Multicomponent synthesis of 1,3-diketone-linked N-substituted

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Multicomponent synthesis of 1,3-diketone-linked N-substituted pyrroles, pyrrolo[1,2-a]pyrazines, pyrrolo[1,4]diazepines, and pyrrolo[1,4]diazocines Sivanna Chithanna, and Ding-Yah Yang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02819 • Publication Date (Web): 03 Jan 2019 Downloaded from http://pubs.acs.org on January 3, 2019

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The Journal of Organic Chemistry

Multicomponent synthesis of 1,3-diketone-linked N-substituted pyrroles, pyrrolo[1,2-a]pyrazines, pyrrolo[1,4]diazepines, and pyrrolo[1,4]diazocines Sivanna Chithanna and Ding-Yah Yang* Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 40704, Taiwan *Corresponding author; Tel: 886-4-2359-7613; Fax: 886-4-2359-0426; Email: [email protected] KEYWORDS pyrrolopyrazine, pyrrolodiazepine, pyrrolodiazocine, furfural, 1,3-diketone. ABSTRACT: A new methodology is developed for the efficient synthesis of 1,3-diketone-linked N-substituted pyrroles, pyrrolo[1,2-a]pyrazines, pyrrolo[1,4]diazepines, and pyrrolo[1,4]diazocines in good yields via Yb(OTf) 3-catalyzed, nitromethanemediated reaction of primary amine/diamine, furfural, and 1,3-diketone. Possible mechanisms for these multicomponent reactions are also proposed.

1. Introduction N-Substituted pyrroles, pyrrolo[1,2-a]pyrazines, and pyrrolo[1,4]diazepines are one of the versatile and important classes of heterocyclic motifs that are present in natural products and drug molecules. For instance, natural products phakellstatins 1a and 1b1 as well as phakellins 2a and 2b,2 a pyrrole-imidazole family of marine sponge derived alkaloids, were found to exhibit antitumor3 and antibiotic4 activities (Figure 1).

Figure 1. Natural products containing pyrrolo[1,2-a]pyrazine core.

Figure 2 lists some biologically active molecules containing a pyrrolo[1,4]diazepine ring system. Lixivaptan (3) is a potential anti-hyponatremia drug currently under phase III clinical trial for the treatment and prevention of cardiovascular diseases.5 Pyrrolo[1,2-d][1,4]benzodiazepinone derivative 4 is a nonnucleoside HIV-1 reverse transcriptase inhibitor.6 Compound 5 is used as a 18F-labeled radiotracer for in vivo imaging of oxytocin receptors with positron emission tomography.7

Figure 2. Biologically active molecules containing pyrrolo[1,4]diazepine ring system.

Owing to their unique structures and associated biological properties,8 the synthesis of pyrrolo[1,2-a]pyrazines, pyrrolo[1,4]diazepines and their analogues has attracted considerable attention among organic chemists. Most of the known methods for the synthesis of pyrrolopyrazines 9 involve the domino reactions of vinyl azides with 1H-2pyrrolecarbaldehydes,10 or acid-catalyzed condensation of pyrrolacetals,11 or catalytic asymmetric intramolecular AzaFriedel-Crafts reactions of N-aminoethylpyrroles with aldehydes.12 On the other hand, the synthesis of pyrrolodiazepines13 are based on the stepwise annulation of diazepine ring to pyrrole moiety, furan ring opening into 1,4-diketone and then followed by reaction with amine, or Paal-Knorr synthesis.14 Few resort to the synthesis of N-substituted pyrroles, pyrrolo[1,2-a]pyrazines, pyrrolo[1,4]diazepines, and pyrrolo[1,4]diazocines via a one-pot, multicomponent manner. Since the multicomponent reactions (MCRs)15 have been proven to be a powerful synthetic methodology for the preparation of pharmaceutically active molecules, the development of new MCR strategies for efficient construction of pyrrolo[1,2-a]pyrazine, and pyrrolo[1,4]diazepine skeleton remains desired in the field of medicinal chemistry. Recently, we have reported16 a one-pot three-component synthesis of β-enaminone derivatives via Mn(OAc)2-catalyzed, nitromethane-mediated coupling of amine, benzaldehyde, and 1,3-diketone. In our continuing efforts to develop new MCRs for the preparation of novel molecular skeletons and subsequently evaluating their potential biological or functional properties, here we report the facile synthesis of diverse Nsubstituted pyrroles, pyrrolo[1,2-a]pyrazines, pyrrolo[1,4]diazepines, and pyrrolo[1,4]diazocines via Yb(OTf) 3catalyzed, nitromethane-mediated reaction of primary amine/diamine, furfural, and 1,3-diketone. The substrate scope and limitation of this MCR are investigated and the plausible mechanisms for the product formation are proposed.

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2. Results and discussion In our initial study, we chose dimedone (6a), furfural (7a), and benzylamine (8a, 2 equiv.) as the starting materials for this MCR. Upon refluxing of three substrates in nitromethane in the presence of a catalytic amount of Mn(OAc)2 and 4 Å molecular sieve under nitrogen atmosphere, no expected Nsubstituted pyrrole 9a was observed. When the catalyst was switched from Mn(OAc)2 to FeCl3, the compound 9a was isolated in 20% yield. In an aim to increase the yield of this pseudo four-component reaction, different Lewis acids, catalyst loadings, and temperature were then screened as listed in Table 1. Table 1. Optimization of Reaction Conditions for Synthesis of 9a

Temp (oC)

Time (h)

Yield (%)a

Entry

Catalyst/(mol%)

1 2

--Mn(OAc)2/(10)

reflux reflux

6 6

0 trace

3

Cu(OAc)2/(10)

reflux

6

trace

4

Fe(OAc)2/(10)

reflux

6

trace

5

FeCl3/(10)

reflux

6

20

6

Yb(OTf)3/(10)

70

12

0

7

Yb(OTf)3/(10)

reflux

6

65

8

Yb(OTf)3/(20)

reflux

6

67

9

Yb(OTf)3/(10)

reflux

12

60

10

Sc(OTf)3/(10)

reflux

6

20

11

Cu(OTf)2/(10)

reflux

12

30

12

Fe(acac)3/(10)

reflux

12

15

13

p-TsOH/(10)

reflux

6

18

14

AlCl3/(10)

reflux

6

15

15

ZnCl2/(10)

reflux

6

15

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tramolecular hydrogen bonding absorption peak around 12.0– 14.5 ppm was observed for all prepared compounds. 1,3diketones such as dimedone, and quinoline-2,4-dione can serve as the valid substrates for this multicomponent reaction. Table 2. Synthesis of 1,3-Diketone-linked N-substituted pyrroles

Reaction conditions: dimedone (6, 0.5 mmol), furfural (7a, 0.5 mmol), amine 8 (1.0 mmol).

When 9b was refluxed in ethanol along with 1.2 equivalents of benzylamine for 2 h, the n-butylamine on the β-enaminone was found to be replaced with benzylamine to afford the compound 10 in 95% yield (Scheme 1). Similarly, when 10 was refluxed in ethanol with 1.5 equivalents of n-butylamine (11), compound 9b was regenerated along with the formation of benzylamine. These observations suggest that the amineswitching between the β-enaminone moiety of 9b and 10 is a reversible process, allowing easy incorporation of different amines onto the β-enaminone moiety of 9a–d. Scheme 1. Amine-Switching between 9b and 10

Reaction conditions: dimedone (6a, 0.5 mmol), furfural (7a, 0.5 mmol), amine 8a (1.0 mmol). aIsolated yield.

