Synthesis of Polycyclic Fused Indoline Scaffolds through a Substrate-Guided Reactivity Switch

Abstract

Zn(II)-catalyzed divergent synthesis of functionalized polycyclic indolines through formal [3 + 2] and [4 + 2] cycloadditions of indoles with 1,2-diaza-1,3-dienes (DDs) is reported. The nature and type of substituents of substrates are found to act as a chemical switch to trigger two distinct reaction pathways and to obtain two different types of products upon the influence of the same catalyst. The mechanism of both [4 + 2] and [3 + 2] cycloadditions was investigated and fully rationalized by density functional theory (DFT) calculations.

Introduction

Functionalized polycyclic fused indoline frameworks are central molecular architectures in nature and pharmaceuticals.¹ As one of the indolines, C2,C3-fused indolines² have attracted extensive research effort over the past decades because scaffolds of this type lead to relatively rigid structures that might be expected to show substantial selectivity in their interactions with enzymes or receptors.³ Representative naturally occurring polycyclic indolines such as vincorine, minfiensine, gliocladin C, kopsnone, pleiomaltinine, and communesin F are shown in Figure 1.

Figure 1.

Examples of naturally occurring compounds containing 2,3-fused indolines.

Among the annelated indolines, the pyrroloindoline, pyridazino indoline skeletons and their related structures, can be found in numerous natural bioactive products, marketed drugs, and other functional molecules.^4,5 The desire to build such appealing polycyclic frameworks, particularly those with bridgehead amino acetal C2 carbons, has inspired the development of elegant methodologies over the past several years. Among the reported methods, dearomatization of indoles via cycloaddition reactions⁶ has been demonstrated as a reliable approach in converting simple planar aromatic molecules into structurally complex and stereoselective ring systems.

Following the initial discovery of the inverse electron-demand [4 + 2] cycloaddition reaction of electron-rich alkenes (furans, pyrroles, and indoles) with 1,2-diaza-1,3-dienes (DDs) by Gilchrist et al.,⁷ other elegant studies by the groups of Wang⁸ and Tan⁹ have been recently reported exploiting indoles as nucleophiles.

By taking advantage of the unique reactivity of DDs¹⁰ and intrigued by these and our recent findings in the manipulation of indolyl cores,¹¹ we reasoned that the proper combination of indole and 1,2-diaza-1,3-diene elements might allow us to design a substrate-controlled divergent approach. In this design, DDs would be used as C2N1 or C2N2 units (1,3 or 1,4 dipole synthons) to realize [3 + 2] and [4 + 2] annulation reactions of indoles, respectively (Scheme 1). Thus, by tuning the substituents of both substrates upon the influence of the same catalyst, two series of fused indoline-based scaffolds such as tetrahydro-1H-pyridazino[3,4-b]indoles and tetrahydropyrrolo[2,3-b]indoles would be generated with chemodivergence.

Scheme 1. Working Hypothesis: Chemodivergent Synthesis of Polycyclic Fused Indoline Scaffolds.

Distinct from previous findings, we herein report our successful development of a substituent-controlled divergent synthesis of fused indoline-based scaffolds. These [4 + 2] and [3 + 2] cycloadditions were realized in a straightforward, pretty challenging, and highly atom-economical/diastereselective manner from rationally designed indole and 1,2-diaza-1,3-diene substrates with C3 and/or C4 position(s) substituted, respectively.

Results and Discussion

We began our work by studying the reaction between indole 1a and cyclic 1,2-diaza-1,3-diene 2a (Table S1, Supporting Information (SI)). No reaction took place, and both compounds remained inactive in the absence of a Lewis acid catalyst. A series of Lewis acid catalysts [such as Sc(OTf)₃, Zn(OAc)₂, ZnSO₄, Zn(OTf)₂, SmCl₃·6H₂O, LiClO₄, LiCl, CuCl₂, Cu(OTf)₂, CuBr₂, InBr₃, ZnBr₂, and ZnCl₂] and solvents [such as dichloromethane (DCM), acetone, tetrahydrofuran, acetonitrile, and cyclohexane] were examined, and the combination of ZnCl₂ and CH₂Cl₂ (heterogeneous catalytic system) was found to be superior for this transformation. Noteworthy, compound 3a was obtained as a single regio- and diastereoisomer (50% yield).

The substrate scope with respect to various 2,3-unsubstituted indoles 1a–n and cyclic DDs 2a–h (see the SI for details) was then examined under the optimized reaction conditions, and a variety of tetrahydro-1H-pyridazino[3,4-b]indoles (tetracyclic fused ring (6-5-6-6/7/8) systems) 3a–x was synthesized (Table 1). As shown in Table 1, indoles 1a–n with different electronic characters were suitable for the reaction, with six-membered cyclic DDs giving the relative fused indoline heterocycles 3a–d in moderate to good yields. The Zn-catalyzed [4 + 2] cycloaddition reactions were further extended to seven- and eight-membered cyclic DDs. We were glad to find that the use of seven-membered DDs gave rise to the best results in terms of isolated yields. Also, the wide functional group tolerance was well demonstrated by the fact that both electron-donating (5-OMe, 5-, 7-Me) and electron-withdrawing (6-Cl, 5-CO₂Me, 5-CN, 5-CHO, 5-NO₂) groups were well tolerated, providing efficient access to the fused indoline heterocycles 3e–s. Interestingly, the use of the 7-azaindole substrate also worked well to give the product 3t in 85% isolated yield. The formal [4 + 2] annulation was then extended to DDs bearing cyclooctane, and the reactions furnished the relative products 3u–x with lower yields than those of seven-membered cyclic DDs. Additionally, the generality of the N-terminal protective group on DDs as well as for the N atom of indoles was explored. Remarkably, free N–H indoles were also compatible with this protocol, albeit slightly lower yields were observed, probably owing to the reduced nucleophilicity at C3 and the reduced electrophilicity at C2 of the starting indole (Scheme 1, 3svs3p, and 3xvs3u).

Table 1. Scope of the Zn(II)-Catalyzed [4 + 2] Cycloaddition Reaction of 2,3-Unsubstituted Indoles (1) and Cyclic Azoalkenes (2)^a,b.

^aReaction conditions: 1 (2.0 mmol), 2 (1.0 mmol), ZnCl₂ (0.1 mmol, 10 mol %), DCM (2.0 mL), 25 °C.

^bIsolated yields.

^cRing-opened product 4 was also isolated.

No annulation occurred when five-membered cyclic DD was employed under the optimized reaction conditions (3y, 0%).¹² The relative configurations of cycloadducts 3 were determined by X-ray diffraction analysis of 3e(13) (see the SI for detailed X-ray crystallography data), and those of other compounds were assigned by analogy.

During the investigation on the ring size effect of the 1,2-diaza-1,3-diene substrate, it was also noted the formation of ring-opened [4 + 2] byproduct 4, highlighting the ease of rearomatization of 3 to give a more stable indole derivative. The sensitivity of 3 to the rearomatization process was confirmed by complete transformation of 3b into 4e in the presence of Amberlyst 15(H) (vide infra, Scheme 4b). This undesirable event appears to be the cause for lowering the [4 + 2] cycloaddition product yields found in some cases. Notably, this pathway remains dominant when the reaction was conducted using N-methyl indole (1a) or 1,2-dimethyl indole (1o) with linear DDs 2j and 2n (Scheme 2) in line with what was previously observed in the reactions of 2,3- (and 3-)unsubstituted indoles with cyclic and noncyclic DDs.^7a,10e

Scheme 4. Control Experiments.

Scheme 2. Other Substrates Scope Studies.

More precisely, the reaction of N-methyl indole (1a) with linear DD 2n afforded the more polar ring-opened [4 + 2] product 4a (48% yield). However, thin-layer chromatography (TLC) analysis revealed the presence of a mixture of the diastereoisomers of pyridazine 3z. Consistent with Gilchrist’s observation,^7b monitoring the progress of the reaction by ¹H NMR, we detected an initial (preferential) formation of (cis,cis)-3z, which then partially isomerized to its isomer (cis,trans)-3z either during the course of the reaction or during chromatographic separation. Despite the isomerization side reaction, both diastereoisomers were isolated ((cis,cis)/(cis,trans) ∼ 2:1, 32% combined yield) and characterized (see the SI for details). On the other hand, the reaction of N-methyl indole (1a) with DD 2j or 1,2-dimethyl indole (1o) with DD 2j or 2a led to the formation of the sole ring-opened [4 + 2] products 4b–d (Scheme 2). Therefore, given the results with the use of both 2,3- and 3-unsubstituted indoles (associated with the [4 + 2] pyridazine-ring-opening reaction) and to further showcase the flexibility of this catalytic annulation strategy, we next moved our attention to exploring the reactivity of C3-blocked indoles (e.g., 3-substituted and 2,3-disubstituted indoles) with DDs. To our surprise, the reaction of 3-methyl indole (1p) with linear DD 2n led to a mixture of two cycloadducts, the expected tetrahydro-1H-pyridazino[3,4-b]indole compound 3ab and the tetrahydropyrrolo[2,3-b]indole compound 5a(14) in a ratio of approximately 1:1, which could possibly be the result of the above-mentioned two competitive reaction pathways¹⁵ (Scheme 2). Interestingly, when 1,3-dimethyl indole (1q) was used in combination with DD 2j, the exclusive formation of product 5b (46% yield) was detected. As expected, when the reaction was repeated using cyclic DD 2c, the exclusive formation of the corresponding [4 + 2] product 3ad (40% yield) (Scheme 2) was observed. Intrigued by the starkly different reaction profile, we next focused our attention on the 2,3-disubstituted indole motif. Unfortunately, the reactions of 2,3-disubstituted indoles such as 2,3-dimethyl indole 1r and 2,3,4,9-tetrahydro-1H-carbazole 1t with cyclic DD such as 2c did not work well, and only a trace amount of the respective formal [4 + 2] cycloaddition product was detected in the complex crude reaction mixture (Scheme 2). Explanations for these findings are not immediately intuited, but the steric effect seems to be playing a major role.

To our pleasure, the reaction of 2,3-dimethyl indole (1r) with DD 2j proved efficient, leading to the relative [3 + 2] cycloadduct 5c (58% yield) as the sole product. Thus, to further extend the substrate scope, a series of differently 2,3-disubstituted indole entities 1r–z containing electron-donating groups (5-OMe and 5-Me) or electron-withdrawing groups (EWGs) (5-Cl) and 4-ester, 4-amide, or 4-phosphonate N-protected linear DDs 2j–s were tested. Pleasantly, all of the reactions proceeded smoothly and furnished the highly crowded tetrahydropyrrolo[2,3-b]indole products 5c–s in good to excellent yields (Table 2).

Table 2. Scope of the Zn(II)-Catalyzed [3 + 2] Cycloaddition Reaction of 2,3-Substituted Indoles (1) and Linear Azoalkenes (2)^a,b.

^aReaction conditions: 1 (0.6 mmol), 2 (0.4 mmol), ZnCl₂ (0.04 mmol, 10 mol %), DCM (2.0 mL), 25 °C.

^bIsolated yields.

The structures of compounds 5a–s were confirmed by subjecting 5s to N–N bond cleavage using the Magnus method.¹⁶ Treatment of compound 5s with ethyl bromoacetate/Cs₂CO₃/MeCN at 50 °C followed by heating to 80 °C resulted in N–N′ bond cleavage to the corresponding NH-free tetrahydropyrrolo[2,3-b]indole 6a in 64% isolated yield (Scheme 4a).

As a synthetic strategy, this [3 + 2] annulation affords, in a single operation, the structurally rigid 6-5-5 tricyclic subunit with a substituent at the 3-position of the indole nucleus, which is the basic structure of pharmaceutically valuable natural products.⁴ Besides, this nonclassical approach provides access to functionalized pyrroloindoline systems with substitution patterns that are otherwise inaccessible using tryptamines¹⁷ as precursors.

The mechanism of the two divergent cycloadditions was studied by density functional theory (DFT) computational chemistry (model chemistry: B3LYP/6-31-G(d)/SCRF = PCM, solvent = DCM,^18,19 Gaussian16 software;²⁰ all details are available in the SI). We focused our attention on the reaction of 1,2-diaza-1,3-diene 2n (DD) with 3-methyl indole 1p (In), since such a combination affords both cycloaddition products, i.e., (cis,cis)-3ab (with a de of 99% by ¹H NMR) and 5a, in the ratio of about 1:1, after column chromatography separation (Scheme 2). To begin with, we assumed a concerted mechanism for the [4 + 2] cycloaddition (Figure 2a) and a two-step mechanism for the nonpericyclic [3 + 2] cycloaddition (Figure 2b).

