Efficient Synthesis of the N‐(buta‐2,3‐dienyl)carboxamide of Isopimaric Acid and the Potential of This Compound towards Heterocyclic Derivatives of Diterpenoids

Abstract

The N‐(2,3‐butadienyl)carboxamide of isopimaric acid, that is, compound 3, was prepared through a two‐step synthetic procedure starting from the natural diterpene isopimaric acid. The Pd‐catalyzed cross‐coupling and subsequent cyclization of terpenoid allene 3 with several aryl iodides and aryl bromides gave access to optically active diterpenoid–oxazoline derivatives in good to excellent yields. The functional group tolerance in the aryl iodides was demonstrated by several examples, including substrates with additional N‐tert‐butoxycarbonyl‐protected amino, hydroxy, and carboxy substituents in the ortho position. The cross‐coupling–cyclization reaction of those compounds with allene 3 proceeded selectively with the formation of cyclization products on the substituent in the aromatic ring. This transformation opens a potential route to the synthesis of hybrid compounds containing a tricyclic diterpenoid and several heterocycles.

1. Introduction

Chemical substances derived from plants have been used to treat human diseases since the dawn of medicine. The use of natural compounds as “privileged structures” in terms of their ability to be useful templates for the synthesis of novel biologically active molecules and as a source of lead compounds for drug discovery has been defined.1, 2 Among the various classes of natural products, tricyclic diterpenes are interesting, structurally diverse secondary metabolites. Diterpenes are widely distributed in the plant kingdom and have long been considered to possess a broad spectrum of biological effects. For example, isopimaric acid (1) is a readily available and versatile tricyclic diterpenoid that is well represented in the resin of conifers of the genera Pinus, Larix, and Picea.3, 4 The attraction of compound 1 as a biorenewable compound and its interesting biological and pharmaceutical properties, which include antibacterial,5, 6, 7 antiviral,8 and anti‐inflammatory9 activities, has stimulated the development of a variety of chemistries for functionality, including oxidative10, 11, 12 and isomeric13 transformations, in addition to several modifications of the carboxyl group.14, 15 The number of examples in the literature detailing the functionalization of isopimaric acid is limited, and they do not result in the generation of evolvable libraries of compounds for structure–activity relationship studies. Very recently, our group realized a one‐pot, two‐step method involving metal catalysis for the synthesis of optically active halogenated oxazole derivatives from isopimaric acid.15a Accordingly, in light of new isopimaranes containing a heterocyclic substituent, we became interested in the targeted preparation of isopimaric acid derivatives through further transformation of its accessible derivatives—N‐propargyl amide 2. On the basis of the development of a straightforward method for the homologation of acetylenes to allenes,16 herein we describe the synthesis of the N‐(2,3‐butadienyl)carboxamide of isopimaric acid, that is, compound 3, and its Pd‐catalyzed cross‐coupling–cyclization reactions with (het)aryl iodides and aryl bromides. This consistent transformation is attractive due to the versatility of N‐(2,3‐butadienyl)carboxamides in synthesis,17, 18 and because it could enable the synthesis of a variety of chiral bioactive heterocyclic derivatives. During this study, we analyzed the scope of this reaction for the synthesis of several “hybrid” compounds by using several aryl iodides having a substituent in the ortho position in this coupling–cyclization reaction.

2. Results and Discussion

As the starting compound, we used the N‐propargyl amide of isopimaric acid, that is, compound 2, which was obtained on a gram scale in two steps from isopimaric acid.10 The CuI‐mediated reaction of terminal alkyne 2 with formaldehyde in the presence of diisopropylamine in dioxane gave isopimaric acid N‐(2,3‐butadienyl)carboxamide 3 (Scheme 1).

Scheme 1.

Synthesis of the N‐(2,3‐butadienyl)carboxamide of isopimaric acid by the method of Grabbe et al. Reagents and conditions: a) 1) (COCl)₂, CH₂Cl₂, 0 °C; 2) propargyl amine hydrochloride, CH₂Cl₂, Et₃N, RT; b) CuI, (HCHO)_n, iPr₂NH, 1,4‐dioxane, 100 °C, 10 h.

Several allenes have become extremely versatile building blocks in organic synthesis. They have notably been involved in transition‐metal‐mediated reactions, and good selectivity has been obtained by modifying the nature of the metal and the associated ligands.19 Our attention was focused on the synthesis of terpenoid oxazolines. The 4,5‐dihydrooxazole ring not only is present in many biologically active natural and unnatural compounds but also serves as a very versatile functionality in organic synthesis.20, 21 The coupling–cyclization reaction of N‐(2,3‐butadienyl)carboxamide 3 with 4‐iodobenzonitrile (4 a) and 1‐iodobenzotrifluoride (4 b) was performed in DMF at 80 C in the presence of Pd(PPh₃)₄ (5 mol %) and K₂CO₃ (2 equiv.).18a Terpenoid‐substituted 5‐[1‐(aryl)vinyl]‐4,5‐dihydrooxazoles 5 a and 5 b were isolated after column chromatography in yields of 87 and 60 % as mixtures of diastereomers (dr=50:50, the ratio was determined by analysis of the crude product by ¹H NMR spectroscopy) (Scheme 2, Table 1).

Scheme 2.

Coupling–cyclization reaction of terpenoid allene 3. [*] Solvent: DMF, entries 1–7; CH₃CN, entry 8; DMF/CH₃CN, entry 10 (Table 1).

Table 1.

Coupling–cyclization reaction of terpenoid N‐buta‐2,3‐dienyl)‐ amide 3 with aryl iodides 4 a–f and 4 h, aryl bromide 4 g, and 2‐iodopyrazine (4 i).

Entry	Compound 4					Base	Compound 5
	R1	R2	R3	R4	X		(yield[a] [%])
1	H	H	CN	H	I	K2CO3	5 a (87)
2	H	CF3	H	H	I	K2CO3	5 b (60)
3	H	H	H	H	I	Cs2CO3	5 c (50)
4	OCH3	H	H	H	I	Cs2CO3	5 d (72)
5	H	OCH3	H	H	I	Cs2CO3	5 e (77)
6	H	H	OCH3	H	I	Cs2CO3	5 f (54)
7	H	CO2Me	NHAc	H	Br	Cs2CO3	5 g (2)
8	H	CO2Me	NHAc	H	Br	Cs2CO3	5 g (61)
9	H	CHO	OH	OCH3	I	Cs2CO3	5 h (18)
10	H	CHO	OH	OCH3	I	Cs2CO3	5 h (65)

[a] Yield of isolated product. All 4,5‐dihydrooxazoles were obtained as mixtures of diastereomers 5 a–i/ 5′ a–i, 50:50.

Terpenoid‐substituted 5‐(S)‐ and 5‐(R)‐oxazolines 5 a and 5′ a were separated by column chromatography on silica gel. The reaction of allene 3 with unsubstituted iodobenzene (4 c) in the presence of K₂CO₃ gave dihydrooxazole 5 c in a low yield (17 %). A higher yield of compound 5 c was obtained by using Cs₂CO₃ (2 equiv.) as a base (Table 1, entry 3). The reaction of methoxy‐substituted aryl iodides 4 d–f with 3 under these conditions led to target 5‐(1‐arylvinyl)‐4,5‐dihydrooxazoles 5 d–f in yields of 54–77 % (Table 1, entries 4–6). The use of these conditions for the reaction of N‐(2,3‐butadienyl)carboxamide 3 with methyl 2‐acetamido‐5‐bromobenzoate (4 g) was unsuccessful; compound 5 g was isolated in 2 % yield (Table 1, entry 7). However, upon conducting the same reaction in CH₃CN, target compound 5 g was delivered in 61 % yield (Table 1, entry 8). By further fine‐tuning the experimental parameters (Table 1, entries 9 and 10), we found that the yield of target diterpenoid dihydrooxazole 5 g could be improved to 65 % by using a mixture of CH₃CN and DMF in a ratio of 5:1. Additionally, 5‐[1‐(phenyl)vinyl]‐4,5‐dihydrooxazole (5 c, 4 % yield) was also isolated in this reaction. So, aryl iodides and aryl bromides with electron‐donating and electron‐withdrawing substituents in the ortho, para, or meta position of the aryl ring were all suitable for this transformation, and they gave the corresponding oxazoline derivatives in good yields. The reaction of heterocyclic 2‐iodopyrazine (4 i) also proceeded smoothly to afford corresponding cross‐coupling product 5 i in excellent yield.

The main synthetic interest in allenes deals with the formation of carbo‐ and heterocycles. The Pd‐catalyzed cross‐coupling of allenes with aromatic iodides containing a nucleophile substituent (e.g., 2‐iodoaniline, 2‐iodophenol, 2‐iodobensoic acid) in the ortho position gave the possibility for cyclization, which could occur through [α,β], [β,α], [β,γ], or [γ,β] attack on the allene function with the formation of an indole, isochromane, or benzofuran system.22, 23, 24, 25 The experimental results revealed the significant influence of the nature of the substituent in the functionalized allene on the direction of cyclization.26 In light of the results obtained from the optimization of the reaction parameters (Table 1), we decided to explore the reaction of N‐(2,3‐butadienyl)carboxamide 3 further by using ortho‐substituted aryl iodides.

Compound 3 was submitted to the reaction with N‐tert‐butoxycarbonyl (N‐Boc)‐protected 2‐iodoaniline (6) (Scheme 3). The reaction in acetonitrile proceeded with the formation of 3‐methyleneindoline 7 as the only isolable product (55 % yield after flash chromatography on silica gel). Upon performing the reaction in DMF, compound 7 (40 % yield) and subsequent indole 8 (15 % yield) were isolated. Treatment of compound 7 with HCl smoothly led to indole 8 (70 % yield) within 1 h. Increasing the amount of HCl and the reaction time to 3 h led to isomerization of the double bonds in the heterocyclic ring and terpenic core. Compounds 8 (38 % yield) and 9 (10 % yield) were isolated. Interestingly, hydrolysis of the Boc protecting group under these conditions did not occur. As a result of the above transformations, we obtained hybrid indole–diterpene compound 8 in a yield up to 70 %.

Scheme 3.

Synthesis of indole‐substituted tricyclic diterpenoids.

From a mechanistic viewpoint and by using the main principles of the palladium catalysis of this reaction,27 the formation of compound 7 can be described as follows: the organic halide adds oxidatively to the palladium(0) catalyst, which forms palladium species A; species A then undergoes carbopalladation with allene 3 to generate regioselectively intermediate B. Finally, nucleophilic attack by the substituent leads to expected compound 7. Indole 8 is the product of isomerization of 3‐methyleneindoline 7 (Scheme 4).

Scheme 4.

Pd‐catalyzed reaction between N‐protected o‐iodoaniline 6 and isopimaric acid N‐(2,3‐butadienyl)carboxamide 3.

The reaction of allene 3 with ortho‐hydroxy‐substituted aryl iodide 10 under the found reaction conditions proceeded with the formation of a complex mixture of compounds (Scheme 5). So, by using CH₃CN as the solvent, heterocyclic compounds 11 a (18 % yield), 11 b (18 % yield), 12 a/12 b (29 % yield), and 13 (4 % yield) as well as styrenes 14 (4 % yield) and 15 (6 % yield) were isolated (Table 2, entry 1). Upon performing the reaction in DMF, 2H‐1‐benzopyranes 11 a (12 % yield) and 11 b (12 % yield), 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b (30 % yield), and N‐(3‐phenylbut‐2‐en‐1‐yl)amide 14 (10 % yield) were obtained (Table 2, entry 2). Treatment of 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b with HCl in methanol (35 equiv., 2 h) resulted in their transformation into 3‐methylbenzofuran 13 (50 % yield). So, diterpenoid 2H‐chromenes 11 a/11 b (isolated in 36 % yield) and diterpenoid–benzofuran hybrid 13 (30 % yield) were obtained in the reaction of allene 3 with aryl iodide 10 in the presence of Pd(PPh₃)₄.

Scheme 5.

Pd‐catalyzed reaction between 2‐iodophenol (10) and terpenoid allene 3.

Table 2.

Coupling–cyclization reaction of terpenoid N‐buta‐2,3‐dienyl)amide 3 with 2‐iodophenol (10).

Entry	Catalyst	Base	Solvent	Products (yield [%])
1	I	Cs2CO3	CH3CN	11 a (18), 11 b (18), 12 a/b (29), 13 (5), 14 (4), 15 (8)
2	I	Cs2CO3	DMF	11 a (12), 11 b (12), 12 a/b (30), 14 (10)
3	II	Cs2CO3	CH3CN	11 a (24), 11 b (24), 12 a/b (5), 13 (3)
4[a]	III	K2CO3	CH3CN/DMF/H2O	11 a (12), 11 b (12), 12 a/b (25)
5	IV	Cs2CO3	DMF	11 a (13), 11 b (13), 12 a/b (22)
6[a]	IV	K2CO3	DMF/H2O	11 a (9), 11 b (9), 11 c (8), 12 a/b (49)
7[a]	IV	K2CO3	CH3CN/DMF/H2O	11 a (9), 11 b (9), 11 c (28), 12 a/12 b (37)

[a] Bu₄NBr was introduced as an additive.

The formation of benzofuran derivatives by the Pd‐catalyzed reaction of 2‐iodophenol (10) with several allenes (e.g., CH₂=C=CHPh, CH₂=C=CHCO₂Et, CH₂=C=CHC₈H₁₇) was established earlier;26 the formation of 2H‐chromene derivatives 11 in the reaction of allenes with 2‐iodophenol (10) was not described. The proposed mechanism for the formation of isomeric compounds 11 a/11 b includes the generation a η³‐allylpalladium intermediate C, which is in equilibrium with less stable σ‐vinylpalladium species D, η¹‐rearrangement, β‐elimination, and finally attack on the activated double bond (Scheme 6).

