Synthesis of Intricate Fused N-Heterocycles via Ring-Rearrangement

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Synthesis of Intricate Fused N-Heterocycles via Ring-Rearrangement Metathesis Sambasivarao Kotha, and Rama Gunta J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01299 • Publication Date (Web): 19 Jul 2017 Downloaded from http://pubs.acs.org on July 19, 2017

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The Journal of Organic Chemistry

Synthesis of Intricate Fused N-Heterocycles via Ring-Rearrangement Metathesis Sambasivarao Kotha* and Rama Gunta Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai-400076, India Fax: 022-25767152; E-mail: [email protected]

ABSTRACT Herein, a facile synthesis of intricate fused N-heterocycles has been disclosed by employing C–H activation and ring-rearrangement metathesis/enyne ring-rearrangement metathesis as key steps. Interestingly, some of these N-heterocyclic products possess the tricyclic core of epimeloscine, deoxycalyciphylline B, daphlongamine H, isodaphlongamine H and a bioactive alkaloid, annotinolide A, which shows anti-aggregation activity against amyloid-β (Aβ)1−42 peptide aggregation. Moreover, various starting materials required in this protocol are easily assembled via C–X bond annulation of 2-bromo-N-protected aniline with norbornadiene or directing groupassisted ruthenium-catalyzed C–H activation of N-methoxybenzamide. INTRODUCTION N-Heterocycles are ubiquitous building blocks present in alkaloids1 (1 and 2a–2g, Figure 1), and medicinally important compounds. Alkaloids exhibit interesting biological properties such as anti-inflammatory action and anti-tumour activity due to the inhibition of protein synthesis.2 For example, annotinolide A (1, Figure 1)) is a Lycopodium alkaloid,3 which shows anti-aggregation activity against amyloid-β (Aβ)1−42 peptide aggregation for the treatment of Alzheimer’s

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disease.4 However, ring-rearrangement metathesis5 (RRM) approach seems to be a powerful tool in assembling complex targets involving non-traditional pathways. These indirect and short synthetic sequences provide new tactics to enhance synthetic efficiency and improve the atomeconomy of the target molecule. Limited number of complex norbornene derivatives are studied in the context of RRM. It is evident from the literature that the C–H activation6 has emerged as an active field of research in recent times. In this regard, unactivated aromatic C–H bonds are functionalized by Catellani reaction using palladium catalysts and norbornene.7

Figure 1. Representative Examples of Fused Alkaloids In view of our interest in RRM, here, we designed a new synthetic strategy to assemble various N-heterocycles by employing RRM or enyne ring-rearrangement metathesis8 (ERRM) in combination with palladium-catalyzed C–X bond annulation7a,9 or ruthenium-catalyzed C–H activation as key steps. We also plan to utilize the ERRM products in the Diels–Alder10 (DA) reaction to enhance the diversity of this methodology. RESULTS AND DISCUSSION A retrosynthetic strategy to N-heterocycles via RRM/ERRM is illustrated in Figure 2. Initially, fused azacycle 3 synthesis would be accomplished from N-allyl precursor 4 by RRM which in turn could be prepared from the N-Boc-protected methanocarbazole 5 (S1, Figure 2). Moreover, the DA adduct 6 can be derived from the corresponding tetracyclic 1,3-diene 7. Further, the diene 7 would be generated from N-propargyl carbazole 8, which can also be synthesized from the NBoc-protected methanocarbazole 5. In another instance, we speculated that the tetracyclic amide


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9 could be derived from functionalized lactam 10 that can be synthesized from the tetracyclic amide 11 (S2, Figure 2). Furthermore, the enyne ring-rearranged product 12 could be produced from N-propargyl precursor 13 which in turn would be obtained from the known11 tetracyclic heterocycle 11.

Figure 2. Retrosynthetic Analysis of N-Heterocycles To realize the strategy S1 depicted in Figure 2, initially, Boc-protected 2-bromoaniline was prepared by using the literature procedure.12 Next, palladium-catalyzed annulation of Bocprotected 2-bromoaniline (15) with norbornadiene (NBD) gave the known N-Boc-protected methanocarbazole 5.9 Then, the Boc group present in 5 was removed by treating with an excess amount of HCl gas (generated by dropwise addition of Conc. H2SO4 to NaCl) in EtOAc at room temperature (rt). Here, the deprotected compound 14 was obtained in quantitative yield (Scheme 1), which was used in the next step without any additional purification. Moreover, alkylation of the compound 14 with allyl bromide in the presence of NaH in dimethylformamide (DMF) gave the RRM precursor 4 in 44% yield (Path A, Scheme 1). Alternatively, the RRM precursor 4 can be synthesized by avoiding protection and deprotection steps (Path B, Scheme 1).13 In this regard, 2-bromo-N-allylaniline (15a) was



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prepared by allylation of 2-bromoaniline by following the literature procedure.14 Next, the aniline derivative 15a was subjected to palladium-catalyzed annulation with NBD in the presence of Cs2CO3 by using tri-tert-butylphosphonium tetrafluoroborate (t-Bu3PHBF4) ligand under toluene reflux conditions. To our delight, the desired N-allyl precursor 4 was formed in 70% yield (Path B, Scheme 1). When the compound 4 was treated with Grubbs first generation (G-I) catalyst in the presence of ethylene, the ring-rearranged product 3 was delivered in 52% yield along with the ring-opened product 16 (35%). However, the ring-opened product 16 can be further converted into the desired tetracyclic compound 3 under similar reaction conditions. The structure of the RRM product 3 has been established on the basis of 1H NMR,

13

C NMR and

HRMS data. Identical spectral data was observed for the tetracyclic product 3 in both these approaches (Paths A and B). The RRM product 3 has been synthesized in two steps via Path B from the readily prepared aniline derivative 15a. Scheme 1. Synthesis of Tetracyclic Derivative 3

To expand the diversity of RRM strategy, the indole derivative 14 was treated with propargyl bromide in the presence of NaH in THF at 70 oC for 8 h to obtain the N-propargyl derivative 8 but in low yield (18%). On the other hand, when this reaction was performed in DMF at rt, the yield of the desired N-propargyl product 8 was increased to 69% (Scheme 2). Subsequently, the propargyl compound 8 was treated with G-I catalyst in the presence of ethylene to produce a


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mixture of enyne ring-rearranged product 7 (69%) and ring-opened product 17 (22%). Moreover, the ring-opened product 17 on treatment with Grubbs second generation (G-II) catalyst underwent enyne metathesis15 (EM) in the presence of ethylene to deliver the desired 1,3-diene 7 in 70% yield. Later, DA reaction of the diene 7 with a dienophile, tetracyanoethylene (TCE) in refluxing toluene gave the DA adduct 6 in 52% yield and its structure has been elucidated on the basis of spectroscopic data and tentatively assigned as 6. Interestingly, the N-heterocycles 3, 6 and 7 possess the tricyclic core of the alkaloids epimeloscine (2c), deoxycalyciphylline B (2e), daphlongamine H (2f) and isodaphlongamine H (2g) (see Figure 1). Scheme 2. Realization of Fused N-Heterocycles 7 and 6 using ERRM-DA Protocol

To generalize the scope of this methodology, next, our efforts were directed towards the synthesis of polycyclic amides 9 and 12 (S2, Figure 2) containing six-membered ring. In this regard, N-methoxybenzamide (18) was prepared starting with benzoic acid by using Guimond and co-workers’ procedure.16 Next, by following Li and co-workers report,11 rutheniumcatalyzed oxidative C–H bond activation of 18 using NBD gave the tetracyclic amide 11 (50%) (Scheme 3). Nevertheless, we have also isolated benzamide (19%) as a byproduct. Further, allylation of the tetracyclic amide 11 was carried out with allyl bromide in the presence of NaH in DMF at rt. Here, the N-allyl precursor 10a was obtained in 95% yield which was then treated