Figure 2.

Catalytic cycles for the model reactants 2n (DD) and 1p (In) catalyzed by ZnCl₂. (a) [4 + 2] cycloaddition: (i) cisoid-DD·ZnCl₂ catalytic complex formation; (ii) exo or endo adduct formation, exo-In·DD·ZnCl₂ or endo-In·DD·ZnCl₂; (iii) cycloaddition through the transition state [TS]^‡ affording the pyridazino indoline product complex, endo-cycle·ZnCl₂ or exo-cycle·ZnCl₂; (iv) substitution with DD affording (cis,cis)-3ab and cisoid-DD·ZnCl₂ restoration. (b) [3 + 2] Cycloaddition: (v) transoid-DD·ZnCl₂ catalytic complex formation; (vi) nonpericyclic In·DD·ZnCl₂ adduct formation; (vii) [1,6]-addition to form the zwitterionic intermediate Zw·ZnCl₂ through the transition state [TS1]^‡; (viii) ring-closure through [TS2]^‡ affording the nonchelated [3 + 2]-cycle·ZnCl₂ complex, (ix) [1,3]-H shift (tautomerization) giving the pyrazolo indoline product complex, PI·ZnCl₂; (x) substitution with DD affording 5b and restoring the transoid-DD·ZnCl₂. For clarity, the H atoms of the DFT-optimized structures are omitted.

The computed [4 + 2] energy reaction paths starting from the cisoid-1,2-diaza-1,3-diene·ZnCl₂·catalytic complex (cisoid-DD·ZnCl₂) leading to the complex endo-cycle·ZnCl₂ and to exo-cycle·ZnCl₂ are reported in Figure 3a; since the reaction is highly exoergonic, both reaction trajectories go through a typical reactant-like transition state [TS]^‡ having pericyclic topology. Both exo and endo transition states ([TS]_exo^‡ and [TS]_endo^‡) are shown in Figure 3b.

Figure 3.

(a) DFT-computed Gibbs free energy profile of the rate-limiting step of the [4 + 2] cycloaddition in CH₂Cl₂ at 298 K for reagents 1,2-diaza-1,3-diene 2n and indole 1p. The energies (kcal mol^–1) are reported with respect to the cisoid-DD·ZnCl₂ and In species. (b) Structures of endo and exo transition states; for clarity, some H atoms have been omitted.

The computations show clearly that the observed high diastereoselectivity toward the formation of the slightly less stable (cis,cis)-3ab pyridazino indoline ((cis,cis) → (cis,trans), ΔG° = −2.66 kcal mol^–1) is obtained under kinetic control. Indeed, since its endo cyclic precursor is substantially more stable than the exo adduct (ΔΔG^‡ = −1.70 kcal mol^–1, mainly for the lack of the steric clashes of the two methyl groups; see Figure 2a), the two associated activation energy barriers are very different (ΔG^‡ = 9.02 vs 10.46 kcal mol^–1); thus, the endo path is kinetically more favorable. Interestingly, in both [TS]^‡, the ratio between the two forming C–C and C–N single bonds is about 1.3 (Figure 3b), which is symptomatic of an asynchronous concerted transition state.²¹

The comparison of the [3 + 2] cycloaddition energy diagram of the two stepwise mechanisms with that of the concerted cycloaddition suggested by Gilchrist et al. with very similar substrates^7b,8 shows clearly that the latter mechanism is not active in our case (Figure 4).

Figure 4.

Computed Gibbs free energy profile of the [3 + 2] cyclization: stepwise mechanism (blue path) vs the concerted mechanism (red path) in CH₂Cl₂ at 298 K. The energies (kcal mol^–1) are reported with respect to the transoid-DD·ZnCl₂ and In species. For clarity, the H atoms of transition-state structures have been omitted.

The stepwise catalytic cycle is based on the formation of the very stable transoid-DD·ZnCl₂ (transoid/cisoid, 99.4:0.6; see the SI), followed by the [1,6]-addition of indole to give the zwitterionic intermediate (Zw·ZnCl₂) through [TS1]^‡; then, the latter ring closes to form the nonchelated [3 + 2]-cycle·ZnCl₂ complex through [TS2]^‡. According to our computations, the energy barriers associated with these two steps are very similar (ΔG₁^‡ = 13.41 kcal mol^–1vs ΔG₂^‡ = 12.04 kcal mol^–1). However, the catalytic cycle ends through the following non-rate-limiting steps: [1,3]-H shift (tautomerization), product delivery, and transoid-DD·ZnCl₂ catalytic complex restoration by substitution with a new molecule of DD.

Finally, as a corollary of the above-reported computations, we used them to evaluate the order of magnitude of the product ratio [(cis,cis)-pyridazinio indoline (3ab)]/[pyrazolo indoline (5b)] in comparison with the value experimentally obtained (∼1:1, after column chromatography separation). To this end, we have conveniently summarized the scheme of the two divergent cyclization reactions as follows

Since the two-reactant catalytic complexes (the cisoid-DD·ZnCl₂ and the transoid-DD·ZnCl₂) are in equilibrium, and their interconversion is much faster than the cycloaddition reaction rates, it is possible to apply the Curtin–Hammet equation,²² which, in our case with a ΔΔG^‡ = [TS]_endo^‡ – [TS1]^‡ = 0.50 kcal mol^–1, gave a ratio of 7:3, (cis,cis)-3ab and pyrazole indoline 5b, respectively. We reckon that this result is fair enough, considering the chemical accuracy attainable via the used model chemistry.

Combining the above experimental results, DFT studies, and available literature,^7,10e a reasonable mechanism for these annulation processes is summarized in Scheme 3. Two competing (and independent) reaction pathways for both the tetrahydro-1H-pyridazino[3,4-b]indole and tetrahydropyrrolo[2,3-b]indole derivatives appeared to take place upon initial ZnCl₂ activation of the 1,2-diaza-1,3-diene substrate. The [4 + 2] cycloaddition (path a) can be simply rationalized as a concerted inverse hetero-Diels–Alder reaction. The preference for an endo cycloaddition transition state, which requires the cisoid conformation for DD 2 (II), supports the high observed diastereoselectivity for product 3.²³ Alternatively, [3 + 2] annulation (path b) can be viewed as proceeding via a stepwise process. Regioselective 1,6-addition of the indole nucleophile 1 on activated DD 2 (I) that is in a transoid conformation affords the zwitterionic intermediate IV, which undergoes intramolecular 5-exo-trig cyclization collapsing to the five-membered azomethine imide V. The subsequent 1,3-H shift furnishes via intermediate VI the tetrahydropyrrolo[2,3-b]indole product 5 and restores the ZnCl₂–diene catalytic complex.²⁴ The fact that the indole 1q gave both [4 + 2] and [3 + 2] cycloadducts using cyclic (R⁴ ≠ H) and linear (R⁴ = H) DDs (3advs5b) supported this mechanism scenario.

Scheme 3. Plausible Reaction Mechanism for Zn(II)-Catalyzed Annulation Reactions.

Likewise, the borderline example of Scheme 2 in which both cycloadducts 3ab and 5a concurrently formed¹⁵ from 1p and 2n illustrates the delicate balance and subtle nuances between the two annulation processes. It is evident that, in the presence of additional substituents on the indole ring (R³ ≠ H), the [3 + 2] mode of addition becomes competitive since the concerted [4 + 2] pathway is more susceptible to steric inhibition. Moreover, it was quite interesting to note that when six-membered cyclic 1,2-diaza-1,3-diene 2i was reacted with 1s, the exclusive formation of the [4 + 2] cycloaddition product 3ae was observed (Scheme 4c). Similarly, the use of linear 1,2-diaza-1,3-diene 2t yielded the product 3af (Scheme 4d). Our control experiments illustrate that the absence of EWG groups like esters, amides, or phosphonates in the C4 position of the starting DD (R⁴ = H; R⁵ ≠ CO₂R, CONR₂, and PO(OR)₂), which likely disfavors the proton transfer process (V → VI), also privileged the [4 + 2] mode of addition.

With this work, we have demonstrated that the nature and type of substituents of both 1,2-diaza-1,3-diene and indole substrates are critical factors dictating chemoselectivity in the annulation process. Notably, the presence of a H atom in the C3 position of the indole ring is responsible for the observed ring-opened [4 + 2] product 4. As already evidenced, this event becomes prevailing when N-methyl indole (1a) or 1,2-dimethyl indole (1o) is used as the nucleophile. To our surprise, when R³ = H, neither the formation of the [3 + 2] annulation product nor the ring-opened [3 + 2] product of type 7 described by Tan and co-workers was observed.²⁵ This result shows that when R³ = H, the indole rearomatization process from 3 (and/or eventually from intermediate IV) to 4 is the preferred one.

Conclusions

In conclusion, we have developed substrate-dependent divergent annulation reactions²⁶ of indoles with 1,2-diaza-1,3-dienes. By virtue of the versatility of these latter in switching reactivities, efficient synthesis of two types of polycyclic fused indoline scaffolds tetrahydro-1H-pyridazino[3,4-b]indoles and tetrahydropyrrolo[2,3-b]indoles was achieved. The DFT study revealed that [4 + 2] cycloadditions are concerted but quite asynchronous, while [3 + 2] reactions go undoubtedly through a stepwise mechanism. Our approach expands the scope of polycyclic fused indoline synthesis and increases the flexibility of synthetic strategies toward heterocycle-based scaffolds. Remarkably, the reactions feature a high step- and atom-economy, high chemo- and diastereoselectivity, broad substrate scope, good functional group tolerance, and readily accessible starting materials. The successful construction of unique rigid polycyclic skeletons, particularly those with challenging bridgehead N,N-aminal quaternary centers, enriches the chemistry of both indoles and 1,2-diaza-1,3-dienes.

Experimental Section

General Experimental Details

Indoles 1a, 1l, 1m, 1o, 1p, 1r, and 1s are commercially available reagents and used without further purification. N-Alkylindole derivatives 1b–k, 1n, and 1q were prepared from corresponding commercially available NH-indoles following literature procedures.²⁷ 3,4-Disubstituted indoles 1t–z were synthesized from corresponding phenylhydrazine hydrochlorides as starting materials via Fisher indole synthesis according to the literature.²⁸ 1,2-Diaza-1,3-dienes (DDs) 2a–t were synthesized from the corresponding hydrazones following literature procedures.²⁹ Chromatographic purification of compounds was carried out on silica gel (60–200 μm). TLC analysis was performed on preloaded (0.25 mm) glass-supported silica gel plates (Kieselgel 60); compounds were visualized by exposure to UV light and by dipping the plates in 1% Ce(SO₄)·4H₂O and 2.5% (NH₄)₆Mo₇O₂₄·4H₂O in 10% sulfuric acid, followed by heating on a hot plate. All ¹H NMR and ¹³C NMR spectra were recorded at 400 and 100 MHz, respectively, using dimethyl sulfoxide (DMSO)-d₆ or CDCl₃ on K₂CO₃ as the solvent. Chemical shifts (δ scale) are reported in parts per million (ppm) relative to the central peak of the solvent and are sorted in a descending order within each group. The following abbreviations are used to describe peak patterns where appropriate: s, singlet; d, doublet; t, triplet; q, quartet; sex, sextet; m, multiplet; and br, broad signal. All coupling constants (J value) are given in hertz (Hz). Structural assignments were made with additional information from gradient correlation spectroscopy (gCOSY), gradient heteronuclear multiple quantum correlation (gHMQC), gradient heteronuclear multiple bond correlation (gHMBC), and nuclear Overhauser enhancement spectroscopy (NOESY) experiments. Fourier transform infrared (FT-IR) spectra were obtained as Nujol mulls or neat. High- and low-resolution mass spectroscopies were performed on a Micromass Q-ToF Micro mass spectrometer (Micromass, Manchester, U.K.) using an electrospray ionization (ESI) source. Melting points were determined in open capillary tubes and are uncorrected. Elemental analyses were within ±0.4 of the theoretical values (C, H, N).