Scheme 6.

Formation of compounds 11 a/11 b in the reaction between 2‐iodophenol (10) and terpenoid allene 3.

Optically active styrene derivatives 14 and 15 were also isolated in the coupling reaction of allene 3 with compound 10 (also, compound 5 c in the reaction of terpenoid 3 with 4 h). Presumably, these products were the result of aryl exchange between the arylpalladium and triphenylphosphine ligand.28 The ease by which the aryl groups in the phosphine ligand can be exchanged with the phenolic residue of 2‐iodophenol was previously shown.26c Scheme 7 shows the possible isomeric transformations of arylpalladium intermediate E into arylpalladium complexes F and G through aryl–aryl exchange between the Pd^II center and the coordinated phosphine ligand. The possibility of the existence of arylpalladium intermediates F and G (as determined by their stability) governs the formation of side products 14 and 15.

Scheme 7.

Formation of compounds 14 and 15.

To avoid the formation of compounds 14 and 15 and also to improve the selectivity, we studied the reaction between terpenoid allene 3 and 2‐iodophenol (10) in more detail. First, we studied the effect of the palladium source in the catalytic system on the yield of the cyclization product (Table 2, entries 3–6). The reaction of allene 3 with 10 under the conditions18b of Pd₂(dba)₃ ⋅CHCl₃ (dba=dibenzylideneacetone) as the palladium source and (R)‐(+)‐2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthalene [(R)‐(+)‐BINAP] as the ligand in acetonitrile with heating at 80 °C for 50 h led to a mixture of diterpenoid 2H‐chromenes 11 a/11 b (isolated in an overall yield of 48 %) and benzofuran derivatives 12 a/12 b/13 (overall yield of 8 %) (Table 2, entry 3). So, the selectively to 2H‐chromene formation was increased without a change in the enantioselectivity. Upon performing the reaction in the presence of the Pd(OAc)₂/(R)‐(+)‐BINAP catalytic system with potassium carbonate as the base in the presence of tetrabutylammonium bromide as an additive in a mixture of CH₃CN/DMF/H₂O (5:5:1, v/v/v) (Table 2, entry 4), desired 2H‐chromenes 11 a/11 b and 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b were obtained in a ratio of about 1:1 (Table 2, entry 4). We also studied the possibility of using palladium catalyst IV, developed Herrmann and Beller,29 in this coupling–cyclization reaction. Changing the catalyst (Table 2, entries 2 and 5) resulted in about the same yields of cyclization products 11 and 12 with a small increase in the selectivity to terpenoid 2H‐chromenes 11 a/11 b. Notably, the use of an organic solvent/water30 combination, particularly DMF/H₂O, and also the addition of tetraalkylammonium salts to the reaction mixture, as proposed by Jeffery,31 is common in the cross‐coupling reactions. The reaction of allene 3 with 2‐iodophenol (10) in the presence of potassium carbonate and tetrabutylammonium bromide as the additive in DMF/water (5:1, v/v) resulted in an improvement in the selectivity and also an increase in the overall yield of the cyclization products (Table 2, entries 6 and 7). Additionally, terpenoid 2H‐chromanes 11 c (two diastereomers) were also obtained by using a palladacycle in an organic solvent/water combination (compare with Table 2, entry 4). The addition of MeCN to the solvent system resulted in a decrease in the selectivity and an increase in the yield of tetrahydrobenzopyran 11 c (Table 2, entry 7). So, the effectiveness of the palladacycle catalyst (Herrmann–Beller palladium catalyst) was demonstrated in the coupling–cyclization reactions of terpenoid allene 3 with 2‐iodophenol (10).

The palladium‐catalyzed reaction of allene 3 with 2‐iodobenzoic acid (16) proceeded with the formation of 4‐methylene‐1‐oxoisochromanes 17 a/17 b (70 % yield) as a mixture of diastereomers (1:1, determined by analysis of the reaction mixture by ¹H NMR spectroscopy) (Scheme 8). Mechanistically, the formation of compounds 17 proceeds according to the above Pd‐catalyzed transformation. The π‐allylpalladium species is generated as an intermediate. Previously, it was inferred that carboxylate displacement occurred at the more highly substituted terminus of π‐allylpalladium compounds.32 4‐Methylene‐1‐oxo‐isochromanes 17 a/17 b were the only products isolated from this reaction.

Scheme 8.

Pd‐catalyzed reaction between 2‐iodobenzoic acid (16) and terpenoid allene 3.

The structures of all new compounds were confirmed by IR, ¹H NMR, and ¹³C NMR spectroscopy, in addition to mass spectrometry (MS) and X‐ray analysis. The structures of compounds 2, 3, 8, and 11 a were unambiguously confirmed by single‐crystal X‐ray diffraction (Figure 1).33

Figure 1.

Structures of molecules 2, 3, 8, and 11 a in the crystals.

The ¹H NMR and ¹³C NMR spectra of all the synthesized compounds agreed with their structures and contained one set of characteristic signals for the tricyclic diterpenoid core and the corresponding substituent. The configurations of 5 a and 5′ a as S or R were confirmed by comparison with literature data for assignment of the related configuration by NMR spectroscopy:34 the coupling constants of the H‐4 with H‐5 protons for the S diastereomers have values of J=7.5 and 10.7 Hz, whereas those for the R diastereomers are J=−8.2 and 10.3 Hz. The X‐ray data revealed that in the four studied structures, the cyclohexane rings have a “chair” conformation and that the cyclohexene rings have a “semichair” conformation. The bond lengths and bond angles are the same as the statistical values.35 In the crystal packings of 2, 3, and 8, intermolecular H‐bonds are observed: N−H⋅⋅⋅O type for 2 and 3 and C−H⋅⋅O for 8. One‐dimensional infinite chains of molecules are formed in the crystal through these H‐bonds. It is interesting to note that in the crystal packing of 11 a, intermolecular short contacts are not observed.

3. Conclusions

In summary, we presented a practical method for the synthesis of compound 3, which is the N‐(2,3‐butadienyl)carboxamide of isopimaric acid. The Pd‐catalyzed cross‐coupling–cyclization of the new allene with several aryl halides was an effective method to prepare a new group of biologically interesting 5‐[1‐(aryl)vinyl]‐4,5‐dihydrooxazoles with a terpenoid substituent. The substrate scope was explored, and the tolerance of our conditions towards additional functionalities was examined. The reaction of the new terpenoid allene with N‐protected 2‐iodoaniline, 2‐iodophenol, and 2‐iodobensoic acid proceeded chemoselectively with the formation of hybrid compounds containing terpenoid and heterocyclic (indole, benzofuran, chromane, chromene, and isochromane) fragments. The effectiveness of a palladacycle catalyst was demonstrated in the coupling–cyclization reactions of allene 3 with 2‐hydroxyaryl iodide 10. The obtained results will be useful in our ongoing work on diterpenic acid transformations and, thus, present an opportunity for biological studies and deepened understanding of the underlying biology of this class of natural products. We are confident that by using this approach for the selective transformations of other natural compounds the field of complex biologically active chemicals will be enriched, thus opening up new avenues in the design and development of new and efficient pharmaceuticals.

Experimental Section

General Information

Melting points were determined by using a Stuart SMP30 melting point apparatus (Bibby Scientific, Staffordshire, UK). Specific rotation [α]_D values were measured at room temperature (23–25 °C) in CHCl₃ with a PolAAr 3005 polarimeter. ¹H NMR and ¹³C NMR spectra were recorded by using a Bruker AV‐300 [300.13 (¹H), 75.48 MHz (¹³C)], AV‐400 [400.13 (¹H), 100.78 MHz (¹³C)], DRX‐500 [500.13 (¹H), 125.77 MHz (¹³C)] or AV‐600 [600.30 (¹H), 150.95 MHz (¹³C)] spectrometer. Chemical shifts were calibrated to tetramethylsilane (Me₄Si) as an internal reference. Chemical shifts are given in ppm and coupling constants (J) are given in Hz; the following abbreviations are used to indicate the multiplicity: s=singlet, d=doublet, t=triplet, m=multiplet. In the description of the ¹H NMR and ¹³C NMR spectra of compounds 3, 5 a–i, 7–9, 11 a/11 b, 12–15, and 17 a/17 b, the tricyclic diterpenoid core atom‐numbering scheme given in structure 1 was used. NMR assignments were supported by using COSY, HMBC, and HMQC spectra if appropriate. IR absorption spectra were obtained for neat thin films by using a Bruker Vector‐22 spectrometer. Mass spectra were recorded with a ThermoScientific DFS high‐resolution mass spectrometer (evaporator temperature 200–250°C, EI ionization at 70 V). X‐ray crystallography study of the crystals of 2, 3, and 11 a was performed with a Bruker Kappa Apex II CCD diffractometer by using ϕ,ω scans of narrow (0.5°) frames with MoKα radiation (λ=0.71073 Å) and a graphite monochromator. A Bruker P4 diffractometer (monochromated MoKα radiation, θ/2 θ scans, 2 θ<50°) was used to measure the unit‐cell dimensions and to collect data for compound 8.

The reaction progress and the purity of the obtained compounds were monitored by TLC on Silufol UV−254 plates (Kavalier, Czech Republic, CHCl₃/EtOH, 100:1; detection under UV light or by spraying the plates with a 10 % water solution of H₂SO₄ followed by heating at 100 °C). Preparative column chromatography was performed with 60H silica gel (0.063–0.200 mm, Merck KGaA, Darmstadt, Germany).

The starting materials 4‐iodobenzonitrile (4 a), 1‐iodo‐3‐(trifluoromethyl)benzene (4 b), iodobenzene (4 c), 1‐iodo‐2‐methoxybenzene (4 d), 1‐iodo‐3‐methoxybenzene (4 e), 1‐iodo‐4‐methoxybenzene (4 f), methyl 2‐acetamido‐5‐bromobenzoate (4 g), 2‐hydroxy‐5‐iodo‐3‐methoxybenzaldehyde (4 h), 2‐iodopyrazine (4 i), tert‐butyl (2‐iodophenyl)carbamate (6), 2‐iodophenol (10), 2‐iodobenzoic acid (16), paraformaldehyde (97 %), CuI, iPr₂NH, Cs₂CO₃, trans‐bis(μ‐acetato)bis[o‐(di‐o‐tolylphosphino)benzyl]dipalladium(II), and Pd(PPh₃)₄ were purchased from Aldrich or Alfa Aesar. Isopimaric acid (1) was isolated from Pinus sibirica R. Mayr sap by the reported method.10 Solvents (1,4‐dioxane, acetonitrile, DMF, and CH₂Cl₂) were purified by standard methods and were distilled in a stream of argon just before use. CHCl₃, ether, petroleum ether (refers to a light petroleum fraction, b.p. 60–75 °C) were used after distillation.

Synthesis and Characterization of Coupling–Isomerization Products

(1R,4aR,4bS,7S,10aR)‐N‐(Buta‐2,3‐dien‐1‐yl)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamide (3): A mixture of paraformaldehyde (70 mg, 2.32 mmol) and CuI (30 mg, 0.15 mmol) in 1,4‐dioxane (5 mL) was stirred at RT for 30 min. Then, iPr₂NH (0.46 mL, 2.1 mmol) and compound 2 (500 mg, 1.51 mmol) were added, and mixture was stirred at 100 °C (external temperature) for 10 h. Then, the solvent was evaporated in vacuo, and the residue was subjected to column chromatography on silica gel (petroleum ether/diethyl ether). Crystallization of the third fraction from CHCl₃ gave compound 3 (0.35 g, 65 %) as colorless prisms: R _f=0.36 (CHCl₃/EtOH, 10:1); m.p. 94–97 °C (CHCl₃); [α]$\genfrac{}{}{0pt}{}{25}{\mathrm{D}}$ =+10.64 (c=0.47 in CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ=0.81 (s, 3 H, C¹⁷H₃), 0.86 (s, 3 H,C²⁰H₃), 1.09–1.14 (m, 1 H, H‐1), 1.23 (s, 3 H, C¹⁹H₃), 1.28–1.34 (m, 2 H, H‐11,12), 1.42–154 (m, 5 H, H‐12, 11, 2, 3, 2), 1.53–1.62 (m, 1 H, H‐6), 1.68–1.75 (m, 2 H, H‐6, 9), 1.79–1.97 (m, 5 H, H‐1, 14, 14, 3, 5), 3.80 (m, 2 H, NCH ₂), 4.80 (m, 3 H, H‐16, C=CH ₂), 4.87 (dd, J=17.2, 1.1 Hz, 1 H, H‐16), 5.20 (q, J=6.5 Hz, 1 H, CH=C=CH₂), 5.23 (d, J=5.8 Hz, 1 H, H‐7), 5.78 (dd, J=17.2, 10.7 Hz, 1 H, H‐15), 5.92 ppm (t, J=5.7 Hz, 1 H, NH); ¹³C NMR (126 MHz, CDCl₃): δ=15.2 (C‐20), 17.2 (C‐19), 18.0 (C‐2), 19.8 (C‐11), 21.3 (C‐17), 24.7 (C‐6), 34.9 (C‐10), 35.9 (C‐12), 36.6 (C‐13), 37.1 (C‐3), 37.2 (C‐1), 38.6 (C‐4), 45.5 (C‐5), 45.9 (C‐14), 46.2 (CH₂), 51.9 (C‐9), 77.7 (CH=C=CH₂), 88.3 (CH=C=CH₂), 109.1 (C‐16), 120.8 (C‐7), 135.4 (C‐8), 150.2 (C‐15), 178.2 (C‐18), 207.6 ppm (CH=C=CH₂); IR: $\tilde{\nu }$ =3355, 2923, 2867, 1957, 1635, 1521, 1473, 1459, 1444, 1427, 1384, 1361, 1311, 1265, 1218, 1197, 1155, 1135, 998, 970, 910, 844, 850, 755, 651 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₄H₃₅NO [M+H]⁺: 353.2713; found: 353.2710.