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with G-I catalyst in the presence of ethylene in CH2Cl2 at rt as well as in reflux conditions. Under these reaction conditions, norbornene ring-opened product 19 was obtained in 14% yield. Interestingly, the metathesis17 sequence was realized when 10a was exposed to G-II catalyst in the presence of ethylene in toluene at 80 °C. The RRM product 9a was afforded in 77% yield (Scheme 3). The structure of 9a has been established on the basis of 1H NMR, 13C NMR, DEPT135 and HRMS data. Its stereochemistry was confirmed by a single-crystal X-ray diffraction analysis (see the Supporting Information).18 It is worth mentioning that the tetracyclic product 9a comprises of tricyclic skeleton of annotinolide A (1) alkaloid. Scheme 3. Synthesis of Tetracyclic Amide 9a by RRM

In view of these promising results, alkenylation of the N-heterocycle 11 was carried out using 4bromo-1-butene and 5-bromo-1-pentene under similar reaction conditions to furnish the RRM precursors 10b (77%) and 10c (89%) respectively in good yields (Scheme 4). Subsequently, norbornene derivative 10b underwent RRM very smoothly with G-I catalyst in the presence of ethylene in CH2Cl2 at rt to afford rearranged tetracyclic amide 9b in excellent yield (98%). Similarly, other norbornene derivative 10c under similar reaction conditions gave the RRM product 9c (73%). Here, RRM of 10c took less reaction time by increasing the catalyst loading from 5 mol % to 10 mol %. The structures of tetracyclic compounds 9b and 9c have been determined by 1H NMR, 13C NMR, DEPT-135 and HRMS data. Along similar lines, hexenyl precursor 10d (91%) was synthesized from the tetracyclic amide 11 and then, it was exposed to Grubbs catalysts (G-I and G-II) in the presence of ethylene in


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refluxing CH2Cl2 or toluene at 80 °C to realize the RRM product 9d. Unfortunately, the desired product 9d was not observed, instead the norbornene ring-opened product 20 was formed in 26% yield (Scheme 5). Apparently, this observation may be explained on the basis of unfavorable transannular steric interactions present in the nine-membered ring which may be responsible for the absence of RRM product 9d. Scheme 4. RRM Route to Tetracyclic Amides 9b and 9c

Scheme 5. Attempted Synthesis of Nine-Membered Cyclic Amide 9d

11

Br ( )4 (2 equiv) NaH, DMF 80 oC, 3 h, 91%

O N

10d

( )4

C2H4 G-II (7 mol %) toluene, 80 oC 3 h, 26% (or) C2H4 G-I (10 mol %) CH2Cl2, reflux 7 h, 10%

O

O N H 20

( )4

N

H

H

H 9d

(expected)

To expand the scope of this methodology, the tetracyclic amide 11 reacted with propargyl bromide in DMF at 35–40 oC to furnish allene derivative 21 (47%) as a major product along with the desired ERRM precursor 13 (23%) (Scheme 6). However, when this reaction was carried out at 0 oC, the propargyl derivative 13 was formed in excellent yield (98%). Next, the ERRM precursor 13 on treatment with G-I catalyst in the presence of ethylene in toluene at 80 °C generated only cross EM product 22 in 24% yield. Surprisingly, under toluene reflux conditions (entry 1, Table 1), we isolated dienamide 23 in 45% yield instead of the expected diene 12



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(Scheme 6). This may be explained as the propargyl derivative 13 had undergone tandem ERRM and olefin isomerization19 to deliver the more stable dienamide 23 than the desired diene 12 due to the extended conjugation with the amide group. When the temperature decreased to 80 oC, a mixture of the dienes 23 (22%) and 12 (9%) were obtained (entry 2, Table 1). We have also tested the one-pot ERRM and DA reaction sequence (entry 3, Table 1). In this context, no DA adduct was observed, on the other hand, the dienamide 23 (43%) was formed. Unfortunately, DA reactions of the 1,3-diene 23 with the dienophiles such as TCE or N-phenyl maleimide in refluxing toluene were unsuccessful which may also account for the extended conjugation of diene moiety with the amide group. Scheme 6. ERRM Approach to Polycyclic Amides 12 and 23 Br (1.5 equiv) 11

N

NaH, DMF 0 oC, 45 min, 98%

Br NaH, DMF 35-40 oC (1.5 equiv) 3.5 h

N

•

21 (47%)

H

N and/or

H 13

23 dienophile CN CN CN

O

O

22

NC

N

N (23%)

O N

conditions table 1

C2H4 G-I (10 mol %) toluene, 80 oC 10 h, 24%

O 13

O

O

H

24 H

Table 1. Reaction Conditions Screened for ERRM of 13 Entry reaction conditions

product (%yield)

1

23 (45)

C2H4, G-II (10 mol %) toluene, reflux, 48 h

2

C2H4, G-II (10 mol %)

23 (22) and 12 (9)

toluene, 80 oC, 53 h 3

C2H4, G-II (10 mol %), Ti(Oi-Pr)4 23 (43) toluene, 100 oC 13 h; then TCE, 2 h (No DA adduct observed)

CONCLUSION


H 12

H

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In summary, for the first time, we have successfully demonstrated that a combination of C–H activation with RRM is a useful strategy to assemble fused N-heterocycles. Additionally, various structurally intricate polycyclic amides 9a–9c and 23, which are difficult to prepare by conventional methods, were synthesized in two step sequence using RRM/ERRM approach. To expand this methodology, the conjugated 1,3-diene 7 was used in the DA reaction. Interestingly, N-heterocycles 3, 6 and 7 possess the tricyclic frame work of the alkaloids epimeloscine (2c), deoxycalyciphylline B (2e), daphlongamine H (2f) and isodaphlongamine H (2g) while fused azacycle 9a contains the tricyclic core of annotinolide A (1). The main advantage of RRM process is that stereochemical information from the starting material is transferred to the product and a broad range of functional groups are tolerated. Since many alkaloids exhibit interesting biological properties our results may be of interest in preparing pharmaceutically important “drug like” molecules.2a,20

EXPERIMENTAL SECTION General Information All reactions were carried out under nitrogen or argon atmosphere in oven-dried glassware. Air and moisture sensitive reactions were performed in degassed solvents. Transfer of moisture sensitive materials were carried out using standard syringe‒septum techniques and monitored by thin-layer chromatography (TLC) using an appropriate mixtures of ethyl acetate (EtOAc) and petroleum ether. Dry dichloromethane (CH2Cl2) and toluene were obtained by distillation over P2O5. Dry dimethylformamide (DMF) was prepared by stirring over CaH2 for 2 h at rt followed by vacuum distillation. Tri-tert-butylphosphonium tetrafluoroborate (t-Bu3PHBF4) was purchased from Alfa Aesar (L19752) whereas 2,2,2-trifluoroethanol (CF3CH2OH or TFE) was purchased from Spectrochem Pvt. Ltd. (Cat. No. 0120114). TFE was dried prior to use by stirring over a mixtute of anhydrous CaSO4 and NaHCO3 (5:1 ratio) at rt for 2 h followed by distillation. All the commercial grade reagents were used without any purification until otherwise specified. Melting points were recorded on a Veego or Büchi melting point apparatus and are uncorrected. Nuclear Magnetic Resonance (NMR) spectra were generally recorded on Bruker (AvanceTM 400 or AvanceTM III 500) spectrometers operated at 400 or 500 MHz for 1H and 100.6 or 125.7 MHz for

