Type 2 Intramolecular N-acylazo Diels-Alder Reaction: Regio- and Stereoselective Synthesis of Bridgehead Bicyclic 1,2-Diazines

Abstract

The type 2 intramolecular N-acylazo Diels-Alder reaction provides a regio- and stereoselective synthesis of bicyclic 1,2-diazine systems. A new method for the generation of N-acylazo dienophiles with tetra-n-butylammonium periodate is reported. X-ray crystallographic analysis allowed the quantification of structural distortions of the non-planar bridgehead olefin and lactam functionalities in 1,2-diazine cycloadducts 11 and 15. Synthesis of caprolactams and enantholactams were formed by stereoselective bridgehead alkene reduction, a process which transfers stereochemistry from the bridgehead lactam nitrogen to the bridgehead carbon. The sequence of transformations offers a convenient route for the diastereoselective synthesis of medium-ring nitrogen heterocycles and 1,4-diamines.

Introduction

Nitrogen-containing heterocycles are ubiquitious in nature. Their importance has led to an ongoing search for selective and efficient methods for their preparation.^1,2 The type 2 intramolecular Diels-Alder (T2IMDA) reaction has served as a useful reaction to assemble polycyclic compounds in a single step from acyclic precursors.³ In many cases, the reaction offers complete regio- and stereochemical control in the cycloaddition step. More recently, the heteroatom variants of the T2IMDA reaction with N-acylimine and N-acylnitroso dienophiles was employed for the synthesis of bridgehead bicyclic lactams and oxazinolactams (Scheme 1, eq 1,2).^3–5 As part of our ongoing interest in the synthesis of nitrogen-containing heterocyclic ring systems, we report T2IMDA reaction with N-acylazo dienophiles (Scheme 1, eq 3).

Scheme 1.

Examples of the hetero type 2 intramolecualr Diels-Alder reaction.

Despite numerous reports utilizing acyclic or cyclic azodicarboxylates as dienophiles in Diels-Alder⁶ reactions, there are relatively few examples of intramolecular variants⁷ of this reaction (Scheme 1). The development of the T2IMDA reaction with N-acylazo dienophiles would allow the rapid assembly of bridgehead bicyclic 1,2-diazines with regio- and stereochemical control. The intermediates would offer the potential for the synthesis of seven and eight membered nitrogen-containing heterocyclic ring systems as well as the stereoselective synthesis of 1,4-diamines.

Results and Discussion

Synthesis of the Diels-Alder precursors

The synthesis of T2IMDA reaction precursors began from the commercially available ethyl 4-bromobutyrate (1) (Scheme 2). The corresponding iodoester 3⁸ was prepared by halide exchange with NaI in acetone. In the presence of 3 mol% Li₂CuCl₄, the coupling reaction of iodoester 3⁸ with chloroprene Grignard (5)⁹ afforded ester 6.⁵ This synthetic sequence was subsequently applied to the synthesis of diene ester 7⁵ from commercially available ethyl 5-bromovalerate (2) in 66% overall yield. The acylation reaction of ester 6 or 7 with phenyl hydrazine and Al(CH₃)₃¹⁰ afforded hydrazides 8 and 9 in 75% yield and 84% yield, respectively (Scheme 2).

Scheme 2.

Synthesis of Hydrazides 8 and 9.

Type 2 Intramolecular N-acylazo Diels-Alder Reaction

Having established a viable route to the Diels-Alder precursors, we next examined oxidation conditions to form the N-acylazo dienophiles. The reactivity of the N-acylazo functional group towards thermal decomposition and cycloaddition was not known; therefore a search for mild reaction conditions was undertaken. Typically, N-acylazo dienophiles are generated by oxidation of N-acylhydrazides with tert-butylhypochlorite¹¹, lead tetraacetate¹², or potassium ferricyanide¹³. Oxidation of hydrazide 8 with Pb(OAc)₄ resulted in a complex mixture of products. The heterogenous oxidation of hydrazide 8 with K₃Fe(CN)₆ and catalytic 2,4,6-triphenylphenol (1 mol %) in 2N NaOH gave cycloadduct 11 in 65% yield. The oxidation presumably produced N-acylazo dienophile 10, which underwent intramolecular Diels-Alder cycloaddition under the reaction conditions. Despite the acceptable result, the harsh basic conditions limited the general utility of this method. Parallels in structure between hydroxamic acids and hydrazides suggested that n-Bu₄NIO₄, a reagent used to oxidize hydroxamic acids to the N-acyl nitroso⁵ intermediate, could be employed for the synthesis of N-acylazo derivatives (Scheme 1). Indeed, oxidation of N-acyl hydrazide 8 proceeded smoothly with 1.3 equiv of n-Bu₄NIO₄ in CH₂Cl₂, to form the N-acylazo Diels-Alder precursor 10. Subsequently, compound 10 underwent cycloaddition under these reaction conditions to afford bicyclic 1,2-diazine 11 in 90% yield (Scheme 3). Diels-Alder reactions carried out in water have displayed a significant rate acceleration.¹⁴ In the presence of 20 mol% of water in THF, cycloadduct 11 was obtained in 63% yield after 40 h. Interestingly, the oxidation of hydrazide 8 was completed after 5 h and was not inhibit by water; however, the slow rate of the cycloaddition allowed the decomposition of the N-acylazo intermediate 10.