General Procedure for the Synthesis of Terpenoid Oxazolines 5 a–i

Compound 4 (1.71 mmol), Cs₂CO₃ (or K₂CO₃) (2.81 mmol), and Pd(PPh₃)₄ (80 mg, 0.07 mmol) were added to a solution of compound 3 (500 mg, 1.41 mmol) in DMF (2 mL) [CH₃CN or DMF/CH₃CN (1:5, 2 mL)] at RT under an argon atmosphere. The mixture was stirred at 80 °C for 4 h (TLC) and was then cooled and diluted with ethyl acetate (10 mL). The separated organic layer was washed with water (3×5 mL), dried with MgSO₄, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/ether, 4:1 to 1:1) to yield a mixture of 5 a and 5′a (560 mg, 87 %). A second chromatography run of the fraction gave compounds 5 a and 5′a.

4‐(1‐{(S)‐2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a–dodecahydrophenanthren‐1‐yl]‐4,5‐dihydrooxazol‐5‐yl}vinyl)benzonitrile (5 a): Yellow oil; R _f=0.35 (CHCl₃/EtOH, 10:1); [α]$\genfrac{}{}{0pt}{}{25}{\mathrm{D}}$ =+34.4 (c=0.40 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ=0.84 (s, 3 H, C²⁰H₃), 0.90 (s, 3 H, C¹⁷H₃), 1.09 (dt, 1 H, J=12.6, 5.2, H‐1), 1.31 (s, 3 H, C¹⁹H₃), 1.24–1.36 (m, 2 H, H‐11, 12), 1.44–1.48 (m, 1 H, H‐12), 1.50–1.66 (m, 5 H, H‐11, 2, 3, 2, 6), 1.69–1.75 (m, 2 H, H‐6, 9), 1.79–1.96 (m, 5 H, H‐1, 14, 14, 3, 5), 3.53 (dd, J=14.0, 7.5 Hz, 1 H, H‐4′), 4.04 (dd, J=14.0, 10.7 Hz, 1 H, H‐4′), 4.84 (dd, J=10.7, 1.6 Hz, 1 H, H‐16), 4.90 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 5.26–5.32 (m, 2 H, H‐7, 5′), 5.44 (s, 1 H, =CH ₂), 5.46 (s, 1 H, =CH ₂), 5.78 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 7.39 (d, J=8.2 Hz, 2 H, H‐2′′, 6′′), 7.60 ppm (d, J=8.2 Hz, 2 H, H‐3′′, 5′′); ¹³C NMR (101 MHz, CDCl₃): δ=15.32 (C‐20), 17.80 (C‐2), 18.30 (C‐19), 19.86 (C‐11), 21.31 (C‐17), 24.64 (C‐6), 34.98 (C‐10), 35.91 (C‐12), 36.66 (C‐13), 36.92 (C‐3), 38.73 (C‐1), 40.65 (C‐4), 44.99 (C‐5), 45.97 (C‐14), 51.85 (C‐9), 60.14 (C‐4′), 79.15 (C‐5′), 109.11 (C‐16), 111.58 (C‐4′′), 115.23 (C‐7′), 118.40 (CN), 120.96 (C‐7), 127.17 (C‐2′′,6′′), 132.17 (C‐3′′,5′′), 135.52 (C‐8), 142.50 (C‐6′), 145.98 (C‐1′′), 150.13 (C‐15), 173.97 ppm (C‐2′); IR: $\tilde{\nu }$ =2927, 2867,2846, 2825, 2229, 1650, 1606, 1502, 1457, 1444, 1384, 1234, 1182, 1139, 1126, 1103, 989, 912, 844, 755, 696 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₁H₃₈N₂O [M+H]⁺: 454.2979; found: 454.2971.

4‐(1‐{(R)‐2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthren‐1‐yl]‐4,5‐dihydrooxazol‐5‐yl}vinyl)benzonitrile (5′ a): Yellow oil; R _f=0.34 (CHCl₃/EtOH, 10:1); ¹H NMR (400 MHz, CDCl₃): δ=0.85 (s, 3 H, C²⁰H₃), 0.90 (s, 3 H, C¹⁷H₃), 1.10 (dt, 1 H, J=12.6, 4.8 Hz, H‐1), 1.18–1.29 (m, 1 H, H‐12), 1.30 (s, 3 H, C¹⁹H₃), 1.30–1.38 (m, 1 H, H‐11), 1.45–1.50 (m, 1 H, H‐12), 1.52–1.68 (m, 5 H, H‐11, 2, 3, 2, 6), 1.70–1.74 (m, 2 H, H‐6, 9), 1.76–1.99 (m, 5 H, H‐1, 14, 14, 3, 5), 3.55 (dd, J=14.2, 8.2 Hz, 1 H, H‐4′), 4.04 (dd, J=14.2, 10.3 Hz, 1 H, H‐4′), 4.86 (dd, J=10.7, 1.3 Hz, 1 H, H‐16), 4.91 (dd, J=17.6, 1.3 Hz, 1 H, H‐16), 5.28–5.34 (m, 2 H, H‐7, 5′), 5.38 (s, 1 H, =CH ₂), 5.43 (s, 1 H, =CH₂), 5.79 (dd, J=17.6, 10.7 Hz, 1 H, H‐15), 7.38 (d, J=8.4 Hz, 2 H, H‐2′′, 6′′), 7.60 ppm (d, J=8.4 Hz, 2 H, H‐3′′, 5′′); ¹³C NMR (101 MHz, CDCl₃): δ=15.41 (C‐20), 17.79 (C‐2), 18.32 (C‐19), 19.94 (C‐11), 21.35 (C‐17), 24.69 (C‐6), 35.04 (C‐10), 35.95 (C‐12), 36.73 (C‐13), 37.03 (C‐3), 38.77 (C‐1), 40.64 (C‐4), 45.22 (C‐5), 46.02 (C‐14), 52.00 (C‐9), 59.98 (C‐4′), 79.33(C‐5′), 109.11 (C‐16), 111.55 (C‐4′′), 115.58 (C‐7′), 118.47 (CN), 120.79 (C‐7), 127.46 (C‐2′′,6′′), 132.16 (C‐3′′,5′′), 135.4 (C‐8), 142.62 (C‐6′), 145.99 (C‐1′′), 150.13 (C‐15), 174.15 ppm (C‐2′); IR: $\tilde{\nu }$ =2927, 2869, 2850, 2825, 2230, 1650, 1606, 1506, 1457, 1446, 1367, 1263, 1234, 1218, 1182, 1139, 1126, 1105, 1056, 1033, 1016, 991, 914, 844, 752, 698 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₁H₃₈N₂O [M+H]⁺: 454.2979; found: 454.2980.

5‐(S,R)‐{1‐[3‐(Trifluoromethyl)phenyl]vinyl}‐2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthren‐1‐yl]‐4,5‐dihydrooxazole (5 b): Yellow oil (420 mg, 60 %); R _f=0.36 (CHCl₃/EtOH, 10:1); ¹H NMR (300 MHz, CDCl₃): δ=0.85 (s, 6 H, 2 C²⁰H₃), 0.91 (s, 6 H, 2 C¹⁷H₃), 1.08–1.13 (m, 2 H, 2 H‐1), 1.31 (s, 3 H, C¹⁹H₃), 1.32 (s, 3 H, C¹⁹H₃), 1.31–1.39 (m, 4 H, 2 H‐11, 12), 1.44–1.49 (m, 2 H, 2 H‐12), 1.53–1.68 (m, 10 H, 2 H‐11, 2, 3, 2, 6), 1.68–1.78 (m, 4 H, 2 H‐6, 9), 1.82–2.08 (m, 10 H, 2 H‐1, 14, 14, 3, 5), 3.53 (dd, J=14.0, 7.5 Hz, 1 H, H‐4′), 3.55 (dd, J=14.0, 10.6 Hz, 1 H, H‐4′), 4.02 (dd, J=14.0, 10.6 Hz, 1 H, H‐4′), 4.04 (dd, J=14.0, 10.5 Hz, 1 H, H‐4′), 4.85 (dd, J=10.9, 1.6 Hz, 1 H, H‐16), 4.87 (dd, J=10.9, 1.6 Hz, 1 H, H‐16), 4.91 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 4.92 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 5.28–5.38 (m, 4 H, 2‐H‐7, 5′), 5.40 (s, 2 H, =CH ₂), 5.42 (s, 1 H, =CH ₂), 5.41 (s, 2 H, =CH ₂), 5.44 (s, 1 H, =CH ₂), 5.78 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 5.80 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 7.18–7.28 (m, 2 H, 2 H‐6′′), 7.38–7.52 (m, 4 H, 2‐H‐4′′, 5′′), 7.53–7.57 ppm (m, 2 H, 2 H‐2′′); ¹³C NMR (75 MHz, CDCl₃): δ=15.01, 15.08 (2 C‐20), 17.51 (2 C‐2), 17.95, 17.99 (2 C‐19), 19.59 (2 C‐11), 21.03 (2 C‐17), 24.35 (2 C‐6), 34.74 (2 C‐10), 35.66 (2 C‐12), 36.37 (2 C‐13), 36.61, 36.85 (2 C‐3), 38.47 (2 C‐1), 40.28 (2 C‐4), 44.69, 45.02 (2 C‐5), 45.70 (2 C‐14), 51.58, 51.63 (2 C‐9), 59.80, 59.92 (2 C‐4′), 79.05, 79.39 (2 C‐5′), 109.11 (2 C‐16), 113.82, 114.16 (2 C‐7′), 120.55, 120.75 (2 C‐7), 123.19, 123.24 (2 C‐2′′), 124.24, 124.30 (2 C‐4′′), 127.64 (2 C‐5′′), 128.53, 128.56 (2‐CF₃), 129.64 (2 C‐6′′), 134.09, 134.34 (2 C‐3′′), 135.22 (2 C‐8), 138.51, 138.56 (2 C‐6′), 145.95 (2 C‐1′′), 149.99 (2 C‐15), 173.61, 173.82 ppm (2 C‐2′); IR: $\tilde{\nu }$ =2927, 2869, 1652, 1606, 1500, 1438, 1384, 1330, 1297, 1257, 1236, 1166, 1128, 1097, 1074, 1056, 991, 910, 806, 754, 696 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₁H₃₈F₃NO [M+H]⁺: 497.2900; found: 497.2893.

5‐(1‐Phenylvinyl)‐2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2, 3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthren‐1‐yl]‐4,5‐dihydrooxazole (5 c): Yellow oil (300 mg, 50 %); R _f=0.4 (CHCl₃/EtOH, 10:1); ¹H NMR (500 MHz, CDCl₃): δ=0.85 (s, 6 H, 2 C²⁰H₃), 0.92 (s, 6 H, 2 C¹⁷H₃), 1.03–1.15 (m, 2 H, 2 H‐1), 1.33 (s, 3 H, C¹⁹H₃), 1.34 (s, 3 H, C¹⁹H₃), 1.27–1.40 (m, 4 H, 2 H‐11, 12), 1.42–1.49 (m, 2 H, 2 H‐12), 1.51–1.78 (m, 12 H, 2 H‐11, 2, 3, 2, 6, 9), 1.80–1.84 (m, 4 H, 2 H‐14, 5), 1.86–2.01 (m, 8 H, 2 H‐14, 6, 3, 1), 3.52 (dd, J=14.0, 7.2 Hz, 1 H, H‐4′), 3.55 (dd, J=14.0, 8.2 Hz, 1 H, H‐4′), 3.97–4.08 (m, 2 H‐4′), 4.85 (dd, J=10.9, 1.6 Hz, 1 H, H‐16), 4.87 (dd, J=10.9, 1.6 Hz, 1 H, H‐16), 4.91 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 4.92 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 5.28–5.40 (m, 4 H, 2 H‐7, 5′), 5.30 (br s, 1 H, =CH ₂), 5.37 (br s, 2 H, =CH ₂), 5.37 (s, 1 H, =CH ₂), 5.72–5.83 (m, 2 H, 2 H‐15), 7.25–7.36 ppm (m, 10 H, 2 Ph‐H); ¹³C NMR (126 MHz, CDCl₃): δ=15.32, 15.40 (2 C‐20), 17.81 (2 C‐2), 18.36, 18.29 (2 C‐19), 19.91 (2 C‐11), 21.30 (2 C‐17), 24.65 (2 C‐6), 34.98 (2 C‐10), 35.92 (2 C‐12), 36.68 (2 C‐13), 36.90, 37.02 (2 C‐3), 38.74 (2 C‐1), 40.57 (2 C‐4), 44.93, 45.16 (2 C‐5), 45.97 (2 C‐14), 51.81, 51.90 (2 C‐9), 60.25, 60.32 (2 C‐4′), 79.50, 79.61 (2 C‐5′), 109.08 (2 C‐16), 111.79, 112.11 (2 C‐7′), 120.91, 121.06 (2 C‐7), 126.36, 126.36 (4 C‐2′′,6′′), 127.84 (2 C‐4′′), 128.32 (4 C‐3′′,5′′), 135.43 (2 C‐8), 137.81, 137.91 (2 C‐6′), 147.18 (2 C‐1′′), 150.16 (2 C‐15), 173.97, 174.12 ppm (2 C‐2′); IR: $\tilde{\nu }$ =2927, 2869, 2850, 1650, 1500, 1384, 1234, 1139, 1105, 1031, 991, 910, 859, 755, 701 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₀H₃₉NO [M+H]⁺: 429.3026; found: 429.3028.