Among them, the Yb(OTf)3 was found to be the most efficient catalyst (entry 7) and the yield can be pushed up to 65%. The increase of the catalyst loading from 10 to 20 mol% had little effect on the yield (entry 8). Hence, refluxing of the three substrates in nitromethane in the presence of 10 mol% of Yb(OTf)3 with 4 Å molecular sieve under nitrogen atmosphere for 6 h was employed as the reaction conditions in the subsequent MCR investigation. Table 2 lists the structures and yields of the four prepared compounds 9a–d via this pseudo four-component reaction. In the proton NMR spectra, an in-

After realizing of the preparation of compounds 9a–d, we then turned our attention to the synthesis of pyrrolo[1,2a]pyrazines, pyrrolo[1,4]diazepines, and pyrrolo[1,4]diazocines. By refluxing of ethylenediamine (12, n = 1) with dimedone and furfural in the presence of 10 mol% of Yb(OTf)3 and 4 Å molecular sieve in nitromethane under nitrogen atmosphere, we were able to isolate the pyrrolo[1,2a]pyrazine 13a in 65% yield as shown in Table 3.

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Table 3. Synthesis of 1,3-Diketone-linked Pyrrolo[1,2a]pyrazines Pyrrolo[1,4]diazepines and Pyrrolo[1,4]diazocines

Scheme 2 can potentially function as protection and deprotection steps for primary amines.18 Scheme 2. Stepwise Synthesis of 13a

Reaction conditions: 1,3-diketone (6, 0.5 mmol), furfural (7, 0.5 mmol), amine 12 (0.5 mmol).

Table 3 lists the structures and yields of the compounds 13a–p prepared by this MCR. To our delight, various 1,3-diketones and substituted furfurals were found to be valid substrates for this three-component reactions. While ethane-1,2-diamine, propane-1,3-diamine, and butane-1,4-diamine can function as the diamine substrate to afford the desired products in moderate to good yields, the diamines bearing five carbons or more such as pentane-1,5-diamine and hexane-1,6-diamine failed to give any corresponding products. This observation may presumably be attributed to the increasing ring strains as the size of the ring increases. All of the prepared compounds were characterized by 1H and 13 C NMR spectroscopy. Similar to the compounds 9a–d, the existence of an intramolecular hydrogen bond between NH proton and carbonyl group oxygen atom of the 1,3-diketone moiety in products 13a–p was observed in the 1H NMR spectroscopy, with the absorption resonating between 12.5–13.8 ppm as a broad singlet. Some molecular structures of the prepared compounds (13d, 13e, 13i, and 13m) were further confirmed by the X-ray crystallographic analysis (see the SI for details).17 To gain insights into the mechanism of this MCR, one equivalent of n-butylamine (11) was reacted with dimedone and furfural in the presence of 10 mol% of Yb(OTf)3 in nitromethane at 70 oC for 4 h, the β-enaminone 14 was isolated in 66% yield as shown in Scheme 2. Further treatment of 14 with ethylenediamine (12) afforded compound 13a, quantitatively, along with the regeneration of n-butylamine (11). Not only does this observation imply that β-enaminone 14 is the intermediate of this MCR but it also suggests the reaction sequence shown in

On the basis of aforementioned information, a plausible mechanism for the formation of 13a from this three-component reaction is then depicted in Scheme 3. It presumably starts with the nitromethane-mediated condensation of dimedone, furfural, and ethylenediamine to give the β-enaminone intermediate 15.16 The nitrogen atom of primary amine of 15 then attacks on C-5 carbon of activated furan ring to generate the enol 16,19 which further undergoes enol-keto tautomerization to produce the ketone 17. The intramolecular cyclization of 17 via the nucleophilic attack of the amine nitrogen to the carbonyl carbon leads to the amino alcohol 18. Final aromatization to the pyrrole ring by removing one molecule of water from 18 affords the pyrrolo[1,2-a]pyrazine 13a. Scheme 3. Proposed Mechanism for the Formation of 13a

Interestingly, when this MCR was carried out via reacting of dimedone and furfural with N-methylethylenediamine rather than ethylenediamine under the optimized reaction conditions, the N-substituted pyrrolo[1,2-a]pyrazine 20a was obtained in 60% yield as shown in Scheme 4. The structure of compound 20a was further confirmed by N-methylation of 13a with methyl iodide in the presence of NaH as a base in THF (Scheme 4). It is worth mentioning that no expected product was observed when N,NꞋ-dimethylethylenediamine (secondary diamine) was employed as the amine substrate for this MCR. Table 4 lists the structures and yields of the prepared compounds 20a–d by this MCR. Since the β-enaminone nitrogen atom of 20a–d was substituted by either methyl or benzyl group, naturally no intramolecular hydrogen bonding absorption peak was observed in 1H NMR spectra.

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Scheme 4. Synthesis of 20a from MCR and from 13a

Table 4. Synthesis of 1,3-Diketone-linked N-Substituted Pyrrolo[1,2-a]pyrazines and Pyrrolo[1,4]diazepines

Reaction conditions: 1,3-diketone (6, 0.5 mmol), furfural (7a, 0.5 mmol), amine 19 (0.5 mmol).

On the basis of aforementioned information, a plausible mechanism for the formation 20a via this MCR is proposed as shown in Scheme 5. Again, it commences with the nitromethane-mediated condensation of dimedone, furfural, and Nmethylethylene diamine to give the β-enaminone intermediate 21.16 Unlike compound 15 shown in Scheme 3, the secondary amine nitrogen of compound 21 cannot undergo intramolecular attack onto the activated furan moiety. Instead, compound 21 undergoes amine-switching with N-methylethylenediamine to yield the thermodynamically less stable N-methylated βenaminone 22. Once formed, compound 22 then follows the same reaction mechanism as described in Scheme 3 to afford the expected cyclized compound 20a. Scheme 5. Proposed Mechanism for the Formation of 20a

3. Conclusions In summary, we have demonstrated that 1,3-diketone-linked N-substituted pyrroles, pyrrolo[1,2-a]pyrazines, pyrrolo[1,4]diazepines, and pyrrolo[1,4]diazocines can be effi-