Scheme 3.

Type 2 intramolecular Diels-Alder reaction with N-acylazo dienophiles 10.

To the best of our knowledge the oxidation reaction of hydrazides by this method is unprecedented. Intrigued by the oxidation of hydrazide 8 with n-Bu₄NIO₄, the generality of this reagent with other hydrazides was examined. Representative examples for this transformation are shown in Scheme 4.¹⁵ Subjecting hydrazides to 1.3 equiv n-Bu₄NIO₄ in CH₂Cl₂ afforded N-acylazo substrates in high yield. This method provides an alternative procedure for the oxidation of hydrazides and hydrazines.¹⁵ n-Bu₄NIO₄ exhibits functional group tolerance that is lacking in other reagents.

Scheme 4.

Oxidation reaction of hydrazides with n-Bu₄NIO₄.

Although oxidation and subsequent intramolecular cycloaddition reaction of hydrazide 8 was complete after 24 h (Scheme 3), the oxidation of hydrazide 9 followed by intramolecular Diels-Alder reaction of N-acylazo dienophile 14 proceeded slowly (Scheme 5). It was established by the ¹H-NMR spectrum of the reaction mixture that the periodate oxidation reaction of hydrazide 9 generated the N-acylazo dienophile species after 3 h. However, the cyclization step proceeded relatively slowly affording bicyclic 1,2-diazine 15 in only 55% yield after 60 h. Attempts to isolate the N-acylazo derivative 14 by chromatographic techniques (SiO₂, Al₂O₃ and deactivated SiO₂) were unsuccessful. This was attributed to instability of the N-acylazo dienophile 14. Efforts to accelerate the cycloaddition by heating the reaction mixture to 50 °C resulted in decomposition of the remaining N-acylazo intermediate. The presence of both 14 and 15 in the reaction mixture and the instability of intermediate 14 resulted in low isolated yields. These results suggested that the problem was not due to the oxidation step but rather the relative low stability and slow rate of cycloaddition of the N-acylazo dienophile 14.

Scheme 5.

Type 2 intramolecular Diels-Alder reaction of N-acylazo dienophile 14.

To overcome this problem a different set of conditions was required for the generation and isolation of N-acylazo derivative 14. Using a protocol described by Evans and coworkers,¹⁸ we found that treating hydrazide 9 with NBS and pyridine in CH₂Cl₂ for 2 h at 0–23°C resulted in N-acylazo dienophile 14 in 96% yield (Scheme 6). Under these reaction conditions cycloadduct 15 was not observed.

Scheme 6.

Oxidation reaction of hydrazide 9.

This result provided an opportunity to examine the cycloaddition reaction of N-acylazo dienophile 14 under both thermal and Lewis acid catalyzed conditions. Efforts to thermally induce cycloaddition are summarized in Table 1. N-acylazo dienophile 14 was found to be unstable at temperatures > 40 °C in benzene. At these elevated temperatures, the reaction generated a complex mixture of products; cycloadduct 15 was not observed. The best results were obtained at 40 °C, producing cycloadduct 15 in 58% yield.

Table 1.

