Two-Step Sequence of Cycloadditions Gives Structurally Complex

May 21, 2018 - Department of Chemistry, University of Vermont, 82 University Place, Burlington , Vermont 05405 , United States. J. Org. Chem. , Articl...
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Cite This: J. Org. Chem. 2018, 83, 6202−6209

Two-Step Sequence of Cycloadditions Gives Structurally Complex Tetracyclic 1,2,3,4-Tetrahydrocinnoline Products Ram Dhakal, Monika Ivancic, and Matthias Brewer* Department of Chemistry, University of Vermont, 82 University Place, Burlington, Vermont 05405, United States S Supporting Information *

ABSTRACT: Intramolecular [4 + 2]-cycloaddition of heteroallene salts gives polycyclic tetrahydrocinnoline structures that contain an N-aminoiminium motif. Deprotonation with mild base gives the corresponding azomethine imines, which readily participate in 1,3-dipolar cycloaddition reactions. The structurally complex tetracyclic 1,2,3,4-tetrahydrocinnoline products typically form as a mixture of two separable diastereomers. The major diastereomer is generally formed by reaction of the dipolarophile with the convex face of the dipole.

H

Scheme 1. Representative Examples of the TMSOTf Mediated Synthesis of 1,2,3,4-Tetrahydrocinnolines

uisgen conceptualized 1,3-dipolar cycloadditions as a general class of reaction while studying the cycloaddition reaction of diazoalkanes with strained double bonds.1,2 This insight provided a mechanistic framework for the known additions of ozone and azides to alkenes and allowed other 1,3diopoles to be recognized and studied. For instance, Huisgen and coworkers soon after documented azomethine imines3 as being 1,3-dipoles and demonstrated their cycloaddition reactivity with alkenes.4,5 To this day, azomethine imines play an important role in synthesis, and their cycloaddition reactions are often the method of choice to prepare structurally complex pyrazolines.6−8 A variety of methods to form azomethine imines are known.9−16 While deprotonation of N-aminoiminium species was one of the first methods used to generate azomethine imines, these 1,3-dipols are more commonly prepared by the reaction of N,N′-substituted hydrazines with aldehydes, or from hydrazones via a prototropic shift.6,17 We recently discovered that 1-aza-2-azoniaallene salts, generated by the reaction of SbCl5 with an α-chloroazo species, can participate in intramolecular [4 + 2]-cycloaddition reactions to give tetracyclic 1,2,3,4-tetrahydrocinnoline products containing an N-aminoiminium motif (Scheme 1).18 Limitations on the preparation of α-chloroazo compounds and the environmental implications of using stoichiometric quantities of SbCl5 limited the full potential of this transformation and prompted us to look for alternative methods to effect this cycloaddition. Ultimately, we discovered that treating α-trifluoroacetoxyazo compounds with TMS-triflate was a milder and more environmentally friendly way to effect this transformation. Importantly, these latter conditions were also more general; substituents on the aryl ring and a variety of alkene substitution patterns were well tolerated, and highly sterically hindered products could be formed in high yield (Scheme 1).19 We recognized that the N-aminoiminium scaffold embedded within these polycyclic tetrahydrocinnoline structures is an Nprotonated azomethine imine. Protonated hydrazones are © 2018 American Chemical Society

known to react in [3⊕ + 2]-cycloadditions,20 but our attempts to react 2a with several alkenes failed to return any desired cycloaddition product. However, we believed that treating these hydrazonium salts with a non-nucleophilic base might generate azomethine imines that would be difficult to prepare by other protocols and that including a dipolarophile in the mix might result in a subsequent 1,3-dipolar cycloaddition reaction to give structurally complex heterocyclic products. The results of these studies are described herein. We began our study by treating tetrahydrocinnoline 2a with diethyl maleate and triethyl amine. We choose diethyl maleate as the cycloaddition partner because its symmetry would minimize the formation of regioisomers and simplify product analysis. The reaction was first run at low temperature (−78 Received: March 16, 2018 Published: May 21, 2018 6202

DOI: 10.1021/acs.joc.8b00683 J. Org. Chem. 2018, 83, 6202−6209

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The Journal of Organic Chemistry

Scheme 2. 1,3-Dipolar Cycloaddition of the Azomethine Imine Derived from 2a and NOEs and Diagnostic Chemical Shifts for 5ai and 6ai

Table 1. Effect of Aryl Ring Substituents on Cycloaddition

°C) in CH2Cl2, which gave the desired cycloaddition product in 23% yield as a mixture of diastereomers (5ai and 6ai) in a 22:1 ratio (Scheme 2 and Table S1). The relative stereochemistry of these compounds was determined through 2D-NOESY NMR studies. The major diastereomer (5ai) forms when the dipolarophile approaches the convex face of the azomethine imine with the ester substituents oriented in an exo manner. The minor diastereomer (6ai) forms when the dipolarophile approaches the concave face of the azomethine imine with the ester substituents oriented in an endo manner. Orienting the ester substituents in an endo fashion on the convex face of the dipolarophile may be hampered by steric interactions between the ester group and the dipole’s axial proton. In the proton NMR spectrum of 5ai, the protons adjacent to the nitrogen atoms are shifted approximately 0.8 ppm upfield of their counterparts in 6ai. This upfield chemical shift is consistent with an antiarrangement between the C−H bonds and the nitrogen lone pair in compound 5ai.21 Raising the reaction temperature to room temperature and extending the reaction time to 2 h improved the yield of the reaction significantly (75%) but caused the diastereomeric ratio to fall to 2.8:1. Changing the solvent to acetonitrile caused the yield to decrease slightly (70%) even after extended reaction times (16 h). However, these reactions had an increased diastereomeric ratio (6.0:1). Changing the solvent to THF gave lower yields and lower diastereomeric ratio. Increasing the reaction temperature to 30 °C with CH2Cl2 as solvent gave a similar yield and diastereomeric ratio as the room temperature result. Running the reaction in acetonitrile for 1 h at 55 °C gave the product in 76% yield as a 4.8:1 ratio of diastereomers, and extending the reaction time to 2 h under these conditions did not change the outcome. The yield improved to 90% without affecting the diastereomeric ratio (4.6:1) when the quantity of triethylamine was lowered to 1.3 equiv. It is not clear why decreasing the base led to higher yield, but it is possible that additional base could cause epimerization of the product,

leading to small amounts of additional diastereomers that were not isolated. In any event, these latter conditions were adopted for the remainder of our study. With these optimized conditions in hand, we next assessed how substituents on the aryl ring of the azomethine imine precursor affected the reaction (Table 1). Incorporating a methyl or chloro substituent para to the nitrogen of the N-aryl ring provided the expected tetracyclic products in good yields (83 and 84%, respectively; entries 1 and 2). These substituents appear to have only a modest effect on the diastereoselectivity of the cycloaddition in that selectivity increased slightly as the aromatic ring became more electron deficient (3.9:1 vs 5.0:1). Changing the location of the N-aryl methyl group to the orthoposition gave the cycloadduct in slightly lower yield (64%). However, in this latter case, the diastereoselectivity was reversed, and 6di became the favored product in a 1:4.8 ratio. This reversal in diastereoselectivity is likely due to a steric interaction between the methyl substituent on the aryl ring and the ethyl ester of the dipolarophile that develops in the transition state, leading to diastereomer 5di. We also assessed the reactivity of these azomethine imine precursors with a variety of other dipolarophiles in cycloaddition reactions (Table 2). Changing the dipolarophile from diethyl maleate to dimethyl maleate resulted in a slight increase in the diastereoselectivity in all cases (entries 1.1−1.4). When the azomethine imines derived from 2a reacted with dimethyl fumarate, two diastereomeric cycloaddition products were isolated in nearly equivalent amounts (entries 2.1−2.3). In this case, the diagnostic chemical shifts of the protons adjacent to the nitrogen atoms and 2D-NOESY NMR studies indicated that both products resulted from reaction of the dipolarophile on the convex face of the azomethine imine. The diastereomer that would form by reacting on the concave face of the azomethine imine was not observed. Interestingly, the azomethine imine derived from 2d, which has a methyl group ortho to the aryl amine, gave diastereomer 5diii-1 as a single 6203