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ciently synthesized via Yb(OTf)3-catalyzed, nitromethanemediated pseudo four component or three component reaction of primary amine or diamine, furfural, and 1,3-diketone in good yields. This method is operationally simple and is also compatible with a wide range of readily available starting materials. 4. Experimental section Melting points were determined on a Mel-Temp melting point apparatus in open capillaries and are uncorrected. Infrared (IR) spectra were recorded using 1725XFT-IR spectrophotometer. High resolution mass spectra (HRMS) were obtained on a Thermo Fisher Scientific Finnigan MAT95XL spectrometer using magnetic sector analyzer. 1H NMR (400 MHz) and 13C NMR (100 or 150 MHz) spectra were recorded on a Varian VXR300 or Bruker 400/600 spectrometer. Chemical shifts were reported in parts per million on the scale relative to an internal standard (tetramethylsilane, or appropriate solvent peaks) with coupling constants given in hertz. 1H NMR multiplicity data are denoted by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Analytical thin-layer chromatography (TLC) was carried out on Merck silica gel 60G-254 plates (25 mm) and developed with the solvents mentioned. Visualization was accomplished by using portable UV light, ninhydrin spray, or iodine chamber. Flash chromatography was performed in columns of various diameters with Merck silica gel (230–400 mesh ASTM 9385 kieselgel 60H) by elution with the solvent systems. Solvents, unless otherwise specified, were reagent grade and distilled once prior to use. All new compounds exhibited satisfactory spectroscopic and analytical data. General Procedure for the Synthesis of Compounds 9a–d. To a stirred solution of 1,3-diketone (0.5 mmol), furfural (0.5 mmol), and amine (1.0 mmol) in nitromethane (5 mL) was added Yb(OTf)3 (10 mol%) at room temperature. The resulting mixture was refluxed for 6 h under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic phase was washed with saturated NaHCO3 solution (10 mL), water (10 mL) and brine (10 mL), dried over anhydrous Mg2SO4, and evaporated under reduced pressure to provide the crude product. The crude product was purified by column chromatography to obtain the desired compound. 2-((1-Benzyl-1H-pyrrol-2-yl)(benzylamino)methylene)-5,5dimethylcyclohexane-1,3-dione (9a). Yellow liquid; Rf = 0.5 (30% EtOAc/hexanes); 135 mg; yield 65%; 1H NMR (CDCl3, 400 MHz) δ 13.31 (bs, 1H), 7.29–7.23 (m, 6H), 7.09–7.06 (m, 2H), 6.99–6.96 (m, 2H), 6.86 (dd, J = 2.4, 1.6 Hz, 1H), 6.26 (dd, J = 3.2, 2.4 Hz, 1H), 6.13 (dd, J = 3.2, 1.6 Hz, 1H), 4.91, 4.72 (ABq, J = 15.6 Hz, 1H each), 4.27, 3.91 (ABdq, J = 15.6, 6.0 Hz, 1H each), 2.53, 2.45 (ABq, J = 16.8 Hz, 1H each), 2.35 (s, 2H), 1.13 (s, 3H), 1.05 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 199.5, 194.7, 163.3, 137.4, 136.3, 128.86 (2C), 128.85 (2C), 128.0, 127.9, 127.7 (2C), 127.3 (2C), 124.4, 124.0, 110.4, 108.6, 108.4, 53.1, 52.4, 51.2, 48.9, 30.4, 28.6, 28.5; IR νmax (KBr) 3476, 3063, 3030, 2955, 2867, 2242, 1953, 1875, 1714, 1648, 1584, 1555, 1453, 1405, 1333, 1324, 1282, 1140, 1073, 1029, 985, 909, 803, 728, 698 cm−1; HRMS (EI) m/z calcd for C27H28N2O2 [M+] 412.2151, found 412.2148.

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2-((1-Butyl-1H-pyrrol-2-yl)(butylamino)methylene)-5,5dimethylcyclohexane-1,3-dione (9b). Yellow liquid; Rf = 0.6 (30% EtOAc/hexanes); 116 mg; yield 67%; 1H NMR (CDCl3, 400 MHz) δ 13.18 (bs, 1H), 6.80 (dd, J = 3.2, 1.6 Hz, 1H), 6.22 (dd, J = 3.6, 3.2 Hz, 1H), 6.06 (dd, J = 3.6, 1.6 Hz, 1H), 3.65–3.62 (m, 2H), 3.33–3.24 (m, 2H), 2.46 (s, 2H), 2.26 (s, 2H), 1.70–1.56 (m, 4H), 1.40 (sextet, J = 7.2 Hz, 2H), 1.28– 1.19 (m, 2H), 1.06 (s, 3H), 1.03 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 199.2, 194.3, 163.6, 124.0, 123.1, 109.4, 108.3, 108.0, 52.9, 52.3, 47.3, 45.0, 33.0, 32.0, 30.3, 28.7, 28.2, 20.0, 19.9, 13.7, 13.6; IR νmax (KBr) 3518, 3104, 2956, 2933, 2870, 1650, 1558, 1458, 1436, 1332, 1141, 1115, 1071, 981, 715 cm −1; HRMS (EI) m/z calcd for C21H32N2O2 [M+] 344.2464, found 344.2468. (E)-3-((1-Butyl-1H-pyrrol-2-yl)(butylamino)methylene)-1methylquinoline-2,4(1H,3H)-dione (9c). Yellow liquid; Rf = 0.4 (30% EtOAc/hexanes); 124 mg; yield 65%; 1H NMR (CDCl3, 400 MHz) δ 14.60 (bs, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.55 (td, J = 8.8, 1.6 Hz, 1H), 7.19–7.15 (m, 2H), 6.87 (dd, J = 2.8, 2.0 Hz, 1H), 6.29 (dd, J = 3.6, 2.8 Hz, 1H), 6.15 (dd, J = 3.6, 2.0 Hz, 1H), 3.71 (t, J = 7.2 Hz, 2H), 3.47 (s, 3H), 3.38 (q, J = 7.2 Hz, 2H), 1.70–1.58 (m, 4H), 1.49–1.39 (m, 2H), 1.26– 1.17 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 180.7, 166.4, 162.2, 141.5, 132.9, 126.6, 124.3, 122.8, 121.1 (2C), 113.8, 108.9, 108.0, 102.4, 47.1, 45.5, 32.9, 32.1, 28.9, 20.0, 19.8, 13.6, 13.5; IR νmax (KBr) 3477, 2958, 2930, 2871, 1931, 1714, 1640, 1607, 1553, 1475, 1409, 1353, 1339, 1320, 1264, 1101, 1040, 949, 804, 759, 716 cm−1; HRMS (EI) m/z calcd for C23H29N3O2 [M+] 379.2260, found 379.2264. (E)-3-((1-(4-Methoxyphenethyl)-1H-pyrrol-2-yl)((4methoxyphenethyl)amino)methylene)-1-methylquinoline2,4(1H,3H)-dione (9d). Yellow liquid; Rf = 0.3 (30% EtOAc/hexanes); 169 mg; yield 63%; 1H NMR (CDCl3, 400 MHz) δ 14.61 (bs, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.20–7.16 (m, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.81–6.79 (m, 3H), 6.70 (d, J = 8.8 Hz, 2H), 6.27 (dd, J = 3.2, 2.8 Hz, 1H), 6.01 (dd, J = 3.2, 1.2 Hz, 1H), 3.90–3.79 (m, 2H), 3.73 (s, 3H), 3.68 (s, 3H), 3.65–3.56 (m, 1H), 3.44 (s, 3H), 3.34–3.21 (m, 1H), 2.85–2.79 (m, 4H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 180.9, 166.4, 162.3, 158.5, 158.3, 141.7, 133.2, 130.3, 129.8 (2C), 129.7 (3C), 126.8, 124.4, 122.7, 121.6, 121.3, 114.1 (2C), 114.0 (3C), 109.0, 108.5, 102.7, 55.21, 55.17, 49.1, 47.5, 36.4, 35.9, 29.0; IR νmax (KBr) 3475, 2931, 2835, 2241, 2059, 1882, 1636, 1608, 1554, 1511, 1476, 1339, 1321, 1245, 1177, 1102, 1035, 908, 823, 760, 725 cm−1; HRMS (EI) m/z calcd for C33H33N3O2 [M+] 535.2471, found 535.2474. General Procedure for Synthesis of Compounds 9b and 10. To a stirred solution of pyrroloenaminone (9b or 10, 0.5 mmol) in ethanol (5 mL) was added amine (8, 0.6 mmol or 11, 1.5 mmol) at room temperature. The resulting mixture was refluxed for 2 h. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous Mg2SO4, and concentrated under reduced pressure to provide the crude product.