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C nuclei. NMR samples were generally made in chloroform-d solvent and chemical shifts

(δ values) were reported in parts per million (ppm) using tetramethylsilane (TMS) as an internal standard. Coupling constants (J values) were reported in hertz (Hz). The high-resolution mass



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spectrometric (HRMS) measurements were carried out using a Bruker (Maxis Impact) spectrometer. Infrared (IR) spectra were recorded on a Nicolet Impact-400 or Cary 630 FT-IR spectrometers. Deprotection of Methanocarbazole 5: A solution of N-Boc-protected methanocarbazole 5 (495 mg, 1.75 mmol) in dry EtOAc (15 mL) was purged with an excess amount of HCl gas which was generated by the slow drop-wise addition of Conc. H2SO4 (30 mL) using a glass addition funnel over NaCl (15 g) in another two-neck round-bottomed flask. After 45 min, the colourless solution turned to brown colour and the reaction was completed (TLC monitoring). The solvent was removed under reduced pressure to get pure titled compound 14 (320 mg) as brown liquid in a quantitative yield. This compound was used in the next step without further purification. 1

H NMR (500 MHz, CDCl3): δ (ppm) = 7.06 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.69

(t, J = 7.3 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 6.29 (dd, J = 5.6, 2.8 Hz, 1H), 6.04 (dd, J = 5.5, 2.9 Hz, 1H), 3.95 (d, J = 8.0 Hz, 1H), 3.44 (d, J = 7.7 Hz, 1H), 2.88 (d, J = 19.4 Hz, 2H), 1.62 (d, J = 9.0 Hz, 1H), 1.49 (d, J = 8.9 Hz, 1H); 13C NMR (125.7 MHz, CDCl3): δ (ppm) = 153.9 (s), 139.8 (d), 135.5 (d), 130.2 (s), 127.9 (d), 124.4 (d), 118.7 (d), 109.5 (d), 64.3 (d), 50.7 (d), 50.5 (d), 48.5 (d), 42.5 (t); HRMS (ESI, Q-ToF) m/z: calculated for C13H14N [M+H]+: 184.1121, found: 184.1126; IR (neat): νmax = 3403, 3054, 2926, 2872, 1601, 1483, 1250, 1157, 796, 699 cm–1. Synthesis of N-Allyl Derivative 4 Path A: To a stirred suspension of NaH (5 equiv) in dry DMF (5 mL), a solution of deprotected methanocarbazole 14 (150 mg, 0.82 mmol) in DMF (5 mL) was added under nitrogen atmosphere at 0 °C (ice–water bath) followed by allyl bromide (0.14 mL, 1.64 mmol). The resulting reaction mixture was heated at 60 °C for 5 h. After the completion of the reaction (TLC monitoring), the excess base was quenched with saturated NH4Cl solution (20 mL) under icewater bath. Next, the reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography using petroleum ether to furnish the N-allyl derivative 4 (80 mg, 44%) as a liquid. On standing, compound 4 changes colour from violet to brown. The spectra of the N-allyl compound 4 synthesized via Path A was provided in the Supporting Information. Path B: To a sealed tube, 2-bromo-N-allylaniline (15a) (100 mg, 0.47 mmol), Pd(OAc)2 (10.6 mg, 10 mol %), Cs2CO3 (153.5 mg, 2 equiv), t-Bu3PHBF4 (30 mg, 22 mol %) were added.


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Subsequently, NBD (0.3 mL, 6 equiv) and dry toluene (3 mL) were added to the above mixture in the presence of nitrogen. While stirring the reaction mixture at rt degassed with N2 for 5 min. Later, the reaction mixture in the sealed tube was heated at 120 oC for 15 h. After the completion of the reaction (TLC monitoring), the reaction mixture was diluted with CH2Cl2 and filtered through a Celite pad using glass sintered funnel, then washed the Celite pad twice with CH2Cl2. The filtrate was concentrated to get the crude product, which was purified by silica gel column chromatography using 2% EtOAc in petroleum ether. The N-allyl derivative 4 was obtained in good yield (74 mg, 70%) as a brown liquid. It has identical spectral data as that of the compound 4 synthesized by Path A. 1

H NMR (400 MHz, CDCl3): δ (ppm) = 7.10‒7.06 (m, 2H), 6.63 (t, J = 7.3 Hz, 1H), 6.36 (d, J =

8.2 Hz, 2H), 6.09 (dd, J = 5.4, 3.0 Hz, 1H), 5.98‒5.88 (m, 1H), 5.31 (dd, J = 17.1, 1.6 Hz, 1H), 5.22 (dd, J = 10.0, 1.4 Hz, 1H), 3.89‒3.88 (m, 2H), 3.85 (d, J = 8.4 Hz, 1H), 3.49 (d, J = 8.3 Hz, 1H), 3.06 (s, 1H), 2.99 (s, 1H), 1.71 (d, J = 8.9 Hz, 1H), 1.55 (dd, J = 8.9, 1.1 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): δ (ppm) = 154.8 (s), 140.1 (d), 135.3 (d), 134.8 (d), 129.5 (s), 127.9 (d), 124.0 (d), 116.3 (d), 116.3 (t), 105.5 (d), 70.4 (d), 50.0 (t), 49.3 (d), 48.5 (d), 47.9 (d), 42.7 (t); HRMS (ESI, Q-ToF) m/z: calculated for C16H18N [M+H]+: 224.1434, found: 224.1438; IR (neat): νmax = 3014, 2820, 1643, 1363, 1219, 1068, 790 cm–1. Synthesis of N-Propargyl Derivative 8: To a stirred suspension of NaH (10 equiv) in dry DMF (5 mL), a solution of deprotected methanocarbazole 14 (300 mg, 1.64 mmol) in DMF (10 mL) was added under nitrogen atmosphere at 0 oC (ice–water bath) followed by excess propargyl bromide (1 mL, 11.43 mmol). The resulting reaction mixture was stirred at rt for 7 h. After the completion of the reaction (monitored by TLC), the excess base was quenched with saturated NH4Cl solution (20 mL) under ice-water bath. Next, the reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 1% EtOAc in petroleum ether to provide the N-propargyl product 8 (250 mg, 69%) as a yellow liquid. 1

H NMR (400 MHz, CDCl3): δ (ppm) = 7.09‒7.03 (m, 2H), 6.66 (td, J = 7.4, 0.9 Hz, 1H), 6.44

(d, J = 7.9 Hz, 1H), 6.32 (dd, J = 5.8, 2.9 Hz, 1H), 6.06 (dd, J = 5.8, 3.1 Hz, 1H), 4.06‒3.91 (m, 2H), 3.87 (d, J = 8.2 Hz, 1H), 3.44 (d, J = 8.2 Hz, 1H), 3.09 (t, J = 1.1 Hz, 1H), 2.92 (s, 1H), 2.13 (t, J = 2.4 Hz, 1H), 1.60 (d, J = 9.0 Hz, 1H), 1.51‒1.47 (m, 1H);