General Procedure for the Formal [4 + 2] Cycloaddition Reactions of Indoles 1 with Cyclic Azoalkenes 2

A mixture of indole 1 (2.0 mmol), azoalkene 2 (1.0 mmol), and zinc dichloride (0.1 mmol, 13.6 mg) was stirred in dry dichloromethane (2 mL). After the disappearance of azoalkene 2 (TLC check), the crude mixture was purified by column chromatography on silica gel to afford product 3. In some cases (see Table 1), a more polar ring-opened [4 + 2] byproduct 4 was also recovered.

(6aS*,11bR*,11cR*)-Ethyl 6-Carbamoyl-7-methyl-2,3,4,6,6a,7,11b,11c-octahydro-1H-indolo[2,3-c]cinnoline-11c-carboxylate (3a)

The product 3a was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 50% yield (178.2 mg); white solid; mp: 183–185 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.19 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.80 (br, 2 H), 6.79 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.50 (d, J = 7.2 Hz, 1H), 4.20–4.35 (m, 2H), 3.44 (d, J = 7.2 Hz, 1H), 2.58 (s, 3H), 2.44–2.51 (m, 1H), 2.26 (dt, J₁ = 12.0 Hz, J₂ = 4.4 Hz, 1H), 1.78–1.84 (m, 1H), 1.50–1.63 (m, 2H), 1.24–1.35 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H), 0.95 (dt, J₁ = 12.0 Hz, J₂ = 4.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 173.3, 157.3, 155.3, 151.7, 129.3, 126.5, 125.7, 118.9, 108.7, 69.4, 61.8, 45.6, 42.4, 35.5, 33.8, 33.1, 27.4, 23.7, 14.3; IR (nujol): υ_max = 3485, 3471, 1724, 1692 cm^–1; MS (ESI) m/z = 357 [M + H]⁺; anal. calcd for C₁₉H₂₄N₄O₃ (356.42): C 64.03, H 6.79, N 15.72; found: C 63.91, H 6.84, N 15.82.

(6aS*,11b*R,11cR*)-Ethyl 7-Methyl-6-(phenylcarbamoyl)-2,3,4,6,6a,7,11b,11c-octahydro-1H-indolo[2,3-c]cinnoline-11c-carboxylate (3b)

The product 3b was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 56% yield (242.3 mg); white solid; mp: 183–185 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (s, 1H), 7.68 (dd, J₁ = 8.4 Hz, J₂ = 1.2 Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.18 (dt, J₁ = 7. 6 Hz, J₂ = 0.8 Hz, 1H), 7.02–7.08 (m, 2H), 6.78 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 5.58 (d, J = 7.2 Hz, 1H), 4.19–4.34 (m, 2H), 3.52 (d, J = 7.2 Hz, 1H), 2.68 (d, J = 13.2 Hz, 1H), 2.60 (s, 3H), 2.30 (dt, J₁ = 12.8 Hz, J₂ = 4.4 Hz, 1H), 1.82–1.84 (m, 1H), 1.62 (d, J = 13.2 Hz, 1H), 1.50–1.52 (m, 1H), 1.30–1.41 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.02 (dt, J₁ = 12.8 Hz, J₂ = 4.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.8, 154.8, 153.4, 151.6, 139.2, 129.5, 128.9, 126.8, 125.8, 123.2, 120.3, 119.2, 109.2, 69.5, 61.9, 45.3, 41.8, 34.9, 34.3, 33.1, 27.3, 23.4, 14.4; IR (nujol): υ_max = 3388, 1728, 1690 cm^–1; MS (ESI) m/z = 433 [M + H]⁺; anal. calcd for C₂₅H₂₈N₄O₃ (432.51): C 69.42, H 6.53, N 12.95; found: C 69.30, H 6.59, N 13.06.

(6aS*,11bR*,11cR*)-Ethyl 6-Carbamoyl-9-chloro-7-methyl-2,3,4,6,6a,7,11b,11c-octahydro-1H-indolo[2,3-c]cinnoline-11c-carboxylate (3c)

The product 3c was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 22% yield (86.1 mg); white solid; mp: 188–190 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.01 (d, J = 8.0 Hz, 1H), 6.77 (br, 2H), 6.76 (dd, J₁ = 8.0 Hz, J₂ = 2.0 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 5.55 (d, J = 7.2 Hz, 1H), 4.18–4.29 (m, 2H), 3.46 (d, J = 7.2 Hz, 1H), 2.56 (s, 3H), 2.45 (d, J = 13.2 Hz, 1H), 2.23 (dt, J₁ = 12.8 Hz, J₂ = 4.4 Hz, 1H), 1.78–1.80 (m, 1H), 1.58 (d, J = 13.2 Hz, 1H), 1.51–1.53 (m, 1H), 1.27–1.32 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H), 0.96 (dt, J₁ = 12.8 Hz, J₂ = 4.4 Hz, 1H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.8, 156.8, 153.5, 153.1, 134.0, 126.9, 125.9, 118.4, 109.0, 69.2, 61.8, 44.8, 41.4, 34.8, 33.6, 32.9, 27.1, 23.3, 14.3; IR (nujol): υ_max = 3280, 3206, 1732, 1692 cm^–1; MS (ESI) m/z = 413 [M + Na]⁺, 391 [M + H]⁺; anal. calcd for C₁₉H₂₃ClN₄O₃ (390.86): C 58.38, H 5.93, N 14.33; found: C 58.51, H 5.98, N 14.23.

(6aS*,11bR*,11cR*)-Ethyl 7-Benzyl-6-carbamoyl-2,3,4,6,6a,7,11b,11c-octahydro-1H-indolo[2,3-c]cinnoline-11c-carboxylate (3d)

The product 3d was isolated by column chromatography (ethyl acetate/cyclohexane 35:65) in 30% yield (129.7 mg); white solid; mp: 162–164 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.19–7.32 (m, 5H), 7.01–7.07 (m, 2H), 6.74 (br, 2H), 6.71 (t, J = 7.6 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H), 5.88 (d, J = 6.8 Hz, 1H), 4.49 (d, J = 16.0 Hz, 1H), 4.20–4.32. (m, 2H), 3.96 (d, J = 16.0 Hz, 1H), 3.49 (d, J = 6.8 Hz, 1H), 2.50–2.55 (m, 1H), 2.26 (dt, J₁ = 12.8 Hz, J₂ = 4.8 Hz, 1H), 1.85–1.89 (m, 1H), 1.50–1.59 (m, 2H), 1.30–1.37 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.03–1.11 (m, 1H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.1, 157.1, 154.1, 150.9, 140.1, 129.3, 128.7, 127.2, 127.1, 126.7, 125.8, 118.7, 108.5, 68.6, 61.8, 50.4, 45.1, 42.2, 35.2, 33.1, 27.6, 23.6, 14.4; IR (nujol): υ_max = 3271, 3194, 1738, 1688 cm^–1; MS (ESI) m/z = 433 [M + H]⁺; anal. calcd for C₂₅H₂₈N₄O₃ (432.51): C 69.42, H 6.53, N 12.95; found: C 69.31, H 6.49, N 13.06.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-8-methyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3e)

The product 3e was isolated by column chromatography (ethyl acetate/cyclohexane 70:30) in 82% yield (292.3 mg); white solid; mp: 171–173 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.51 (t, J = 7.6 Hz, 1H), 6.35 (br, 2H), 6.28 (d, J = 8.0 Hz, 1H), 6.03 (d, J = 9.6 Hz, 1H), 4.57 (d, J = 9.6 Hz, 1H), 3.60 (s, 3H), 2.69 (s, 3H), 2.52–2.58 (m, 1H), 2.20–2.27 (m, 1H), 2.01–2.05 (m, 1H), 1.72–1.86 (m, 4H), 1.46–1.56 (m, 1H), 1.20–1.34 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.1, 170.6, 157.1, 152.5, 128.6, 126.1, 124.3, 116.2, 104.8, 73.4, 54.2, 53.1, 52.1, 32.6, 31.6, 30.2, 24.9, 24.6, 24.8; IR (nujol): υ_max = 3262, 3194, 1718, 1696 cm^–1; MS (ESI) m/z = 357 [M + H]⁺; anal. calcd for C₁₉H₂₄N₄O₃ (356.42): C 64.03, H 6.79, N 15.72; found: C 64.19, H 6.71, N 15.60.

(7aS*,12bR*,12cR*)-Methyl 8-Methyl-7-(phenylcarbamoyl)-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3f)

The product 3f was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 65% yield (281.2 mg); white solid; mp: 140–142 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 7.61 (dd, J₁ = 8.4 Hz, J₂ = 0.8 Hz, 2H), 7.29 (t, J = 8.0 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.01–7.06 (m, 2H), 6.55 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 6.16 (d, J = 9.6 Hz, 1H), 4.65 (d, J = 9.6 Hz, 1H), 3.60 (s, 3H), 2.73 (s, 3H), 2.70 (d, J = 6.8 Hz, 1H), 2.28–2.35 (m, 1H), 2.05–2.10 (m, 1H), 1.80–1.93 (m, 4H), 1.54–1.64 (m, 1H), 1.22–1.38 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.4, 172.3, 154.0, 152.8, 139.3, 129.1, 128.9, 126.6, 124.7, 123.2, 120.4, 116.9, 105.5, 74.5, 55.7, 53.4, 52.7, 37.1, 33.1, 32.3, 30.6, 25.4, 25.1; IR (nujol): υ_max = 3345, 1725, 1691 cm^–1; MS (ESI) m/z = 433 [M + H]⁺; anal. calcd for C₂₅H₂₈N₄O₃ (432.51): C 69.42, H 6.53, N 12.95; found: C 69.29, H 6.58, N 13.06.

(7aS*,12bR*,12cR*)-7-tert-Butyl 12c-Methyl 8-methyl-1,2,3,4,5,7a,8,12c-octahydrocyclohepta[5,6]pyridazino[3,4-b]indole-7,12c(12bH)-dicarboxylate (3g)

The product 3g was isolated by column chromatography (ethyl acetate/cyclohexane 15:85) in 62% yield (256.4 mg); white solid; mp: 124–126 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.18 (d, J = 7.6 Hz, 1H), 7.01 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.51 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 5.92 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 9.2 Hz, 1H), 3.59 (s, 3H), 2.71 (s, 3H), 2.47 (d, J = 7.6 Hz, 2H), 2.30 (t, J = 14.0 Hz, 1H), 2.03 (dd, J₁ = 14.0 Hz, J₂ = 7.2 Hz, 1H), 1.69–1.82 (m, 4H), 1.46 (s, 9H), 1.18–1.34 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 174.0, 173.6, 152.6, 129.2, 129.1, 126.6, 124.4, 116.7, 105.2, 80.8, 76.1, 54.9, 54.1, 52.5, 36.9, 33.0, 31.4, 30.8, 28.3, 25.3, 24.9; IR (nujol): υ_max = 1732, 1730 cm^–1; MS (ESI) m/z = 414 [M + H]⁺; anal. calcd for C₂₃H₃₁N₃O₄ (413.51): C 66.81, H 7.56, N 10.16; found: C 66.96, H 7.60, N 10.05.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-10-chloro-8-methyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3h)

The product 3h was isolated by column chromatography (ethyl acetate/cyclohexane 45:55) in 90% yield (351.8 mg); white solid; mp: 161–163 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (dd, J₁ = 8.0 Hz, J₂ = 0.8 Hz, 1H), 6.50 (dd, J₁ = 8.0 Hz, J₂ = 2.0 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 6.10 (d, J = 9.6 Hz, 1H), 4.57 (d, J = 9.6 Hz, 1H), 3.60 (s, 3H), 2.69 (s, 3H), 2.52–2.60 (m, 1H), 2.15–2.21 (m, 1H), 2.01–2.04 (m, 1H), 1.74–1.89 (m, 4H), 1.51–1.56 (m, 1H), 1.16–1.35 (m, 3H), 0.81–0.87 (m, 1H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.4, 171.6, 157.3, 154.2, 134.1, 127.7, 123.8, 115.7, 104.7, 74.0, 54.7, 53.2, 52.6, 37.1, 32.9, 31.6, 30.6, 25.3, 25.0; IR (nujol): υ_max = 3287, 3215, 1730, 1701 cm^–1; MS (ESI) m/z = 391 [M + H]⁺; anal. calcd for C₁₉H₂₃ClN₄O₃ (390.86): C 58.38, H 5.93, N 14.33; found: C 58.51, H 5.97, N 14.25.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-8,9-dimethyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3i)

The product 3i was isolated by column chromatography (ethyl acetate/cyclohexane 40:60) in 54% yield (200.1 mg); yellow oil; ¹H NMR (400 MHz, DMSO-d₆) δ 7.07 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.58 (t, J = 7.6 Hz, 1H), 6.40 (br, 2H), 5.81 (d, J = 10.0 Hz, 1H), 4.66 (d, J = 10.0 Hz, 1H), 3.59 (s, 3H), 2.91 (s, 3H), 2.53 (dd, J₁ = 14.0 Hz, J₂ = 7.2 Hz, 1H), 2.21–2.32 (m, 1H), 2.17 (s, 3H), 2.03 (dd, J₁ = 14.0 Hz, J₂ = 7.2 Hz, 1H), 1.71–1.83 (m, 4H), 1.45–1.56 (m, 1H), 1.18–1.33 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.2, 169.0, 157.4, 152.1, 131.4, 126.6, 123.8, 118.8, 118.6, 76.8, 54.3, 52.9, 52.1, 36.7, 33.1, 30.3, 24.9, 24.7, 18.9, 14.1; IR (nujol): υ_max = 3227, 3217, 1735, 1693 cm^–1; MS (ESI) m/z = 371 [M + H]⁺; anal. calcd for C₂₀H₂₆N₄O₃ (370.44): C 64.84, H 7.07, N 15.12; found: C 64.69, H 6.99, N 15.24.