The crude product was then purified by column chromatography to give the desired compound 9b or 10. 2-((Benzylamino)(1-butyl-1H-pyrrol-2-yl)methylene)-5,5dimethylcyclohexane-1,3-dione (10). Yellow liquid; Rf = 0.5 (30% EtOAc/hexanes); 180 mg; yield 95%; 1H NMR (CDCl3, 400 MHz) δ 13.52 (bs, 1H), 7.37–7.29 (m, 3H), 7.20–7.19 (m, 2H), 6.81 (dd, J = 2.8, 2.0 Hz, 1H), 6.22 (dd, J = 4.0, 2.8 Hz, 1H), 6.10 (dd, J = 4.0, 2.0 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 3.63–3.56 (m, 2H), 2.51, 2.45 (ABq, J = 17.2 Hz, 1H each), 2.29 (s, 2H), 1.59−1.49 (m, 2H), 1.24–1.15 (m, 2H), 1.07 (s, 3H), 1.04 (s, 3H), 0.83 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 199.1, 194.0, 163.2, 136.3, 128.6 (2C), 127.5, 126.9 (2C), 123.4, 123.0, 109.4, 108.3, 107.8, 52.6, 52.0, 48.5, 46.9, 32.6, 29.9, 28.4, 27.9, 19.7, 13.3; IR ν max (KBr) 3497, 3104, 3030, 2956, 2931, 2868, 2241, 1953, 1714, 1651, 1585, 1560, 1405, 1306, 1280, 1071, 907, 803, 728, 697 cm−1; HRMS (EI) m/z calcd for C24H30N2O2 [M+] 378.2307, found 378.2305. General Procedure for the Synthesis of Compounds 13a–p and 20a–d. To a stirred solution of 1,3-diketone (0.5 mmol), furfural (0.5 mmol), and amine (0.5 mmol) in nitromethane (5 mL) was added Yb(OTf)3 (10 mol%) at room temperature. The resulting mixture was refluxed for 6 h under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (25 mL) and the organic phase was washed with saturated NaHCO3 solution (10 mL), water (10 mL) and brine (10 mL), dried over anhydrous Mg2SO4, and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography to obtain the desired compound. 2-(3,4-Dihydropyrrolo[1,2-a]pyrazin-1(2H)-ylidene)-5,5dimethylcyclohexane-1,3-dione (13a). Yellow solid; Rf = 0.3 (5% MeOH/CH2Cl2); 84 mg; yield 65%; mp 180–182 oC; 1H NMR (CDCl3, 400 MHz) δ 13.24 (bs, 1H), 7.19 (dd, J = 4.0, 1.6 Hz, 1H), 6.79 (dd, J = 2.0, 1.6 Hz, 1H), 6.24 (dd, J = 4.0, 2.0 Hz, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.69–3.66 (m, 2H), 2.42 (s, 4H), 1.09 (s, 6H); 13C{1H} NMR (CDCl3, 150 MHz) δ 196.4 (2C), 157.8, 125.9, 121.1, 121.0, 109.8, 105.1, 52.5 (2C), 43.0, 40.3, 30.2, 28.3 (2C); IR ν max (KBr) 3104, 2950, 2938, 2889, 2872, 2339, 1738, 1714, 1624, 1558, 1526, 1452, 1430, 1352, 1314, 1290, 1225, 1141, 1082, 1075, 1039, 1009, 944, 923, 887, 825, 771, 755, 701 cm−1; HRMS (EI) m/z calcd for C15H18N2O2 [M+] 258.1368, found 258.1373. (E)-3-(5a,6,7,8,9,9a-Hexahydropyrrolo[1,2-a]quinoxalin4(5H)-ylidene)chroman-2,4-dione (13b). Yellow solid; Rf = 0.4 (3% MeOH/CH2Cl2); 87 mg; yield 52%; mp 178–180 oC; 1 H NMR (CDCl3, 400 MHz) δ 13.64 (bs, 1H), 8.03 (dd, J = 8.4, 2.4 Hz, 1H), 7.58 (dd, J = 4.4, 1.6 Hz, 1H), 7.55–7.51 (m, 1H), 7.25–7.22 (m, 2H), 6.96 (dd, J = 2.4, 1.6 Hz, 1H), 6.33 (dd, J = 4.4, 2.4 Hz, 1H), 4.26–4.22 (m, 1H), 4.05–4.00 (m, 1H), 2.07–1.93 (m, 3H), 1.87–1.77 (m, 2H), 1.70–1.65 (m, 2H), 1.51–1.41 (m, 1H); 13C{1H} NMR (CDCl3, 150 MHz) δ 150.7, 162.8, 159.7, 153.7, 133.3, 125.9, 125.6, 123.3, 122.8, 120.9, 119.5, 116.4, 110.5, 93.0, 53.9, 51.2, 28.5 (2C), 22.4, 20.7; IR νmax (KBr) 2943, 2862, 2248, 1958, 1695, 1605, 1565, 1460, 1448, 1353, 1293, 1100, 947, 814, 754, 726 cm −1;