5‐(S,R)‐[1‐(2‐Methoxyphenyl)vinyl]‐2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthren‐1‐yl]‐4,5‐dihydrooxazole (5 d): Yellow oil (470 mg, 72 %); R _f=0.22 (CHCl₃/EtOH, 10:1); ¹H NMR (400 MHz, CDCl₃): δ=0.85 (s, 6 H, 2‐C²⁰H₃), 0.91 (s, 6 H, 2‐C¹⁷H₃), 1.07–1.16 (m, 2 H, 2 H‐1), 1.19–1.28 (m, 2 H, 2 H‐11), 1.30 (s, 3 H, C¹⁹H₃), 1.32 (s, 3 H, C¹⁹H₃), 1.31–1.39 (m, 2 H, 2 H‐3), 1.41–1.49 (m, 2 H, 2 H‐12), 1.50–1.68 (m, 10 H, 2 H‐11, 6, 2, 12, 2), 1.68–1.78 (m, 4 H, 2 H‐6, 9),1.79–2.03 (m, 10 H, 2 H‐1, 14, 14, 3, 5), 3.55 (dd, J=14.0, 7.2 Hz, 1 H, H‐4′), 3.59 (1 H, dd, J=14.0, 8.6 Hz, H‐4′), 3.79 (s, 6 H, 2‐OCH₃), 3.84 (dd, J=14.0, 10.6 Hz, 1 H, H‐4′), 3.86 (dd, J=14.0, 10.5 Hz, 2 H, H‐4′), 4.85 (dd, J=10.9, 1.6 Hz, 2 H, 2 H‐16), 4.91 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 4.92 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 5.31 (s, 2 H, =CH ₂), 5.30 (s, 1 H, =CH ₂), 5.37 (s, 1 H, =CH ₂), 5.40–5.46 (m, 4 H, 2‐H‐7, 5′), 5.76 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 5.81 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 6.84 (d, J=8.0 Hz, 2 H, 2 H‐3′′), 6.91 (dd, J=8.6, 8.2 Hz, 2 H, 2 H‐5′′), 7.13 (dd, J=8.6, 8.0 Hz, 2 H, 2 H‐4′′), 7.27 ppm (d, J=8.2 Hz, 2 H, 2 H‐6′′); ¹³C NMR (75 MHz, CDCl₃): δ=15.36 (2 C‐20), 17.89 (2 C‐2), 18.30, 18.35 (2 C‐19), 19.96 (2 C‐11), 21.37 (2 C‐17), 24.68 (2 C‐6), 35.02 (2 C‐10), 36.00 (2 C‐12), 36.45 (2 C‐13), 36.90, 37.06 (2 C‐3), 38.81 (2 C‐1), 40.57 (2 C‐4), 44.89, 45.11 (2 C‐5), 46.04 (2 C‐14), 51.96 (2 C‐9), 55.22 (OCH₃), 59.75, 59.97 (2 C‐4′), 79.23, 79.41 (2 C‐5′), 109.09 (2 C‐16), 110.44 (2 C‐3′′), 113.10, 113.50 (2 C‐7′), 120.58 (2 C‐5′′), 121.20 (2 C‐7), 128.11 (2 C‐6′), 129.16 (2 C‐4′′), 130.67 (2 C‐6′′), 135.31 (2 C‐8), 147.45, 147.73 (2 C‐1′′), 150.30 (2 C‐15), 156.36 (2 C‐2′′), 174.11 ppm (2 C‐2′); IR: $\tilde{\nu }$ =2935, 2869, 2846, 1648, 1598, 1500, 1461, 1436, 1384, 1292, 1247, 1240, 1182, 1139, 1126, 1095, 1047, 1027, 985, 912, 870, 754 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₁H₄₁NO₂ [M+H]⁺: 459.3132; found: 459.3131.

5‐(S,R)‐[1‐(3‐Methoxyphenyl)vinyl]‐2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthren‐1‐yl]‐4,5‐dihydrooxazole (5 e): Yellow oil (490 mg, 77 %); R _f=0.22 (CHCl₃/EtOH, 10:1); ¹H NMR (500 MHz, CDCl₃): δ=0.85 (s, 6 H, 2‐C²⁰H₃), 0.92 (s, 6 H, 2‐C¹⁷H₃), 1.07–1.15 (m, 2 H, 2 H‐1), 1.19–1.29 (m, 2 H, 2 H‐11), 1.32 (s, 3 H, C¹⁹H₃), 1.34 (s, 3 H, C¹⁹H₃), 1.31–1.39 (m, 2 H, 2 H‐12), 1.44–1.49 (m, 2 H, 2 H‐12), 1.52–1.68 (m, 10 H, 2 H‐11, 2, 3, 2, 6), 1.70–1.78 (m, 4 H, 2 H‐6, 9), 1.82–2.01 (m, 10 H, 2 H‐1, 14, 14, 3, 5), 3.52 (dd, J=14.0, 7.0 Hz, 1 H, H‐4′), 3.55 (dd, J=14.0, 8.2 Hz, 1 H, H‐4′), 3.78 (s, 6 H, 2‐OCH₃), 4.00 (dd, J=14.0, 10.2 Hz, 1 H, H‐4′), 4.03 (dd, J=14.0, 10.6 Hz, 1 H, H‐4′), 4.85 (dd, J=10.9, 1.6 Hz, 1 H, H‐16), 4.87 (dd, J=10.9, 1.6 Hz, 1 H, H‐16), 4.91 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 4.92 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 5.28–5.38 (m, 4 H, 2‐H‐7, 5′), 5.32 (s, 2 H, =CH ₂), 5.34 (s, 2 H, =CH ₂), 5.36 (s, 1 H, =CH ₂), 5.76 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 5.81 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 6.78–6.93 (m, 6 H, 2 H‐2′′, 4′′, 6′′), 7.19–7.22 ppm (m, 2 H, 2 H‐5′′); ¹³C NMR (126 MHz, CDCl₃): δ=15.30, 15.37 (2 C‐20), 17.81 (2 C‐2), 18.26, 18.31 (2 C‐19), 19.90 (2 C‐11), 21.29 (2 C‐17), 24.66 (2 C‐6), 34.98 (2 C‐10), 35.93 (2 C‐12), 36.66 (2 C‐13), 36.91, 37.08 (2 C‐3), 38.74 (2 C‐1), 40.55, 40.60 (2 C‐4), 44.93, 45.21 (2 C‐5), 45.95 (2 C‐14), 51.81, 51.88 (2 C‐9), 55.02 (OCH₃), 60.41 (2 C‐4′), 79.27, 79.40 (2 C‐5′), 109.04 (2 C‐16), 111.74, 111.86 (2 C‐7′), 112.42, 112.49(2 C‐4′′), 113.01 (2 C‐2′′), 118.79 (2 C‐6′′), 120.88, 121.07 (2 C‐7), 129.31 (2 C‐5′′), 135.41 (2 C‐8), 139.42 (2 C‐6′), 147.19 (2 C‐1′′), 150.17 (2 C‐15), 159.43 (2 C‐3′′), 173.88, 174.03 ppm (2 C‐2′); IR: $\tilde{\nu }$ =3301, 2935, 2867, 1652, 1598, 1500, 1488, 1459, 1384, 1288, 1226, 1182, 1139, 1126, 1105, 1309, 1317, 1365, 1074, 1051,1016, 989, 910, 881, 860, 833, 782, 755, 728, 696, 665 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₁H₄₁NO₂ [M+H]⁺: 459.3132; found: 459.3140.

5‐(S,R)‐[1‐(4‐Methoxyphenyl)vinyl]‐2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthren‐1‐yl]‐4,5‐dihydrooxazole (5 f): Yellow oil (350 mg, 54 %); R _f=0.22 (CHCl₃/EtOH, 10:1); ¹H NMR (400 MHz, CDCl₃): δ=0.85 (s, 6 H, 2‐C²⁰H₃), 0.92 (s, 6 H, 2‐C¹⁷H₃), 1.08–1.15 (m, 2 H, 2 H‐1), 1.19–1.29 (m, 2 H, 2 H‐11), 1.32 (s, 6 H, 2‐C¹⁹H₃), 1.34 (s, 3 H, C¹⁹H₃), 1.31–1.39 (m, 2 H, 2 H‐12), 1.42–1.49 (m, 2 H, 2 H‐12), 1.50–1.68 (m, 10 H, 2 H‐11, 2, 3, 2, 6), 1.70–1.78 (m, 4 H, 2 H‐6, 9), 1.83–2.01 (m, 10 H, 2 H‐1, 14, 14, 3, 5), 3.50 (dd, J=14.0, 7.6 Hz, 1 H, H‐4′), 3.54 (dd, J=14.0, 8.4 Hz, 1 H, H‐4′), 3.79 (s, 6 H, 2‐OCH₃), 4.01 (dd, J=14.0, 10.2 Hz, 1 H, H‐4′), 4.03 (dd, J=14.0, 10.5 Hz, 1 H, H‐4′), 4.85 (dd, J=10.9, 1.6 Hz, 2 H, 2 H‐16), 4.91 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 4.92 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 5.21 (s, 1 H, =CH ₂), 5.29 (s, 1 H, =CH ₂), 5.30 (s, 2 H, =CH ₂), 5.28–5.36 (m, 4 H, 2‐H‐7, 5′), 5.77 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 5.81 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 6.83 (d, J=8.6 Hz, 2 H, H‐3′′, 5′′), 6.85 (d, J=8.8 Hz, 2 H, H‐3′′, 5′′), 6.83 (d, J=8.6 Hz, 2 H, H‐2′′, 6′′), 6.85 ppm (d, J=8.8 Hz, 2 H,H‐2′′, 6′′); ¹³C NMR (75 MHz, CDCl₃): δ=15.33, 15.37 (2 C‐20), 17.87 (2 C‐2), 18.34 (2 C‐19), 19.88 (2 C‐11), 21.31 (2 C‐17), 24.64 (2 C‐6), 34.99 (2 C‐10), 35.94 (2 C‐12), 36.71 (2 C‐13), 36.93, 37.06 (2 C‐3), 38.77 (2 C‐1), 40.59, 40.64 (2 C‐4), 44.96, 45.23 (2 C‐5), 45.99 (2 C‐14), 51.84, 51.92 (2 C‐9), 55.11 (OCH₃), 60.40, 60.44 (2 C‐4′), 79.62, 79.74 (2 C‐5′), 109.07 (2 C‐16), 110.28, 110.64 (2 C‐7′), 113.74, 112.49 (4 C‐3′′,5′′), 120.91, 121.10 (2 C‐7), 127.49 (4 C‐2′′,6′′), 130.28 (2 C‐8), 135.43, 135.48 (2 C‐6′), 146.54 (2 C‐1′′), 150.21 (2 C‐15), 159.29 (2 C‐4′′), 173.99, 174.13 ppm (2 C‐2′); IR: $\tilde{\nu }$ =2995, 2950, 2867, 2848, 1652, 1608, 1573, 1511, 1459, 1432, 1384, 1365, 1294, 1268, 1249, 1180, 1139, 1126, 1103, 1076, 1054, 1033, 989, 910, 860, 833, 808, 755, 698 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₁H₄₁NO₂ [M+H]⁺: 459.3132; found: 459.3130.

5‐(S,R)‐Methyl 2‐acetamido‐5‐(1‐{2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthren‐1‐yl]‐4,5‐dihydrooxazol‐5‐yl}vinyl)benzoate (5 g): Yellowish solid (480 mg, 61 %); R _f=0.13 (CHCl₃/EtOH, 10:1); m.p. 72–75 °C (petroleum ether); ¹H NMR (400 MHz, CDCl₃): δ=0.83 (s, 6 H, 2‐C²⁰H₃), 0.90 (s, 6 H, 2‐C¹⁷H₃), 1.07–1.15 (m, 2 H, 2 H‐1), 1.19–1.29 (m, 2 H, 2 H‐11), 1.32 (s, 3 H, C¹⁹H₃), 1.34 (s, 3 H, C¹⁹H₃), 1.30–1.37 (m, 2 H, 2 H‐12), 1.42–1.51 (m, 2 H, 2 H‐12), 1.53–1.68 (m, 10 H, 2 H‐11, 2, 3, 2, 6), 1.70–1.78 (m, 4 H, 2 H‐6, 9), 1.81–1.98 (m, 10 H, 2 H‐1, 14, 14, 3, 5), 2.21 (s, 6 H, 2‐CH₃), 3.50 (dd, J=14.2, 7.4, 1 H, H‐4′), 3.54 (dd, J=14.0, 8.2 Hz, 1 H, H‐4′), 3.90 (s, 6 H, 2‐OCH₃), 4.01 (dd, J=14.2, 10.7 Hz, 1 H, H‐4′), 4.03 (dd, J=14.0, 10.4 Hz, 1 H, H‐4′), 4.88 (dd, J=10.8, 1.6 Hz, 2 H, 2 H‐16), 4.90 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 4.91 (dd, J=17.7, 1.6 Hz, 1 H, H‐16), 5.29 (s, 1 H, =CH ₂), 5.31 (s, 1 H, =CH ₂), 5.35 (s, 1 H, =CH ₂), 5.37 (s, 1 H, =CH ₂), 5.28–5.38 (m, 4 H, 2 H‐7, 5′), 5.75 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 5.77 (dd, J=17.7, 10.7 Hz, 1 H, H‐15), 7.46 (d, J=8.6 Hz, 1 H, H‐5′′), 7.49 (d, J=8.8 Hz, 1 H, H‐5′′), 7.95 (d, J=2.0 Hz, 2 H, 2 H‐2′′), 8.65 (dd, J=8.8, 2.0 Hz, 2 H, 2 H‐6′′), 11.01 ppm (2 H, s, 2 NH); ¹³C NMR (126 MHz, CDCl₃): δ=15.34, 15.37 (2 C‐20), 17.77 (2 C‐2), 18.19, 18.27 (2 C‐19), 19.82, 19.88 (2 C‐11), 21.26 (2 C‐17), 24.59, 24.65 (2 C‐6), 25.31 (CH₃), 34.95 (2 C‐10), 35.87 (2 C‐12), 36.63 (2 C‐13), 36.80, 37.08 (2 C‐3), 38.70 (2 C‐1), 40.57, 40.63 (2 C‐4), 44.93, 45.27 (2 C‐5), 45.88, 45.93 (2 C‐14), 51.79, 51.84 (2 C‐9), 52.27 (OCH₃), 59.92, 60.10 (2 C‐4′), 79.12, 79.64 (2 C‐5′), 109.05 (2 C‐16), 112.03, 112.71 (2 C‐7′), 114.52, 114.58 (2 C‐3′′), 120.28 (2 C‐5′′), 120.73, 120.98 (2 C‐7), 128.56 (2 C‐2′′), 131.87 (2 C‐1′′), 132.48, 132.66 (2 C‐6′′), 135.43, 135.48 (2 C‐8), 141.04 (2 C‐4′′), 145.63, 145.75 (2 C‐6′), 150.21 (2 C‐15), 168.27 (C=O), 168.91 (C=O), 174.10, 174.28 ppm (2 C‐2′); IR: $\tilde{\nu }$ =3413, 3317, 2950, 2869, 2827, 1691, 1652, 1599, 1517, 1438, 1367, 1297, 1384, 1409, 1236, 1187, 1159, 1124, 1087, 1054, 1033, 991, 910, 846, 792, 754, 702 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₄H₄₄N₂O₄ [M+H]⁺: 544.3296; found: 544.3302.