DOI: 10.1021/acs.joc.8b00683 J. Org. Chem. 2018, 83, 6202−6209

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The Journal of Organic Chemistry Table 2. Scope of Reaction with a Variety of Dipolarophiles

temperature for 12 h gave the expected cycloaddition products (5aiv−5civ) as single diastereomers in near quantitative yield (entries 3.1−3.3). Changing the dipolarophile to the unsymmetric methyl vinyl ketone allowed us to observe both the regiochemical and stereochemical outcome of the cycloaddition. In all cases examined, a single regioisomer was isolated as a mixture of two diastereomers (entries 4.1−4.3). The regioisomer obtained is consistent with a dipole HOMO controlled reaction, leading to incorporation of the ketone at the 4-position of the pyrazolidine ring.22 The diastereomers

product. Again, it appears that steric interactions between the aryl methyl substituent and the dienophile control the diastereoselectivity of the reaction. In changing from dimethyl maleate to dimethyl fumarate there was no crossover between the products formed. The stereospecific nature of this reaction is consistent with a concerted 1,3-dipolar cycloaddition mechanism. When the dipolarophile was changed to maleic anhydride, the standard reaction conditions gave complex product mixtures. However, conducting these reactions at room 6204

DOI: 10.1021/acs.joc.8b00683 J. Org. Chem. 2018, 83, 6202−6209

Note

The Journal of Organic Chemistry

rel-Diethyl (1S,2S,2aR,4aR)-2a-Methyl-2,2a,3,4,4a,5-hexahydro1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5ai). Rf = 0.45 in Hexane/EtOAc = 3:1. Yield 74% (47 mg). 1H NMR (500 MHz, CDCl3) δ 7.09 (t, J = 7.1, 1H), 7.06, (d, J = 8.1 Hz, 1H), 6.88 (td, J = 7.5, 1.1 Hz, 1H), 6.78 (dd, J = 8.1, 1.1 Hz, 1H), 4.44−4.36 (m, 1H), 4.34−4.26 (m, 2H), 4.24−4.11 (m, 2H), 3.65 (d, J = 11.3 Hz, 1H), 2.90−2.76 (m, 2H), 2.61 (ddd, J = 10.2, 7.9, 4.5 Hz, 1H), 2.37 (dt, J = 13.6, 9.4 Hz, 1H), 2.16 (ddd, J = 10.9, 9.3, 5.4, 1.3 Hz, 1H), 1.92 (ddd, J = 13.4, 10.5, 1.3 Hz, 1H), 1.69 (dt, J = 21.8, 10.9 Hz, 1H), 1.52 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 171.6, 169.3, 146.1, 129.7, 126.8, 124.7, 121.7, 118.9, 70.9, 69.5, 61.5, 61.0, 56.9, 56.0, 35.5, 35.4, 28.7, 23.4, 14.3, 14.2. HRMS (ESI) m/z: [M + H] + calcd for [C20H26N2O4H]+: 359.1971, found: 359.1955. rel-Diethyl (1S,2S,2aS,4aR)-2a-Methyl-2,2a,3,4,4a,5-hexahydro1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (6ai). Rf = 0.53 in Hexane/EtOAc = 3:1. Yield 16% (10 mg). 1H NMR (500 MHz, CDCl3) δ 7.08−7.02 (m, 2H), 6.87 (d, J = 7.8 Hz, 1H), 6.81 (apptd, J = 5.9, 2.9 Hz, 1H), 4.96 (d, J = 9.3 Hz, 1H), 4.22−4.10 (m, 2H), 4.02−3.82 (m, 2H), 3.62 (dd, J = 9.1, 4.7 Hz, 1H), 3.49− 3.41 (m, 1H), 2.85−2.72 (m, 2H), 2.44−2.34 (m, 1H), 2.01 (ddd, J = 11.3, 6.7, 4.5 Hz, 1H), 1.88 (dd, J = 12.9, 6.6 Hz, 1H), 1.64−1.45 (m, 1H), 1.52 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 171.1, 170.2, 143.5, 141.8, 130.0, 126.4, 125.8, 121.0, 119.5, 69.0, 68.0, 60.9, 60.2, 55.9, 35.7, 35.4, 32.5, 29.1, 14.3, 13.8. HRMS (ESI) m/z: [M + H] + calcd for [C20H26N2O4H]+: 359.1971, found: 359.1956. rel-Diethyl (1S,2S,2aR,4aR)-2a,7-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5bi). Rf = 0.23 in Hexane/EtOAc = 3:1. Yield 66% (43.5 mg). 1H NMR (500 MHz, CDCl3) δ 6.90 (d, J = 8.2 Hz, 1H), 6.87 (s, 1H), 6.70 (d, J = 8.2 Hz, 1H), 4.39 (dq, J = 10.6, 7.1 Hz, 1H), 4.30 (dq, J = 10.4, 7.1 Hz, 1H), 4.25−4.11 (m, 3H), 3.65 (d, J = 11.4 Hz, 1H), 2.82 (dd, J = 15.0, 3.6 Hz, 1H), 2.76 (dd, J = 15.0, 10.8 Hz, 1H), 2.67−2.55 (m, 1H), 2.36 (appdt, J = 13.5, 9.3 Hz, 1H), 2.25 (s, 3H), 2.19−2.09 (m, 1H), 1.91 (dd, J = 12.7, 11.4 Hz, 1H), 1.74−1.59 (m, 1H), 1.50 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.7, 169.4, 143.9, 131.2, 130.1, 127.6, 124.7, 119.1, 70.9, 69.6, 61.5, 61.0, 57.0, 55.8, 35.3, 28.6, 23.3, 20.7, 20.7, 14.3, 14.2. HRMS (ESI) m/z: [M + H]+ calcd for [C21H28N2O4H]+: 373.2127, found: 373.2114. rel-Diethyl (1S,2S,2aS,4aR)-2a,7-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (6bi). Rf = 0.44 in Hexane/EtOAc = 3:1. Yield 17% (11 mg). 1H NMR (500 MHz, CDCl3) δ 6.87 (s, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 4.92 (d, J = 9.3 Hz, 1H), 4.20−4.12 (m, 2H), 3.97 (dq, J = 10.8, 7.1 Hz, 1H), 3.89 (dq, J = 10.8, 7.1 Hz, 1H), 3.61 (d, J = 9.3 Hz, 1H), 3.49−3.40(m, 1H), 2.75−2.72 (m, 2H), 2.36 (apptd, J = 12.3, 6.9 Hz, 1H), 2.23 (s, 3H), 2.03−1.96 (m, 1H), 1.87 (dd, J = 13.0, 6.7 Hz, 1H), 1.57−1.49 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.0, 170.1, 140.8, 130.3, 130.1, 126.5, 126.1, 119.2, 68.8, 68.0, 60.7, 60.7, 60.1, 55.8, 35.5, 35.1, 32.4, 28.9, 20.7, 14.1, 13.7. HRMS (ESI) m/z: [M + H]+ calcd for [C21H28N2O4H]+: 373.2127, found: 373.2107. rel-Diethyl (1S,2S,2aR,4aR)-7-Chloro-2a-methyl-2,2a,3,4,4a,5hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5ci). Rf = 0.36 in Hexane/EtOAc = 3:1. Yield 70% (49 mg). 1H NMR (500 MHz, CDCl3) δ 7.06−7.00 (m, 2H), 6.73−6.68 (m, 1H), 4.38 (dq, J = 10.8, 7.2 Hz, 1H), 4.29 (dq, J = 10.8, 7.2 Hz, 1H), 4.25−4.08 (m, 3H), 3.64 (d, J = 11.3 Hz, 1H), 2.83 (dd, J = 15.3, 3.5 Hz, 1H), 2.77 (dd, J = 15.3, 10.3 Hz, 1H), 2.62−2.53 (m, 1H), 2.37 (appdt, J = 13.7, 9.3 Hz, 1H), 2.20−2.12 (m, 1H), 1.96−1.88 (m, 1H), 1.73−1.61 (m, 1H), 1.50 (s, J = 7.1 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.3, 169.1, 144.8, 129.3, 126.9, 126.7, 126.5, 120.0, 70.9, 69.4, 61.6, 61.1, 56.9, 55.7, 35.5, 35.3, 28.5, 23.2, 14.3, 14.1. HRMS (ESI) m/z: [M + H]+ calcd for [C20H25 ClN2O4H]+: 393.1581, found: 393.1578. rel-Diethyl (1S,2S,2aS,4aR)-7-Chloro-2a-methyl-2,2a,3,4,4a,5hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (6ci). Rf = 0.51 in Hexane/EtOAc = 3:1. Yield 14% (10 mg). 1H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 2.4 Hz, 1H), 7.02