(7aS*,12bR*,12cR*)-Dimethyl 7-Carbamoyl-8-methyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-11,12c-dicarboxylate (3j)

The product 3j was isolated by column chromatography (ethyl acetate/cyclohexane 50:50) in 89% yield (368.9 mg); white solid; mp: 218–220 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (s, 1H), 7.67 (s, 1H), 6.50 (br, 2H), 6.31 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 9.6 Hz, 1H), 4.65 (d, J = 9.6 Hz, 1H), 3.76 (s, 3H), 3.62 (s, 3H), 2.76 (s, 3H), 2.57 (dd, J₁ = 14.0 Hz, J₂ = 6.8 Hz, 1H), 2.07–2.19 (m, 2H), 1.77–1.83 (m, 4H), 1.53 (q, J = 12.4 Hz, 1H), 1.16–1.33 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.3, 172.3, 166.6, 157.3, 156.4, 132.2, 127.6, 124.6, 116.8, 103.7, 73.7, 54.8, 53.1, 52.7, 51.8, 37.0, 32.8, 30.9, 30.7, 25.3, 24.9; IR (nujol): υ_max = 3267, 3211, 1729, 1727, 1684 cm^–1; MS (ESI) m/z = 415 [M + H]⁺; anal. calcd for C₂₁H₂₆N₄O₅ (414.45): C 60.86, H 6.32, N 13.52; found: C 70.01, H 6.26, N 13.41.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-11-cyano-8-methyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3k)

The product 3k was isolated by column chromatography (ethyl acetate/cyclohexane 45:55) in 84% yield (320.4 mg); white solid; mp: 273–275 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (s, 1H), 7.44 (dd, J₁ = 8.4 Hz, J₂ = 1.2 Hz, 1H), 6.55 (br, 2H), 6.37 (d, J = 8.4 Hz, 1H), 6.21 (d, J = 9.6 Hz, 1H), 4.65 (d, J = 9.6 Hz, 1H), 3.61 (s, 3H), 2.75 (s, 3H), 2.57 (dd, J₁ = 14.0 Hz, J₂ = 6.8 Hz, 1H), 2.15–2.22 (m, 1H), 2.05 (dd, J₁ = 14.0 Hz, J₂ = 6.8 Hz, 1H), 1.78–1.91 (m, 4H), 1.48–1.59 (m, 1H), 1.32–1.41 (m, 1H), 1.16–1.25 (m, 1H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.2, 172.5, 157.2, 155.7, 134.9, 129.9, 125.6, 121.0, 104.6, 96.7, 73.5, 54.6, 53.1, 52.7, 37.0, 32.7, 30.8, 30.5, 25.3, 24.9; IR (nujol): υ_max = 3293, 3219, 1724, 1686 cm^–1; MS (ESI) m/z = 382 [M + H]⁺; anal. calcd for C₂₀H₂₃N₅O₃ (381.43): C 62.98, H 6.08, N 18.36; found: C 62.83, H 6.15, N 18.47.

(7aS*,12bR*,12cR*)-Dimethyl 7-Carbamoyl-8-methyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-11,12c-dicarboxylate (3l)

The product 3l was isolated by column chromatography (ethyl acetate/cyclohexane 60:40) in 89% yield (342.2 mg); white solid; mp: 212–214 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 7.61 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.62 (br, 2H), 6.40 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 10.0 Hz, 1H), 4.68 (d, J = 10.0 Hz, 1H), 3.61 (s, 3H), 2.79 (s, 3H), 2.57 (dd, J₁ = 14.4 Hz, J₂ = 7.2 Hz, 1H), 2.08–2.24 (m, 2H), 1.73–1.87 (m, 4H), 1.48–1.57 (m, 1H), 1.15–1.35 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 190.1, 173.3, 172.7, 157.5, 157.2, 134.8, 127.3, 126.1, 125.4, 103.9, 73.8, 54.8, 52.8, 52.7, 37.1, 32.8, 30.8, 30.7, 25.3, 24.9; IR (nujol): υ_max = 3261, 3213, 1736, 1725, 1690 cm^–1; MS (ESI) m/z = 385 [M + H]⁺; anal. calcd for C₂₀H₂₄N₄O₄ (384.43): C 62.49, H 6.29, N 14.57; found: C 62.35, H 6.33, N 14.44.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-8-methyl-11-nitro-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3m)

The product 3m was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 92% yield (369.3 mg); yellow solid; mp: 180–182 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (dd, J₁ = 9.2 Hz, J₂ = 2.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 6.61 (br, 2H), 6.39 (d, J = 9.2 Hz, 1H), 6.31 (d, J = 9.6 Hz, 1H), 4.72 (d, J = 9.6 Hz, 1H), 3.62 (s, 3H), 2.81 (s, 3H), 2.54–2.61 (m, 1H), 2.14–2.17 (m, 2H), 1.73–1.94 (m, 4H), 1.48–1.59 (m, 1H), 1.19–1.39 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.6, 172.5, 157.2, 156.6, 136.4, 127.5, 124.8, 122.6, 102.8, 73.5, 54.2, 52.3, 52.2, 36.5, 32.1, 30.4, 30.1, 24.9, 24.4; IR (nujol): υ_max = 3362, 3347, 1736, 1692 cm^–1; MS (ESI) m/z = 402 [M + H]⁺; anal. calcd for C₁₉H₂₃N₅O₅ (401.41): C 56.85, H 5.78, N 17.45; found: C 57.02, H 5.69, N 17.33.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-11-methoxy-8-methyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3n)

The product 3n was isolated by column chromatography (ethyl acetate/cyclohexane 40:60) in 71% yield (274.4 mg); white solid; mp: 164–166 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 6.79 (d, J = 2.4 Hz, 1H), 6.64 (dd, J₁ = 8.4 Hz, J₂ = 2.4 Hz, 1H), 6.50 (br, 2H), 6.24 (d, J = 8.4 Hz, 1H), 5.95 (d, J = 9.6 Hz, 1H), 4.51 (d, J = 9.6 Hz, 1H), 3.65 (s, 3H), 3.61 (s, 3H), 2.64 (s, 3H), 2.56 (dd, J₁ = 14 Hz, J₂ = 6.8 Hz, 1H), 2.14–2.22 (m, 1H), 1.89–2.03 (m, 2H), 1.70–1.81 (m, 3H), 1.47–1.55 (m, 1H), 1.15–1.35 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.6, 169.6, 157.7, 151.8, 147.5, 126.5, 114.5, 113.3, 106.0, 74.7, 56.0, 54.3, 53.3, 52.7, 37.1, 33.6, 32.9, 30.5, 25.4, 25.1; IR (nujol): υ_max = 3274, 3215, 1726, 1676 cm^–1; MS (ESI) m/z = 387 [M + H]⁺; anal. calcd for C₂₀H₂₆N₄O₄ (386.44): C 62.16, H 6.78, N 14.50; found: C 62.31, H 6.84, N 14.39.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-8-ethyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3o)

The product 3o was isolated by column chromatography (ethyl acetate/cyclohexane 40:60) in 56% yield (207.5 mg); white solid; mp: 115–117 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.47 (t, J = 7.6 Hz, 1H), 6.35 (br, 2H), 6.25 (d, J = 7.6 Hz, 1H), 6.15 (d, J = 10.0 Hz, 1H), 4.59 (d, J = 10.0 Hz, 1H), 3.59 (s, 3H), 3.30 (q, J = 6.8 Hz, 2H), 3.07 (sex, J = 7.2 Hz, 1H), 2.57 (dd, J₁ = 14.0 Hz, J₂ = 7.2 Hz, 1H), 2.19–2.28 (m, 1H), 1.97–2.06 (m, 1H), 1.73–1.88 (m, 3H), 1.47–1.57 (m, 1H), 1.15–1.34 (m, 2H), 0.96 (t, J = 6.8 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.2, 171.1, 157.1, 151.2, 128.6, 126.4, 124.2, 115.7, 104.4, 71.6, 54.2, 53.4, 52.1, 38.5, 36.7, 32.7, 30.3, 24.9, 24.5, 11.3; IR (nujol): υ_max = 3372, 3346, 1729, 1691 cm^–1; MS (ESI) m/z = 371 [M + H]⁺; anal. calcd for C₂₀H₂₆N₄O₃ (370.44): C 64.84, H 7.07, N 15.12; found: C 64.71, H 7.11, N 15.23.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-11-methyl-8-propyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3p)

The product 3p was isolated by column chromatography (ethyl acetate/cyclohexane 40:60) in 71% yield (283.0 mg); white solid; mp: 119–121 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 6.96 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.42 (br, 2H), 6.15 (d, J = 8.0 Hz, 1H), 6.12 (d, J = 10.0 Hz, 1H), 4.56 (d, J = 10.0 Hz, 1H), 3.60 (s, 3H), 3.11–3.20 (m, 1H), 2.90–2.98 (m, 1H), 2.57 (dd, J₁ = 13.2 Hz, J₂ = 7.2 Hz, 1H), 2.23 (q, J = 13.2 Hz, 3H), 2.16 (s, 3H), 2.02 (dd, J₁ = 13.2 Hz, J₂ = 7.2 Hz, 1H), 1.71–1.93 (m, 3H), 1.16–1.59 (m, 4H), 0.78 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.8, 171.3, 157.5, 150.2, 129.2, 127.6, 124.7, 124.5, 104.8, 72.9, 54.6, 53.9, 52.6, 46.9, 37.2, 33.2, 30.7, 25.5, 25.0, 20.9, 20.1, 11.8; IR (nujol): υ_max = 3291, 3219, 1732, 1688 cm^–1; MS (ESI) m/z = 399 [M + H]⁺; anal. calcd for C₂₂H₃₀N₄O₃ (398.50): C 66.31, H 7.59, N 14.06; found: C 66.46, H 7.63, N 13.96.