2‐Hydroxy‐3‐methoxy‐5‐(S,R)‐(1‐{2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydro‐phenanthren‐1‐yl]‐4,5‐dihydrooxazol‐5‐yl}vinyl)benzaldehyde (5 h): Yellow oil (430 mg, 61 %); R _f=0.10 (CHCl₃/EtOH, 10:1); ¹H NMR (400 MHz, CDCl₃): δ=0.82 (s, 6 H, 2‐C²⁰H₃), 0.89 (s, 6 H, 2‐C¹⁷H₃), 1.06–1.13 (m, 2 H, 2 H‐1), 1.19–1.29 (m, 2 H, 2 H‐11), 1.30 (s, 3 H, C¹⁹H₃), 1.31 (s, 3 H, C¹⁹H₃), 1.30–1.37 (m, 2 H, 2 H‐12), 1.42–1.49 (m, 2 H, 2 H‐12), 1.51–1.64 (m, 10 H, 2 H‐11, 2, 3, 2, 6), 1.68–1.75 (m, 4 H, 2 H‐6, 9), 1.82–1.94 (m, 10 H, 2 H‐1, 14, 14, 3, 5), 3.54 (dd, J=13.8, 7.4, 1 H, H‐4′), 3.57 (dd, J=14.0, 8.2, 1 H, H‐4′), 3.89 (s, 6 H, 2‐OCH₃), 4.01 (dd, J=14.0, 10.8, 1 H, H‐4′), 4.03 (dd, J=13.8, 10.6, 1 H, H‐4′), 4.82 (d, J=10.7 Hz, 2 H, 2 H‐16), 4.88 (d, J=17.6 Hz, 2 H, 2 H‐16), 5.25 (s, 1 H, =CH ₂), 5.31 (s, 2 H, =CH ₂), 5.33 (s, 1 H, =CH ₂), 5.25–5.35 (m, 4 H, 2 H‐7, 5′), 5.73 (dd, J=17.7, 10.6 Hz, 1 H, H‐15), 5.78 (dd, J=17.7, 10.6 Hz, 1 H, H‐15), 7.06 (br s, 2 H, 2 H‐2′′), 7.23 (br s, 2 H, 2 H‐6′′), 9.86 (br s, 2 H, 2 CHO), 11.06 ppm (br s, 2 H, 2‐OH); ¹³C NMR (101 MHz, CDCl₃): δ=15.31 (2 C‐20), 17.79 (2 C‐2), 18.33 (2 C‐19), 19.85 (2 C‐11), 21.29 (2 C‐17), 24.64, 24.68 (2 C‐6), 34.97 (2 C‐10), 35.88 (2 C‐12), 36.64 (2 C‐13), 36.96, 37.11 (2 C‐3), 38.72 (2 C‐1), 40.61, 40.64 (2 C‐4), 45.03, 45.27 (2 C‐5), 45.95 (2 C‐14), 51.84 (2 C‐9), 56.19 (OCH₃), 59.99, 60.12 (2 C‐4′), 79.45, 79.79 (2 C‐5′), 109.10 (2 C‐16), 112.62, 112.86 (2 C‐7′), 116.36 (2 C‐6′′), 120.11 (2 C‐1′′), 120.81, 120.95 (2 C‐7), 122.10 (2 C‐2′′), 129.74 (2 C‐3′′), 135.51, 135.60 (2 C‐8), 145.73, 145.82 (2 C‐6′), 148.19 (2 C‐4′′), 150.10 (2 C‐15), 151.42 (2 C‐5′′), 174.10, 174.12(2 C‐2′), 196.22 ppm (2‐CHO); IR: $\tilde{\nu }$ =3330, 3079, 2925, 2867, 2850, 2820, 1656, 1602, 1496, 1463, 1427, 1413, 1386, 1344, 1268, 1218, 1139, 1184, 1097, 1078, 1056, 1031, 1018, 991, 966, 910, 871, 842, 802, 754, 710 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₂H₄₁NO₄ [M+H]⁺: 503.3030; found: 503.3026.

5‐(S,R)‐[1‐(Pyrazin‐2‐yl)vinyl]‐2‐[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydro‐phenanthren‐1‐yl]‐4,5‐dihydrooxazole (5 i): Yellow oil (550 mg, 91 %); R _f=0.22 (CHCl₃/EtOH, 10:1); ¹H NMR (400 MHz, CDCl₃): δ=0.84 (s, 6 H, 2‐C²⁰H₃), 0.91 (s, 6 H, 2‐C¹⁷H₃), 1.06–1.15 (m, 2 H, 2 H‐1), 1.18–1.24 (m, 2 H, 2 H‐11), 1.27–1.37 (m, 2 H, 2 H‐12),1.33 (s, 3 H, C¹⁹H₃), 1.34 (s, 3 H, C¹⁹H₃), 1.42–1.49 (m, 2 H, 2 H‐12), 1.51–1.60 (m, 10 H, 2 H‐11, 2, 3, 2, 6), 1.62–1.78 (m, 4 H, 2 H‐6, 9), 1.82–1.99 (m, 10 H, 2 H‐1, 14, 14, 3, 5), 3.52 (dd, J=14.0, 7.3 Hz, 1 H, H‐4′), 3.55 (dd, J=14.0, 8.5 Hz, 1 H, H‐4′), 4.21 (dd, J=14.0, 10.8 Hz, 1 H, H‐4′), 4.23 (dd, J=14.0, 10.6 Hz, 1 H, H‐4′), 4.84 (d, J=10.7 Hz, 2 H, 2 H‐16), 4.90 (d, J=17.6 Hz, 2 H, 2 H‐16), 5.31 (m, 2 H, 2 H‐7), 5.54 (s, 1 H, =CH ₂), 5.63 (s, 1 H, =CH ₂), 5.52 (d, J=7.3 Hz, 1 H, H‐5′), 5.60 (d, J=8.5 Hz, 1 H, H‐5′), 5.75 (dd, J=17.7, 10.6 Hz, 1 H, H‐15), 5.79 (dd, 1 H, J=17.7, 10.6 Hz, H‐15), 5.88 (s, 1 H, =CH ₂), 8.44 (d, J=9.6 Hz, 4 H, 2 H‐3′′, 4′′), 8.82 ppm (s, 2 H, 2 H‐6′′); ¹³C NMR (101 MHz, CDCl₃): δ=15.36 (2 C‐20), 17.81 (2 C‐2), 18.27 (2 C‐19), 19.59 (2 C‐11), 21.26 (2 C‐17), 24.58, 24.64 (2 C‐6), 34.95 (2 C‐10), 35.86 (2 C‐12), 36.62 (2 C‐13), 36.93, 37.01 (2 C‐3), 38.74 (2 C‐1), 40.57, 40.62 (2 C‐4), 44.89, 45.26 (2 C‐5), 45.92 (2 C‐14), 51.82, 51.90 (2 C‐9), 61.17, 61.32 (2 C‐4′), 77.61, 79.79 (2 C‐5′), 109.03 (2 C‐16), 114.18, 114.38 (2 C‐7′), 120.72, 121.03 (2 C‐7), 131.83 (2 C‐4′′), 135.35, 135.59 (2 C‐8), 142.02 (2 C‐6′′), 142.82, 143.09 (2 C‐3′′), 144.97 (2 C‐6′), 150.14 (2 C‐15), 151.26 (2 C‐1′′), 173.65, 173.83 ppm (2 C‐2′); IR: $\tilde{\nu }$ =3305, 2927, 2868, 1652, 1610, 1580, 1520, 1467, 1411, 1384, 1234, 1182, 1162, 1139, 1120, 1054, 1031, 1014, 989, 914, 860, 755, 715 cm⁻¹; HRMS (ESI+): m/z calcd for C₂₈H₃₇N₃O [M+H]⁺: 431.2931; found: 431.2933.

Reaction of Terpenoid N‐(2,3‐Butadienyl)carboxamide 3 with N‐Boc‐(2‐iodophenyl)aniline 6

Conditions A: Compound 6 (550 mg, 1.71 mmol), Cs₂CO₃ (920 mg, 2.81 mmol), and Pd(PPh₃)₄ (80 mg, 0.07 mmol) were added to a stirred solution of 3 (500 mg, 1.41 mmol) in DMF (2 mL) at RT under an argon atmosphere. The mixture was heated at 80 °C for 3 h, cooled, diluted with ethyl acetate (10 mL), washed with water (3×5 mL), dried with K₂CO₃, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/ether, 10:1→1:1) to give 3‐methyleneindoline 7 (400 mg, 31 %) and 3‐methyl‐1H‐indole 8 (150 mg, 12 %).

Conditions B: Compound 6 (550 mg, 1.71 mmol), Cs₂CO₃ (920 mg, 2.81 mmol), and Pd(PPh₃)₄ (80 mg, 0.07 mmol) were added to a stirred solution of 3 (500 mg, 1.41 mmol) in MeCN (2 mL) under an argon atmosphere. The mixture was heated at 80 °C for 3 h, cooled, diluted with ethyl acetate (20 mL), washed with water (3×5 mL), dried with K₂CO₃, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/diethyl ether, 1:1) to give 3‐methyleneindoline 7 (420 mg, 55 %) as a yellow oil.

2‐(S,R)‐tert‐Butyl 3‐methylene‐2‐{[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8, 10,10a‐dodecahydrophenanthrene‐1‐carboxamido]methyl}indoline‐1‐carboxylate (7): R _f=0.12 (CHCl₃/EtOH, 10:1); ¹H NMR (500 MHz, CDCl₃): δ=0.81 (s, 6 H, 2‐C²⁰H₃), 0.82 (s, 6 H, 2 C¹⁷H₃), 0.81–0.90 (m, 1 H, H‐1), 0.94–1.05 (m, 1 H, H‐1), 1.16–1.26 (m, 2 H, 2 H‐11), 1.30 (s, 3 H, C¹⁹H₃), 1.31 (s, 3 H, C¹⁹H₃), 1.28–1.41 (m, 4 H, 2 H‐12, 3), 1.43–1.55 (m, 8 H, 2 H‐12, 11, 2, 6), 1.57 (s, 9 H, (CH₃)₃), 1.58 (s, 9 H, (CH₃)₃), 1.60–1.79 (m, 12 H, 2 H‐12, 2, 5, 3, 6, 9), 1.82–1.90 (m, 6H, 2 H‐1, 14, 14), 3.25–3.50 (m, 4H, 2‐CH ₂), 4.82–4.91 (m, 2 H, 2 H‐2′), 4.83 (dd, J=10.7, 1.2 Hz, 1 H, H‐16), 4.84 (dd, J=10.7, 1.2 Hz, 1 H, H‐16), 4.89 (dd, J=17.6, 1.2 Hz, 1 H, H‐16), 4.90 (dd, J=17.6, 1.2 Hz, 1 H, H‐16), 5.07 (br s, 1 H, NH), 5.08 (br s, 1 H, NH), 5.19 (m, 1 H, H‐7), 5.22 (m, 1 H, H‐7), 5.55 (br s, 1 H, H‐3′a), 5.56 (br s, 1 H, H‐3′a), 5.76 (dd, J 17.6, 10.7 Hz, 1 H, H‐15), 5.78 (dd, J 17.6, 10.7 Hz, 1 H, H‐15), 6.95–7.01 (m, 4 H, 2 H‐5′, 6′), 7.23 (m, 2 H, 2 H‐4′), 7.38–7.41 ppm (m, 2 H, 2 H‐7′); ¹³C NMR (126 MHz, CDCl₃): δ=14.00 (2 C‐20), 15.11 (2 C‐11), 17.95 (2 C‐2), 19.70 (2 C‐19), 21.28 (2 C‐17), 24.57 (C‐6), 28.25 (6 C‐2 (CH₃)₃), 34.90 (2 C‐10), 35.95 (2 C‐12), 36.64 (2 C‐3), 37.08 (2 C‐1), 38.54 (2 C‐13), 41.72 (2 C‐4), 45.23 (2 C‐5), 46.84 (2 C‐14), 46.05 (2 C‐(CH₂)), 51.70 (2 C‐9), 60.18 (2 C(CH₃)₃), 62.98 (2 C‐2′), 109.00 (2 C‐16), 109.88, 110.64 (2 C‐8′), 120.82 (2 C‐7′), 120.01, 120.22 (2 C‐3′a), 120.99 (2 C‐7), 122.73 (2 C‐5′), 128.14, 128.52 (2 C‐4′), 129.86 (2 C‐6′), 135.04 (2 C‐8), 135.17, 135.26 (2 C‐7′a), 145.96 (2 C‐3′), 150.17 (2 C‐15), 170.92 (2 C‐OC(=O)), 178.66 ppm (2 C‐C(=O)NH); IR: $\tilde{\nu }$ =3463, 3374, 3079, 2971, 2925, 2869, 1710, 1681, 1644, 1604, 1513, 1473, 1384, 1348, 1321, 1294,1251, 1162, 1120, 1045, 1024, 1002, 971, 910, 879, 852, 754, 710, 665 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₅H₄₈N₂O₃ [M+H]⁺: 544.3660; found: 544.3655.