formed represent the endo and exo approach of the dienophile from the convex face of the dipole. The ratios of the diastereomers formed in these reactions are suspect because the product with the ketone oriented trans to the adjacent methyl group epimerized to give the other diastereomer upon standing at room temperature. Finally, we carried out this reaction with dimethyl acetylene dicarboxylate (vi). This doubly activated alkyne dipolarophile reacted smoothly under optimized conditions to give the desired cycloaddition products in excellent yields (86−99%) as a mixture of diastereomers. In most of these reactions (entries 5.1−5.3), the selectivity for convex vs concave approach of the dipolarophile was low, with a slight preference for convex face approach. However, incorporating a methyl substituent at the ortho-position of the azomethine imine again changed the selectivity and preferentially gave the product derived from approach of the dipolarophile from the concave face of the dipole (entry 5.4). In summary, the polycyclic tetrahydrocinnoline structures formed by intramolecular [4 + 2]-cycloaddition of heteroallene salts contain an N-aminoiminium motif that gives the corresponding azomethine imines when treated with base. These tricyclic azomethine imines readily participate in 1,3dipolar cycloaddition reactions with activated dipolarophiles to give structurally complex products typically as a mixture of two diastereomers. The major diastereomer is generally formed by reaction of the dipolarophile with the convex face of the dipole, but steric interactions between the dipolarophile and an ortho substituent on the aryl ring can cause the dipolarophile to approach from the concave face of the dipole. The azomethine imines generated in this sequence are uncommon in that they have the C−N and N−N bonds incorporated into two different rings. This two-step sequence of cycloadditions ([4 + 2] then [3 + 2]) results in a significant increase in structural complexity, giving tetracyclic products that have a fairly rigid architecture.

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EXPERIMENTAL SECTION

General Experimental Details. All reactions were performed under an atmosphere of nitrogen in flame-dried glassware. Solvents were removed in vacuo using a rotary evaporator attached to a selfcleaning dry vacuum pump, and samples were further dried under reduced pressure on a high vacuum line. Acetonitrile (HPLC grade) was dried via a solvent dispensing system. Triethylamine was freshly distilled from CaH2 before use. Reactions were warmed to 55 °C by immersion in an oil bath. Silica gel flash column chromatography was performed using 230−400 mesh silica gel, and TLC analysis was carried out using silica on glass plates. Visualization of TLC plates was achieved using ultraviolet light, polyphosphomolybdic acid and cerium sulfate in EtOH with H2SO4, ceric ammonium molybdate, or iodine. 1 H and 13C NMR data were collected at room temperature on a 500 MHz spectrometer in CDCl3 or CD3CN. 1H NMR chemical shifts are reported in ppm (δ units) downfield from tetramethylsilane. Solvent peaks were used as internal references for all 13C NMR. Accurate mass data were acquired in ESI mode using an orbitrap mass analyzer. Representative Experimental Procedure for the Cycloaddition Reactions. A solution of protonated azomethine amine salt 2a (60 mg, 0.178 mmol, 1 equiv) in acetonitrile (7 mL) was warmed to 55 °C under a nitrogen atmosphere. Diethyl maleate (i, 37 mg, 0.035 mL, 0.21 mmol, 1.2 equiv) and triethylamine (23 mg, 0.032 mL, 0.23 mmol, 1.3 equiv) were added sequentially in a dropwise manner. After 2 h, the reaction was cooled to room temperature; the solvent was removed by rotary evaporation, and the residue was purified by silica gel flash chromatography to give 5ai (47 mg, 74% yield) and 6ai (10 mg, 16% yield). Reactions involving maleic anhydride (iv) were conducted at room temperature for 12 h. 6205

DOI: 10.1021/acs.joc.8b00683 J. Org. Chem. 2018, 83, 6202−6209

Note

The Journal of Organic Chemistry

m/z: [M + H]+ calcd for [C19H24 N2O4H]+: 345.1814, found: 345.1796. rel-Dimethyl (1S,2S,2aS,4aR)-2a,7-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (6bii). Rf = 0.43 in Hexane/EtOAc = 3:1. Yield 9% (5 mg). 1 H NMR (500 MHz, CDCl3) δ 6.88 (s, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 4.96 (d, J = 9.7 Hz, 1H), 3.71 (s, 3H), 3.66 (d, J = 9.7 Hz, 1H), 3.56−3.40 (m, 1H), 3.50 (s, 3H), 2.79 (dd, J = 15.0, 3.4 Hz, 1H) 2.73 (dd, J = 15.0, 10.5 Hz, 1H), 2.29−2.15 (m, 1H), 2.23 (s, 3H), 2.01 (m, 1H), 1.84 (dd, J = 13.0, 6.8 Hz, 1H), 1.62−1.44 (m, 1H), 1.52 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.5, 170.9, 141.0, 130.5, 130.2, 126.8, 126.2, 118.8, 69.3, 68.0, 60.6, 55.9, 52.0, 52.0, 35.5, 35.3, 32.4, 29.1, 20.9. HRMS (ESI) m/z: [M + H]+ calcd for [C19H24 N2O4H]+: 345.1814, found: 345.1798. rel-Dimethyl (1S,2S,2aR,4aR)-7-Chloro-2a-methyl-2,2a,3,4,4a,5hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5cii). Rf = 0.26 in Hexane/EtOAc = 3:1. Yield 71% (46 mg). 1H NMR (500 MHz, CDCl3) δ 7.06 (m, 2H), 6.74−6.55 (m, 1H), 4.28 (d, J = 11.3 Hz, 1H), 3.90 (s, 3H), 3.74 (s, 3H), 3.69 (d, J = 11.3 Hz, 1H), 2.85 (dd, J = 15.3, 3.4 Hz, 1H), 2.79 (dd, J = 15.3, 10.2 Hz, 1H), 2.65−2.52 (m, 1H), 2.38 (dt, J = 13.7, 9.3 Hz, 1H), 2.22− 2.09 (m, 1H), 1.95 (ddd, J = 13.6, 10.5, 1.4 Hz, 1H), 1.76−1.62 (m, 1H), 1.49 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.9, 169.7, 144.7, 129.4, 127.0, 126.6, 120.1, 71.0, 69.3, 57.0, 55.8, 52.8, 52.3, 35.5, 35.3, 28.6, 23.3. HRMS (ESI) m/z: [M + H]+ calcd for [C18H21Cl N2O4H]+: 365.1268, found: 365.1261. rel-Dimethyl (1S,2S,2aS,4aR)-7-Chloro-2a-methyl-2,2a,3,4,4a,5hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (6cii). Rf = 0.48 in Hexane/EtOAc = 3:1. Yield 11% (7 mg). 1H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 2.5 Hz, 1H), 7.02 (dd, J = 8.5, 2.5 Hz, 1H) 6.74 (d, J = 8.5 Hz, 1H), 4.96 (d, J = 9.7 Hz, 1H), 3.71 (s, 3H), 3.67 (d, J = 9.7 Hz, 1H), 3.52 (s, 3H), 3.49−3.42 (m, 1H), 2.82 (dd, J = 15.1, 3.4 Hz, 1H), 2.76 (dd, J = 15.1, 10.3 Hz, 1H), 2.26−2.17 (m, 1H), 2.06−1.99 (m, 1H), 1.86 (dd, J = 13.3, 7.4 Hz, 1H), 1.58−1.52 (m, 1H), 1.52 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.2, 170.7, 142.3, 129.8, 128.2, 126.2, 126.0, 120.0, 69.5, 68.0, 60.6, 55.6, 52.2, 35.6, 35.4, 32.3, 29.1. HRMS (ESI) m/z: [M + H]+ calcd for [C18H21Cl N2O4H]+: 365.1268, found: 365.1267. rel-Dimethyl (1S,2S,2aR,4aR)-2a,9-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5dii). Rf = 0.23 in Hexane/EtOAc = 3:1. Yield 8% (5 mg). 1 H NMR (500 MHz, CDCl3) δ 6.97 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.88 (t, J = 7.3 Hz, 1H), 4.25 (d, J = 11.0 Hz, 1H), 3.79 (s, 3H), 3.76−3.69 (m, 4H), 2.99−2.91 (m, 1H), 2.84−2.69 (m, 2H), 2.43−2.33 (m, 1H), 2.20 (s, 3H), 2.18−2.10 (m, 1H), 1.87 (ddd, J = 13.3, 11.0, 2.0 Hz, 1H), 1.70−1.55 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 172.4, 170.0, 144.9, 130.9, 130.1, 127.6, 126.7, 123.0, 77.1, 70.8, 68.0, 56.5, 52.1, 52.0, 35.8, 34.3, 28.1, 22.6, 19.8. HRMS (ESI) m/z: [M + H]+ calcd for [C19H24 N2O4H]+: 345.1814, found: 345.1808. rel-Dimethyl (1S,2S,2aS,4aR)-2a,9-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (6dii). Rf = 0.40 in Hexane/EtOAc = 3:1. Yield 49% (30 mg). 1 H NMR (500 MHz, CDCl3) δ 6.96 (d, J = 7.4 Hz, 1H), 6.91 (d, J = 7.0 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 5.01 (d, J = 10.2 Hz, 1H), 3.71 (s, 3H), 3.66 (d, J = 10.2 Hz, 1H), 3.44 (s, 3H), 3.44−3.36 (m, 1H), 2.97 (dd, J = 15.3, 3.5 Hz, 1H), 2.75 (dd, J = 15.3, 11.0 Hz, 1H), 2.20 (s, 3H), 2.16−2.07 (m, 1H), 2.06−1.96 (m, 1H), 1.88 (dd, J = 13.4, 8.4 Hz, 1H), 1.54 (s, 3H), 1.55−1.45 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 171.5, 171.4, 142.0, 128.4, 128.2, 127.5, 127.4, 122.4, 77.1, 69.0, 66.1, 61.1, 55.5, 52.0, 35.4, 34.3, 31.6, 29.2, 19.4. HRMS (ESI) m/z: [M + H]+ calcd for [C19H24 N2O4H]+: 345.1814, found: 345.1811. rel-Dimethyl (1R,2S,2aR,4aR)-2a-Methyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5aiii-1). Rf = 0.56 in Hexane/EtOAc = 3:1. Yield 43% (25.5 mg). 1 H NMR (500 MHz, CDCl3) δ 7.07−7.01 (m, 2H), 6.83 (td, J = 7.4, 1.1 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.12 (d, J = 8.9 Hz, 1H), 3.77 (s, 3H), 3.63 (d, J = 9.0 Hz, 1H), 3.47 (s, 3H), 3.24−3.14 (m, 1H), 2.92 (dd, J = 15.2, 3.2 Hz, 1H), 2.74 (dd, J = 15.2, 10.8 Hz, 1H), 2.43 (dt, J = 13.6, 9.3 Hz, 1H), 2.23−2.14 (m, 1H), 1.92 (ddd, J = 13.5, 10.4, 1.2