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C NMR (100.6 MHz,


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CDCl3): δ (ppm) = 153.8 (s), 140.3 (d), 135.3 (d), 130.3 (s), 127.9 (d), 124.3 (d), 117.9 (d), 106.9 (d), 80.1 (s), 71.2 (d), 70.1 (d), 49.6 (d), 48.5 (d), 47.6 (d), 43.1 (t), 36.6 (t); HRMS (ESI, Q-ToF) m/z: calculated for C16H15KN [M+K]+: 260.0836, found: 260.0837; IR (neat): νmax = 3437, 2929, 2393, 1613, 1461, 1224, 1119, 939 cm–1. General Procedure for RRM/ERRM A solution of 4/8 in dry CH2Cl2 (20 mL) was degassed with N2 gas for 5 min and purged with ethylene gas for another 5 min. Next, Grubbs first generation (G-I) catalyst (5-10 mol %) was added at rt in the presence of ethylene atmosphere and the reaction mixture was stirred at rt for 126 h. After the completion of the reaction (TLC monitoring), the solvent was removed on rotatory evaporator and the crude product was purified by silica gel column chromatography using 1-2% EtOAc in petroleum ether to deliver a mixture of the rearranged product 3/7 along with the ring-opened product 16/17. Ring-Rearranged Product 3: Obtained from 4 (77 mg, 0.34 mmol), G-I catalyst (14.20 mg, 5 mol %), time: 1 h, brown liquid (40 mg, 52%), eluent: 2% EtOAc‒petroleum ether. 1


6.9 Hz, 1H), 5.96‒5.89 (m, 1H), 5.62‒5.61 (m, 1H), 5.12‒5.05 (m, 2H), 5.00‒4.97 (m, 1H), 3.94‒3.83 (m, 2H), 3.76‒3.72 (m, 1H), 3.36‒3.31 (m, 1H), 2.72‒2.65 (m, 1H), 2.57‒2.50 (m, 1H), 1.95‒1.90 (m, 1H), 1.50‒1.40 (m, 1H);

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C NMR (125.7 MHz, CDCl3): δ (ppm) = 141.6,

140.9, 140.9, 128.0, 128.0, 123.8, 123.8, 114.8, 114.5, 74.2, 74.0, 52.3, 52.3, 52.2, 40.3, 40.3; HRMS (ESI, Q-ToF) m/z: calculated for C16H18N [M+H]+: 224.1434, found: 224.1435; IR (neat): νmax = 3077, 2920, 1605, 1486, 1357, 1253, 914 cm–1. Ring-Opened N-Allyl Derivative 16: Pale brown liquid (30 mg, 35%), eluent: 1% EtOAc‒ petroleum ether. 1


8.1 Hz, 1H), 5.99‒5.90 (m, 2H), 5.88‒5.79 (m, 1H), 5.24‒5.14 (m, 4H), 5.09‒5.04 (m, 2H), 3.98 (dd, J = 10.5, 5.5 Hz, 1H), 3.91‒3.76 (m, 2H), 3.39 (t, J = 9.8 Hz, 1H), 2.79‒2.71 (m, 1H), 2.62‒ 2.53 (m, 1H), 1.99‒1.93 (m, 1H) 1.51, 1.46 (ABq, JAB = 12.0 Hz, 1H);

13

C NMR (100.6 MHz,

CDCl3): δ (ppm) = 150.7 (s), 141.6 (d), 140.9 (d), 134.0 (d), 131.4 (s), 128.0 (d), 123.8 (d), 117.0 (t), 116.7 (d), 114.9 (t), 114.6 (t), 106.3 (d), 74.3 (d), 52.8 (d), 52.4 (d), 52.3 (d), 49.6 (t), 40.3 (t); HRMS (ESI, Q-ToF) m/z: calculated for C18H22N [M+H]+: 252.1747, found: 252.1745; IR (neat): νmax = 3079, 2920, 2853, 1638, 1569, 1481, 1252, 1017, 915 cm–1.


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Enyne Ring-Rearranged Product 7: Obtained from 8 (22 mg, 0.10 mmol), G-I catalyst (8.20 mg, 10 mol %), rt, 26 h, colourless liquid (17 mg, 69%), eluent: 1% EtOAc‒petroleum ether. 1


8.2 Hz, 1H), 6.36 (dd, J = 17.7, 11.1 Hz, 1H), 6.23 (br s, 1H), 6.12‒6.03 (m, 1H), 5.20 (d, J = 17.4 Hz, 2H), 5.07 (dd, J = 10.2, 0.7 Hz, 1H), 5.02 (d, J = 11.1 Hz, 1H), 4.44 (dd, J = 17.0, 1.6 Hz, 1H) 3.80 (d, J = 17.0 Hz, 1H), 3.43 (t, J = 8.9 Hz, 1H), 3.31 (dd, J = 8.7, 3.7 Hz, 1H), 3.01‒ 2.94 (m, 1H), 2.29 (br s, 1H), 2.07‒2.01 (m, 1H), 1.42‒1.32 (m, 1H);

13

C NMR (100.6 MHz,

CDCl3): δ (ppm) = 152.0 (s), 142.7 (d), 137.3 (d), 135.8 (s), 133.9 (s), 131.9 (d), 128.1 (d), 125.2 (d), 119.1 (d), 113.5 (t), 111.0 (t), 110.2 (d), 70.2 (d), 52.9 (d), 48.0 (d), 47.3 (t), 41.0 (d), 34.2 (t); HRMS (ESI, Q-ToF) m/z: calculated for C18H20N [M+H]+: 250.1590, found: 250.1592; IR (neat): νmax = 3020, 2930, 1610, 1470, 1131, 1023, 678 cm–1. Ring-Opened N-Propargyl Derivative 17: Yellow liquid (5.50 mg, 22%), eluent: 0.5% EtOAc‒petroleum ether. 1

H NMR (400 MHz, CDCl3): δ (ppm) = 7.15‒7.07 (m, 2H), 6.68 (td, J = 7.4, 0.8 Hz, 1H), 6.53

(d, J = 7.8 Hz, 1H), 6.02‒5.87 (m, 2H), 5.20 (dt, J = 17.1, 1.4 Hz, 1H), 5.11‒5.04 (m, 3H), 4.10‒ 4.01 (m, 2H), 3.88 (dd, J = 18.0, 2.4 Hz, 1H), 3.37 (t, J = 9.9 Hz, 1H), 2.81‒2.73 (m, 1H), 2.58‒ 2.50 (m, 1H), 2.09 (t, J = 2.4 Hz, 1H), 2.03‒1.94 (m, 1H) 1.53, 1.48 (ABq, JAB = 12.0 Hz, 1H); 13

C NMR (125.7 MHz, CDCl3): δ (ppm) = 149.7, 141.5, 140.7, 132.0, 128.0, 124.0, 118.4,

115.0, 115.0, 114.7, 107.7, 79.3, 74.1, 71.6, 52.5, 51.9, 40.6, 36.4; HRMS (ESI, Q-ToF) m/z: calculated for C18H20N [M+H]+: 250.1590, found: 250.1591; IR (neat): νmax = 3436, 2927, 2345, 1604, 1566, 1418, 1219, 1045, 915 cm–1. Synthesis of the 1,3-Diene 7 from Propargyl Derivative 17 via EM: A solution of 17 (75 mg, 0.30 mmol) in dry CH2Cl2 (30 mL) was degassed with N2 gas for 5 min and purged with ethylene gas for another 5 min. Next, Grubbs second generation G-II catalyst (26 mg, 10 mol %) was added at rt in the presence of ethylene atmosphere and the reaction mixture was stirred at rt for 3 h. After the completion of the reaction (monitored by TLC), the solvent was removed on rotatory evaporator and the crude product was purified by silica gel column chromatography using 1% EtOAc in petroleum ether to get the desired 1,3-diene 7 (53 mg, 70%) as a brown liquid. Synthesis of DA Adduct 6 from 1,3-Diene 7: In a sealed tube, a solution of 7 (45 mg, 0.18 mmol) in dry toluene (4 mL) was taken. Next, the dienophile TCE (30 mg, 0.23 mmol) was