tert‐Butyl 3‐methyl‐2‐{[(1R,4aR,4bS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamido]methyl}‐1H‐indole‐1‐carboxylate (8): Crystallization of the second fraction (conditions A) from EtOH gave compound 8 as colorless plates: R _f=0.32 (CHCl₃/EtOH, 10:1); m.p. 187–189 °C (EtOH); ¹H NMR (600 MHz, CDCl₃): δ=0.82 (s, 3 H, C²⁰H₃), 0.86 (s, 3 H, C¹⁷H₃), 1.12–1.21 (m, 1 H, H‐1), 1.22 (s, 3 H, C¹⁹H₃), 1.21–1.33 (m, 2 H, H‐11, 12), 1.38–1.51 (m, 6 H, H‐12, 11, 2, 2, 3, 6), 1.65–1.72 (m, 3 H, H‐6, 14, 9), 1.70 (s, 9 H, C(CH₃)₃), 1.72–1.88 (m, 4 H, H‐1, 14, 5, 3), 2.36 (s, 3H, C^8′H₃), 4.67 (d, J=8.2 Hz, 1 H, CH₂), 4.69 (d, J=8.2 Hz, 1 H, CH₂), 4.84 (dd, J=10.7, 1.3 Hz, 1 H, H‐16), 4.91 (dd, J=17.5, 1.3 Hz, 1 H, H‐16), 5.10–5.14 (m, 1 H, H‐7), 5.77 (dd, J=17.5, 10.7 Hz, 1 H, H‐15), 7.01 (t, J=6.2 Hz, 1 H, NH), 7.21 (dd, J=7.0, 7.2 Hz, 1 H, H‐5′), 7.29 (ddd, J=7.2, 6.8, 1.8 Hz, 1 H, H‐6′), 7.46 (dd, J=7.0, 1.8 Hz, 1 H, H‐4′), 7.95 ppm (d, 1 H, J=7.2 Hz, H‐7′); ¹³C NMR (151 MHz, CDCl₃): δ=8.5 (C‐3′a), 15.1 (C‐20), 17.1 (C‐19), 18.0 (C‐2), 19.8 (C‐11), 20.3 (C‐17), 24.5 (C‐6), 28.1 (3 C‐(CH₃)₃), 34.8 (CH₂), 34.9 (C‐10), 35.8 (C‐12), 36.9 (C‐13), 36.8 (C‐3), 38.6 (C‐1), 45.4 (C‐5), 45.8 (C‐14), 46.1 (C‐4), 51.8 (C‐9), 84.1 (C(CH₃)₃), 109.0 (C‐16), 115.4 (C‐7′), 117.2 (C‐3′), 118.9 (C‐4′), 120.9 (C‐7), 122.5 (C‐5′), 124.2 (C‐6′), 130.4 (C‐3′a), 132.7 (C‐7′a), 135.0 (C‐2′), 135.1 (C‐8), 150.2 (C‐15), 151.1 (C=O), 177.9 ppm (C=O); IR: $\tilde{\nu }$ =3477, 2973, 2946, 2869, 1714, 1664, 1605, 1498, 1475, 1446, 1382, 1369, 1346, 1324, 1253, 1220, 1157, 1135, 1015, 975, 920, 866, 750, 710 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₅H₄₈N₂O₃ [M+H]⁺: 544.3660; found: 544.3665.

Isomerization of 3‐Methyleneindoline 7

Conditions A: A 36 % aq solution of HCl (1.0 mL) was added to a stirred solution of 7 (200 mg, 0.37 mmol) in MeOH (5 mL). After stirring at RT for 1 h, the mixture was diluted with CHCl₃ (10 mL), washed with water (3×5 mL), dried with MgSO₄, filtered, and concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (petroleum ether/ether, 2:1) to give compound 8 (140 mg, 70 %).

Conditions B: An 36 % aq solution of HCl (2.0 mL) was added to a stirred solution of 7 (200 mg, 0.37 mmol) in MeOH (5 mL). After stirring at RT for 1 h, the mixture was diluted with CHCl₃ (10 mL), washed with H₂O (3×5 mL), dried with MgSO₄, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/ether) to give compounds 8 (80 mg, 38 %) and 9 (20 mg, 10 %) as a yellow oil.

tert‐Butyl 3‐methyl‐2‐{[(1R,4aS,7S,10aR)‐1,4a,7‐trimethyl‐7‐vinyl‐1,2,3, 4,4a,5,6,7,8,9,10,10a‐dodecahydrophenanthrene‐1‐carboxamido]methyl}‐1H‐indole‐1‐carboxylate (9): R _f=0.33 (CHCl₃/EtOH, 10:1); ¹H NMR (400 MHz, CDCl₃): δ=0.92 (s, 3 H, C²⁰H₃), 0.93 (s, C¹⁷H₃), 1.11–1.19 (m, 1 H, H‐1), 1.13 (s, 3 H, C¹⁹H₃), 1.19–1.29 (m, 2 H, 3 H, H−11, 12), 1.38–1.56 (m, 5 H, H‐12, 6, 11, 2, 3), 1.62–1.71 (m, 2 H, H‐2, 6), 1.70 (s, 9 H, C(CH₃)₃), 1.72–1.89 (m, 7H, H‐6, 14, 1, 14, 5, 3, 7), 2.36 (s, 3H, C^8′H₃), 4.67 (d, J=8.2 Hz, 1 H, CH₂), 4.71 (d, J=8.2 Hz, 1 H, CH₂), 4.83 (dd, J=10.7, 1.3 Hz, 1 H, H‐16), 4.89 (dd, J=17.5, 1.3 Hz, 1 H, H‐16), 5.71 (dd, J=17.5, 10.7 Hz, 1 H, H‐15), 7.03 (t, J=6.2 Hz, 1 H, NH), 7.22 (dd, J=7.0, 7.2 Hz, 1 H, H‐5′), 7.28 (ddd, J=7.2, 6.8, 1.8 Hz, 1 H, H‐6′), 7.46 (dd, J=7.0, 1.8 Hz, 1 H, H‐4′), 7.94 ppm (d, J=7.2 Hz, 1 H, H‐7′); ¹³C NMR (126 MHz, CDCl₃): δ=8.5 (C‐3′a), 15.1 (C‐20), 16.2 (C‐19), 18.1 (C‐2), 19.5 (C‐17), 20.6 (C‐11), 20.8 (C‐6), 28.1 (3 C‐(CH₃)₃), 31.6 (C‐7), 34.7 (C‐10), 34.8 (CH₂), 35.4 (C‐12), 36.6 (C‐13), 36.8 (C‐3), 38.6 (C‐1), 41.8 (C‐4), 46.7 (C‐5), 47.1 (C‐14), 84.0 (C(CH₃)₃), 110.7 (C‐16), 115.3 (C‐7′), 117.1 (C‐3′), 118.9 (C‐4′), 122.5 (C‐5′), 124.2 (C‐6′), 124.3 (C‐8), 130.4 (C‐3′a), 132.9 (C‐7′a), 134.9 (C‐2′), 136.3 (C‐9), 145.9 (C‐15), 151.1 (C=O), 177.9 ppm (C=O). HRMS (ESI+): m/z calcd for C₃₅H₄₈N₂O₃ [M+H]⁺: 544.3660; found: 544.3667.

Reaction of Terpenoid N‐(2,3‐Butadienyl)carboxamide 3 with 2‐Iodophenol (10) (Table 2)

Entry 1: Compound 10 (380 mg, 1.71 mmol), Cs₂CO₃ (920 mg, 2.81 mmol), and Pd(PPh₃)₄ (80 mg, 0.07 mmol) were added to a stirred solution of 3 (500 mg, 1.41 mmol) in MeCN (2 mL) at RT under an argon atmosphere. The mixture was heated at 80 °C for 3 h, cooled, diluted with ethyl acetate (20 mL), washed with water (3×5 mL), dried with K₂CO₃, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (petroleum ether/ether, 4:1→1:1) to give 4‐methyl‐2H‐chromene 11 a (110 mg, 18 %), 4‐methyl‐2H‐chromene 11 b (110 mg, 18 %), 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b (180 mg, 29 %), 3‐methylbenzofuran 13 (30 mg, 5 %), compound 14 (20 mg, 4 %), and compound 15 (40 mg, 8 %).

Entry 2: Compound 10 (380 mg, 1.71 mmol), Cs₂CO₃ (920 mg, 2.81 mmol), and Pd(PPh₃)₄ (80 mg, 0.07 mmol) were added to a stirred solution of 3 (500 g, 1.41 mmol) in DMF (2 mL) at RT under an argon atmosphere. The mixture was heated at 80 °C for 3 h, cooled, diluted with ethyl acetate (10 mL), washed with water (3×5 mL), dried with MgSO₄, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (petroleum ether/diethyl ether, 4:1→1:1) to give 4‐methyl‐2H‐chromene 11 a (80 mg, 12 %), 4‐methyl‐2H‐chromene 11 b (80 mg, 12 %), 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b (210 mg, 30 %), and compound 14 (60 mg, 12 %).

Entry 3: Compound 10 (380 mg, 1.71 mmol), Cs₂CO₃ (920 mg, 2.81 mmol), (R)‐(+)‐BINAP (70 mg, 0.10 mmol), and Pd₂(dba)₃ ⋅CHCl₃ (30 mg, 0.035 mmol) were added to a stirred solution of 3 (500 mg, 1.41 mmol) in anhydrous MeCN (2 mL) under a stream of argon, and the mixture was heated at 80 °C for 6 h. At that point, the conversion of the reaction was not complete (as determined by NMR spectroscopy), and the addition of (R)‐(+)‐BINAP (70 mg, 0.10 mmol) and Pd₂(dba)₃ ⋅CHCl₃ (30 mg, 0.035 mmol) was repeated. After 50 h of heating at 80 °C, the mixture was cooled, diluted with ethyl acetate (10 mL), washed with water (3×5 mL), dried with K₂CO₃, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/diethyl ether, 4:1→1:1) to give 4‐methyl‐2H‐chromene 11 a (160 mg, 24 %), 4‐methyl‐2H‐chromene 11 b (160 mg, 24 %), 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b (30 mg, 5 %), and 3‐methylbenzofuran 13 (20 mg, 3 %).

Entry 4: Compound 10 (380 mg, 1.71 mmol), K₂CO₃ (390 mg, 2.81 mmol), (R)‐(+)‐BINAP (130 mg, 0.21 mmol), and Pd(OAc)₂ (30 mg, 0.14 mmol) were added to a solution of 3 (500 mg, 1.41 mmol) in DMF/MeCN/H₂O (5:5:1, 2 mL) under a stream of argon, and the mixture was heated at 80 °C for 6 h. The mixture was cooled, diluted with ethyl acetate (10 mL), washed with water (3×5 mL), dried with K₂CO₃, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/diethyl ether, 4:1→1:1) to give 4‐methyl‐2H‐chromene 11 a (80 mg, 12 %), 4‐methyl‐2H‐chromene 11 b (80 mg, 12 %), and 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b (160 mg, 25 %).

Entry 5: Compound 11 (380 mg, 1.71 mmol), Cs₂CO₃ (920 mg, 2.81 mmol), and trans‐bis(μ‐acetato)bis[o‐(di‐o‐tolylphosphino)benzyl]dipalladium(II) (70 mg, 0.07 mmol) were added to a solution of 3 (500 mg, 1.41 mmol) in anhydrous DMF (2 mL), and the mixture was heated at 80 °C for 3 h. Then, the mixture was cooled, diluted with ethyl acetate (10 mL), washed with H₂O (3×5 mL), dried with K₂CO₃, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/diethyl ether, 4:1→1:1) to give 4‐methyl‐2H‐chromene 11 a (87 mg, 13 %), 4‐methyl‐2H‐chromene 11 b (87 mg, 13 %), and 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b (140 mg, 22 %).

Entry 6: Compound 11 (380 mg, 1.71 mmol), K₂CO₃ (390 mg, 2.81 mmol), nBu₄NBr (450 mg, 1.41 mmol), and trans‐bis(μ‐acetato)bis[o‐(di‐o‐tolylphosphino)benzyl]dipalladium(II) (70mg, 0.07 mmol) were added to a solution of 3 (500 mg, 1.41 mmol) in DMF/H₂O (5:1, 2 mL) under a stream of argon, and the mixture was heated at 80 °C for 3 h. Then, the mixture was cooled, diluted with ethyl acetate (10 mL), washed with H₂O (3×5 mL), dried with K₂CO₃, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/diethyl ether, 4:1→1:1) to give 4‐methyl‐2H‐chromene 11 a (62 mg, 9 %), 4‐methyl‐2H‐chromene 11 b (61 mg, 9 %), 4‐methylene‐2H‐dihydrochromene 11 c (52 mg, 8 %), and 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b (315 mg, 49 %).