(dd, J = 8.6, 2.4 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.93 (d, J = 9.4 Hz, 1H), 4.20−4.13 (m, 2H), 4.02−3.87 (m, 2H), 3.62 (d, J = 9.4 Hz, 1H), 3.45−3.38 (m, 1H), 2.82−2.71 (m, 2H), 2.40−2.30 (m, 1H), 2.02 (ddd, J = 11.4, 6.8, 4.5 Hz, 1H), 1.88 (dd, J = 13.0, 6.7 Hz, 1H), 1.57−1.48 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 170.8, 170.1, 142.2, 129.7, 128.2, 125.9, 125.9, 120.5, 69.1, 68.0, 61.1, 61.0, 60.2, 55.6, 35.6, 35.4, 32.4, 29.0, 14.3, 13.9. HRMS (ESI) m/z: [M + H]+ calcd for [C20H25 ClN2O4H]+: 393.1581, found: 393.1578. rel-Diethyl (1S,2S,2aR,4aR)-2a,9-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5di). Rf = 0.44 in Hexane/EtOAc = 3:1. Yield 11% (7 mg). 1H NMR (500 MHz, CDCl3) δ 7.02−6.77 (m, 3H), 4.35−4.05 (m, 5H), 3.73 (d, J = 11.0 Hz, 1H), 3.02−2.91 (m, 1H), 2.85−2.71 (m, 2H), 2.41 (ddd, J = 13.5, 9.7, 8.8 Hz, 1H), 2.23 (s, 3H), 2.20−2.08 (m, 1H), 1.87 (ddd, J = 13.3, 11.0, 2.0 Hz, 1H), 1.72−1.59 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.9, 169.4, 144.9, 131.0, 130.1, 127.6, 126.7, 122.9, 70.7, 68.3, 61.20, 61.0, 56.5, 56.5, 35.9, 34.4, 28.2, 22.6, 19.9, 14.3, 13.9. HRMS (ESI) m/z: [M + H]+ calcd for [C21H28N2O4H]+: 373.2127, found: 373.2122. rel-Diethyl (1S,2S,2aS,4aR)-2a,9-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (6di). Rf = 0.63 in Hexane/EtOAc = 3:1. Yield 53% (35 mg). 1H NMR (500 MHz, cdcl3) δ 6.94 (d, J = 7.4 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.84 (appt, J = 7.4 Hz, 1H), 4.99 (d, J = 9.8 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.95−3.87 (m, 1H), 3.86−3.78 (m, 1H), 3.61 (d, J = 9.8 Hz, 1H), 3.45−3.33 (m, 1H), 2.92 (dd, J = 15.3, 3.4 Hz, 1H), 2.75 (dd, J = 15.2, 11.1 Hz, 1H), 2.36−2.25 (m, 1H), 2.23 (s, 3H), 2.05− 1.94 (m, 1H), 1.89 (dd, J = 13.4, 7.9 Hz, 1H), 1.56−1.43 (m, 1H), 1.54 (s, 3H) 1.27 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.1 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 171.2, 170.9, 142.2, 128.7, 128.2, 127.5, 127.4, 122.3, 68.6, 66.2, 60.9, 60.8, 60.7, 55.6, 35.5, 34.4, 31.8, 29.1, 19.5, 14.3, 13.7. HRMS (ESI) m/z: [M + H] + calcd for [C21H28N2O4H]+: 373.2127, found: 373.2118. rel-Dimethyl (1S,2S,2aR,4aR)-2a-Methyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5aii). Rf = 0.22 in Hexane/EtOAc = 3:1. Yield 77% (45 mg). 1H NMR (500 MHz, CDCl3) δ 7.08 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H),, 6.89 (td, J = 7.5, 1.1 Hz, 1H), 6.77−6.70 (d, J = 8.0 Hz, 1H), 4.31 (d, J = 11.3 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.67 (d, J = 11.3 Hz, 1H), 2.87 (dd, J = 15.1, 3.4 Hz, 1H), 2.80 (dd, J = 15.1, 10.4 Hz, 1H), 2.65−2.54 (m, 1H), 2.36 (dt, J = 13.6, 9.3 Hz, 1H), 2.20−2.09 (m, 1H), 1.92 (ddd, J = 13.5, 10.5, 1.4 Hz, 1H), 1.75−163 (m, 1H), 1.48 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.1, 169.9, 146.0, 129.7, 126.8, 124.7, 121.8, 118.9, 71.0, 69.3, 56.9, 56.0, 52.6, 52.1, 35.4, 35.3, 28.6, 23.3. HRMS (ESI) m/z: [M + H]+ calcd for [C18H22 N2O4H]+: 331.1658, found: 331.1653. rel-Dimethyl (1S,2S,2aS,4aR)-2a-Methyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (6aii). Rf = 0.41 in Hexane/EtOAc = 3:1. Yield 15% (9 mg). 1H NMR (500 MHz, CDCl3) δ 7.10−7.02 (m, 2H), 6.85−6.80 (m, 2H), 5.00 (d, J = 9.7 Hz, 1H), 3.71 (s, 3H), 3.68 (d, J = 9.7 Hz, 1H), 3.55− 3.46 (m, 1H), 3.50 (s, 3H), 2.84 (dd, J = 14.9, 3.9 Hz, 1H), 2.78 (dd, J = 14.9, 10.3 Hz, 1H), 2.28−2.19 (m, 1H), 2.03 (ddd, J = 11.4, 6.8, 4.4 Hz, 1H), 1.86 (dd, J = 13.0, 6.7 Hz, 1H), 1.59−1.48 (m, 1H), 1.53 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.3, 170.8, 143.5, 130.1, 126.3, 126.0, 121.1, 118.9, 69.3, 68.0, 60.5, 55.9, 52.1, 52.0, 35.6, 35.4, 32.4, 29.2. HRMS (ESI) m/z: [M + H]+ calcd for [C18H22 N2O4H]+: 331.1658, found: 331.1656. rel-Dimethyl (1S,2S,2aR,4aR)-2a,7-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5bii). Rf = 0.23 in Hexane/EtOAc = 3:1. Yield 69% (42 mg). 1 H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 8.1 Hz, 1H) 6.87 (s, 1H), 6.66 (d, J = 8.1 Hz, 1H), 4.25 (d, J = 11.4 Hz, 1H), 3.88 (s, 3H), 3.72 (s, 3H), 3.67 (d, J = 11.4 Hz, 1H), 2.82 (dd, J = 15.1, 3.6 Hz, 1H), 2.76 (d, J = 15.1, 10.3 Hz, 1H), 2.65−2.54 (m, 1H), 2.35 (dt, J = 13.7, 9.3 Hz, 1H), 2.24 (s, 3H), 2.18−2.09 (m, 1H), 1.91 (ddd, J = 13.5, 10.6, 1.4 Hz, 1H), 1.72−1.60 (m, 1H), 1.47 (s, 3H).13C NMR (126 MHz, CDCl3) δ 172.2, 170.0, 143.8, 131.3, 130.1, 127.6, 124.7, 119.0, 71.0, 69.4, 57.0, 55.9, 52.6, 52.1, 35.3, 35.3, 28.5, 23.3, 20.7. HRMS (ESI) 6206