(7aS*,12bR*,12cR*)-Methyl 8-Benzyl-7-carbamoyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3q)

The product 3q was isolated by column chromatography (ethyl acetate/cyclohexane 35:65) in 79% yield (341.7 mg); white solid; mp: 158–160 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.16–7.30 (m, 6H), 6.91 (t, J = 7.6 Hz, 1H), 6.51 (t, J = 7.6 Hz, 1H), 6.30 (d, J = 10.0 Hz, 1H), 6.20 (br, 2H), 6.09 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 10.0 Hz, 1H), 4.61 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 3.60 (s, 3H), 2.65 (dd, J₁ = 14.0 Hz, J₂ = 6.8 Hz, 1H), 2.30 (t, J = 12.4 Hz, 1H), 2.07 (dd, J₁ = 14.0 Hz, J₂ = 6.8 Hz, 1H), 1.92 (t, J = 12.4 Hz, 1H), 1.72–1.86 (m, 3H), 1.57 (q, J = 12.4 Hz, 1H), 1.19–1.37 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.3, 171.5, 157.2, 151.8, 138.7, 128.5, 128.3, 126.8, 126.6, 126.5, 124.3, 116.4, 105.2, 72.9, 54.3, 53.7, 52.2, 49.1, 36.8, 32.8, 30.3, 25.0, 24.6; IR (nujol): υ_max = 3279, 3208, 1733, 1678 cm^–1; MS (ESI) m/z = 433 [M + H]⁺; anal. calcd for C₂₅H₂₈N₄O₃ (432.51): C 69.42, H 6.53, N 12.95; found: C 69.57, H 6.59, N 12.84.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3r)

The product 3r was isolated by column chromatography (ethyl acetate/cyclohexane 50:50) in 89% yield (304.7 mg); white solid; mp: 165–167 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (d, J = 7.6 Hz, 1H), 6.92 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.49 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.44 (d, J = 7.6 Hz, 1H), 6.47 (br, 2H), 6.40 (d, J = 2.0 Hz, 1H), 5.75 (dd, J₁ = 9.6 Hz, J₂ = 2.0 Hz, 1H), 4.29 (d, J = 9.6 Hz, 1H), 3.65 (s, 3H), 2.55 (dd, J₁ = 14.4 Hz, J₂ = 5.6 Hz, 1H), 2.32 (t, J = 12.8 Hz, 1H), 1.98 (t, J = 12.8 Hz, 2H), 1.71–1.82 (m, 3H), 1.41–1.55 (m, 1H), 1.20–1.35 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.8, 161.9, 157.6, 151.6, 128.2, 125.6, 124.5, 116.8, 108.0, 69.0, 53.1, 52.3, 51.1, 36.7, 32.2, 29.6, 25.2, 24.8; IR (nujol): υ_max = 3426, 3251, 3228, 1737, 1692 cm^–1; MS (ESI) m/z = 343 [M + H]⁺; anal. calcd for C₁₈H₂₂N₄O₃ (342.39): C 63.14, H 6.48, N 16.36; found: C 62.97, H 6.56, N 16.49.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-11-methyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3s)

The product 3s was isolated by column chromatography (ethyl acetate/cyclohexane 40:60) in 66% yield (235.2 mg); white solid; mp: 198–200 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 6.95 (s, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.41 (br, 2H), 6.38 (d, J = 7.6 Hz, 1H), 6.09 (s, 1H), 5.74 (dd, J₁ = 9.2 Hz, J₂ = 2.0 Hz, 1H), 4.20 (d, J = 9.2 Hz, 1H), 3.67 (s, 3H), 2.56 (dd, J₁ = 14.4 Hz, J₂ = 5.6 Hz, 1H), 2.31 (t, J = 12.8 Hz, 1H), 2.05 (t, J = 12.8 Hz, 1H), 1.95 (dd, J₁ = 14.4 Hz, J₂ = 5.6 Hz, 1H), 2.16 (s, 3H), 1.71–1.86 (m, 3H), 1.23–1.51 (m, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.7, 160.7, 157.4, 149.1, 128.5, 126.1, 125.4, 124.9, 108.1, 69.1, 52.8, 52.1, 50.7, 36.6, 31.9, 29.3, 25.2, 24.7, 20.5; IR (nujol): υ_max = 3327, 3271, 1734, 1693 cm^–1; MS (ESI) m/z = 357 [M + H]⁺; anal. calcd for C₁₉H₂₄N₄O₃ (356.41): C 64.03, H 6.79, N 15.72; found: C 63.90, H 6.83, N 15.84.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-8-methyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[c]pyrido[3′,2′:4,5]pyrrolo[3,2-e]pyridazine-12c-carboxylate (3t)

The product 3t was isolated by column chromatography (ethyl acetate/cyclohexane 80:20) in 85% yield (303.8 mg); white solid; mp: 222–224 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.74 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 6.59 (br, 1H), 6.40 (t, J = 6.8 Hz, 1H), 6.27 (br, 1H), 6.12 (d, J = 10.0 Hz, 1H), 4.58 (d, J = 10.0 Hz, 1H), 3.60 (s, 3H), 2.76 (s, 3H), 2.58 (dd, J₁ = 14.4 Hz, J₂ = 6.8 Hz, 1H), 2.14–2.20 (m, 1H), 1.98–2.05 (m, 1H), 1.77–1.85 (m, 4H), 1.51 (q, J = 12.4 Hz, 1H), 1.16–1.32 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.2, 172.2, 162.4, 157.4, 147.1, 133.6, 118.7, 112.0, 71.1, 54.8, 52.7, 51.7, 37.1, 32.9, 30.7, 29.2, 25.3, 24.9; IR (nujol): υ_max = 3355, 3296, 1736, 1689 cm^–1; MS (ESI) m/z = 358 [M + H]⁺; anal. calcd for C₁₈H₂₃N₅O₃ (357.41): C 60.49, H 6.49, N 19.59; found: C 60.63, H 6.41, N 19.48.

(8aS*,13bR*,13cR*)-Ethyl 8-Carbamoyl-9-methyl-2,3,4,5,6,8,8a,9,13b,13c-decahydro-1H-cycloocta[5,6]pyridazino[3,4-b]indole-13c-carboxylate (3u)

The product 3u was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 46% yield (177.5 mg); white solid; mp: 182–184 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.72 (s, 2H), 6.67 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 5.61 (dd, J = 8.4 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.72 (d, J = 8.4 Hz, 1H), 2.74 (s, 3H), 2.33–2.40 (m, 2H), 1.90–1.98 (m, 1H), 1.47–1.75 (m, 7H), 1.28 (t, J = 7.2 Hz, 3H), 1.21–1.30 (m, 2H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.2, 157.6, 156.4, 151.7, 128.7, 125.5, 124.7, 117.7, 106.8, 71.4, 61.0, 50.2, 45.9, 34.1, 33.1, 29.0, 25.9, 25.8, 25.7, 23.4, 13.8; IR (nujol): υ_max = 3408, 3394, 1720, 1684 cm^–1; MS (ESI) m/z = 385 [M + H]⁺; anal. calcd for C₂₁H₂₈ N₄ O₃ (384.47): C 65.60, H 7.34, N 14.57; found: C 65.74, H 7.39, N 14.43.

(8aS*,13bR*,13cR*)-8-tert-Butyl 13c-Ethyl 9-methyl-3,4,5,6,8a,9,13b,13c-octahydro-1H-cycloocta[5,6]pyridazino[3,4-b]indole-8,13c(2H)-dicarboxylate (3v)

The product 3v was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 43% yield (189.9 mg); white solid; mp: 157–159 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.14 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.53 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.74 (d, J = 9.2 Hz, 1H), 4.40 (d, J = 9.2 Hz, 1H), 3.98–4.18 (m, 2H), 3.37 (s, 1H), 2.72 (s, 3H), 2.25–2.34 (m, 1H), 2.14–2.18 (m, 1H), 1.91–2.13 (m, 2H), 1.52–1.70 (m, 6H), 1.47 (s, 9H), 1.31–1.42 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 171.8, 170.2, 152.5, 151.9, 128.6, 125.2, 124.4, 116.7, 105.3, 80.4, 74.9, 60.9, 53.3, 53.2, 32.6, 31.3, 31.0, 27.8, 27.7, 25.6, 25.2, 24.7, 13.7; IR (nujol): υ_max = 1732, 1724 cm^–1; MS (ESI) m/z = 442 [M + H]⁺; anal. calcd for C₂₅H₃₅N₃O₄ (441.56): C 68.00, H 7.99, N 9.52; found: C 67.87, H 7.93, N 9.64.

(8aS*,13bR*,13cR*)-8-tert-Butyl 13c-Ethyl 9-benzyl-3,4,5,6,8a,9,13b,13c-octahydro-1H-cycloocta[5,6]pyridazino[3,4-b]indole-8,13c(2H)-dicarboxylate (3w)

The product 3w was isolated by column chromatography (ethyl acetate/cyclohexane 10:90) in 50% yield (258.8 mg); yellowish oil; ¹H NMR (400 MHz, DMSO-d₆) δ 7.17–7.32 (m, 6H), 6.92 (t, J = 7.6 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H), 6.10 (d, J = 8.0 Hz, 1H), 6.02 (d, J = 9.6 Hz, 1H), 4.73 (d, J = 9.6 Hz, 1H), 4.65 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.2 Hz, 1H), 3.93–4.14 (m, 2H), 2.43–2.49 (m, 1H), 2.26–2.30 (m, 1H), 2.11–2.16 (m, 1H), 1.93–2.01 (m, 1H), 1.38–1.78 (m, 8H), 1.23 (s, 9H), 1.17 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.5, 171.9, 152.4, 151.1, 138.7, 128.5, 128.4, 126.6, 126.1, 125.6, 124.1, 116.6, 104.9, 80.2, 75.5, 60.8, 55.8, 53.8, 49.2, 32.3, 31.7, 28.3, 27.5, 25.8, 25.6, 24.5, 13.7; IR (nujol): υ_max = 1731, 1723 cm^–1; MS (ESI) m/z = 518 [M + H]⁺; anal. calcd for C₃₁H₃₉N₃O₄ (517.66): C 71.93, H 7.59, N 8.12; found: C 71.76, H 7.65, N 8.26.

(8aS*,13bR*,13cR*)-Ethyl 8-Carbamoyl-2,3,4,5,6,8,8a,9,13b,13c-decahydro-1H-cycloocta[5,6]pyridazino[3,4-b]indole-13c-carboxylate (3x)

The product 3x was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 37% yield (136.9 mg); white solid; mp: 168–170 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.01 (t, J = 7.2 Hz, 1H), 6.71 (s, 2H), 6.70 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.59 (t, J = 7.2 Hz, 1H), 6.10 (d, J = 4.0 Hz, 1H), 5.55 (dd, J₁ = 8.8 Hz, J₂ = 4.0 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.44 (d, J = 8.8 Hz, 1H), 2.66 (dd, J₁ = 14.4 Hz, J₂ = 6.8 Hz, 1H), 2.37–2.46 (m, 1H), 1.90–1.99 (m, 1H), 1.32–1.64 (m, 8H), 1.29 (t, J = 7.2 Hz, 3H), 1.07–1.19 (m, 1H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.0, 158.1, 151.9, 150.3, 128.6, 124.9, 124.3, 117.8, 109.4, 68.3, 61.1, 49.3, 45.6, 35.1, 27.9, 26.0, 24.2, 21.9, 21.3, 13.9; IR (nujol): υ_max = 3332, 3315, 3298, 1731, 1688 cm^–1; MS (ESI) m/z = 371 [M + H]⁺; anal. calcd for C₂₀H₂₆ N₄ O₃ (370.44): C 64.84, H 7.07, N 15.12; found: C 64.98, H 6.99, N 15.02.

(4S*,4aS*,9aS*)-Ethyl 1-Carbamoyl-3,9-dimethyl-4,4a,9,9a-tetrahydro-1H-pyridazino[3,4-b]indole-4-carboxylate ((cis,cis)-3z)

The more polar product was isolated by column chromatography (ethyl acetate/cyclohexane 20:80); amorphous white solid; ¹H NMR (400 MHz, DMSO-d₆) δ 7.01–7.07 (m, 2H), 6.64 (s, 2H), 6.59 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.74 (d, J = 8.0 Hz, 1H), 3.94 (t, J = 8.0 Hz, 1H), 3.71–3.88 (m, 2H), 3.54 (d, J = 8.0 Hz, 1H), 2.63 (s, 3H), 1.92 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 169.0, 157.5, 151.9, 151.7, 129.1, 127.3, 125.4, 117.8, 107.1, 70.8, 60.9, 44.6, 33.0, 23.0, 14.1; IR (nujol): υ_max = 3309, 3298, 1729, 1678 cm^–1; MS (ESI) m/z = 317 [M + H]⁺; anal. calcd for C₁₆H₂₀ N₄ O₃ (316.35): C 60.75, H 6.37, N 17.71; found: C 60.64, H 6.49, N 17.56.

During the course of the reaction, the following workup, and the long standing in DMSO-d₆ solution at 20 °C for 24 h, the diastereomer (cis,cis)-3z gives a partial isomerization to more stable (cis,trans)-3z together with the ring-opening reaction leading to the byproduct 4a. Diastereomers 3z were isolated in a combined yield of 32%, based on the amount of 1,2-diaza-1,3-diene consumed.

The relative configurations of diastereomers 3z were assigned by means of two-dimensional (2D) NOESY experiments.