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added to the above solution and the reaction mixture was refluxed for 3 h. Afterwards, the solvent was removed on rotatory evaporator under reduced pressure. Later, the crude product was purified by silica gel column chromatography using 15% EtOAc in petroleum ether to obtain the DA adduct 6 (35.60 mg, 52%) as a brown thick liquid. 1


(td, J = 7.4, 0.7 Hz, 1H), 6.53 (d, J = 7.9 Hz, 1H), 6.08‒5.99 (m, 1H), 5.70 (br s, 1H), 5.25 (dt, J = 17.0, 1.2 Hz, 1H), 5.13 (dt, J = 10.2, 1.1 Hz, 1H), 4.24 (d, J = 16.5 Hz, 1H), 4.13 (dt, J = 16.4, 1.6 Hz, 1H), 3.74 (t, J = 9.1 Hz, 1H), 3.43 (dd, J = 8.6, 3.7 Hz, 1H), 3.25 (d, J = 12.1 Hz, 1H), 3.09‒3.02 (m, 3H), 2.30‒2.24 (m, 1H), 1.90‒1.80 (m, 1H), 1.65‒1.56 (m, 1H); 13C NMR (100.6 MHz, CDCl3): δ (ppm) = 148.4 (s), 141.1 (d), 133.4 (s), 132.8 (s), 128.1 (d), 125.8 (d), 119.8 (d), 115.0 (d), 114.8 (t), 111.5 (s), 110.9 (s), 110.3 (s), 108.8, (d) 108.4 (s), 71.7 (d), 51.3 (d), 50.5 (t), 48.4 (d), 45.9 (d), 43.6 (d), 42.8 (s), 38.1 (s), 34.2 (t), 32.1 (t); HRMS (ESI, Q-ToF) m/z: calculated for C24H20N5 [M+H]+: 378.1713, found: 378.1712; IR (neat): νmax = 3030, 2255, 1607, 1473, 1041, 915 cm–1. General Procedure for Alkylation of the Tetracyclic Amide 11 To a stirred suspension of NaH (5 equiv) in dry DMF (5 mL), a solution of tetracyclic amide 11 (1 equiv) in DMF (3‒5 mL) was added under nitrogen atmosphere at 0 oC (ice–water bath) followed by alkyl bromide (1.5 equiv). The resulting reaction mixture was stirred at 0 oC/rt/70 oC for 45 min‒11 h. After the completion of the reaction (monitored by TLC), the excess base was quenched with saturated NH4Cl solution (5‒10 mL) under ice–water bath. Next, the reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude products were purified by silica gel column chromatography using an appropriate mixture of EtOAc and petroleum ether (6‒15% EtOAc in petroleum ether) to deliver the alkylated products 10a‒10d/13 as liquids in 77‒98% yield. N-Allyl Precursor 10a: Obtained from 11 (60 mg, 0.28 mmol), DMF (8 mL), rt, 2 h, brown liquid (68 mg, 95%). This compound was used in the next step without any purification by column chromatography. 1


(t, , J = 8.4 Hz, 2H), 6.38 (dd, J = 5.7, 2.8 Hz, 1H), 6.15 (dd, J = 5.4, 3.0 Hz, 1H), 5.95‒5.85 (m, 1H), 5.24‒5.17 (m, 2H), 4.73 (dd, J = 15.4, 4.7 Hz, 1H), 3.85 (dd, J = 15.3, 6.6 Hz, 1H), 3.60 (d,


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J = 8.9 Hz, 1H), 3.13 (d, J = 10.0 Hz, 2H), 2.93 (br s, 1H), 1.51 (d, J = 9.4 Hz, 1H), 1.41 (d, J = 9.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): δ (ppm) = 162.6 (s), 139.4 (s), 139.0 (d), 135.5 (d), 133.2 (d), 132.1 (d), 128.3 (d), 127.9 (d), 126.7 (s), 126.5 (d), 117.2 (t), 59.9 (d), 53.1 (d), 49.6 (t), 48.4 (d), 42.7 (t), 39.1 (d); HRMS (ESI, Q-ToF) m/z: calculated for C17H17NNaO [M+Na]+: 274.1202, found: 274.1203; IR (neat): νmax = 3062, 2924, 2870, 1636, 1578, 1470, 1287, 1017, 911 cm–1. N-Butenyl Precursor 10b: Obtained from 11 (150 mg, 0.71 mmol), DMF (10 mL), rt, 11 h, pale yellow liquid (32 mg, 77%, on the basis of 70% starting material recovered), eluent: 15% EtOAc‒petroleum ether. 1

H NMR (400 MHz, CDCl3): δ (ppm) = 8.15 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.31‒

7.26 (m, 2H), 6.39 (dd, J = 5.6, 2.8 Hz, 1H), 6.18 (dd, J = 5.5, 3.0 Hz, 1H), 5.90‒5.80 (m, 1H), 5.11 (dd, J = 17.1, 1.2 Hz, 1H), 5.04 (d, J = 10.2 Hz, 1H), 4.20‒4.13 (m, 1H), 3.60 (d, J = 8.9 Hz, 1H), 3.20‒3.11 (m, 3H), 2.93 (br s, 1H), 2.54‒2.39 (m, 2H), 1.50 (d, J = 9.4 Hz, 1H), 1.41 (d, J = 9.4 Hz, 1H);

13

C NMR (125.7 MHz, CDCl3): δ (ppm) = 162.6 (s), 139.3 (s), 139.1 (d),

135.6 (d), 135.5 (d), 132.0 (d), 128.2 (d), 127.9 (d), 127.1 (s), 126.5 (d), 116.8 (t), 60.5 (d), 53.3 (d), 48.8 (d), 46.9 (t), 42.7 (t), 39.1 (d), 31.8 (t); HRMS (ESI, Q-ToF) m/z: calculated for C18H19NNaO [M+Na]+: 288.1359, found: 288.1359; IR (neat): νmax = 3010, 1638, 1478, 1319, 1124, 919 cm–1. N-Pentenyl Precursor 10c: Obtained from 11 (108 mg, 0.51 mmol), DMF (10 mL), 70 oC, 3 h, yellow liquid (127 mg, 89%), eluent: 8% EtOAc‒petroleum ether. 1

H NMR (400 MHz, CDCl3): δ (ppm) = 8.15 (d, J = 7.8 Hz, 1H), 7.44 (td, J = 7.4, 1.3 Hz, 1H),

7.31‒7.25 (m, 2H), 6.39 (dd, J = 5.7, 2.9 Hz, 1H), 6.17 (dd, J = 5.6, 3.1 Hz, 1H), 5.89‒5.78 (m, 1H), 5.05 (dq, J = 17.1, 1.5 Hz, 1H), 4.98 (dd, J = 10.2, 1.3 Hz, 1H), 4.11‒4.04 (m, 1H), 3.59 (dd, J = 8.9, 1.4 Hz, 1H), 3.15‒3.08 (m, 3H), 2.92 (br s, 1H), 2.12 (q, J = 7.4 Hz, 2H), 1.84‒1.74 (m, 2H), 1.50 (d, J = 9.4 Hz, 1H), 1.40 (dt, J = 9.4, 1.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): δ (ppm) = 162.5 (s), 139.2 (s), 139.0 (d), 138.0 (d), 135.6 (d), 131.9 (d), 128.1 (d), 127.9 (d), 127.1 (s), 126.5 (d), 115.1 (t), 60.3 (d), 53.2 (d), 48.8 (d), 46.9 (t), 42.6 (t), 39.0 (d), 31.4 (t), 26.4 (t); HRMS (ESI, Q-ToF) m/z: calculated for C19H21NNaO [M+Na]+: 302.1515, found: 302.1517; IR (neat): νmax = 3066, 2978, 1641, 1602, 1473, 1308, 910, 698 cm–1. N-Hexenyl Precursor 10d: Obtained from 11 (100 mg, 0.47 mmol), DMF (10 mL), 80 oC, 3 h, colourless thick liquid (127 mg, 91%), eluent: 6% EtOAc‒petroleum ether.