DOI: 10.1021/acs.joc.8b00683 J. Org. Chem. 2018, 83, 6202−6209

Note

The Journal of Organic Chemistry Hz, 1H), 1.67−1.56 (m, 1H), 1.32 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.7, 171.1, 143.3, 129.9, 125.9, 125.4, 121.5, 119.0, 70.5, 69.6, 59.8, 55.3, 52.3, 52.3, 35.1, 34.8, 28.8, 22.8. HRMS (ESI) m/z: [M + H]+ calcd for [C18H22N2O4H]+: 331.1658, found: 331.1651. rel-Dimethyl (1S,2R,2aR,4aR)-2a-Methyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5aiii-2). Rf = 0.41 in Hexane/EtOAc = 3:1. Yield 36% (21 mg). 1 H NMR (500 MHz, CDCl3) δ 7.11−7.05 (m, 2H), 6.96 (td, J = 7.4, 1.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 4.59 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.36 (d, J = 8.0 Hz, 1H), 3.08−3.00 (m, 1H), 2.86 (dd, J = 15.3, 3.2 Hz, 1H), 2.76 (dd, J = 15.3, 10.9 Hz, 1H), 2.03−1.94 (m, 1H), 1.90−1.79 (m, 2H), 1.61 (s, 3H), 1.58−1.50 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 172.7, 172.6, 145.5, 130.0, 126.6, 126.4, 123.2, 121.1, 70.7, 70.2, 63.7, 53.7, 52.7, 52.3, 35.1, 33.7, 30.9, 28.4. HRMS (ESI) m/z: [M + H]+ calcd for [C18H22N2O4H]+: 331.1658, found: 331.1649. rel-Dimethyl (1R,2S,2aR,4aR)-2a,7-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a 1 ,9b-diazapentaleno[1,6-ab]naphthalene-1,2dicarboxylate(5biii-1). Rf = 0.49 in Hexane/EtOAc = 3:1. Yield 35% (21.5 mg). 1H NMR (500 MHz, CDCl3) δ 6.85 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.09 (d, J = 8.9 Hz, 1H), 3.76 (s, 3H), 3.62 (d, J = 8.9 Hz, 1H), 3.48 (s, 3H), 3.19 (tdd, J = 11.1, 5.3, 3.4 Hz, 1H), 2.86 (dd, J = 15.2, 3.2 Hz, 1H), 2.69 (dd, J = 15.2, 10.8 Hz, 1H), 2.42 (dt, J = 13.6, 9.3 Hz, 1H), 2.22 (s, 3H), 2.20−2.14 (m, 1H), 1.91 (ddd, J = 13.5, 10.4, 1.3 Hz, 1H), 1.66−1.55 (m, 1H), 1.31 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.8, 171.2, 140.9, 130.7, 130.3, 126.7, 125.2, 118.9, 70.5, 69.6, 59.8, 55.3, 52.3, 52.3, 35.0, 34.8, 28.8, 22.8, 20.8. HRMS (ESI) m/z: [M + H]+ calcd for [C19H24N2O4H]+: 345.1814, found: 345.1808. rel-Dimethyl (1S,2R,2aR,4aR)-2a,7-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5biii-2). Rf = 0.35 in Hexane/EtOAc = 3:1. Yield 32% (20 mg). 1H NMR (500 MHz, CDCl3) δ 6.90 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 4.53 (d, J = 8.3 Hz, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.36 (d, J = 8.3 Hz, 1H), 3.04 (tdd, J = 11.1, 4.8, 3.5 Hz, 1H), 2.81 (dd, J = 15.3, 3.3 Hz, 1H), 2.71 (dd, J = 15.2, 10.9 Hz, 1H), 2.25 (s, 3H), 2.01−1.94 (m, 1H), 1.89−1.78 (m, 2H), 1.60 (s, 3H), 1.58−1.48 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 172.7, 172.6, 143.0, 132.7, 130.4, 127.2, 126.5, 121.2, 70.6, 70.3, 63.8, 53.6, 52.6, 52.3, 34.9, 33.7, 30.9, 28.3, 20.8. HRMS (ESI) m/z: [M + H]+ calcd for [C19H24N2O4H]+: 345.1814, found: 345.1805. rel-Dimethyl (1R,2S,2aR,4aR)-7-Chloro-2a-methyl-2,2a,3,4,4a,5hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5ciii-1). Rf = 0.37 in Hexane/EtOAc = 3:1. Yield 43% (28 mg). 1H NMR (500 MHz, CDCl3) δ 7.05 (d, J = 2.3 Hz, 1H) 7.01 (dd, J = 8.6, 2.3 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 5.09 (d, J = 8.9 Hz, 1H), 3.77 (s, 3H), 3.62 (d, J = 8.9 Hz, 1H), 3.51 (s, 3H), 3.16 (tdd, J = 11.1, 5.3, 3.3 Hz, 1H), 2.89 (dd, J = 15.4, 3.2 Hz, 1H), 2.71 (dd, J = 15.4, 10.8 Hz, 1H), 2.43 (dt, J = 13.7, 9.3 Hz, 1H), 2.23−2.15 (m, 1H), 1.93 (ddd, J = 13.6, 10.4, 1.2 Hz, 1H), 1.68−1.50 (m, 1H), 1.30 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.4, 170.9, 142.0, 129.6, 127.2, 126.4, 126.1, 120.0, 70.5, 69.6, 59.9, 54.9, 52.4, 52.4, 35.0, 34.9, 28.7, 22.8. HRMS (ESI) m/z: [M + H]+ calcd for [C18H21ClN2O4H]+: 365.1268, found: 365.1266. rel-Dimethyl (1S,2R,2aR,4aR)-7-Chloro-2a-methyl-2,2a,3,4,4a,5hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5ciii-2). Rf = 0.32 in Hexane/EtOAc = 3:1. Yield 39% (19 mg). 1H NMR (500 MHz, CDCl3) δ 7.08 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.7, 2.4 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 4.55 (d, J = 7.9 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.35 (d, J = 7.9 Hz, 1H), 3.01 (tdd, J = 11.1, 4.9, 3.4 Hz, 1H), 2.83 (dd, J = 15.5, 3.2 Hz, 1H), 2.73 (dd, J = 15.4, 10.9 Hz, 1H), 2.03−1.95 (m, 1H), 1.91−1.80 (m, 2H), 1.59 (s, 3H), 1.58−1.47 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 172.6, 172.4, 144.2, 129.6, 128.5, 128.3, 126.6, 122.2, 70.7, 70.3, 63.6, 53.4, 52.8, 52.4, 35.0, 33.6, 30.8, 28.2. HRMS (ESI) m/z: [M + H]+ calcd for [C18H21ClN2O4H]+: 365.1268, found: 365.1248. rel-Dimethyl (1R,2S,2aR,4aR)-2a,9-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (5diii-1). Rf = 0.5 in Hexane/EtOAc = 3:1. Yield 73% (45 mg). 1H NMR (500 MHz, CDCl3) δ 6.94−6.90 (m, 2H), 6.84 (t, J = 7.5 Hz, 1H), 5.09 (d, J = 8.3 Hz, 1H), 3.78 (s, 3H), 3.69 (d, J = 8.3 Hz,