Entry 7: Compound 11 (380 mg, 1.71 mmol), K₂CO₃ (390 mg, 2.81 mmol), nBu₄NBr (450 mg, 1.41 mmol), and trans‐bis(μ‐acetato)bis[o‐(di‐o‐tolylphosphino)benzyl]dipalladium(II) (70 mg, 0.07 mmol) were added to a solution of 3 (500 mg, 1.41 mmol) in DMF/MeCN/H₂O (5:5:1, 2 mL) under a stream of argon, and the mixture was heated at 80 °C for 6 h. Then, the mixture was cooled, diluted with ethyl acetate (10 mL), washed with H₂O (3×5 mL), dried with K₂CO₃, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/diethyl ether, 4:1→1:1) to give 4‐methyl‐2H‐chromene 11 a (60 mg, 9 %), 4‐methyl‐2H‐chromene 11 b (62 mg, 9 %), 4‐methylene‐2H‐dihydrochromene 11 c (190 mg, 28 %), and 3‐methylene‐2,3‐dihydrobenzofurans 12 a/12 b (240 mg, 37 %).

(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐N‐[(R)‐4‐methyl‐2H‐chromen‐2‐yl]‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamide (11 a): Yellowish needles; R _f=0.31 (CHCl₃/EtOH, 10:1); m.p. 168–170 °C (EtOH); ¹H NMR (600 MHz, CDCl₃): δ=0.82 (s, 3 H, C²⁰H₃), 0.85 (s, 3 H, C¹⁷H₃), 1.11 (dt, 1 H, J=13.7, 6.8 Hz, H‐1), 1.16 (s, 3 H, C¹⁹H₃), 1.26–1.35 (m, 2 H, H‐11,12), 1.43–1.54 (m, 5 H, H‐12, 3, 11, 2, 2), 1.55–1.61 (m, 1 H, H‐6), 1.64–1.70 (m, 2 H, H‐6, 9), 1.73–1.99 (m, 5 H, H‐1, 3, 14, 14, 5), 2.10 (s, 3 H, CH₃), 4.85 (dd, J=10.7, 1.2 Hz, 1 H, H‐16), 4.90 (dd, J=17.5, 1.2 Hz, 1 H, H‐16), 5.21–5.26 (m, 1 H, H‐7), 5.54 (d, J=4.2 Hz, 1 H, H‐3′), 5.77 (dd, 1 H, J=17.5, 10.7 Hz, H‐15), 6.31 (br d, J=8.8 Hz, 1 H, NH), 6.47 (dd, J=8.8, 4.2 Hz, 1 H, H‐2′), 6.88 (d, J=8.1 Hz, 1 H, H‐8′), 6.94 (dd, J=8.0, 7.8 Hz, 1 H, H‐6′), 7.16 (dd, J=8.1, 8.0 Hz, 1 H, H‐7′), 7.23 ppm (d, J=7.8 Hz, 1 H, H‐5′); ¹³C NMR (151 MHz, CDCl₃): δ=14.9 (C‐20), 16.8 (C‐19), 17.5 (C‐2), 17.6 (CH₃), 19.5 (C‐11), 21.0 (C‐17), 24.3 (C‐6), 34.7 (C‐10), 35.6 (C‐12), 36.3 (C‐13), 36.6 (C‐3), 38.2 (C‐1), 45.3 (C‐5), 45.6 (C‐14), 46.1 (C‐4), 51.5 (C‐9), 72.7 (C‐2′), 108.8 (C‐16), 115.0 (C‐8′), 116.7 (C‐6′), 120.3 (C‐7), 120.8 (C‐7′), 121.5 (C‐4′a), 123.2 (C‐5′), 129.1 (C‐3′), 132.1 (C‐4′), 135.1 (C‐8), 149.9 (C‐15), 151.0 (C‐8′a), 177.9 ppm (C=O); IR: $\tilde{\nu }$ =3438, 2971, 2941, 2915, 2904, 2863, 2844, 1664, 1608, 1490, 1473, 1448, 1380, 1363, 1322, 1243, 1274, 1209, 1149, 1122, 1081, 1037, 1000, 971,939, 923, 906, 889, 827, 752 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₀H₃₉NO₂ [M+H]⁺: 445.2975; found: 445.2969.

(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐N‐[(S)‐4‐methyl‐2H‐chromen‐2‐yl]‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamide (11 b): Yellow oil; R _f=0.30 (CHCl₃/EtOH, 10:1); [α]$\genfrac{}{}{0pt}{}{25}{\mathrm{D}}$ =+68.6 (c=0.18 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ=0.81 (s, 6 H, C²⁰H₃ and C¹⁷H₃), 1.16 (dt, J=13.9, 6.2 Hz, 1 H, H‐1), 1.14 (s, 3 H, C¹⁹H₃), 1.28–1.35 (m, 2 H, H‐11, 12), 1.40–1.58 (m, 5 H, H‐12, 3, 11, 2, 2), 1.60–1.64 (m, 1 H, H‐6), 1.72–1.79 (m, 2 H, H‐6,9), 1.81–1.99 (m, 5 H, H‐1, 3, 14, 14, 5), 2.10 (s, 3 H, CH₃), 4.89 (dd, J=10.6, 1.2 Hz, 1 H, H‐16), 4.95 (dd, J=17.5, 1.2 Hz, 1 H, H‐16), 5.21 (d, J=4.4 Hz, 1 H, H‐7), 5.56 (d, J=4.5 Hz, 1 H, H‐3′), 5.80 (dd, J=17.5, 10.6 Hz, 1 H, H‐15), 6.33 (d, J=8.5 Hz, 1 H, NH), 6.51 (dd, J=8.5, 4.5 Hz, 1 H, H‐2′), 6.95 (d, J=8.0 Hz, 1 H, H‐8′), 7.01 (dd, J=8.1, 7.8 Hz, 1 H, H‐6′), 7.24 (dd, J=8.1, 8.0 Hz, 1 H, H‐7′), 7.29 ppm (d, J=7.8 Hz, 1 H, H‐5′); ¹³C NMR (101 MHz, CDCl₃): δ=15.1 (C‐20), 17.0 (C‐19), 17.8 (C‐2), 17.9 (CH₃), 19.8 (C‐11), 21.3 (C‐17), 24.3 (C‐6), 34.9 (C‐10), 35.8 (C‐12), 36.3 (C‐13), 36.6 (C‐3), 38.5 (C‐1), 45.7 (C‐5), 45.8 (C‐14), 46.3 (C‐4), 51.7 (C‐9), 72.8 (C‐2′), 109.1 (C‐16), 116.8 (C‐8′), 116.9 (C‐6′), 120.6 (C‐7), 121.1 (C‐7′), 121.9 (C‐4′a), 123.5 (C‐5′), 129.4 (C‐3′), 132.5 (C‐4′), 135.3 (C‐8), 150.1 (C‐15), 151.3 C‐8′a), 178.3 ppm (C=O); IR: $\tilde{\nu }$ =3438, 2941, 2917, 2865, 2846, 1664, 1605, 1499, 1460, 1420, 1382, 1211, 1124, 1037, 1080, 1000, 911, 866, 752, 700 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₀H₃₉NO₂ [M+H]⁺: 445.2975; found: 445.2969.

(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐N‐[(R,S)‐4‐methylene‐chroman‐2‐yl]‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamide (11 c): Yellowish solid; R _f=0.31 (CHCl₃/EtOH, 10:1); m.p. 142–145 °C (CHCl₃); ¹H NMR (600 MHz, CDCl₃): δ=0.81 (s, 3 H, C²⁰H₃), 0.83 (s, 3 H, C¹⁷H₃), 1.11 (dt, 1 H, J=12.6, 4.2 Hz, H‐1), 1.16 (s, 3 H, C¹⁹H₃), 1.31 (t, 1 H, J=9.5 Hz, H‐11), 1.45–1.54 (m, 6 H, H‐2, 2, 6, 12, 3, 12), 1.58 (br s, 1 H, H‐6), 1.70 (s, 1 H, H‐9), 1.79–1.84 (m, 5 H, H‐1, 12, 3, 14, 14), 1.82 (m, 1 H, H‐5), 2.52 (dd, 1 H, J=14.3, 4.8 Hz, H‐3′), 2.88 (ddd, 1 H, J=14.3, 1.8, 1.5 Hz, H‐3′), 4.85 (dd, 1 H, J=10.7, 1.1 Hz, H‐16), 4.90 (dd, 1 H, J=17.5, 1.1 Hz, H‐16), 5.01 (br s, 1 H, H‐9′), 5.13 (br d, 1 H, J=4.4 Hz, H‐7), 5.64 (br s, 1 H, H‐9′), 5.77 (dd, 1 H, J=17.5, 10.7 Hz, H‐15), 6.04 (dd, 1 H, J 7.2, 4.8 Hz, H‐2′), 6.45 (m, 1 H, NH), 6.86 (dd, 1 H, J=8.1, 1.1 Hz, H‐8′), 6.92 (td, 1 H, J=7.5, 1.1 Hz, H‐6′), 7.19 (ddd, 1 H, J=8.1, 7.5, 1.5 Hz, H‐7′), 7.53 ppm (dd, 1 H, J=7.5, 1.5 Hz, H‐5′); ¹³C NMR (150 MHz, CDCl₃): δ=15.2 (C‐20), 16.9 (C‐19), 17.9 (C‐2), 19.8 (C‐11), 21.3 (C‐17), 24.3 (C‐6), 34.9 (C‐10), 35.5 (C‐3′), 35.9 (C‐12), 36.5 (C‐13), 36.6 (C‐3), 38.6 (C‐1), 45.8 (C‐5), 45.8 (C‐14), 46.3 (C‐4), 51.8 (C‐9), 75.1 (C‐2′), 109.1 (C‐16), 110.4 (C‐9′), 117.9 (C‐8′), 120.7 (C‐7), 120.7 (C‐4a′), 121.0 (C‐6′), 124.1 (C‐5′), 130.1 (C‐7′), 134.2 (C‐4′), 135.3 (C‐8), 150.2 (C‐15), 151.9 (C‐8′a), 178.4 ppm (C=O); IR: $\tilde{\nu }$ =3386, 3079, 2923, 2850, 1727, 1654, 1639, 1610, 1573, 1519, 1479, 1456, 1349, 1319, 1299, 1278, 1255, 1218, 1201, 1162, 1155, 1126, 1081, 1039, 1000, 908, 883, 848, 833, 811, 804, 754, 728, 676, 667, 649 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₀H₃₉NO₂ [M+H]⁺: 445.2975; found: 445.2982.

(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐N‐[(R,S)‐(3‐methylene‐2,3‐dihydrobenzofuran‐2‐yl)methyl]‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamides (12 a/12 b): Yellow oil; R _f=0.12 (CHCl₃/EtOH, 10:1); ¹H NMR (400 MHz, CDCl₃): δ=0.82 (s, 3 H, 2 C²⁰H₃), 0.83 (s, 3 H, 2 C²⁰H₃), 0.85 (s, 3 H, C¹⁷H₃), 0.88 (s, 3 H, C¹⁷H₃), 1.09 (m, 2 H, H‐1), 1.14 (s, 3 H, C¹⁹H₃), 1.17 (s, 3 H, C¹⁹H₃), 1.31 (m, 4 H, 2 H‐11, 12), 1.39–1.51 (m, 10 H, 2 H‐12, 3, 11, 2, 2), 1.64–1.70 (m, 4 H, 2 H‐6, 9), 1.73–1.96 (m, 12 H, 2 H‐6, 1, 3, 14, 14, 5), 3.28–3.32 (m, 1 H, CH₂), 3.36–3.42 (m, 1 H, CH₂), 3.75–3.83 (m, 1 H, CH₂), 3.96–4.04 (m, 1 H, CH₂), 4.84 (dd, J=10.7, 1.6 Hz, 2 H, H‐16), 4.89 (dd, J=17.5, 1.6 Hz, 2 H, H‐16), 5.03 (d, J=3.2 Hz, 1 H, H‐2′), 5.04 (br s, 1 H, H‐2′), 5.18–5.26 (m, 4 H, 2 H‐7, 2′a), 5.38 (s, 1 H, H‐8′), 5.45 (s, 1 H, H‐8′), 5.77 (dd, J=17.5, 10.7 Hz, 2 H, H‐15), 6.10 (m, 2 H, 2‐NH), 6.83 (d, J=7.2 Hz, 2 H, H‐7′), 6.89 (dd, J=7.6, 7.8 Hz, 2 H, H‐5′), 7.19 (dd, J=7.8, 7.2 Hz, 2 H, H‐6′), 7.30 ppm (d, J=7.6 Hz, 2 H, H‐4′); ¹³C NMR (75 MHz, CDCl₃): δ=15.2 (2 C‐20), 17.1 (2 C‐19), 18.0, 18.2 (2 C‐2), 19.8 (2 C‐11), 21.4 (2 C‐17), 24.5, 24.7 (2 C‐6), 35.0, 35.0 (2 C‐10), 35.9 (2 C‐12), 37.0, 37.1 (2 C‐3), 38.6, 38.7 (2 C‐1), 36.66 (2 C‐13), 46.3 (2 C‐4), 44.1, 44.1 (2 C‐(CH₂)), 45.3, 45.6 (2 C‐5), 45.9 (2 C‐14), 51.8, 51.9 (2 C‐9), 84.4, 84.4 (2 C‐2′), 109.1 (2 C‐16), 101.75, 101.7 (2 C‐8′), 110.4, (2 C‐7′), 125.6, 125.7 (2 C‐3′a), 120.9 (2 C‐7), 120.9 (2 C‐5′), 130.6 (2 C‐4′), 129.86 (2 C‐6′), 135.3, 135.4 (2 C‐8), 144.2, 144.3 (2 C‐3′), 150.2 (2 C‐15), 161.9 (2 C‐7′a), 178.7 ppm (2 C‐OC(=O); HRMS (ESI+): m/z calcd for C₃₀H₃₉NO₂ [M+H]⁺: 445.2975; found: 445.2966.