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HRMS (EI) m/z calcd for C20H18N2O3 [M+] 334.1317, found 334.1315. (E)-6-Methyl-3-(6-methyl-3,4-dihydropyrrolo[1,2a]pyrazin-1(2H)-ylidene)-2H-pyran-2,4(3H)-dione (13c). Yellow solid; Rf = 0.35 (5% MeOH/CH2Cl2); 78 mg; yield 60%; mp 212–214 oC; 1H NMR (CDCl3, 400 MHz) δ 13.59 (bs, 1H), 7.53 (d, J = 4.0 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 5.70 (s, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.72 (t, J = 6.0 Hz, 2H), 2.29 (s, 3H), 2.13 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 184.0, 164.0, 162.0, 159.3, 136.1, 123.0, 120.0, 110.4, 107.6, 92.3, 40.3, 39.4, 19.6, 11.8; IR ν max (KBr) 3132, 2987, 2322, 1738, 1708, 1686, 1664, 1555, 1528, 1502, 1470, 1335, 1303, 1227, 1206, 1151, 1024, 997, 921, 820, 785, 717, 702 cm −1; HRMS (EI) m/z calcd for C14H14N2O3 [M+] 258.1004, found 258.1006. (E)-3-(3,4-Dihydropyrrolo[1,2-a]pyrazin-1(2H)ylidene)chroman-2,4-dione (13d). Yellow solid; Rf = 0.4 (5% MeOH/CH2Cl2); 89 mg; yield 63%; mp 228–230 oC; 1H NMR (CDCl3, 400 MHz) δ 13.68 (bs, 1H), 8.04 (dd, J = 8.4, 1.6 Hz, 1H), 7.56–7.52 (m, 2H), 7.23 (t, J = 8.4 Hz, 2H), 6.90 (s, 1H), 6.33 (dd, J = 4.4, 2.4 Hz, 1H) 4.30 (t, J = 5.6 Hz, 2H), 3.81 (q, J = 5.6 Hz, 2H); 13C{1H} NMR (CDCl3, 150 MHz) δ 180.7, 163.0, 160.2, 153.7, 133.4, 127.2, 125.8, 123.4, 122.6, 120.9, 120.8, 116.4, 110.5, 93.1, 43.0, 40.7; IR νmax (KBr) 3156, 3120, 3106, 2923, 2347, 1965, 1912, 1845, 1736, 1715, 1675, 1608, 1562, 1530, 1462, 1433, 1363, 1346, 1302, 1231, 1198, 1170, 1149, 1085, 1062, 1030, 1007, 960, 942, 890, 861, 781, 740 cm−1; HRMS (EI) m/z calcd for C16H12N2O3 [M+] 280.0848, found 280.0840. 5,5-Dimethyl-2-(2,3,4,5-tetrahydro-1H-pyrrolo[1,2a][1,4]diazepin-1-ylidene)cyclohexane-1,3-dione (13e). White solid; Rf = 0.5 (5% MeOH/CH2Cl2); 92 mg; yield 67%; mp 210–212 oC; 1H NMR (CDCl3, 400 MHz) δ 12.61 (bs, 1H), 6.84 (dd, J = 2.4, 1.6 Hz, 1H), 6.49 (dd, J = 4.0, 1.6 Hz, 1H), 6.18 (dd, J = 4.0, 2.4 Hz, 1H), 4.21 (t, J = 6.8 Hz, 2H), 3.25 (q, J = 6.8 Hz, 2H), 2.39 (s, 4H), 2.25 (quintet, J = 6.8 Hz, 2H), 1.09 (s, 6H); 13C{1H} NMR (CDCl3, 150 MHz) δ 196.8 (2C), 163.7, 125.3, 124.9, 117.4, 108.9, 107.2, 52.6 (2C), 44.8, 41.3, 32.3, 30.2, 28.4 (2C); IR νmax (KBr) 3102, 2958, 2922, 2865, 2361, 1730, 1715, 1630, 1574, 1560, 1536, 1476, 1454, 1441, 1398, 1358, 1343, 1286, 1272, 1235, 1177, 1151, 1096, 1078, 1024, 995, 932, 860, 786, cm−1; HRMS (EI) m/z calcd for C16H20N2O2 [M+] 272.1525, found 272.1516. 2-(2,3,4,5-Tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin-1ylidene)cyclohexane-1,3-dione (13f). Brown solid; Rf = 0.35 (5% MeOH/CH2Cl2); 80 mg; yield 65%; mp 176–178 oC; 1H NMR (CDCl3, 400 MHz) δ 12.63 (bs, 1H), 6.84 (dd, J = 2.8, 1.2 Hz, 1H), 6.51 (dd, J = 4.0, 1.2 Hz, 1H), 6.18 (dd, J = 4.0, 2.8 Hz, 1H), 4.21 (t, J = 6.8 Hz, 2H), 3.27 (q, J = 6.8 Hz, 2H), 2.48 (t, J = 6.8 Hz, 4H), 2.26 (quintet, J = 6.8 Hz, 2H), 1.96 (quintet, J = 6.8 Hz, 2H); 13C{1H} NMR (CDCl3, 150 MHz) δ 197.5 (2C), 164.1, 125.4, 125.1, 117.4, 108.9, 108.4, 44.8, 41.3, 38.7 (2C), 32.3, 19.4; IR ν max (KBr) 3099, 2959, 2935, 2868, 1738, 1717, 1638, 1577, 1555, 1534, 1475, 1455, 1437, 1396, 1346, 1329, 1274, 1232, 1172, 1133, 1095, 999, 987, 922, 862, 813, 770, 742 cm−1; HRMS (EI) m/z calcd for C14H16N2O2 [M+] 244.1212, found 244.1219. 2-(7-Bromo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2a][1,4]diazepin-1-ylidene)-5,5-dimethylcyclohexane-1,3-dione

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(13g). Yellow solid; Rf = 0.5 (3% MeOH/CH2Cl2); 53 mg; yield 30%; mp 196–198 oC; 1H NMR (CDCl3, 400 MHz) δ 12.70 (bs, 1H), 6.49 (d, J = 4.0 Hz, 1H), 6.24 (d, J = 4.0 Hz, 1H), 4.23 (t, J = 6.4 Hz, 2H), 3.22 (q, J = 6.4 Hz, 2H), 2.40 (s, 4H), 2.20 (quintet, J = 6.4 Hz, 2H), 1.09 (s, 6H); 13C{1H} NMR (CDCl3, 150 MHz) δ 196.9 (2C), 162.5, 126.4, 117.2, 111.7, 107.0, 106.7, 52.6 (2C), 42.7, 41.1, 31.6, 30.2, 28.4 (2C); IR νmax (KBr) 3146, 2961, 2886, 2864, 2323, 1738, 1718, 1636, 1576, 1554, 1533, 1445, 1387, 1347, 1333, 1284, 1271, 1249, 1150, 1126, 1101, 1073, 1022, 982, 922, 870, 838, 791, 759, 713 cm−1; HRMS (EI) m/z calcd for C16H19BrN2O2 [M+] 350.0630, found 350.0627. (E)-3-(2,3,4,5-Tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin1-ylidene)chroman-2,4-dione (13h). Yellow solid; Rf = 0.4 (5% MeOH/CH2Cl2); 96 mg; yield 65%; mp 178–180 oC; 1H NMR (CDCl3, 400 MHz) δ 13.23 (bs, 1H), 8.04 (dd, J = 8.4, 1.2 Hz, 1H), 7.54 (td, J = 8.4, 1.2 Hz, 1H), 7.27–7.20 (m, 2H), 6.94 (s, 1H), 6.82 (dd, J = 4.0, 1.2 Hz, 1H), 6.28 (dd, J = 4.0, 2.4 Hz, 1H), 4.28 (t, J = 6.4 Hz, 2H), 3.40 (q, J = 6.4 Hz, 2H), 2.36 (quintet, J = 6.4 Hz, 2H); 13C{1H} NMR (CDCl3, 150 MHz) δ 181.0, 166.7, 162.8, 154.0, 133.7, 126.8, 125.9, 124.0, 123.4, 121.0, 119.6, 116.6, 109.5, 95.2, 45.0, 42.2, 32.4; IR νmax (KBr) 3099, 2970, 2878, 1698, 1607, 1556, 1464, 1355, 1296, 1226, 1158, 1084, 1030, 994, 943, 901, 829, 769, 756, 748 cm−1; HRMS (EI) m/z calcd for C17H14N2O3 [M+] 294.1004, found 294.1007. (E)-3-(7-Methyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2a][1,4]diazepin-1-ylidene)chroman-2,4-dione (13i). Yellow solid; Rf = 0.55 (3% MeOH/CH2Cl2); 104 mg; yield 67%; mp 186–188 oC; 1H NMR (CDCl3, 400 MHz) δ 13.06 (bs, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.51 (t, J = 6.8 Hz, 1H), 7.24–7.20 (m, 2H), 6.78 (d, J = 4.0 Hz, 1H), 6.08 (d, J = 4.0 Hz, 1H), 4.14 (t, J = 6.8 Hz, 2H), 3.37 (q, J = 6.8 Hz, 2H), 2.30 (s, 3H), 2.29 (quintet, J = 6.8 Hz, 2H); 13C{1H} NMR (CDCl3, 150 MHz) δ 180.8, 166.2, 163.0, 154.0, 135.1, 133.5, 125.8, 123.9, 123.3, 121.1, 119.2, 116.6, 109.6, 94.9, 42.2, 41.0, 32.2, 12.3; IR νmax (KBr) 3406, 3115, 2950, 2929, 2341, 1704, 1606, 1557, 1491, 1464, 1356, 1339, 1309, 1222, 1178, 1118, 1076, 1029, 985, 951, 920, 898, 821, 758, 717 cm−1; HRMS (EI) m/z calcd for C18H16N2O3 [M+] 308.1161, found 308.1163. (E)-6-Chloro-3-(2,3,4,5-tetrahydro-1H-pyrrolo[1,2a][1,4]diazepin-1-ylidene)chroman-2,4-dione (13j). White solid; Rf = 0.4 (3% MeOH/CH2Cl2); 96 mg; yield 58%; mp 254–256 oC; 1H NMR (CDCl3, 400 MHz) δ 13.10 (bs, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.47 (dd, J = 8.8, 2.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 2.4, 1.6 Hz, 1H), 6.82 (dd, J = 4.0, 1.6 Hz, 1H), 6.28 (dd, J = 4.0, 2.4 Hz, 1H), 4.29 (t, J = 6.8 Hz, 2H), 3.42 (q, J = 6.8 Hz, 2H), 2.38 (quintet, J = 6.8 Hz, 2H); 13C{1H} NMR (CDCl3, 150 MHz) δ 179.6, 166.7, 162.3, 152.3, 133.5, 128.9, 127.1, 125.5, 123.8, 122.1, 119.9, 118.2, 109.6, 95.0, 45.0, 42.4, 32.4; IR ν max (KBr) 2993, 2931, 2360, 2322, 1905, 1709, 1602, 1566, 1474, 1459, 1440, 1357, 1349, 1333, 1317, 1295, 1277, 1240, 1218, 1186, 1157, 1127, 1089, 1035, 949, 836, 825, 796, 736, 705 cm −1; HRMS (EI) m/z calcd for C17H13ClN2O3 [M+] 328.0615, found 328.0606. (E)-3-(2,3,4,5-Tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepin1-ylidene)quinoline-2,4(1H,3H)-dione (13k). White solid; Rf = 0.4 (3% MeOH/CH2Cl2); 103 mg; yield 70%; mp 322–324 oC;