1H), 3.39 (s, 3H), 3.38−3.31 (m, 1H), 3.00 (dd, J = 15.5, 3.6 Hz, 1H), 2.71 (dd, J = 15.4, 11.1 Hz, 1H), 2.42 (dt, J = 13.6, 9.3 Hz, 1H), 2.30 (s, 3H), 2.22−2.12 (m, 1H), 1.94−1.87 (m, 1H), 1.67−1.51 (m, 1H), 1.34 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.9, 171.4, 141.7, 129.8, 128.3, 127.2, 126.7, 122.9, 70.3, 68.1, 60.1, 54.9, 52.3, 52.3, 35.0, 34.6, 28.6, 22.5, 18.9. HRMS (ESI) m/z: [M + H]+ calcd for [C19H24 N2O4H]+: 345.1814, found: 345.1798. rel-(3aS,3bR,5aR,10cS)-3b-Methyl-3a,4,5,5a,6,10c-hexahydro3H-2-oxa-3b 1 ,10b-diazacyclopenta[2,3]pentaleno[1,6-ab]naphthalene-1,3(3bH)-dione (5aiv). Yield 99% (50 mg). 1H NMR (500 MHz, CDCl3) δ 7.62 (dd, J = 8.1, 0.8 Hz, 1H), 7.27−7.22 (m, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.03 (td, J = 7.5, 1.1 Hz, 1H), 4.68 (d, J = 10.0 Hz, 1H), 3.79 (d, J = 10.0 Hz, 1H), 2.92 (dd, J = 15.4, 3.2 Hz, 1H), 2.81 (dd, J = 15.4, 10.8 Hz, 1H), 2.57 (tdd, J = 11.0, 5.5, 3.3 Hz, 1H), 2.38 (dt, J = 13.8, 9.3 Hz, 1H), 2.27−2.19 (m, 1H), 2.11−2.03 (m, 1H), 1.76−1.65 (m, 1H), 1.47 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.2, 168.5, 145.2, 129.4, 127.3, 125.0, 123.5, 121.4, 71.7, 70.9, 57.4, 56.0, 35.7, 34.7, 28.3, 22.5. HRMS (ESI) m/z: [M + H]+ calcd for [C16H16N2O3H]+: 285.1239, found: 285.1226. rel-(3aS,3bR,5aR,10cS)-3b,8-Dimethyl-3a,4,5,5a,6,10c-hexahydro-3H-2-oxa-3b 1 ,10b-diazacyclopenta[2,3]pentaleno[1,6-ab]naphthalene-1,3(3bH)-dione (5biv). Yield 99% (53 mg). 1H NMR (500 MHz, DMSO) δ 7.31 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.93 (s, 1H), 4.76 (d, J = 9.7 Hz, 1H), 4.14 (d, J = 9.8 Hz, 1H), 2.82 (d, J = 12.7 Hz, 1H), 2.67−2.53 (m, 2H), 2.34 (dt, J = 13.3, 9.2 Hz, 1H), 2.23 (s, 3H), 2.13 (ddd, J = 10.5, 9.3, 5.6 Hz, 1H), 1.87 (dd, J = 12.2, 10.3 Hz, 1H), 1.56−1.45 (m, 1H), 1.25 (s, 3H). 13C NMR (126 MHz, DMSO) δ 172.0, 169.9, 143.5, 131.4, 129.7, 127.4, 125.1, 120.2, 71.9, 70.3, 57.3, 54.8, 34.8, 34.1, 27.9, 22.3, 20.2. HRMS (ESI) m/z: [M + H]+ calcd for [C17H18N2O3H]+: 299.1396, found: 299.1397. rel-(3aS,3bR,5aR,10cS)-8-Chloro-3b-methyl-3a,4,5,5a,6,10c-hexahydro-3H-2-oxa-3b1,10b-diazacyclopenta[2,3]pentaleno[1,6-ab]naphthalene-1,3(3bH)-dione (5civ). Yield 99% (56 mg). 1H NMR (500 MHz, DMSO) δ 7.41 (d, J = 8.7 Hz, 1H), 7.29 (dd, J = 8.7, 2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 4.86 (d, J = 9.8 Hz, 1H), 4.17 (d, J = 9.8 Hz, 1H), 2.95−2.85 (m, 1H), 2.67−2.57 (m, 2H), 2.36 (dt, J = 13.2, 9.3 Hz, 1H), 2.19−2.09 (m, 1H), 1.89 (dd, J = 12.3, 10.5 Hz, 1H), 1.57−1.45 (m, 1H), 1.25 (s, 3H). 13C NMR (126 MHz, DMSO) δ 171.9, 169.6, 144.7, 128.9, 127.6, 126.7, 126.4, 121.7, 71.8, 70.3, 57.3, 54.6, 34.9, 34.0, 27.9, 22.3. HRMS (ESI) m/z: [M + H]+ calcd for [C16H15ClN2O3H]+: 319.0849, found: 319.0859. rel-1-((2S,2aR,4aR)-2a-Methyl-2,2a,3,4,4a,5-hexahydro-1H2a1,9b-diazapentaleno[1,6-ab]naphthalen-2-yl)ethan-1-one (5av1). Rf = 0.44 in Hexane/EtOAc/Et3N = 70:30:1. Yield 55% (25 mg). 1H NMR (500 MHz, CDCl3) δ 7.12 (appt, J = 8.0, Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.86 (d J = 8.0 Hz, 1H), 6.83 (dd, J = 8.0, 7.5 Hz, 1H) 4.39 (dd, J = 8.6, 7.1 Hz, 1H), 3.45 (dt, J = 18.8, 10.1 Hz, 2H), 2.86 (dd, J = 15.0, 3.3 Hz, 1H), 2.79 (dd, J = 15.0, 10.3 Hz, 1H), 2.72− 2.65 (m, 1H), 2.42 (dt, J = 13.2, 9.3 Hz, 1H), 2.25 (s, 3H), 2.25−218 (m, 1H), 2.07−2.01 (m, 1H), 1.77−1.67 (m, 1H), 1.25 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 205.1, 147.2, 129.6, 126.6, 123.74, 120.4, 119.2, 70.15, 61.3, 55.4, 54.7, 36.0, 35.2, 30.6, 29.0, 23.2. HRMS (ESI) m/z: [M + H]+ calcd for [C16H20N2OH]+: 257.1654, found: 257.1651. rel-1-((2R,2aR,4aR)-2a-Methyl-2,2a,3,4,4a,5-hexahydro-1H2a1,9b-diazapentaleno[1,6-ab]naphthalen-2-yl)ethan-1-one (5av2). Rf = 0.44 in Hexane/EtOAc/Et3N = 70:30:1. Yield 43% (20 mg). 1H NMR (500 MHz, CDCl3) δ 7.12−7.03 (m, 2H), 6.95 (d, J = 7.8 Hz, 1H), 6.89 (t, J = 7.2 Hz, 1H), 3.70 (dt, J = 17.8, 9.9 Hz, 2H), 3.41 (dd, J = 10.4, 8.0 Hz, 1H), 2.95−2.86 (m, 1H), 2.80−2.74 (m, 2H), 2.22 (s, 3H), 2.02−1.94 (m, 1H), 1.82−1.75 (m, 2H), 1.63 (s, 3H), 1.61−1.50 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 206.7, 146.6, 129.7, 126.1, 125.9, 121.5, 121.0, 68.8, 64.8, 55.0, 52.0, 34.8, 34.0, 31.8, 31.3, 28.3. HRMS (ESI) m/z: [M + H]+ calcd for [C16H20N2OH]+: 257.1654, found: 257.1656. rel-1-((2S,2aR,4aR)-2a,7-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H2a1,9b-diazapentaleno[1,6-ab]naphthalen-2-yl)ethan-1-one (5bv1). Rf = 0.30 in Hexane/EtOAc/Et3N = 80:20:1. Yield 52% (25 mg). 1H NMR (500 MHz, CDCl3) δ 6.94 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.78 (d, J = 8.1 Hz, 1H), 4.35 (appt, J = 8.8 Hz, 1H), 3.49−3.43 (m, 1H), 3.35 (t, J = 9.9 Hz, 1H), 2.85−2.61 (m, 3H), 2.40 (dt, J = 6207