T2IMDA reaction of N-acylazo dienophile 14.

entry	temp (°C)	time (h)	yield (%)
1	23	60	45–55
2	40	10	58
3	60	4	mixture
4	80	4	mixture

^aBenzene solvent

^bConcentration 0.010 M

The thermal route did not offer any improvement to the cycloaddition reaction of N-acylazo dienophile 14. We next turned our attention to Lewis acid catalysis. It was found that the cycloaddition of N-acylazo dienophile 14 proceeded smoothly in the presence of 10 mol % ZnCl₂ in CH₂Cl₂ after 5 h to afford cycloadduct 15 in 78% yield (Scheme 7). The two step protocol of oxidation and subsequent Lewis acid catalyzed cycloaddition proved to be the most efficient method for the synthesis of cycloadduct 15. Significantly, this result provides a new method for the Lewis acid-catalyzed Diels-Alder reaction of azo compounds, as the examples of Lewis acid catalyzed Diels-Alder reaction of azo compounds are limited in the literature.^6l,6m

Scheme 7.

Lewis acid catalyzed T2IMDA reaction of N-acylazo dienophile 14.

X-ray Crystallography of the Cycloadducts

X-ray crystallographic studies of cycloadducts diamines 11 and 15 reveal structural distortions from the optimal planar olefin and lactam geometry. These distortions are expressed as torsional deformation and are quantified by the angle τ, a value determined from the calculated projection of the two p-orbitals.^3–5 The p-orbital overlap in the π bond is presumed to be optimal with τ = 0.0° and lowest at τ = 90.0°. The torsion angle τ is not directly measured but can be calculated from the X-ray crystallographic data.¹⁹ Torsional distortions (τ) calculated for bridgehead olefins 11 and 15 are 5.48° and 3.65° respectively with a slightly larger value of τ for the smaller bridgehead alkene 11. Interestingly, the torsional distortion quantified in bridgehead olefins 11 and 15 has little effect on the observed C=C bond lengths. The double bond distances for bridgehead olefins 11 and 15 are 1.3339(15) Å and 1.3327(16) Å respectively, and are within error of the value for cyclohexene (1.335 (3) Å).⁵

Analysis of the amide linkage of 11 and 15 show significant differences in torsional deformation. For bridgehead lactam 11 the torsional distortion is τ = 0.745(10)° and for 15 τ = 17.56(13)° respectively. It is likely that the somewhat surprising inverse relationship between ring size and τ results from compression in accomodating the five atom bridge in cycloadduct 15. The absence of correlations between bridge size and torsional distortions was previously observed in a series of bridgehead lactams.⁴

The C-N bond length for bridgehead lactam 15 is slightly longer (1.4013(14) Å) than bridgehead lactam 11 (1.3941(13)Å). In contrast, the C=O bond distance of bridgehead lactam 11 (C=O = 1.2163(12) Å) and bridgehead lactam 15 (C=O = 1.2198(13)Å) are not sensitive to the difference in τ values.

Functionalization of Bicyclic 1,2-diazines

To examine the chemical behavior of the bicyclic 1,2-diazines, a series of transformations were carried out that include reduction of the bridgehead double bond and hydrogenolysis of the N-N bond. When carried out in this order, this sequence transfers stereochemistry from the bridgehead nitrogen to the sp³ bridgehead carbon. The reduction of the bridgehead double bond in cycloadducts 11 and 15 was achieved by catalytic hydrogenation in the presence of 10% Pd/C in EtOH to give the saturated cycloadduct 16 in 95% yield and 18 in 89% (Scheme 8). Several methods have been reported for the N-N bond cleavage including reduction by zinc in acetic acid,²⁰ SmI₂,²¹ and Raney/Ni.²² The most effective method for the cleavage of N-N bond resulted from the treatment of compounds 14 and 18 with Raney/Nickel in ethanol to afford 6-substituted caprolactam 17 in 80% and 7-substituted enantholactam 19 in 87% yield, respectively. This method provides a convenient route for the synthesis of seven and eight member nitrogen-containing heterocyclic ring systems.

Scheme 8.

Synthesis of lactams 17 and 19.

π–facial selectivity in T2IMDA reaction

Analysis of the X-ray crystal structure of cycloadduct 11 revealed a distance of 2.18 Å between the endo hydrogen at C10 and the exo hydrogen at C3 (Figure 1). Based on previous studies⁵ with N-acylnitroso dienophiles, we anticipated that π–facial selectivity of the T2IMDA reaction with N-acylazo dienophiles would be influenced by the introduction of substituents on the tether at α-position of Diels-Alder precursor. To evaluate the π–facial selectivity in cycloaddition precursors that incorporate substituents at α-position, two derivatives were synthesized (Scheme 9). The synthesis of the α-benzylated esters 20⁵ and 22 was achieved by deprotonation of ester 6 or 7 with LDA, followed by alkylation with benzyl bromide to afford the α-substituted ester derivative 20⁵ in 65% yield and ester 22 in 74% yield. Coupling reaction of ester 20 or 22 with phenylhydrazine and Al(CH₃)₃ provided hydrazide 21 and 23 in 76% yield and 85% yield, respectively.