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H NMR (CDCl3, 400 MHz) δ 13.72 (bs, 1H), 9.04 (bs, 1H), 8.11 (dd, J = 8.4, 1.6 Hz, 1H), 7.43 (td, J = 8.4, 1.6 Hz, 1H), 7.11 (td, J = 8.4, 1.6 Hz, 1H), 6.93–6.90 (m, 2H), 6.80 (dd, J = 4.0, 1.2 Hz, 1H), 6.27 (dd, J = 4.0, 2.8 Hz, 1H), 4.29 (t, J = 6.8 Hz, 2H), 3.37 (q, J = 6.8 Hz, 2H), 2.33 (quintet, J = 6.8 Hz, 2H); 13C{1H} NMR (DMSO-d6, 150 MHz) δ 179.4, 164.7, 163.9, 139.9, 132.3, 125.8, 125.6, 124.8, 120.8, 120.5, 117.3, 114.9, 108.1, 99.3, 44.1, 41.5, 31.8; IR ν max (KBr) 3296, 3021, 2924, 2313, 1737, 1716, 1652, 1607, 1555, 1456, 1437, 1365, 1351, 1281, 1235, 1182, 1162, 1150, 1095, 1079, 1037, 973, 868, 824, 772, 732 cm−1; HRMS (EI) m/z calcd for C17H15N3O2 [M+] 293.1164, found 293.1170. (E)-1-Methyl-3-(2,3,4,5-tetrahydro-1H-pyrrolo[1,2a][1,4]diazepin-1-ylidene)quinoline-2,4(1H,3H)-dione (13l). Yellow solid; Rf = 0.5 (3% MeOH/CH2Cl2); 119 mg; yield 77%; mp 202–204 oC; 1H NMR (CDCl3, 400 MHz) δ 13.72 (bs, 1H), 8.22 (dd, J = 7.6, 2.0 Hz, 1H), 7.55 (td, J = 7.6, 2.0 Hz, 1H), 7.20–7.14 (m, 2H), 6.88 (dd, J = 2.4, 1.2 Hz, 1H), 6.66 (dd, J = 3.6, 1.2 Hz, 1H), 6.26 (dd, J = 3.6, 2.4 Hz, 1H), 4.29 (t, J = 6.8 Hz, 2H), 3.52 (s, 3H), 3.37–3.34 (m, 2H), 2.32 (quintet, J = 6.8 Hz, 2H); 13C{1H} NMR (DMSO-d6, 150 MHz) δ 178.2, 164.9, 162.7, 141.1, 132.8, 125.9, 125.8, 125.2, 121.8, 120.8, 117.0, 114.3, 108.2, 99.4, 44.1, 41.7, 31.8, 28.5; IR νmax (KBr) 3105, 3002, 2929, 2323, 1923, 1717, 1632, 1611, 1574, 1553, 1494, 1474, 1410, 1361, 1324, 1299, 1246, 1224, 1158, 1104, 1078, 1040, 1034, 946, 859, 812, 798, 749 cm−1; HRMS (EI) m/z calcd for C18H17N3O2 [M+] 307.1321, found 307.1325. 5,5-Dimethyl-2-(3,4,5,6-tetrahydropyrrolo[1,2a][1,4]diazocin-1(2H)-ylidene)cyclohexane-1,3-dione (13m).White solid; Rf = 0.5 (3% MeOH/CH2Cl2); 101 mg; yield 70%; mp 221–223 oC; 1H NMR (CDCl3, 400 MHz) δ 12.68 (bs, 1H), 6.80 (dd, J = 2.8, 2.0 Hz, 1H), 6.21 (dd, J = 3.6, 2.8 Hz, 1H), 6.13 (dd, J = 3.6, 2.0 Hz, 1H), 4.21 (dd, J = 14.4, 4.8 Hz, 1H), 3.82 (dd, J = 14.4, 11.2 Hz, 1H), 3.52–3.45 (m, 1H), 2.76–2.68 (m, 1H), 2.41 (s, 2H), 2.38 (s, 2H), 2.05– 1.93 (m, 2H), 1.73–1.65 (m, 2H), 1.08 (s, 6H); 13C{1H} NMR (CDCl3, 150 MHz) δ 198.0, 196.0, 162.9, 125.3, 123.1, 111.2, 109.5, 108.9, 52.4 (2C), 47.3, 43.2, 30.3, 28.7, 28.5 (2C), 28.4; IR νmax (KBr) 3104, 2957, 2932, 2864, 2360, 1725, 1716, 1648, 1577, 1565, 1549, 1478, 1443, 1403, 1365, 1335, 1286, 1277, 1226, 1168, 1138, 1074, 1009, 979, 859, 823, 735 cm−1; HRMS (EI) m/z calcd for C17H22N2O2 [M+] 286.1681, found 286.1680. (E)-6-Methyl-3-(3,4,5,6-tetrahydropyrrolo[1,2a][1,4]diazocin-1(2H)-ylidene)-2H-pyran-2,4(3H)-dione (13n). Brown solid; Rf = 0.5 (5% MeOH/CH2Cl2); 99 mg; yield 72%; mp 200–202 oC; 1H NMR (CDCl3, 400 MHz) δ 13.50 (bs, 1H), 6.87 (dd, J = 2.4, 1.6 Hz, 1H), 6.39 (dd, J = 3.6, 1.6 Hz, 1H), 6.28 (dd, J = 3.6, 2.4 Hz, 1H), 5.72 (s, 1H), 4.24 (dd, J = 14.8, 4.8 Hz, 1H), 3.81 (dd, J = 14.8, 11.6 Hz, 1H), 3.62–3.55 (m, 1H), 2.77–2.70 (m, 1H), 2.12 (s, 3H), 2.06–2.00 (m, 2H), 1.81–1.67 (m, 2H); 13C{1H} NMR (CDCl3, 150 MHz) δ 180.5, 165.7, 163.3, 162.8, 124.2, 123.7, 112.9, 109.8, 107.3, 96.4, 47.5, 44.1, 28.4, 28.1, 19.9; IR ν max (KBr) 3112, 2970, 2951, 2929, 2322, 1993, 1710, 1665, 1567, 1544, 1475, 1461, 1413, 1370, 1358, 1326, 1288, 1228, 1217, 1159,