(4R*,4aS*,9aS*)-Ethyl 1-Carbamoyl-3,9-dimethyl-4,4a,9,9a-tetrahydro-1H-pyridazino[3,4-b]indole-4-carboxylate ((cis,trans)-3z)

The less polar product was isolated by column chromatography (ethyl acetate/cyclohexane 20:80); amorphous white solid; ¹H NMR (400 MHz, DMSO-d₆) δ 7.03–7.11 (m, 2H), 6.34 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.58 (s, 2H), 6.46 (d, J = 7.6 Hz, 1H), 5.72 (d, J = 8.4 Hz, 1H), 4.11–4.24 (m, 2H), 3.84 (dd, J₁ = 8.4 Hz, J₂ = 6.0 Hz, 1H), 3.29 (d, J = 6.0 Hz, 1H), 2.68 (s, 3H), 1.90 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 170.2, 157.3, 151.8, 150.8, 129.1, 129.0, 123.6, 118.3, 107.3, 70.3, 61.6, 46.4, 33.0, 23.1, 14.4; IR (nujol): υ_max = 3314, 3306, 1736, 1682 cm^–1; MS (ESI) m/z = 317 [M + H]⁺; anal. calcd for C₁₆H₂₀ N₄ O₃ (316.35): C 60.75, H 6.37, N 17.71; found: C 60.64, H 6.49, N 17.56.

(4S*,4aS*,9aS*)-Ethyl 1-Carbamoyl-3,4a-dimethyl-4,4a,9,9a-tetrahydro-1H-pyridazino[3,4-b]indole-4-carboxylate ((cis,cis)-3ab)

NOESY correlations allowed the assignment of the relative stereochemistry. The compound partially isomerized to (cis,trans)-3ab when allowed to stand in a CDCl₃ solution at 20 °C for 24 h, while no conversion was observed using DMSO-d₆ as a solvent. The product was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 24% yield (75.9 mg); white solid; mp: 171–173 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.21 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.58–6.65 (m, 3H), 6.54 (d, J = 7.6 Hz, 1H), 5.97 (d, J = 2.8 Hz, 1H), 5.25 (d, J = 2.8 Hz, 1H), 3.57–3.80 (m, 2H), 3.28 (s, 1H), 1.91 (s, 3H), 1.34 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 168.5, 157.5, 149.5, 145.2, 131.6, 128.5, 124.4, 118.0, 109.7, 73.1, 60.8, 51.1, 44.2, 25.4, 23.1, 13.9; IR (nujol): υ_max = 3338, 3306, 3301, 1728, 1694 cm^–1; MS (ESI) m/z = 317 [M + H]⁺; anal. calcd for C₁₆H₂₀ N₄ O₃ (316.35): C 60.75, H 6.37, N 17.71; found: C 60.59, H 6.31, N 17.58.

(7aS*,12bR*,12cR*)-Methyl 7-Carbamoyl-8,12b-dimethyl-1,2,3,4,5,7,7a,8,12b,12c-decahydrocyclohepta[5,6]pyridazino[3,4-b]indole-12c-carboxylate (3ad)

The product 3ad was isolated by column chromatography (ethyl acetate/cyclohexane 60:40) in 40% yield (148.2 mg); white solid; mp: 127–129 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.17 (d, J = 7.6 Hz, 1H), 7.02 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.58 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.45 (br, 2H), 6.38 (d, J = 7.6 Hz, 1H), 5.39 (s, 1H), 3.59 (s, 3H), 2.71 (s, 3H), 2.53–2.57 (m, 1H), 2.13–2.24 (m, 1H), 1.91–2.05 (m, 2H), 1.65–1.80 (m, 3H), 1.52 (s, 3H), 1.12–1.43 (m, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.2, 166.0, 156.5, 150.9, 132.0, 128.2, 123.6, 117.3, 106.0, 78.6, 55.7, 52.3, 51.5, 36.2, 31.8, 29.7, 29.0, 25.1, 24.9, 22.2; IR (nujol): υ_max = 3347, 3298, 1729, 1698 cm^–1; HRMS (ESI) calcd for C₂₀H₂₇N₄O₃[M + H]+: 371.2083; found: 371.2069.

N-Phenyl-3,4,7,11c-tetrahydro-1H-6a,11b-propanoindolo[2,3-c]cinnoline-6(2H)-carboxamide (3ae)

The product 3ae was isolated by column chromatography (ethyl acetate/cyclohexane 15:85) in 67% yield (258.9 mg); whitish oil; ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.41–7.58 (m, 2H), 7.26 (t, J = 7.6 Hz, 2H), 6.93–7.01 (m, 3H), 6.14–6.61 (m, 3H), 1.40–2.18 (m, 15H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 156.2, 150.1, 139.5, 133.5, 128.6, 127.1, 122.9, 121.8, 118.5, 117.8, 113.2, 108.9, 100.6, 68.9, 26.4, 25.2, 25.1, 22.4, 22.1, 21.2, 20.8, 20.7; IR (nujol): υ_max = 3375, 3246, 1696 cm^–1; MS (ESI) m/z = 387 [M + H]⁺; anal. calcd for C₂₄H₂₆N₄O (386.49): C 74.58, H 6.78, N 14.50; found: C 74.42, H 6.86, N 14.62.

Methyl 3,4a,9a-Trimethyl-4-phenyl-4,4a,9,9a-tetrahydro-1H-pyridazino[3,4-b]indole-1-carboxylate (3af)

The product 3af was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 22% yield (76.9 mg); white solid; mp: 186–188 °C, ¹H NMR (400 MHz, CDCl₃) δ 7.01–7.12 (m, 3H), 6.88 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.81–6.85 (m, 2H), 6.67 (d, J = 8.0 Hz, 1H), 6.62 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H), 5.38 (s, 1H), 3.90 (s, 3H), 3.39 (s, 1H), 2.10 (s, 3H), 1.67 (s, 3H), 1.49 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 157.8, 155.3, 147.7, 134.2, 131.5, 130.0, 128.3, 127.4, 127.1, 123.9, 118.3, 108.9, 82.8, 54.9, 53.5, 52.3, 24.3, 23.4, 21.7; IR (nujol): υ_max = 3290, 1736 cm^–1; MS (ESI) m/z = 433 [M + H]+; anal. calcd for C₂₁H₂₃N₃O₂ (349.43): C 72.18, H 6.63, N 12.03; found: C 72.03, H 6.72, N 12.17.

General Procedure for the Formal [3 + 2] Cycloaddition Reactions of Indoles 1 with Linear Azoalkenes 2

A mixture of indole 1 (0.6 mmol), azoalkene 2 (0.4 mmol), and zinc dichloride (0.04 mmol, 5.45 mg) was stirred in dry dichloromethane (2 mL). After the disappearance of azoalkene 2 (TLC check), the crude mixture was purified by column chromatography on silica gel to afford product 5.

(3aR*,8aS*)-Ethyl 2,3a-Dimethyl-1-ureido-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5a)

The product 5a was isolated by column chromatography (ethyl acetate/cyclohexane 40:60) in 27% yield (85.3 mg); white solid; mp: 218–220 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (s, 1H), 9.23 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.23 (br, 2H), 4.94 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 2.20 (s, 3H), 1.82 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 170.1, 157.6, 145.1, 136.2, 128.8, 128.5, 121.5, 118.7, 118.5, 111.6, 108.4, 61.3, 52.0, 15.6, 14.5, 8.8; IR (nujol): υ_max = 3478, 3464, 3328, 3321, 1725, 1688 cm^–1; MS (ESI) m/z = 317 [M + H]⁺; anal. calcd for C₁₆H₂₀ N₄ O₃ (316.35): C 60.75, H 6.37, N 17.71; found: C 60.88, H 6.29, N 17.84.

(3aR*,8aS*)-Methyl 1-((Methoxycarbonyl)amino)-2,3a,8-trimethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5b)

The product 5b was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 46% yield (60.9 mg); white solid; mp: 127–129 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 7.6 Hz, 1H), 7.09 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.84 (br, 1H), 6.72 (dt, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H), 6.45 (d, J = 7.6 Hz, 1H), 4.92 (s, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.96 (s, 3H), 2.09 (s, 3H), 1.67 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.5, 160.0, 156.1, 149.7, 134.7, 127.9, 124.9, 118.8, 106.9, 106.6, 96.1, 54.5, 53.2, 50.5, 34.8, 25.4, 12.5; IR (nujol): υ_max = 3287, 1739, 1701 cm^–1; HRMS (ESI) calcd for C₁₇H₂₂N₃O₄[M + H]⁺: 332.1610; found: 332.1639.

(3aR*,8aS*)-Methyl 1-((Methoxycarbonyl)amino)-2,3a,8a-trimethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5c)

The product 5c was isolated by column chromatography on silica gel (ethyl acetate/cyclohexane 20:80) in 58% yield (76.9 mg); white solid; mp: 128–130 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.55 (t, J = 7.6 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 6.13 (s, 1H), 3.65 (s, 3H), 3.59 (s, 3H), 2.01 (s, 3H), 1.46 (s, 3H), 1.26 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 165.5, 159.1, 157.1, 148.7, 133.7, 126.9, 124.7, 117.3, 107.9, 102.8, 92.8, 55.3, 52.1, 49.8, 19.6, 18.6, 12.0; IR (nujol): υ_max = 3274, 1739, 1698 cm^–1; MS (ESI) m/z = 332 [M + H]+; anal. calcd for C₁₇H₂₁N₃O₄ (331.36): C 61.62, H 6.39, N 12.68; found: C 61.74, H 6.31, N 12.57.

(3aR*,8aS*)-Benzyl 1-((tert-Butoxycarbonyl)amino)-2,3a,8a-trimethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5d)

The product 5d was isolated by column chromatography on silica gel (ethyl acetate/cyclohexane 20:80) in 88% yield (158.3 mg); white solid; mp: 149–151 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 7.29–7.54 (m, 5H), 7.20 (d, J = 7.6 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.45 (t, J = 7.6 Hz, 1H), 6.41 (d, J = 7.6 Hz, 1H), 6.13 (s, 1H), 5.10 (s, 2H), 2.03 (s, 3H), 1.46 (s, 3H), 1.43 (s, 9H), 1.27 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 164.9, 159.9, 155.6, 148.6, 137.1, 133.9, 128.3, 127.9, 127.7, 126.8, 124.9, 117.2, 107.8, 101.5, 92.8, 79.5, 64.1, 55.4, 27.9, 19.8, 18.4, 12.1; IR (nujol): υ_max = 3363, 3324, 1741, 1696 cm^–1; HRMS (ESI) calcd for C₂₆H₃₂N₃O₄[M + H]⁺: 450.2393; found: 450.2411.

(3aR*,8aS*)-Ethyl 2,3a,8a-Trimethyl-1-ureido-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5e)

The product 5e was isolated by column chromatography on silica gel (ethyl acetate/cyclohexane 70:30) in 68% yield (89.9 mg); white solid; mp: 171–173 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (s, 1H), 7.30 (d, J = 6.4 Hz, 1H), 6.88 (t, J = 6.4 Hz, 1H), 6.56 (t, J = 6.4 Hz, 1H), 6.43 (d, J = 6.4 Hz, 1H), 6.17 (br, 2H), 6.01 (br, 1H), 4.05 (q, J = 7.2 Hz, 2H), 2.07 (s, 3H), 1.51 (s, 3H), 1.28 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 164.9, 159.7, 159.3, 148.9, 133.1, 126.7, 124.9, 117.0, 107.7, 102.5, 92.9, 58.2, 55.2, 18.6, 15.1, 14.3, 12.1; IR (nujol): υ_max = 3482, 3467, 3338, 3325, 1731, 1684 cm^–1; HRMS (ESI) calcd for C₁₇H₂₃N₄O₃[M + H]⁺: 331.1770; found: 331.1791.

(3aR*,8aS*)-Methyl 2,3a,8a-Trimethyl-1-(3-phenylureido)-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5f)

The product 5f was isolated by column chromatography on silica gel (ethyl acetate/cyclohexane 70:30) in 88% yield (138.1 mg); white solid; mp: 226–228 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (br, 2H), 7.19–7.77 (m, 5H), 6.86–7.05 (m, 2H), 6.41–6.72 (m, 2H), 6.15 (br, 1H), 3.62 (s, 3H), 2.10 (s, 3H), 1.54 (s, 3H), 1.33 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 165.5, 159.6, 155.6, 148.6, 139.1, 133.3, 128.5, 126.9, 124.8, 122.1, 118.9, 118.3, 117.6, 108.1, 93.0, 55.4, 49.8, 20.6, 18.8, 12.3; IR (nujol): υ_max = 3389, 3282, 3270, 1726, 1694 cm^–1; HRMS (ESI) calcd for C₂₂H₂₅N₄O₃[M + H]⁺: 393.1927; found: 393.1963.

