protein Engineering. Biopolymers 2008, 89, 380−391. 5868

DOI: 10.1021/acs.joc.8b00811 J. Org. Chem. 2018, 83, 5859−5868