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1

Page 16 of 23

H NMR (400 MHz, CDCl3): δ (ppm) = 8.15 (d, J = 7.8 Hz, 1H), 7.43 (td, J = 7.5, 1.3 Hz, 1H),

7.30‒7.25 (m, 2H), 6.38 (dd, J = 5.6, 2.8 Hz, 1H), 6.17 (dd, J = 5.3, 3.0 Hz, 1H), 5.85‒5.75 (m, 1H), 5.00 (dd, J = 17.1, 1.5 Hz, 1H), 4.94 (d, J = 10.2 Hz, 1H), 4.12‒4.05 (m, 1H), 3.58 (d, J = 8.9 Hz, 1H), 3.13‒3.07 (m, 3H), 2.91 (br s, 1H), 2.10 (q, J = 7.0 Hz, 2H), 1.77‒1.63 (m, 2H), 1.50‒1.38 (m, 4H);

13

C NMR (125.7 MHz, CDCl3): δ (ppm) = 162.4 (s), 139.2 (d), 139.0 (d),

138.6 (s), 135.5 (d), 131.8 (d), 128.1 (d), 127.8 (d), 127.1 (s), 126.4 (d), 114.7 (t), 60.1 (d), 53.2 (d), 48.7 (d), 47.1 (t), 42.6 (t), 39.0 (d), 33.6 (t), 26.7 (t), 26.5 (t); HRMS (ESI, Q-ToF) m/z: calculated for C20H23NNaO [M+Na]+: 316.1672, found: 316.1671; IR (neat): νmax = 3056, 2979, 1640, 1602, 1475, 1309, 912, 699 cm–1. N-Propargyl Precursor 13: Obtained from 11 (190 mg, 0.90 mmol), DMF (15 mL), 0 oC, 45 min, yellow thick liquid (220 mg, 98%), eluent: 12% EtOAc‒petroleum ether. 1


7.27 (m, 2H), 6.41 (dd, J = 5.4, 2.6 Hz, 1H), 6.19 (dd, J = 5.3, 3.0 Hz, 1H), 4.83 (dd, J = 17.4, 2.1 Hz, 1H), 4.13 (dd, J = 17.4, 2.2 Hz, 1H), 3.84 (d, J = 9.0 Hz, 1H), 3.27 (br s, 1H), 3.16 (d, J = 9.0 Hz, 1H), 2.93 (br s, 1H), 2.26 (t, J = 2.4 Hz, 1H), 1.49 (d, J = 9.4 Hz, 1H), 1.42 (d, J = 9.4 Hz, 1H);

13

C NMR (100.6 MHz, CDCl3): δ (ppm) = 162.4, 139.4, 139.1, 135.3, 132.2, 128.3,

128.0 , 126.5, 126.4, 79.1, 72.0, 59.7, 53.1, 47.9, 42.6, 39.4, 35.9; HRMS (ESI, Q-ToF) m/z: calculated for C17H15NNaO [M+Na]+: 272.1046, found: 272.1045; IR (neat): νmax = 3303, 3063, 2980, 2119, 1642, 1602, 1471, 1308, 1166, 699 cm–1. Allene Derivative 21: Obtained from 11 (430 mg, 2.03 mmol), DMF (20 mL), 35‒40 oC, 3.5 h, yellow thick liquid (240 mg, 47%), eluent: 7% EtOAc‒petroleum ether. Note: When propargylation was carried out at 35‒40 oC a mixture of allene derivative 21 (47%) and Npropargyl product 13 (115 mg, 23%) were produced. 1


(td, J = 7.5, 1.2 Hz, 1H), 7.32‒7.29 (m, 2H), 6.36 (dd, J = 5.5, 2.6 Hz, 1H), 6.17 (dd, J = 5.4, 3.0 Hz, 1H), 5.55 (dd, J = 10.0, 6.5 Hz, 1H), 5.39 (dd, J = 10.0, 6.4 Hz, 1H), 3.69 (d, J = 8.9 Hz, 1H), 3.18 (d, J = 9.4 Hz, 2H), 2.93 (br s, 1H), 1.42 (d, J = 9.5 Hz, 1H), 1.36 (d, J = 9.5 Hz, 1H); 13

C NMR (125.7 MHz, CDCl3): δ (ppm) = 203.5 (s), 160.8 (s), 139.8 (s), 138.6 (d), 135.9 (d),

132.6 (d), 128.8 (d), 128.2 (d), 126.7 (d), 126.4 (s), 99.5 (d), 86.9 (t), 58.4 (d), 53.1 (d), 48.9 (d), 42.7 (t), 38.8 (d); HRMS (ESI, Q-ToF) m/z: calculated for C17H15NNaO [M+Na]+: 272.1046,


Page 17 of 23

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found: 272.1048; IR (neat): νmax = 3060, 2976, 2872, 1642, 1601, 1463, 1306, 1157, 752, 698 cm–1. General Procedure for RRM of 10a‒10d A solution of 10a‒10d (1 equiv) in dry CH2Cl2 or toluene was degassed with N2 gas for 5 min and purged with ethylene gas for another 5 min. Next, G-I or G-II catalyst (5-10 mol %) was added at rt in the presence of ethylene atmosphere and then the reaction mixture was either stirred at rt or refluxed or heated at 80 oC for 1.5-26 h. After completion of the reaction (TLC monitoring), the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography using an appropriate mixture of EtOAc and petroleum ether as an eluent to furnish the ring-rearranged products 9a‒9c and/or ROM products 19 and 20. Ring-Opened Product 19: Obtained from 10a (65 mg, 0.26 mmol), G-I catalyst (11 mg, 5 mol %), CH2Cl2 (12 mL), rt, 7 h; reflux, 16 h, colourless liquid (5 mg, 14%, on the basis of 50% starting material recovered), eluent: 6% EtOAc‒petroleum ether. 1

H NMR (400 MHz, CDCl3): δ (ppm) = 8.16 (dd, J = 7.8, 1.2 Hz, 1H), 7.43 (td, J = 7.5, 1.4 Hz,

1H), 7.33 (t, J = 7.5 Hz, 1H), 7.26‒7.24 (m, 1H), 5.96‒5.78 (m, 3H), 5.21‒5.17 (m, 2H), 5.14‒ 5.02 (m, 4H), 4.80 (ddt, J = 15.8, 4.4, 1.7, 1H), 3.83 (t, J = 7.8 Hz, 1H), 3.80 (dd, J = 6.7 Hz, 1H), 3.24 (t, J = 7.2 Hz, 1H), 2.98‒2.90 (m, 1H), 2.86‒2.78 (m, 1H), 2.10‒2.03 (m, 1H), 1.49‒ 1.40 (m, 1H);