DOI: 10.1021/acs.joc.8b00683 J. Org. Chem. 2018, 83, 6202−6209

Note

The Journal of Organic Chemistry

53.2, 51.3, 37.6, 33.9, 27.7, 26.1, 20.9. HRMS (ESI) m/z: [M + H]+ calcd for [C19H22N2O4H]+: 343.1658, found: 343.1653. rel-Dimethyl (2aS,4aR)-2a,7-Dimethyl-2a,3,4a,5-tetrahydro-4H2a 1 ,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (8bvi). Rf = 0.18 in Hexane/EtOAc = 3:1. Yield 36% (22 mg). 1H NMR (500 MHz, CDCl3) δ 6.98−6.91 (m, 3H), 3.82 (s, 3H), 3.75− 3.69 (m, 1H), 3.69 (s, 3H), 3.12 (dd, J = 16.1, 7.6 Hz, 1H), 2.67 (dd, J = 16.0, 6.7 Hz, 1H), 2.47 (ddd, J = 12.9, 7.1, 2.6 Hz, 1H), 2.29 (s, 3H), 2.17−2.09 (m, 1H), 1.91 (ddd, J = 12.9, 11.1, 6.5 Hz, 1H), 1.77−1.67 (m, 1H), 1.58 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.3, 162.6, 144.3, 135.7, 134.8, 129.9, 128.7, 127.3, 119.4, 103.8, 75.8, 65.3, 53.0, 50.8, 39.1, 32.7, 30.8, 26.9, 21.0. HRMS (ESI) m/z: [M + H]+ calcd for [C19H22N2O4H]+: 343.1658, found: 343.1653. rel-Dimethyl (2aR,4aR)-7-Chloro-2a-methyl-2a,3,4a,5-tetrahydro-4H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (7cvi). Rf = 0.45 in Hexane/EtOAc = 3:1. Yield 60% (39 mg). 1H NMR (500 MHz, CDCl3) δ 7.15 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 3.86 (s, 3H), 3.73 (s, 3H), 3.07−2.99 (m, 1H), 2.95−2.88 (m, 2H), 2.49 (ddd, J = 13.4, 11.4, 8.4 Hz, 1H), 2.11 (dd, J = 13.5, 8.3 Hz, 1H), 1.97 (ddd, J = 12.3, 8.2, 4.5 Hz, 1H), 1.62−1.50 (m, 1H), 1.42 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.5, 162.8, 145.1, 136.9, 130.0, 129.7, 129.5, 126.9, 120.3, 111.2, 71.1, 62.1, 53.3, 51.5, 37.5, 33.9, 27.6, 26.0. HRMS (ESI) m/z: [M + H]+ calcd for [C18H19ClN2O4H]+: 363.1112, found: 363.1105. rel-Dimethyl (2aS,4aR)-7-Chloro-2a-methyl-2a,3,4a,5-tetrahydro-4H-2a1,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (8cvi). Rf = 0.27 in Hexane/EtOAc = 3:1. Yield 37% (24 mg). 1H NMR (500 MHz, CDCl3) δ 7.15 (d, J = 2.3 Hz, 1H), 7.10 (dd, J = 8.5, 2.3 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 3.84 (s, 3H), 3.75−3.71 (m, 1H), 3.70 (s, 3H), 3.16 (dd, J = 16.4, 7.7 Hz, 1H), 2.68 (dd, J = 16.3, 6.3 Hz, 1H), 2.47 (ddd, J = 13.0, 7.1, 2.4 Hz, 1H), 2.18−2.09 (m, 1H), 1.91 (ddd, J = 13.0, 11.2, 6.5 Hz, 1H), 1.77−1.65 (m, 1H), 1.59 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.2, 162.5, 143.8, 136.0, 131.6, 131.0, 128.3, 126.9, 120.6, 10.3, 76.1, 65.0, 53.3, 51.1, 39.4, 32.8, 30.6, 27.0. HRMS (ESI) m/z: [M + H]+ calcd for [C18H19ClN2O4H]+: 363.1112, found: 363.1106. rel-Dimethyl (2aR,4aR)-2a,9-Dimethyl-2a,3,4a,5-tetrahydro-4H2a 1 ,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (7dvi). Rf = 0.41 in Hexane/EtOAc = 3:1. Yield 12% (7 mg). 1H NMR (500 MHz, CDCl3) δ 7.06−6.89 (m, 3H), 3.78 (s, 3H), 3.73 (s, 3H), 3.25−3.14 (m, 1H), 3.03 (dd, J = 16.0, 3.7 Hz, 1H), 2.86 (dd, J = 16.0, 11.6 Hz, 1H), 2.48 (ddd, J = 13.6, 10.6, 9.1 Hz, 1H), 2.18 (s, 3H), 2.06−1.99 (m, 1H), 1.97−1.91 (m, 1H), 1.58−1.51 (m, 1H), 1.50 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.8, 162.7, 145.4, 137.3, 130.8, 129.4, 128.9, 127.4, 125.2, 112.8, 70.9, 61.2, 53.0, 51.4, 36.1, 34.1, 27.5, 24.9, 18.0. HRMS (ESI) m/z: [M + H]+ calcd for [C19H22N2O4H]+: 343.1658, found: 343.1655. rel-Dimethyl (2aS,4aR)-2a,9-Dimethyl-2a,3,4a,5-tetrahydro-4H2a 1 ,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (8dvi). Rf = 0.24 in Hexane/EtOAc = 3:1. Yield 74% (45 mg). 1H NMR (500 MHz, CDCl3) δ 7.12 (appt, J = 7.5 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 3.69 (s, 3H), 3.68−3.60 (m, 1H), 3.66 (s, 3H), 2.95 (dd, J = 14.5, 5.5 Hz, 1H), 2.81 (ddd, J = 12.9, 7.0, 1.8 Hz, 1H), 2.65 (dd, J = 14.3, 11.4 Hz, 1H), 2.32 (s, 3H), 2.24− 2.14 (m, 1H), 2.06−1.95 (m, 1H), 1.69−1.61 (m, 1H), 1.55 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 164.0, 162.5, 149.8, 137.7, 136.7, 134.6, 128.9, 128.1, 124.7, 107.2, 75.2, 67.9, 52.8, 51.1, 36.0, 34.7, 34.1, 24.4, 16.9. HRMS (ESI) m/z: [M + H]+ calcd for [C19H22N2O4H]+: 343.1658, found: 343.1656.