(3aR*,8aS*)-Methyl 2-Ethyl-1-((methoxycarbonyl)amino)-3a,8a-dimethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5g)

The product 5g was isolated by column chromatography on silica gel (ethyl acetate/cyclohexane 25:75) in 73% yield (100.9 mg); white solid; mp: 157–159 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 7.6 Hz, 1H), 7.01 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.80 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 6.38 (br, 1H), 3.86 (br, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 2.47–2.68 (m, 2H), 1.62 (s, 3H), 1.42 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.8, 163.8, 156.9, 147.6, 134.2, 127.5, 126.0, 120.1, 109.5, 105.9, 93.4, 56.4, 53.1, 50.4, 20.0, 19.7, 19.4, 12.5; IR (nujol): υ_max = 3332, 3275, 1727, 1692 cm^–1; HRMS (ESI) calcd for C₁₈H₂₄N₃O₄[M + H]⁺: 346.1767; found: 346.1761.

(3aS*,8bR*)-Methyl 11-((Methoxycarbonyl)amino)-10-methyl-1,2,3,4-tetrahydro-3a,8b-(epiminoetheno)cyclopenta[b]indole-9-carboxylate (5h)

The product 5h was isolated by column chromatography on silica gel (ethyl acetate/cyclohexane 20:80) in 98% yield (134.8 mg); white solid; mp: 150–152 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J = 7.6 Hz, 1H), 7.02 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.79 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.62 (br, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.16 (br, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.16–2.45 (m, 3H), 2.14 (s, 3H), 1.60–1.88 (m, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.6, 159.5, 157.3, 148.7, 135.4, 127.8, 125.9, 120.7, 110.3, 104.3, 99.9, 67.3, 53.2, 50.5, 41.0, 40.2, 25.3, 12.4; IR (nujol): υ_max = 3370, 3302, 1718, 1662 cm^–1; HRMS (ESI) calcd for C₁₈H₂₂N₃O₄ [M + H]⁺: 344.1610; found: 344.1606.

(4bR*,8aS*)-Methyl 10-((Methoxycarbonyl)amino)-11-methyl-6,7,8,9-tetrahydro-5H-8a,4b-(epiminoetheno)carbazole-12-carboxylate (5i)

The product 5i was isolated by column chromatography on silica gel (ethyl acetate/cyclohexane 30:70) in 95% yield (135.8 mg); yellowish solid; mp: 121–123 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.27 (s, 1H), 7.26 (d, J = 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.57 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 7.6 Hz, 1H), 6.04 (s, 1H), 3.64 (s, 3H), 3.58 (s, 3H), 2.04 (s, 3H), 1.40 (s, 8H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 165.6, 159.2, 157.1, 149.6, 132.6, 126.8, 124.4, 117.4, 108.3, 103.4, 91.3, 55.0, 52.0, 49.8, 30.3, 26.3, 18.9, 18.5, 12.0; IR (nujol): υ_max = 3370, 3302, 1736, 1697 cm^–1; HRMS (ESI) calcd for C₁₉H₂₄N₃O₄ [M + H]⁺: 358.1767; found: 358.1782.

(3aR*,8aS*)-Methyl 5-Chloro-3a-ethyl-1-((methoxycarbonyl)amino)-2,8a-dimethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5j)

The product 5j was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 85% yield (129.2 mg); white solid; mp: 113–115 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H), 7.19 (d, J = 2.0 Hz, 1H), 6.89 (dd, J₁ = 8.4 Hz, J₂ = 2.0 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 6.27 (br, 1H), 3.64 (s, 3H), 3.58 (s, 3H), 2.26–2.42 (m, 1H), 2.05 (s, 3H), 1.63–1.79 (m, 1H), 1.31 (s, 3H), 0.60–0.89 (m, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 165.3, 160.0, 156.9, 148.1, 134.8, 126.5, 124.9, 120.3, 108.6, 99.5, 93.3, 59.2, 52.1, 49.9, 17.9, 15.1, 11.9, 9.0; IR (nujol): υ_max = 3360, 3266, 1739, 1694 cm^–1; HRMS (ESI) calcd for C₁₈H₂₃N₃O₄Cl [M + H]⁺: 380.1377; found: 380.1374.

(3aR*,8aS*)-Methyl 3a-Ethyl-5-methoxy-1-((methoxycarbonyl)amino)-2,8a-dimethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5k)

The product 5k was isolated by column chromatography (ethyl acetate/cyclohexane 40:60) in 98% yield (147.2 mg); white solid; mp: 153–155 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (s, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.49 (dd, J₁ = 8.0 Hz, J₂ = 2.4 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 5.64 (s, 1H), 3.64 (s, 3H), 3.63 (s, 3H), 3.58 (s, 3H), 2.27–2.45 (m, 1H), 2.06 (s, 3H), 1.60–1.79 (m, 1H), 1.30 (s, 3H), 0.69–0.91 (m, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 166.1, 160.5, 157.6, 152.5, 143.6, 134.6, 112.5, 112.3, 108.5, 100.3, 93.9, 59.9, 55.8, 52.5, 50.3, 25.0, 18.5, 12.4, 9.6; IR (nujol): υ_max = 3369, 3267, 1754, 1693 cm^–1; HRMS (ESI) calcd for C₁₉H₂₆N₃O₅[M + H]⁺: 376.1872; found: 376.1837.

(5aS*,10aR*)-Methyl 2-Methoxy-13-((methoxycarbonyl)amino)-12-methyl-5,6,7,8,9,10-hexahydro-5a,10a-(epiminoetheno)cyclohepta[b]indole-11-carboxylate (5l)

The product 5l was isolated by column chromatography on silica gel (ethyl acetate/cyclohexane 30:70) in 60% yield (96.4 mg); brown solid; mp: 166–168 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.14 (d, J = 2.8 Hz, 1H), 6.72 (br, 1H), 6.57 (dd, J₁ = 8.4 Hz, J₂ = 2.8 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.69 (s, 3H), 3.62 (br, 1H), 2.16 (s, 3H), 1.42 (s, 10H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.2, 160.1, 156.9, 154.3, 140.7, 137.3, 113.1, 112.0, 110.2, 103.7, 95.9, 63.2, 55.9, 52.9, 50.3, 35.8, 33.9, 30.8, 27.0, 25.5, 12.9; IR (nujol): υ_max = 3392, 3317, 1738, 1691 cm^–1; MS (ESI) m/z = 332 [M + H]⁺; anal. calcd for C₂₁H₂₇N₃O₅ (401.45): C 62.83, H 6.78, N 10.47; found: C 62.98, H 6.70, N 10.36.

(3aR*,8aS*)-Ethyl 1-((Ethoxycarbonyl)amino)-2,3a,5,8a-tetramethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5m)

The product 5m was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 47% yield (70.2 mg); white solid; mp: 151–153 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 7.13 (d, J = 1.2 Hz, 1H), 6.69 (dd, J₁ = 8.0 Hz, J₂ = 1.2 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 5.88 (s, 1H), 3.98–4.20 (m, 4H), 2.15 (s, 3H), 2.02 (s, 3H), 1.44 (s, 3H), 1.15–1.31 (m, 9H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 165.2, 159.2, 156.5, 146.3, 133.8, 127.1, 125.5, 125.4, 107.7, 102.3, 93.0, 60.6, 58.1, 55.3, 20.6, 19.7, 18.4, 14.4, 14.3, 11.9; IR (nujol): υ_max = 3343, 3306, 1734, 1689 cm^–1; HRMS (ESI) calcd for C₂₀H₂₈N₃O₄ [M + H]⁺: 374.2080; found: 374.2091.

(3aR*,8aS*)-tert-Butyl 1-((tert-Butoxycarbonyl)amino)-2,3a,8a-trimethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5n)

The product 5n was isolated by column chromatography (ethyl acetate/cyclohexane 20:50) in 50% yield (85.9 mg); whitish oil; ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.69 (dd, J₁ = 8.0 Hz, J₂ = 0.8 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H), 5.86 (s, 1H), 2.16 (s, 3H), 1.97 (s, 3H), 1.49 (s, 3H), 1.46 (s, 9H), 1.43 (s, 9H), 1.23 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 165.1, 158.8, 155.8, 146.4, 134.4, 127.0, 125.4, 124.8, 107.8, 103.3, 92.9, 79.3, 77.9, 55.3, 28.4, 27.9, 20.6, 19.8, 18.3, 11.9; IR (nujol): υ_max = 3439, 3304, 1738, 1696 cm^–1; MS (ESI) m/z = 430 [M + H]⁺; anal. calcd for C₂₄H₃₅N₃O₄ (429.52): C 67.11, H 8.21, N 9.78; found: C 67.26, H 8.12, N 9.69.

(3aR*,8aS*)-Methyl 1-((Methoxycarbonyl)amino)-3a,5,8a-trimethyl-2-propyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5o)

The product 5o was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 74% yield (110.6 mg); white solid; mp: 163–165 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.30 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 6.31 (br, 1H), 3.80 (br, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.47 (q, J = 7.2 Hz, 1H), 2.42–2.64 (m, 2H), 2.28 (s, 3H), 1.61 (s, 3H), 1.40 (s, 3H), 1.21 (t, J = 7.2 Hz, 1H), 0.92 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 165.9, 162.4, 156.9, 145.3, 134.4, 129.3, 128.0, 126.7, 109.4, 106.5, 93.7, 65.9, 56.4, 50.3, 28.1, 21.1, 20.1, 19.5, 15.4, 14.3; IR (nujol): υ_max = 3394, 3272, 1729, 1691 cm^–1; HRMS (ESI) calcd for C₂₀H₂₈N₃O₄ [M + H]⁺: 374.2080; found: 374.2091.

(7aS*,10aR*)-Methyl 8-((Methoxycarbonyl)amino)-7a,9,10a-trimethyl-7,7a,8,10a-tetrahydrobenzo[e]pyrrolo[2,3-b]indole-10-carboxylate (5p)

The product 5p was isolated by column chromatography (ethyl acetate/cyclohexane 20:80) in 38% yield (58.1 mg); white solid; mp: 137–139 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 5.26 (s, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 2.06 (s, 3H), 1.79 (s, 3H), 1.63 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 166.8, 159.5, 157.1, 148.2, 131.3, 130.9, 129.8, 129.5, 126.9, 121.6, 121.5, 120.5, 113.7, 104.5, 79.8, 65.9, 53.4, 50.6, 21.2, 17.4, 12.5; IR (nujol): υ_max = 1732, 1730 cm^–1; MS (ESI) m/z = 414 [M + H]⁺; anal. calcd for C₂₁H₂₃N₃O₄ (381.42): C 66.13, H 6.08, N 11.02; found: C 65.98, H 6.16, N 11.16.

(3aR*,8aS*)-N,N,2,3a,8a-Pentamethyl-1-ureido-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxamide (5q)

The product 5q was isolated by column chromatography (methanol/ethyl acetate 05:95) in 52% yield (68.5 mg); white solid; mp: 191–193 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 7.04 (br, 1H), 6.89 (t, J = 7.2 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.53 (t, J = 7.2 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 6.16 (br, 2H), 6.04 (s, 1H), 2.73 (s, 3H), 2.32 (s, 3H), 1.58 (s, 3H), 1.46 (s, 3H), 1.25 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 167.2, 159.9, 148.9, 142.7, 132.3, 127.0, 121.8, 117.3, 109.8, 107.9, 92.6, 56.9, 20.7, 18.9, 18.0, 11.0; IR (nujol): υ_max = 3489, 3337, 3326, 3297, 1698, 1689 cm^–1; HRMS (ESI) calcd for C₁₇H₂₄N₅O₂[M + H]⁺: 330.1930; found: 330.1932.

Methyl ((4bS*,8aS*)-12-(Dimethoxyphosphoryl)-11-methyl-6,7,8,9-tetrahydro-5H-8a,4b-(epiminoetheno)carbazol-10-yl)carbamate (5r)

The product 5r was isolated by column chromatography (ethyl acetate/cyclohexane 90:10) in 31% yield (50.6 mg); white solid; mp: 198–200 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6, 1H), 6.59 (t, J = 7.6, 1H), 6.46 (d, J = 7.6 Hz, 1H), 6.01 (s, 1H), 3.62 (s, 3H), 3.35 (s, 3H), 3.18 (s, 3H), 1.91 (s, 3H), 1.75–1.96 (m, 1H), 0.91–1.54 (m, 7H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 160.0, 157.0, 149.7, 131.5, 127.0, 124.1, 117.4, 108.4, 97.0, 91.7, 59.7, 56.1 (²J_CP = 10.1 Hz), 51.9, 50.9 (²J_CP = 4.3 Hz), 31.5, 26.3, 20.7, 19.3, 11.6; IR (nujol): υ_max = 3319, 3283, 1695 cm^–1; MS (ESI) m/z = 408 [M + H]⁺; anal. calcd for C₁₉H₂₆N₃O₅P (407.40): C 56.01, H 6.43, N 10.31; found: C 56.16, H 6.35, N 10.18.