13

C NMR (100.6 MHz, CDCl3): δ (ppm) = 163.0 (s), 141.3 (d), 140.3 (d), 139.9

(s), 133.6 (d), 132.0 (d), 128.7 (d), 127.5 (s), 127.1 (d), 126.9 (d), 117.0 (t), 116.2 (t), 115.2 (t), 63.9 (d), 50.0 (d), 49.8 (d), 48.3 (t), 45.4 (d), 36.6 (t); HRMS (ESI, Q-ToF) m/z: calculated for C19H21NNaO [M+Na]+: 302.1515, found: 302.1514; IR (neat): νmax = 3040, 2922, 1647, 1579, 1469, 1294, 1164, 918 cm–1. Ring-Rearranged Product 9a: Obtained from 10a (30 mg, 0.12 mmol), G-II catalyst (10 mg, 10 mol %), toluene (10 mL), 80 oC, 1.5 h, white solid (23 mg, 77%), eluent: 10% EtOAc‒ petroleum ether. Mp: 86–88 oC 1


1H), 7.35‒7.28 (m, 2H), 6.12‒6.04 (m, 1H), 5.99 (dd, J = 10.0, 1.8 Hz, 1H), 5.71‒5.66 (m, 1H), 5.25 (dt, J = 17.0, 1.1 Hz, 1H), 5.13 (d, J = 10.2 Hz, 1H), 5.05 (dq, J = 18.7, 3.0 Hz, 1H), 3.80‒ 3.71 (m, 1H), 3.56 (t, J = 10.8 Hz, 1H), 3.44 (dd, J = 10.9, 5.4 Hz, 1H), 3.06‒2.99 (m, 1H), 2.50‒ 2.44 (m, 1H), 2.06‒2.00 (m, 1H), 1.28‒1.18 (m, 1H); 13C NMR (100.6 MHz, CDCl3): δ (ppm) = 161.0 (s), 142.4 (d), 141.3 (s), 132.5 (d), 129.1 (d), 128.5 (d), 126.9 (s), 126.8 (d), 126.4 (d),



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Page 18 of 23

125.9 (d), 114.5 (t), 61.5 (d), 53.3 (d), 44.7 (t), 43.5 (d), 39.1 (d), 34.2 (t); HRMS (ESI, Q-ToF) m/z: calculated for C17H17NNaO [M+Na]+: 274.1202, found: 274.1203; IR (neat): νmax = 3019, 2857, 1651, 1626, 1472, 1324, 1271, 1156, 914 cm–1. Ring-Rearranged Product 9b: Obtained from 10b (25 mg, 0.09 mmol), G-I catalyst (4 mg, 7 mol %), CH2Cl2 (15 mL), rt, 3 h, white solid (24.5 mg, 98%), eluent: 15% EtOAc‒petroleum ether. Mp: 67.5–68.2 oC. 1


7.26 (m, 2H), 6.08‒5.99 (m, 1H), 5.91‒5.85 (m, 1H), 5.72 (d, J = 11.2 Hz, 1H), 5.20 (d, J = 17.0 Hz, 1H), 5.12 (d, J = 10.2 Hz, 1H), 4.69 (dq, J = 13.3, 3.1 Hz, 1H), 3.67 (t, J = 10.5 Hz, 1H), 3.50 (dd, J = 10.3, 5.6 Hz, 1H), 2.96‒2.88 (m, 1H), 2.84‒2.77 (m, 1H), 2.73‒2.69 (m, 1H), 2.53‒ 2.46 (m, 1H), 2.40‒2.33 (m, 1H), 2.09‒2.03 (m, 1H), 1.43, 1.38 (ABq, JAB = 12.7 Hz, 1H);

13

C

NMR (100.6 MHz, CDCl3): δ (ppm) = 161.5 (s), 142.6 (d), 141.6 (s), 132.8 (d), 132.3 (d), 130.9 (d), 128.3 (d), 126.7 (d), 126.6 (s), 126.3 (d), 114.6 (t), 65.4 (d), 51.4 (d), 47.9 (d), 46.8 (t), 42.3 (d), 36.6 (t), 29.6 (t); HRMS (ESI, Q-ToF) m/z: calculated for C18H19NNaO [M+Na]+: 288.1359, found: 288.1362; IR (neat): νmax = 3078, 2925, 1644, 1602, 1472, 1302, 1163, 916 cm–1. Ring-Rearranged Product 9c: Obtained from 10c (50 mg, 0.18 mmol), G-I catalyst (15 mg, 10 mol %), CH2Cl2 (20 mL), reflux, 3 h, yellow liquid (36.5 mg, 73%), eluent: 12% EtOAc‒ petroleum ether. Note: When the same reaction was exposed to 5 mol % G-I catalyst in CH2Cl2 at rt the reaction took longer period of time (17 h) for completion. 1

H NMR (400 MHz, CDCl3): δ (ppm) = 8.11 (d, J = 7.7 Hz, 1H), 7), 7.45‒7.41 (m, 1H), 7.36 (d,

J = 7.7 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 6.07‒5.99 (m, 1H), 5.72‒5.65 (m, 1H), 5.58 (dd, J = 10.5, 5.8 Hz, 1H), 5.22 (d, J = 17.1 Hz, 1H), 5.11 (d, J = 10.2 Hz, 1H), 4.22 (dd, J = 13.2, 5.3 Hz, 1H), 3.51‒3.41 (m, 2H), 3.06‒2.99 (m, 1H), 2.89‒2.79 (m, 2H), 2.67‒2.58 (m, 1H), 2.17‒ 2.06 (m, 2H), 2.03‒1.98 (m, 1H), 1.48‒1.35 (m, 2H); 13C NMR (100.6 MHz, CDCl3): δ (ppm) = 162.7 (s), 142.9 (d), 141.5 (s), 132.4 (d), 132.2 (d), 131.4 (d), 128.0 (d), 126.9 (s), 126.7 (d), 125.8 (d), 114.3 (t), 68.6 (d), 50.2 (d), 48.7 (t), 44.5 (d), 42.5 (d), 36.9 (t), 26.8 (t), 23.9 (t); HRMS (ESI, Q-ToF) m/z: calculated for C19H21NNaO [M+Na]+: 302.1515, found: 302.1513; IR (neat): νmax = 3074, 2976, 1642, 1601, 1476, 1354, 1299, 916 cm–1. Ring-Opened Product 20: Obtained from 10d (46 mg, 0.16 mmol), G-II catalyst (9 mg, 7 mol %), toluene (10 mL), 80 oC, 3 h, colourless liquid (13 mg, 26%), eluent: 4% EtOAc‒petroleum ether.