13.1, 9.3 Hz, 1H), 2.27−2.12 (m, 7H), 2.08−1.99 (m, 1H), 1.76−1.64 (m, 1H), 1.25 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 205.3, 144.9, 129.95, 129.9, 127.4, 123.8, 119.4, 70.2, 61.5, 55.6, 54.4, 35.9, 35.1, 30.6, 28.9, 23.2, 20.6. HRMS (ESI) m/z: [M + H]+ calcd for [C17H22N2OH]+: 271.1810, found: 271.1801. rel-1-((2R,2aR,4aR)-2a,7-Dimethyl-2,2a,3,4,4a,5-hexahydro-1H2a1,9b-diazapentaleno[1,6-ab]naphthalen-2-yl)ethan-1-one (5bv2). Rf = 0.31 in Hexane/EtOAc/Et3N = 80:20:1. Yield 31% (15 mg). 1H NMR (500 MHz, CDCl3) δ 6.90 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.84 (d, J = 8.1 Hz, 1H), 3.70−3.59 (m, 2H), 3.38 (dd, J = 10.4, 8.0 Hz, 1H), 2.94−2.86 (m, 1H), 2.74−2.70 (m, 2H), 2.25 (s, 3H), 2.20 (s, 3H), 1.99−1.93 (m, 1H), 1.80−1.74 (m, 2H), 1.61 (s, 3H), 1.58−1.48 (m, 1H).13C NMR (126 MHz, CDCl3) δ 207.2, 144.4, 131.2, 130.3, 127.1, 126.3, 121.2, 69.1, 65.3, 55.4, 52.2, 34.9, 34.3, 32.1, 31.7, 28.6, 20.8. HRMS (ESI) m/z: [M + H] + calcd for [C17H22N2OH]+: 271.1810, found: 271.1811. rel-1-((2S,2aR,4aR)-7-Chloro-2a-methyl-2,2a,3,4,4a,5-hexahydro1H-2a1,9b-diazapentaleno[1,6-ab]naphthalen-2-yl)ethan-1-one (5cv-1). Rf = 0.38 in Hexane/EtOAc/Et3N = 80:20:1. Yield 29% (15 mg). 1H NMR (500 MHz, CDCl3) δ 7.08 (dd, J = 8.6, 2.2 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.36 (dd, J = 9.5, 8.1 Hz, 1H), 3.46 (dd, J = 10.0, 8.2 Hz, 1H), 3.37 (t, J = 9.9 Hz, 1H), 2.83 (dd, J = 15.3, 3.4 Hz, 1H), 2.76 (dd, J = 15.3, 10.2 Hz, 1H), 2.69−2.59 (m, 1H), 2.42 (dt, J = 13.2, 9.3 Hz, 1H), 2.25 (s, 3H), 2.24−2.18 (m, 1H), 2.09−2.00 (m, 1H), 1.75−1.65 (m, 1H), 1.27−1.22 (m, 4H).13C NMR (126 MHz, CDCl3) δ 204.8, 145.8, 129.1, 126.7, 125.5, 125.3, 120.2, 70.2, 61.2, 55.7, 54.4, 35.9, 35.1, 30.6, 28.90, 23.1. HRMS (ESI) m/z: [M + H]+ calcd for [C16H19ClN2OH]+: 291.1264, found: 291.1259. rel-1-((2R,2aR,4aR)-7-Chloro-2a-methyl-2,2a,3,4,4a,5-hexahydro-1H-2a1,9b-diazapentaleno[1,6-ab]naphthalen-2-yl)ethan-1one (5cv-2). Rf = 0.32 in Hexane/EtOAc/Et3N = 80:20:1. Yield 48% (25 mg). 1H NMR (500 MHz, CDCl3) δ 7.09−7.03 (m, 2H), 6.86 (d, J = 9.2 Hz, 1H), 3.71−3.62 (m, 2H), 3.40 (dd, J = 10.3, 8.1 Hz, 1H), 2.90−2.80 (m, 1H), 2.77−2.73 (m, 2H), 2.22 (s, 3H), 2.03−1.95 (m, 1H), 1.84−1.74 (m, 2H), 1.62 (s, 3H), 1.60−1.49 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 206.9, 145.5, 129.5, 128.2, 126.8, 126.4, 122.4, 69.2, 65.1, 55.3, 52.0, 34.9, 34.2, 32.0, 31.6, 28.4. HRMS (ESI) m/z: [M + H]+ calcd for [C16H19ClN2OH]+: 291.1264, found: 291.1262. rel-Dimethyl (2aR,4aR)-2a-Methyl-2a,3,4a,5-tetrahydro-4H2a 1 ,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (7avi). Rf = 0.60 in Hexane/EtOAc = 3:1. Yield 63% (37 mg). 1H NMR (500 MHz, CDCl3) δ 7.15 (d, J = 7.6 Hz, 1H), 7.11 (td, J = 8.0, 1.4 Hz, 1H), 7.04 (td, J = 7.6, 1.4 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.12−3.04 (m, 1H), 2.97−2.89 (m, 2H), 2.49 (ddd, J = 13.4, 11.4, 8.4 Hz, 1H), 2.11 (dd, J = 13.4, 8.3 Hz, 1H), 2.00−1.93 (m, 1H), 1.65−1.48 (m, 1H), 1.43 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.7, 163.0, 145.3, 138.1, 130.2, 127.6, 126.7, 124.5, 119.1, 110.4, 71.0, 62.6, 53.2, 51.4, 37.6, 34.0, 27.7, 26.1. HRMS (ESI) m/z: [M + H]+ calcd for [C18H20N2O4H]+: 329.1501, found: 329.1501. rel-Dimethyl (2aS,4aR)-2a-Methyl-2a,3,4a,5-tetrahydro-4H2a 1 ,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (8avi). Rf = 0.38 in Hexane/EtOAc = 3:1. Yield 36% (21 mg). 1H NMR (500 MHz, CDCl3) δ 7.18−7.07 (m, 3H)), 7.04 (dd, J = 7.8, 1.5 Hz, 1H), 3.84 (s, 3H), 3.77−3.1(m, 1H), 3.70 (s, 3H), 3.19 (dd, J = 16.2, 7.8 Hz, 1H), 2.71 (dd, J = 16.2, 6.3 Hz, 1H), 2.47 (ddd, J = 12.9, 7.1, 2.5 Hz, 1H), 2.19−2.08 (m, 1H), 1.91 (ddd, J = 12.9, 11.2, 6.5 Hz, 1H), 1.79−1.69 (m, 1H), 1.60 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.4, 162.7, 144.0, 137.4, 129.8, 128.4, 126.8, 125.8, 119.4, 104.4, 76.0, 65.3, 53.2, 51.0, 39.5, 32.8, 30.7, 27.2. HRMS (ESI) m/z: [M + H]+ calcd for [C18H20N2O4H]+: 329.1501, found: 329.1504. rel-Dimethyl (2aR,4aR)-2a,7-Dimethyl-2a,3,4a,5-tetrahydro-4H2a 1 ,9b-diazapentaleno[1,6-ab]naphthalene-1,2-dicarboxylate (7bvi). Rf = 0.33 in Hexane/EtOAc = 3:1. Yield 54% (33 mg). 1H NMR (500 MHz, CDCl3) δ 6.95 (s, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H), 3.12−3.04 (m, 1H), 2.90−2.86 (m, 2H), 2.49 (ddd, J = 13.4, 11.4, 8.4 Hz, 1H), 2.27 (s, 3H), 2.09 (dd, J = 13.4, 8.1 Hz, 1H), 1.98−1.90 (m, 1H), 1.64− 1.51 (m, 1H), 1.42 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.8, 163.1, 145.5, 135.6, 134.1, 130.7, 127.4, 127.4, 118.9, 110.0, 70.9, 62.7,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00683. 1 H and 13C NMR spectra of all new compounds and Table S1: optimization of the 1,3-dipolar cycloaddition of the azomethine imine derived from 2a (PDF) 6208

DOI: 10.1021/acs.joc.8b00683 J. Org. Chem. 2018, 83, 6202−6209

Note

The Journal of Organic Chemistry

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Hydrohydrazination Approach. J. Org. Chem. 2013, 78 (17), 8847− 8852. (17) Snyder, J. P.; Heyman, M.; Gundestrup, M. Diazenium cations. 3. Formation and oxidation of a cis-trialkylhydrazine: cis-azomethinimines. J. Org. Chem. 1978, 43 (11), 2224−2231. (18) Bercovici, D. A.; Ogilvie, J. M.; Tsvetkov, N.; Brewer, M. Intramolecular Polar [4⊕+2] Cycloadditions of Aryl-1-aza-2-azoniaallene Salts: Unprecedented Reactivity Leading to Polycyclic Protonated Azomethine Imines. Angew. Chem., Int. Ed. 2013, 52 (50), 13338− 13341. (19) Dhakal, R. C.; Brewer, M. Intramolecular (4 + 2) cycloaddition of aryl-1-aza-2-azoniaallene salts: a practical approach to highly sterically-congested polycyclic protonated azomethine imines. Tetrahedron 2016, 72 (26), 3718−3728. (20) Le Fevre, G.; Sinbandhit, S.; Hamelin, J. Addition d’hydrazone aux oléfines en milieu acide: cycloaddition polaire cationique [3⊕ + 2]. Tetrahedron 1979, 35 (15), 1821−1824. (21) Breuer, E.; Melumad, D. Nuclear magnetic resonance spectra of cyclic amines. Shielding of.alpha. protons trans to a lone pair and cis to an N-methyl group in pyrrolidines. J. Org. Chem. 1973, 38 (8), 1601− 1602. (22) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. Origin of reactivity, regioselectivity, and periselectivity in 1,3-dipolar cycloadditions. J. Am. Chem. Soc. 1973, 95 (22), 7301−7315.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Ram Dhakal: 0000-0002-7618-0680 Matthias Brewer: 0000-0003-4250-7195 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. N. Tsvetkov for conducting a preliminary study in this area. We are grateful to the National Scientific Foundation for financial support of this research through Grant CHE-1362286. Mass spectrometry data was acquired by Bruce O’Rourke.

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REFERENCES

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DOI: 10.1021/acs.joc.8b00683 J. Org. Chem. 2018, 83, 6202−6209