1076, 1038, 997, 959, 900, 837, 826, 730 cm −1; HRMS (EI) m/z calcd for C15H16N2O3 [M+] 272.1161, found 272.1155. (E)-3-(3,4,5,6-Tetrahydropyrrolo[1,2-a][1,4]diazocin1(2H)-ylidene)chroman-2,4-dione (13o). Yellow solid; Rf = 0.65 (3% MeOH/CH2Cl2); 108 mg; yield 70%; mp 196–198 o C; 1H NMR (CDCl3, 400 MHz) δ 13.32 (bs, 1H), 8.04 (dd, J = 8.0, 1.6 Hz, 1H), 7.53 (td, J = 8.0, 1.6 Hz, 1H), 7.25–7.19 (m, 2H), 6.90 (dd, J = 2.8, 2.0 Hz, 1H), 6.40 (dd, J = 4.0, 2.0 Hz, 1H), 6.30 (dd, J = 4.0, 2.8 Hz, 1H), 4.29 (dd, J = 14.4, 4.4 Hz, 1H), 3.88 (dd, J = 14.4, 12.0 Hz, 1H), 3.69–3.63 (m, 1H), 2.85–2.77 (m, 1H), 2.09–2.04 (m, 2H), 1.85–1.70 (m, 2H); 13 C{1H} NMR (CDCl3, 150 MHz) δ 180.1, 166.0, 160.2, 154.1, 133.7, 125.9, 124.5, 124.0, 123.4, 120.9, 116.7, 113.0, 110.0, 97.0, 47.6, 44.3, 28.4, 28.1; IR ν max (KBr) 3404, 3133, 3118, 2957, 2938, 2330, 1986, 1708, 1606, 1570, 1540, 1465, 1401, 1362, 1337, 1235, 1215, 1158, 1143, 1080, 1064, 1036, 1021, 946, 931, 898, 876, 855, 821, 792, 762, 735, 662 cm −1; HRMS (EI) m/z calcd for C18H16N2O3 [M+] 308.1161, found 308.1165. (E)-7-Methoxy-3-(3,4,5,6-tetrahydropyrrolo[1,2a][1,4]diazocin-1(2H)-ylidene)chroman-2,4-dione (13p). Brown solid; Rf = 0.55 (3% MeOH/CH2Cl2); 116 mg; yield 68%; mp 248–250 oC; 1H NMR (CDCl3, 400 MHz) δ 13.45 (bs, 1H), 7.95 (d, J = 8.8 Hz, 1H), 6.89 (dd, J = 2.8, 1.6 Hz, 1H), 6.79 (dd, J = 8.8, 2.8 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 6.69 (dd, J = 4.0, 1.6 Hz, 1H), 6.30 (dd, J = 4.0, 2.8 Hz, 1H), 4.28 (dd, J = 14.4, 4.4 Hz, 1H), 3.91–3.84 (m, 4H), 3.68–3.60 (m, 1H), 2.83–2.75 (m, 1H), 2.08–2.01 (m, 2H), 1.84–1.68 (m, 2H); 13C{1H} NMR (CDCl3, 150 MHz) δ 180.1, 165.9, 164.4, 162.1, 156.0, 127.3, 124.21, 124.17, 114.1, 112.8, 111.6, 110.0, 100.1, 96.3, 55.7, 47.5, 44.2, 28.5, 28.2; IR ν max (KBr) 3398, 3124, 3099, 2998, 2947, 2332, 1904, 1707, 1607, 1566, 1538, 1473, 1437, 1354, 1332, 1230, 1196, 1150, 1020, 977, 824, 754, 744 cm−1; HRMS (EI) m/z calcd for C19H18N2O4 [M+] 338.1267, found 338.1271. 5,5-Dimethyl-2-(2-methyl-3,4-dihydropyrrolo[1,2a]pyrazin-1(2H)-ylidene)cyclohexane-1,3-dione (20a). Yellow solid; Rf = 0.5 (10% MeOH/CH2Cl2); 82 mg; yield 60%; mp 208–210 oC; 1H NMR ( CDCl3, 400 MHz ) δ 6.93–6.92 (m, 2H), 6.29 (dd, J = 4.0, 2.8 Hz, 1H), 4.32 (t, J = 6.0 Hz, 2H), 3.95 (d, J = 6.0 Hz, 2H), 2.36, 2.30 (ABq, J = 16.0 Hz, 2H each), 1.18 (s, 3H), 1.10 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 191.1 (2C), 164.0, 128.5, 124.5, 123.1, 112.0, 103.6, 50.9 (2C), 50.1, 42.8, 41.9, 30.9, 28.8, 28.1; IR ν max (KBr) 3383, 3235, 3090, 2953, 2888, 2223, 1672, 1597, 1568, 1510, 1428, 1418, 1353, 1264, 1208, 1146, 1120, 1078, 1043, 906, 861, 766, 720 cm−1; HRMS (EI) m/z calcd for C16H20N2O2 [M+] 272.1525, found 272.1514. 2-(2-Benzyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)ylidene)-5,5-dimethylcyclohexane-1,3-dione (20b). Yellow solid; Rf = 0.6 (10% MeOH/CH2Cl2); 102 mg; yield 58%; mp 252–254 oC; 1H NMR ( CDCl3, 400 MHz ) δ 7.38–7.35 (m, 5H), 7.02 (dd, J = 4.0, 1.6 Hz, 1H), 6.91 (dd, J = 2.4, 1.6 Hz, 1H), 6.31 (dd, J = 4.0, 2.4 Hz, 1H), 4.79 (s, 2H), 4.07 (dd, J = 7.2, 5.6 Hz, 2H), 3.82 (dd, J = 7.2, 5.6 Hz, 2H), 2.41, 2.32 (ABq, J = 16.4 Hz, 2H each), 1.21 (s, 3H), 1.07 (s, 3H); 13 C{1H} NMR (CDCl3, 100 MHz) δ 192.0 (2C), 164.9, 134.4, 129.4 (3C), 128.9, 128.8 (2C), 125.2, 124.7, 112.9, 104.0,