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1


(t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 5.97‒5.90 (m, 1H), 5.87‒5.75 (m, 2H), 5.13‒5.04 (m, 4H), 5.00 (dd, J = 17.1, 1.2 Hz, 1H), 4.94 (dd, J = 10.1, 1.0 Hz, 1H), 4.14‒4.08 (m, 1H), 3.77 (t, J = 7.8 Hz, 1H), 3.25 (t, J = 6.6 Hz, 1H), 3.08‒3.02 (m, 1H), 2.97‒2.91 (m, 1H), 2.79‒2.73 (m, 1H), 2.10‒2.04 (m, 2H), 1.69‒1.58 (m, 3H), 1.49‒1.38 (m, 3H);

13

C NMR (125.7 MHz,

CDCl3): δ (ppm) = 162.9 (s), 141.5 (d), 140.2 (d), 139.8 (s), 138.8 (d), 131.9 (d), 128.6 (d), 127.8 (s), 127.0 (d), 126.8 (d), 116.2 (t), 115.0 (t), 114.8 (t), 64.6 (d), 50.1 (d), 49.4 (d), 46.4 (t), 45.4 (d), 36.4 (t), 33.7 (t), 27.3 (t), 26.4 (t); HRMS (ESI, Q-ToF) m/z: calculated for C22H27NNaO [M+Na]+: 344.1985, found: 344.1983; IR (neat): νmax = 3076, 2926, 1643, 1602, 1473, 1298, 914 cm–1. Synthesis of Cross EM Product 22 A solution of 13 (72 mg, 0.29 mmol) in dry toluene (8 mL) was degassed with N2 gas for 5 min and purged with ethylene gas for another 5 min. Next, G-I catalyst (24 mg, 10 mol %) was added at rt in the presence of ethylene atmosphere and the reaction mixture was heated at 80 oC for 10 h. Later, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography using 7% EtOAc and petroleum ether as an eluent to get the cross EM product 22 [15 mg, 24% (on the basis of 20% starting material recovered)] as a colourless liquid instead of desired ERRM product 12. 1

H NMR (500 MHz, CDCl3): δ (ppm) = 8.18 (dd, J = 7.8, 1.2 Hz, 1H), 7.46 (t, J = 7.5, 1.4 Hz,

1H), 7.32‒7.28 (m, 2H), 6.41 (dd, J = 17.7, 11.0 Hz, 1H), 6.37 (dd, J = 5.7, 2.9 Hz, 1H), 6.13 (dd, J = 5.6, 3.0 Hz, 1H), 5.33 (d, J = 17.7 Hz, 1H), 5.19‒5.05 (m, 4H), 3.92 (d, J = 15.7 Hz, 1H), 3.54 (dd, J = 9.0, 1.5 Hz, 1H), 3.14 (d, J = 9.5 Hz, 2H), 2.94 (br s, 1H), 1.53 (d, J = 9.3 Hz, 1H), 1.43‒1.40 (m, 1H);

13

C NMR (125.7 MHz, CDCl3): δ (ppm) = 162.8 (s), 140.7 (s), 139.5

(s), 139.0 (d), 136.9 (d), 135.7 (d), 132.2 (d), 128.7 (d), 128.0 (d), 126.9 (s), 126.6 (d), 116.9 (t), 114.9 (t), 59.3 (d), 53.3 (d), 48.2 (d), 47.1 (t), 42.8 (t), 39.1 (d); HRMS (ESI, Q-ToF) m/z: calculated for C19H19NNaO [M+Na]+: 300.1359, found: 300.1362; IR (neat): νmax = 2987, 1638, 1601, 1472, 1309, 1156, 909 cm–1. Synthesis of the Dienamide 23 via ERRM Followed by Double Bond Isomerization A solution of 13 (50 mg, 0.20 mmol) in dry toluene (10 mL) was degassed with N2 gas for 5 min and purged with ethylene gas for another 5 min. Next, G-II catalyst (17 mg, 10 mol %) was added at rt in the presence of ethylene atmosphere and the reaction mixture was refluxed for 48



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Page 20 of 23

h. Then, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography using 7% EtOAc in petroleum ether as an eluent. Although, the desired ERRM product 12 was not observed, ERRM followed by double bond isomerized product 23 (25 mg, 45%) was furnished as a pale yellow solid. Mp: 95–95.6 oC. 1

H NMR (400 MHz, CDCl3): δ (ppm) = 8.15 (d, J = 7.6 Hz, 1H), 7.45‒7.41 (m, 1H), 7.32‒7.28

(m, 2H), 6.24 (dd, J = 7.5, 2.1 Hz, 1H), 6.04‒5.96 (m, 1H), 5.67 (d, J = 11.5 Hz, 1H), 5.34 (s, 1H), 5.20‒5.12 (m, 3H), 4.90 (d, J = 14.6 Hz, 1H), 4.03 (d, J = 14.6 Hz, 1H), 3.92 (t, J = 10.2 Hz, 1H), 3.47 (dd, J = 10.0, 6.1, Hz, 1H), 2.93‒2.82 (m, 2H), 2.12‒2.06 (m, 1H), 1.41‒1.32 (m, 1H); 13C NMR (125.7 MHz, CDCl3): δ (ppm) = 161.4 (s), 141.9 (d), 141.8 (s), 141.0 (s), 132.2 (d), 131.4 (d), 131.1 (d), 128.3 (d), 126.8 (d), 126.7 (d), 120.5 (t), 115.0 (t), 63.8 (d), 52.5 (t), 51.0 (d), 48.3 (d), 42.7 (d), 36.4 (t); HRMS (ESI, Q-ToF) m/z: calculated for C19H19NNaO [M+Na]+: 300.1359, found: 300.1358; IR (neat): νmax = 3075, 2920, 2855, 1642, 1601, 1470, 1295, 997, 695 cm–1. Synthesis of the 1,3-Diene 12 via ERRM A solution of 13 (100 mg, 0.40 mmol) in dry toluene (20 mL) was degassed with N2 gas for 5 min and purged with ethylene gas for another 5 min. Next, G-II catalyst (34 mg, 10 mol %) was added at rt in the presence of ethylene atmosphere and the reaction mixture was heated at 80 oC for 53 h. Then, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography using 7% EtOAc and petroleum ether as an eluent. Here, along with the isomerized diene 23 (25 mg, 22%), desired enyne ring-rearranged product 12 was furnished as a white solid in low yield (10 mg, 9%). Mp: 121–122.3 oC. 1


1H), 7.36‒7.30 (m, 2H), 6.30 (dd, J = 17.8, 11.0 Hz, 1H), 6.13‒6.04 (m, 1H), 6.02 (br s, 1H), 5.32‒5.05 (m, 5H), 3.90 (d, J = 17.6 Hz, 1H), 3.57 (t, J = 10.8 Hz, 1H), 3.46 (dd, J = 10.9, 5.3, Hz, 1H), 3.10‒3.03 (m, 1H), 2.57 (s, 1H), 2.10‒2.04 (m, 1H), 1.33‒1.28 (m, 1H);

13

C NMR

(100.6 MHz, CDCl3): δ (ppm) = 161.1 (s), 142.3 (d), 141.2 (s), 136.7 (d), 135.2 (s), 132.6 (d), 130.0 (d), 128.7 (d), 127.0 (s), 126.9 (d), 126.5 (d), 114.6 (t), 112.9 (t), 61.7 (d), 53.6 (d), 44.2 (t), 43.9 (d), 39.1 (d), 34.2 (t); HRMS (ESI, Q-ToF) m/z: calculated for C19H19NNaO [M+Na]+: 300.1356, found: 300.1359; IR (neat): νmax = 3066, 2920, 2853, 1649, 1625, 1472, 1349, 1269, 989, 896 cm–1.

ASSOCIATED CONTENT


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Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Single-crystal X-ray data for 9a (CIF). Copies of 1H NMR, 13C NMR spectra for all new compounds and DEPT-135 spectra for selected compounds (PDF).

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]

ACKNOWLEDGMENTS S. K. thanks the Department of Science and Technology (DST), New Delhi for the award of a J. C. Bose fellowship, Praj industries, Pune for Chair Professorship (Green Chemistry) and Council of Scientific and Industrial Research (CSIR), New Delhi [02(0272)/16/EMR-II] for the financial support. R. G. thanks the University Grants Commission (UGC), New Delhi for the award of a research fellowship. We thank Mr. Darshan Mhatre for his help while collecting crystal data.

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Synthesis of Intricate Fused N-Heterocycles via Ring-Rearrangement

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