(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐N‐[(3‐methylbenzofuran‐2‐yl)methyl]‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamide (13): Yellow oil; R _f=0.32 (CHCl₃/EtOH, 10:1); [α]$\genfrac{}{}{0pt}{}{25}{\mathrm{D}}$ =+21.9 (c=0.36 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ=0.83 (s, 3 H, C²⁰H₃), 0.89 (s, 3 H, C¹⁷H₃), 1.06–1.14 (m, 1 H, H‐1), 1.16–1.23 (m, 2 H, H‐11, 12), 1.26 (s, 3 H, C¹⁹H₃), 1.29–1.37 (m, 1 H, H‐2), 1.43–1.55 (m, 4 H, H‐12, 3, 11, 2, 2), 1.59–1.62 (m, 1 H, H‐6), 1.68–1.74 (m, 2 H, H‐6, 9), 1.80–1.96 (m, 5 H, H‐1, 3, 14, 14, 5), 2.07 (s, 3 H, H‐8′), 3.98–4.06 (m, 2 H, CH₂), 4.84 (dd, J=10.7, 1.8 Hz, 1 H, H‐16), 4.89 (dd, J=17.5, 1.8 Hz, 1 H, H‐16), 5.20–5.28 (m, 1 H, H‐7), 5.74 (m, 1 H, NH), 5.78 (dd, 1 H, J=17.5, 10.7 Hz, H‐15), 7.32 (dd, 1 H, J=7.2, 7.0 Hz, H‐5′), 7.38 (dd, J=7.2, 6.8 Hz, 1 H, H‐6′), 7.67 (d, 1 H, J=6.8 Hz, H‐7′), 7.85 ppm (d, 1 H, J=7.0 Hz, H‐4′); ¹³C NMR (126 MHz, CDCl₃): δ=7.3 (C‐8′), 15.2 (C‐20), 17.9 (C‐19), 17.9 (C‐2), 19.8 (C‐11), 21.3 (C‐17), 24.6 (C‐6), 34.9 (C‐10), 35.2 (C‐12), 35.8 (C‐13), 36.6 (C‐3), 37.0 (C‐2a), 38.6 (C‐1), 45.6 (C‐5), 45.8 (C‐14), 46.3 (C‐4), 51.8 (C‐9), 109.0 (C‐16), 110.7 (C‐7′), 112.4 (C‐3′), 119.3 (C‐4′), 120.7 (C‐7), 122.2 (C‐5′), 124.2 (C‐6′), 129.6 (C‐3′a), 135.3 (C‐8), 148.9 (C‐2′), 150.1 (C‐15), 153.8 (C‐7′a), 178.3 ppm (C=O); IR: $\tilde{\nu }$ =3353, 2921, 2865, 2823, 1647, 1607, 1519, 1475, 1454, 1384, 1332, 1278, 1238, 1195, 1180, 1153, 1130, 1105, 1002, 986, 910, 868, 811, 746, 705 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₀H₃₉NO₂ [M+H]⁺: 445.2975; found: 445.2971.

(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐N‐(3‐phenylbut‐2‐en‐1‐yl)‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamide (14): Yellow oil; ¹H NMR (500 MHz, CDCl₃): δ=0.83 (s, 3 H, C²⁰H₃), 0.89 (s, 3 H, C¹⁷H₃), 1.12–1.22 (m, 1 H, H‐1), 1.27 (s, 3 H, C¹⁹H₃), 1.26–1.37 (m, 2 H, H‐11, 12), 1.44–1.55 (m, 5 H, H‐12, 3, 11, 2, 2), 1.58–1.62 (m, 1 H, H‐6), 1.65–1.74 (m, 2 H, H‐6,9), 1.78–1.95 (m, 5 H, H‐1, 3, 14, 14, 5), 2.07 (s, 3 H, CH₃), 3.99 (dd, J=13.9, 6.2 Hz, 1 H, H‐3′), 4.07 (dd, J=13.9, 6.2 Hz, 1 H, H‐3′), 4.84 (dd, J=10.7, 1.8 Hz, 1 H, H‐16), 4.90 (dd, J=17.6, 1.8 Hz, 1 H, H‐16), 5.22–5.30 (m, 1 H, H‐7), 5.72 (t, J=6.2 Hz, 1 H, CH=), 5.75 (m, 1 H, NH), 5.77 (dd, J=17.6, 10.7 Hz, 1 H, H‐15), 7.04 (m, 2 H, H‐2′′, 6′′), 7.26 (m, 2 H, H‐3′′, 5′′), 7.31 ppm (m, 2 H, H‐4′′); ¹³C NMR (126 MHz, CDCl₃): δ=15.2 (C‐20), 16.0 (CH₃), 17.3 (C‐19), 18.1 (C‐2), 19.8 (C‐11), 21.4 (C‐17), 24.8 (C‐6), 35.1 (C‐10), 35.9 (C‐12), 36.7 (C‐13), 37.2 (C‐3), 38.4 (C‐4′), 38.7 (C‐1), 45.7 (C‐5), 45.9 (C‐14), 46.3 (C‐4), 51.9 (C‐9), 109.1 (C‐16), 120.8 (C‐7), 123.5 (C‐5′), 125.6 (C‐2′′,6′′), 127.2 (C‐4′′), 128.2 (C‐3′′,5′′), 135.5 (C‐8), 138.4 (C‐6′), 142.7 (C‐1′′), 150.2 (C‐15), 178.4 ppm (C=O); IR: $\tilde{\nu }$ =3398, 3079, 2865, 1727, 1646, 1600, 1521, 1496, 1452, 1380, 1315, 1261, 1240, 1135, 1101, 1072, 1027, 975, 912, 860, 768, 700 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₀H₄₁NO [M+H]⁺: 431.3175; found: 431.3165.

(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐N‐(3‐phenylbut‐3‐en‐1‐yl)‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamide (15): Yellow oil; R _f=0.18 (CHCl₃/EtOH, 10:1); ¹H NMR (500 MHz, CDCl₃): δ=0.83 (3 H, s, C²⁰H₃), 0.86 (s, 3 H, C¹⁷H₃), 1.08–1.12 (m, 1 H, H‐1), 1.23 (s, 3 H, C¹⁷H₃), 1.28–1.35 (m, 2 H, H‐11, 12), 1.44–1.54 (m, 4 H, H‐12, 3, 11, 2), 1.54–1.61 (m, 2 H, H‐2, 6), 1.72–1.75 (m, 2 H, H‐6, 9), 1.77–1.98 (m, 5 H, H‐1, 3, 14, 14, 5), 2.70 (d, J=6.7 Hz, 1 H, H‐4′), 2.72 (d, J=6.7 Hz, 1 H, H‐4′), 3.29 (dd, J=6.5, 7.0 Hz, H, H‐3′), 3.29 (dd, J=6.5, 7.0 Hz, 1 H, H‐3′), 4.84 (dd, J=10.7, 1.4 Hz, 1 H, H‐16), 4.90 (d, J=17.4, 1.4 Hz, 1 H, H‐16), 5.09 (d, J=1.2 Hz, 1 H, H‐6′), 5.20–5.26 (m, 1 H, H‐7), 5.35 (d, J=1.2 Hz, 1 H, H‐6′), 5.72 (t, 1 H, J=6.5 Hz, NH), 5.77 (dd, 1 H, J=17.7, 10.7 Hz, H‐15), 7.04 (m, 1 H, H‐4′′), 7.30 (m, 2 H, H‐3′′, 5′′), 7.38 ppm (m, 2 H, H‐2′′, 6′′); ¹³C NMR (126 MHz, CDCl₃): δ=15.2 (C‐20), 17.0 (C‐19), 18.0 (C‐2), 19.8 (C‐11), 21.3 (C‐17), 24.6 (C‐6), 29.5, 34.8 (C‐10), 34.9 (C‐4′), 35.8 (C‐12), 36.6 (C‐13), 36.9 (C‐3), 38.3 (C‐3′), 38.6 (C‐1), 45.4 (C‐5), 45.8 (C‐14), 46.2 (C‐4), 51.8 (C‐9), 109.0 (C‐16), 114.3 (C‐6′), 120.7 (C‐7), 125.9 (C‐2′′,6′′), 127.6 (C‐4′′), 128.4 (C‐3′′,5′′), 135.4 (C‐8), 142.5 (C‐1′′), 145.7 (C‐5′), 150.2 (C‐15), 178.3 ppm (C=O); IR: $\tilde{\nu }$ =3355, 3079, 2923, 2863, 1367, 1259, 1384, 1448, 1523, 1631, 1203, 1102, 1056, 998, 906, 860, 777, 754, 701 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₀H₄₁NO [M+H]⁺: 431.3175; found: 431.3168.

Reaction of Terpenoid N‐(2,3‐Butadienyl)carboxamide 3 with 2‐Iodobenzoic acid (16)

Compound 16 (420 mg, 1.71 mmol), Cs₂CO₃ (920 mg, 2.81 mmol), and Pd(PPh₃)₄ (80 mg, 0.07 mmol) were added to a stirred solution of 3 (500 mg, 1.41 mmol) in anhydrous DMF (2 mL) under an argon atmosphere. The mixture was heated at 80 °C for 3 h, cooled, diluted with ethyl acetate (10 mL), washed with water (3×5 mL), dried with K₂CO₃, filtered, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether/ether, 2:1), and crystallization (chloroform) of the solid from gave 17 a/17 b (470 mg, 70 %).

(1R,4aR,4bS,7S,10aR)‐1,4a,7‐Trimethyl‐N‐[(4‐methylene‐1‐oxoisochroman‐3‐yl)methyl]‐7‐vinyl‐1,2,3,4,4a,4b,5,6,7,8,10,10a‐dodecahydrophenanthrene‐1‐carboxamides (17 a/17 b): Colorless solid; R _f=0.13 (CHCl₃/EtOH, 10:1); m.p. 176–180 °C (CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ=0.82 (s, 3 H, C²⁰H₃), 0.87 (s, 3 H, C²⁰H₃), 0.93 (s, 3 H, C¹⁷H₃), 0.95 (s, 3 H, C¹⁷H₃), 1.09–1.20 (m, 2 H, 2 H‐1), 1.23 (s, 6 H, 2 C¹⁹H₃), 1.26–1.36 (m, 4 H, 2 H‐11, 12), 1.42–1.55 (m, 10 H, 2 H‐12, 3, 11, 2, 6), 1.62–1.77 (m, 6 H, 2 H‐2, 6, 9), 1.79–1.95 (m, 10 H, 2 H‐1, 3, 14, 14, 5), 3.48–3.59 (m, 2 H, 2‐H‐3′a), 3.76–3.87 (m, 2 H, 2‐H‐3′a), 4.83 (dd, J=10.7, 1.6 Hz, 2 H, 2 H‐16), 4.88 (dd, J=17.5, 1.6 Hz, 2 H, 2 H‐16), 5.10–5.14 (m, 2 H, 2 H‐3′), 5.18–5.27 (m, 2 H, 2 H‐7), 5.43 (1 H, s, H‐9′), 5.44 (s, 1 H, H‐9′), 5.75 (dd, 2 H, J=17.5, 10.7 Hz, 2 H‐15), 5.78 (s, 2 H, 2 H‐9′), 6.24 (m, 2 H, 2‐NH), 7.45 (dd, J=7.3, 7.5 Hz, 2 H, 2 H‐7′), 7.59 (d, J=7.0 Hz, 2 H, 2 H‐5′), 7.61 (dd, J=7.5, 7.0 Hz, 2 H, 2 H‐6′), 8.08 ppm (d, J=7.3, 2 H, 2 H‐8′); ¹³C NMR (126 MHz, CDCl₃): δ=15.3 (C‐20), 17.3 (C‐19), 18.0, 18.1 (C‐2), 19.9 (C‐11), 21.4 (C‐17), 24.9 (C‐6), 35.1, 35.8 (C‐10), 36.7, 37.2 (C‐12), 37.3 (C‐13), 38.7 (C‐3), 41.3 (C‐1), 45.5, 45.7 (C‐3′a), 46.1 (C‐14), 48.3 (C‐5), 48.9 (C‐4), 52.0 (C‐9), 79.9, 80.1 (C‐3′), 111.9 (C‐16), 118.2, 118.3 (C‐9′), 123.1 (C‐7), 125.7 (C‐8′a), 126.8 (C‐5′), 130.2 (C‐7′), 130.9 (C‐8′), 135.8 (C‐6′), 135.9 (C‐4′), 138.7 (C‐8), 138.8, 138.9 (C‐4′a), 150.3 (C‐15), 164.5 (C‐1′), 179.2 ppm (C‐18); IR: $\tilde{\nu }$ =3400, 2925„ 2867, 1726, 1639, 1606, 1525, 1459, 1410, 1324, 1265, 1201, 1160, 1116, 1078, 1039, 1000, 920, 860, 816, 720 cm⁻¹; HRMS (ESI+): m/z calcd for C₃₁H₃₉NO₃ [M+H]⁺: 473.2925; found: 473.2919.

X‐ray Diffraction Analysis

The structures of 2, 3, 8, and 11 a were solved by direct methods and were refined by the full‐matrix least‐squares method against all F2 in anisotropic approximation by using the SHELX‐97 programs set.36 The positions of the hydrogen atoms were calculated with the riding model. Absorption corrections were applied by using the empirical multiscan method with the SADABS program37 for 2, 3, and 11 a; absorption corrections was not applied for 9. The terminal CH=CH₂ groups were disordered in all of the molecules of compounds 2, 3, 8, and 11 a. The molecular structures of compounds 2, 3, 8, and 11 a are illustrated in Figure 1. The obtained crystal structures were analyzed for short contacts between nonbonded atoms by using PLATON38 and MERCURY programs.39 The structure of 2 is formed by two crystallographically independent molecules, one of which is shown in Figure 1.

Supporting information

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Supplementary

M. A. Gromova, Y. V. Kharitonov, I. Y. Bagryanskaya, E. E. Shults, ChemistryOpen 2018, 7, 890.