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58.0, 51.3 (2C), 46.5, 43.2, 31.5, 29.2, 28.5; IR ν max (KBr) 3118, 3022, 2947, 2924, 2860, 2320, 1737, 1713, 1559, 1526, 1499, 1420, 1354, 1230, 1217, 1204, 1118, 1068, 1041, 982, 854, 757, 712 cm−1; HRMS (EI) m/z calcd for C22H24N2O2 [M+] 348.1838, found 348.1836. 5,5-Dimethyl-2-(2-methyl-2,3,4,5-tetrahydro-1Hpyrrolo[1,2-a][1,4]diazepin-1-ylidene)cyclohexane-1,3-dione (20c). Yellow solid; Rf = 0.5 (8% MeOH/CH2Cl2); 94 mg; yield 65%; mp 224–226 oC; 1H NMR (CDCl3, 400 MHz) δ 6.97 (dd, J = 2.4, 1.6 Hz, 1H), 6.61 (dd, J = 4.0, 1.6 Hz, 1H), 6.17 (dd, J = 4.0, 2.4 Hz, 1H), 4.24 (t, J = 7.2 Hz, 2H), 3.57 (t, J = 7.2 Hz, 2H), 3.29 (s, 3H), 2.44 (quintet, J = 7.2 Hz, 2H), 2.37, 2.27 (ABq, J = 16.0 Hz, 2H each), 1.17 (s, 3H), 1.06 (s, 3H); 13C{1H} NMR (CDCl3, 150 MHz) δ 193.2 (2C), 167.0, 129.0, 128.6, 121.4, 110.1, 108.2, 51.9, 51.8, 44.6, 43.1, 30.8, 30.3, 29.6, 28.8, 28.4; IR ν max (KBr) 3112, 2950, 2925, 2861, 2323, 1739, 1714, 1617, 1560, 1543, 1520, 1416, 1382, 1360, 1338, 1318, 1183, 1138, 1066, 1028, 903, 893, 846, 761, 742, 721 cm−1; HRMS (EI) m/z calcd for C17H22N2O2 [M+] 286.1681, found 286.1677. (E)-3-(2-Methyl-2,3,4,5-tetrahydro-1H-pyrrolo[1,2a][1,4]diazepin-1-ylidene)chroman-2,4-dione (20d). Brown solid; Rf = 0.4 (5% MeOH/CH2Cl2); 96 mg; yield 62%; mp 176–178 oC; 1H NMR (CDCl3, 400 MHz) δ 8.04 (dd, J = 8.4, 1.6 Hz, 1H), 7.50 (td, J = 8.4, 1.6 Hz, 1H), 7.20–7.14 (m, 2H), 7.13–7.10 (m, 1H), 6.81 (dd, J = 4.0, 1.6 Hz, 1H), 6.23 (dd, J = 4.0, 2.8 Hz, 1H), 4.32 (t, J = 6.8 Hz, 2H), 3.70 (t, J = 6.8 Hz, 2H), 3.50 (s, 1H), 2.58–2.50 (m, 2H); 13C{1H} NMR (CDCl3, 150 MHz) δ 176.0, 166.8, 162.8, 154.4, 132.6, 130.5, 128.1, 125.9, 123.5, 123.1, 121.6, 116.6, 111.0, 95.2, 52.8, 44.9, 43.2, 30.5; IR ν max (KBr) 3462, 3103, 3050, 2937, 2359, 2330, 2249, 2114, 1933, 1673, 1602, 1568, 1550, 1461, 1421, 1215, 1158, 1057, 1020, 952, 904, 758, 730 cm −1; HRMS (EI) m/z calcd for C18H16N2O3 [M+] 308.1161, found 308.1166. Procedure for the Synthesis of Compound 14. To a stirred solution of dimedone (6, 0.5 mmol), furural (7, 0.5 mmol) and n-butylamine (11, 0.5 mmol) in nitromethane (5 mL) was added, Yb(OTf)3 (10 mol%) at room temperature. The resulting mixture was stirred at 70 oC for 4 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic phase was washed with saturated NaHCO3 solution (10 mL), water (10 mL) and brine (10 mL), dried over anhydrous Mg2SO4 and evaporated under reduced pressure to provide the crude product. The crude product was purified by column chromatography to afford the compound 14. 2-((Butylamino)(furan-2-yl)methylene)-5,5dimethylcyclohexane-1,3-dione (14). Brown solid; Rf = 0.5 (50% EtOAc/hexanes); 96 mg; yield 66%; mp 82–84 oC; 1H NMR (CDCl3, 400 MHz) δ 12.84 (bs, 1H), 7.56 (dd, J = 1.6, 0.4 Hz, 1H), 6.52 (dd, J = 3.6, 1.6 Hz, 1H), 6.50 (dd, J = 3.6, 0.4 Hz, 1H), 3.32 (q, J = 7.2 Hz, 2H), 2.38 (s, 4H), 1.60 (quintet, J = 7.2 Hz, 2H), 1.38 (sextet, J = 7.2 Hz, 2H), 1.06 (s, 6H), 0.90 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 150 MHz) δ 197.0 (2C), 159.8, 144.7, 143.6, 111.9, 111.0, 108.3, 52.4 (2C), 44.9, 32.0, 30.4, 28.3 (2C), 19.8, 13.5; IR νmax (KBr) 2943, 2345, 2322, 1738, 1716, 1647, 1597, 1565, 1425, 1367,

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1217, 1072, 1023, 877, 776, 749 cm−1; HRMS (EI) m/z calcd for C17H23NO3 [M+] 289.1678, found 289.1671. Procedure for the Synthesis of Compound 13a from 14. To a stirred solution of compound 14 (0.5 mmol) in ethanol (5 mL) was added ethylenediamine (0.6 mmol) at room temperature. The resulting mixture was refluxed for 2 h. After completion of the reaction, the mixture was cooled to room temperature and diluted with dichloromethane (50 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous Mg2SO4 and evaporated under reduced pressure to provide the crude product. The crude product was purified by column chromatography to give the compound 13a (128 mg, 99%) as a yellow solid. Procedure for the Synthesis of Compound 20a from 13a. To a suspension of NaH (0.6 mmol) in dry THF (3 mL) was added sequentially 13a (0.5 mmol) dissolved in 3 mL of dry THF) and methyl iodide (1.0 mmol) at 0 oC. After the addition, the reaction mixture was warmed to room temperature and was further stirred for 2 h under nitrogen atmosphere. The reaction was then quenched by ice water and the product was extracted with DCM (5 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous Mg2SO4, and concentrated in vacuo. The residue was purified by column chromatography to get the compound 20a (134 mg, 98%) as a yellow solid. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Copies of 1H and 13C NMR spectra of the synthesized compounds (PDF) Crystallographic details for 13d (CIF) Crystallographic details for 13e (CIF) Crystallographic details for 13i (CIF) Crystallographic details for 13m (CIF) AUTHOR INFORMATION

Corresponding Author *Email: [email protected]

ORCID Ding-Yah Yang: 0000-0002-3611-2042 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank the Ministry of Science and Technology of the Republic of China, Taiwan, for financially supporting this research under Contract No. MOST 107-2113-M-029-002.

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Multicomponent synthesis of 1,3-diketone-linked N-substituted

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