(3aR*,8aS*)-Methyl 1-((Methoxycarbonyl)amino)-2,3a,8,8a-tetramethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (5s)

The product 5s was isolated by column chromatography (ethyl acetate/cyclohexane 25:75) in 94% yield (129.9 mg); white solid; mp: 155–157 °C. Notably, compound 5q at NMR analysis shows two sets of peaks. This fact is probably ascribable to the presence of a second axis along the N–N bond that determines the existence of syn/anti rotamers of carbamates.^9,301H NMR (400 MHz, DMSO-d₆) δ 9.59 and 9.38 (s, 1H), 7.32 and 7.29 (d, J = 7.6 Hz, 1H), 7.01 and 6.96 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.59 and 6.56 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.37 and 6.33 (d, J = 7.6 Hz, 1H), 3.67 and 3.66 (s, 3H), 3.63 and 3.59 (s, 3H), 2.75 and 2.69 (s, 3H), 1.99 and 1.95 (s, 3H), 1.45 and 1.39 (s, 3H), 1.30 and 1.26 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 166.1 and 165.5, 160.9 and 158.8, 157.0 and 156.4, 149.4 and 148.8, 134.4 and 133.1, 127.4 and 127.2, 124.2 and 123.4, 117.5 and 117.1, 105.7 and 104.9, 102.8 and 102.5, 95.5 and 95.1, 55.6 and 55.0, 52.3 and 52.1, 50.1 and 49.8, 29.8 and 27.9, 21.1 and 19.8, 14.2 and 13.6, 12.0 and 11.8; IR (nujol): υ_max = 3369, 1741, 1693 cm^–1; MS (ESI) m/z = 346 [M + H]⁺; anal. calcd for C₁₈H₂₃N₃O₄ (345.39): C 62.59, H 6.71, N 12.17; found: C 62.43, H 6.80, N 12.31.

Ethyl 3-(2-Carbamoylhydrazono)-2-(1-methyl-1H-indol-3-yl)butanoate (4a)

The product 4a was isolated by column chromatography (ethyl acetate/cyclohexane 80:20) in 48% yield (151.8 mg); white solid; mp: 189–191 °C, ¹H NMR (400 MHz, CDCl₃) δ 8.73 (br, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.08–7.13 (m, 2H), 5.99 (br, 1H), 5.67 (br, 1H), 4.87 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 1.86 (s, 3H), 1.29 (s, J = 7.8 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 171.0, 158.2, 147.4, 137.0, 128.0, 127.2, 121.9, 119.5, 119.2, 109.4, 108.1, 61.2, 52.0, 32.8, 14.2, 13.9; IR (nujol): υ_max = 3502, 3387, 3177, 1738, 1693 cm^–1; MS (ESI) m/z = 317 [M + H]⁺; anal. calcd for C₁₆H₂₀N₄O₃ (316.35): C 60.75, H 6.37, N 17.71; found: C 60.61, H 6.25, N 17.82.

Methyl 2-(4-Methoxy-3-(1-methyl-1H-indol-3-yl)-4-oxobutan-2-ylidene)hydrazinecarboxylate (4b)

The product 4b was isolated by column chromatography (ethyl acetate/cyclohexane 40:60) in 70% yield (222.2 mg); white solid; mp: 189–191 °C, ¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.16 (dt, J₁ = 8.0 Hz, J₂ = 1.2 Hz, 1H), 7.03 (dt, J₁ = 8.0 Hz, J₂ = 1.2 Hz, 1H), 4.87 (s, 1H), 3.77 (s, 3H), 3.68 (s, 6H), 1.79 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 171.6, 155.1, 151.5, 137.0, 129.0, 127.3, 121.8, 119.5, 119.2, 110.3, 108.0, 52.4, 52.3, 51.8, 32.9, 14.9; IR (nujol): υ_max = 3354, 1740, 1726, 1696 cm^–1; MS (ESI) m/z = 318 [M + H]⁺; anal. calcd for C₁₆H₁₉N₃O₄ (317.33): C 60.56, H 6.03, N 13.24; found: C 60.42, H 6.12, N 13.31.

Methyl 2-(3-(1,2-Dimethyl-1H-indol-3-yl)-4-methoxy-4-oxobutan-2-ylidene)hydrazinecarboxylate (4c)

The product 4c was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 52% yield (172.3 mg); white solid; mp: 223–225 °C, ¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 7.35–7.42 (m, 2H), 7.08 (dt, J₁ = 8.0 Hz, J₂ = 1.2 Hz, 1H), 6.97 (dt, J₁ = 8.0 Hz, J₂ = 1.2 Hz, 1H), 4.85 (s, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.63 (s, 3H), 2.34 (s, 3H), 1.75 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.1, 155.0, 152.3, 136.7, 136.1, 127.0, 120.7, 119.4, 118.6, 109.7, 104.6, 52.2, 52.1, 51.5, 29.9, 15.5, 10.6; IR (nujol): υ_max = 3365, 1743, 1732, 1701 cm^–1; MS (ESI) m/z = 332 [M + H]⁺; anal. calcd for C₁₇H₂₁N₃O₄ (331.36): C 61.62, H 6.39, N 12.68; found: C 61.57, H 6.50, N 12.52.

Ethyl 2-(2-Carbamoylhydrazono)-1-(1,2-dimethyl-1H-indol-3-yl)cyclohexanecarboxylate (4d)^10e

The product 4d was isolated by column chromatography on silica gel (ethyl acetate/cyclohexane 60:40) in 61% yield (113.0 mg); white solid; mp: 207–210 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 7.37 (t, J = 9.2 Hz, 2H), 7.04 (dt, J₁ = 8.0 Hz, J₂ = 0.8 Hz, 1H), 6.91 (dt, J₁ = 8.0 Hz, J₂ = 0.8 Hz, 1H), 5.84 (br, 2H), 3.94–4.13 (m, 2H), 3.64 (s, 3H), 2.67–2.91 (m, 2H), 2.25 (s, 3H), 2.14–2.23 (m, 2H), 1.38–1.59 (m, 4H), 1.09 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 173.2, 157.4, 152.6, 136.2, 135.0, 126.3, 119.8, 119.4, 118.6, 109.3, 108.1, 60.3, 56.9, 35.7, 29.3, 25.5, 24.8, 21.5, 13.9, 11.6; IR (nujol): υ_max = 3510, 3393, 3182, 1734, 1687 cm^–1; MS (ESI) m/z = 371 [M + H]⁺; anal. calcd for C₂₀H₂₆N₄O₃ (370,45): C 64.84, H 7.07, N 15.12; found: C 64.69, H 6.99, N 14.99.

Procedure for the Ring-Opening Reaction of Tetrahydro-1H-pyridazino[3,4-b]indole (3b)

To a solution of compound 3b (0.4 mmol) in dichloromethane (2 mL), Amberlyst 15(H) (500 mg/mmol) was added. After the disappearance of starting 3b (TLC check, 20 h), the crude mixture was purified by column chromatography on silica gel to afford product 4e.

Ethyl 1-(1-Methyl-1H-indol-3-yl)-2-(2-(phenylcarbamoyl)hydrazono)cyclohexanecarboxylate (4e)

The product 4e was isolated by column chromatography (ethyl acetate/cyclohexane 25:75) in 71% yield (122.8 mg); white solid; mp: 210–212 °C, ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 7.51 (t, J = 8.4 Hz, 2H), 7.33 (s, 1H), 7.25 (s, 1H), 7.18 (dt, J₁ = 8.4 Hz, J₂ = 1.2 Hz, 1H), 7.07 (t, J = 8.4 Hz, 2H), 6.96 (dt, J₁ = 8.4 Hz, J₂ = 1.2 Hz, 1H), 6.85 (dt, J₁ = 8.4 Hz, J₂ = 1.2 Hz, 1H), 6.48 (d, J = 8.4 Hz, 2H), 4.05–4.19 (m, 2H), 3.79 (s, 3H), 3.04 (d, J = 14.4 Hz, 1H), 2.68 (d, J = 14.4 Hz, 1H), 2.11–2.23 (m, 2H), 1.79–1.85 (m, 2H), 1.44–1.55 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.5, 153.3, 151.0, 138.1, 137.1, 128.3, 127.5, 126.6, 121.9, 120.9, 120.8, 118.8, 117.5, 113.5, 109.8, 60.7, 55.5, 35.6, 32.4, 25.5, 25.3, 22.6, 13.9; IR (nujol): υ_max = 3190, 3088, 1726, 1681 cm^–1; MS (ESI) m/z = 433 [M + H]⁺; anal. calcd for C₂₅H₂₈N₄O₃ (432.51): C 69.42, H 6.53, N 12.95; found: C 69.57, H 6.44, N 12.87.

Ethyl 2-(2-Carbamoylhydrazono)-1-(1-methyl-1H-indol-3-yl)cyclopentanecarboxylate (4f)

The product 4f (see Scheme 1) was isolated by column chromatography (ethyl acetate/cyclohexane 90:10) in 67% yield (229.4 mg); white solid; mp: 168–170 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.12 (dt, J₁ = 8.0 Hz, J₂ = 0.8 Hz, 1H), 7.09 (s, 1H), 6.98 (dt, J₁ = 8.0 Hz, J₂ = 0.8 Hz, 1H), 5.92 (br, 2H), 4.04–4.12 (m, 2H), 3.73 (s, 3H), 2.43–2.56 (m, 3H), 2.29–2.36 (m, 1H), 1.62–1.87 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 172.7, 156.9, 156.4, 137.2, 127.5, 126.1, 121.0, 120.2, 118.4, 113.4, 109.8, 60.6, 56.8, 36.2, 32.3, 27.9, 21.4, 14.1; IR (nujol): υ_max = 3470, 3200, 3160, 1733, 1696 cm^–1; MS (ESI) m/z = 343 [M + H]⁺; anal. calcd for C₁₈H₂₂N₄O₃ (342.39): C 63.14, H 6.48, N 16.36; found: C 62.98, H 6.58, N 16.45.

Ethyl Bromoacetate-Assisted Cleavage of the N–N Bond in 5s (Magnus’ Procedure¹⁶)

Ethyl 2-bromoacetate (1.5 equiv) and Cs₂CO₃ (2.5 equiv) were added to a solution of compound 5s (0.3 mmol) in acetonitrile (2 mL). The reaction mixture was stirred in an oil bath heated at 50 °C until the starting material was consumed (TLC check, 1 h) and then refluxed for an additional 1.5 h (TLC check). The crude mixture was filtered and then purified by column chromatography on silica gel to afford the product 6a. The NMR experiments show that the title compound has no rotamers.

(3aR*,8aR*)-Methyl 2,3a,8,8a-Tetramethyl-1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-3-carboxylate (6a)

The product 6a was isolated by column chromatography (ethyl acetate/cyclohexane 30:70) in 64% yield (52.3 mg); whitish oil; ¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (s, 1H), 7.26 (dd, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.92 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.52 (dt, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 6.30 (dd, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H), 3.55 (s, 3H), 2.67 (s, 3H), 2.03 (s, 3H), 1.39 (s, 3H), 1.27 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-d₆) δ 165.9, 159.3, 149.3, 134.7, 126.8, 123.8, 116.9, 104.9, 101.6, 90.9, 56.4, 49.3, 28.2, 19.8, 17.4, 14.5; IR (nujol): υ_max = 3369, 1741 cm^–1; MS (ESI) m/z = 273 [M + H]⁺; anal. calcd for C₁₆H₂₀N₂O₂ (272.34): C 70.56, H 7.40, N 10.29; found: C 70.41, H 7.47, N 10.39.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.0c01489.

• Structures of starting materials (Figure S1), optimization for reaction of 1a with cyclic azoalkene 2a (Table S1), copies of NMR spectra for all products (PDF)

• Crystal data of compounds 3e (CIF)

• Cartesian coordinates of all computed structures for the reaction of 2n with 1p (PDF)

The authors declare no competing financial interest.