Figure 1.

ORTEP plots of cycloadducts 11 and 15 at the 50% probability level.

Scheme 9.

Synthesis of hydrazide 21 and 23.

Under optimized reaction conditions using n-Bu₄NIO₄, the oxidation of hydrazide 21 generated the N-acylazo dienophile in situ, which underwent intramolecular cycloaddition to afford cycloadduct 24 after 24 h in 91% yield. The product consisted of a single diastereomer as determined by ¹H NMR analysis of the crude reaction mixture. The endo diastereomer was established by NOE analysis (Scheme 10).

Scheme 10.

Diastereoselective T2IMDA reaction of hydrazide 21.

Addition of hydrogen to the bridgehead double bond, which occurs in a syn-exo matter, transfers the stereochemistry of the bridgehead nitrogen to the bridgehead carbon.³ However, hydrogenation of cycloadduct 24 in the presence of 10% Pd/C and H₂ in resulted a mixture of products that included saturated cycloadduct 25 (68%), 26 (23%), and 27 (2%) (Scheme 11). Bridgehead alkene isomerization competes with hydrogenation resulting in formation of alkenes with less strain than the starting material.

Scheme 11.

Catalytic hydrogenation of cycloadduct 24.

Complete hydrogenation of the bridgehead alkene 22 was achieved in the presence of 10% Pd/C under high pressure (50 psi) to afford saturated cycloadduct 25 in 86% yield. Following hydrogenation the cis-3,6-disubstituted caprolactam 28 was prepared by a reductive N-N bond cleavage using Ra/Ni and 1N NaOH under H₂ in 72% yield.

The synthesis of N-acylazo dienophile 29 was achieved using NBS and pyridine in 92% yield. Subsequently, the intramolecular cycloadditon of N-acylazo dienophile 29 proceeded smoothly in the presence of ZnCl₂ to afford cycloadduct 30. Only a single endo diastereomer was observed in the ¹H NMR spectrum of the crude reaction mixture and the stereochemistry of cycloadduct 30 was established by NOE experiments. Cycloadduct 30 was subjected to a catalytic hydrogenation at 50 psi in the presence of 10% Pd/C to produce saturated bicyclic 1,2-diazine 31 in 90% yield. The stage was now set for the synthesis of cis-3,7-disubstituted enantholactam 32, which was achieved in 77% yield by reductive N-N bond cleavage using Raney/Nickel.

Conclusion

In summary, we have developed the type 2 intramolecular Diels-Alder reaction with N-acylazo dienophiles for the regio- and stereoselective synthesis of bicyclic 1,2-diazines. In the course of our investigation, a new reagent was identified for the oxidation of hydrazides. X-ray crystallographic analysis allowed the quantification of structural distortions of the non-planar bridgehead olefin and lactam functionalities in cycloadducts 11 and 15. The T2IMDA reaction with N-acylazo dienophiles, incorporating substituents at the α-position, underwent stereoselective cycloaddition. These cycloadducts were subsequently elaborated to caprolactams and enantholactams derivatives.

Experimental Section

General Procedure for preparation of the hydrazides.¹⁰

To a solution of phenylhydrazine (2.0 equiv) in CHCl₃ was added Al(CH₃)₃ (2.0 equiv, 2.0 M solution in toluene) dropwise. The reaction mixture was stirred at room temperature for 1 h and diene ester (1 equiv) was added dropwise. After 10 h (TLC monitoring), the reaction mixture was cooled to 0 °C and then carefully poured into a solution of HCl (2N) and was allowed to stir for 30 min. The aqueous layer was separated and extracted with 3 portions CHCl₃. The combined organic extracts were washed with H₂O dried Na₂SO₄ and concentrated to give a pale yellow oil.

5-Methylene-hept-6-enoic acid N′-phenyl-hydrazide (8)

Diene ester 6⁵ (1.08 g, 6.42 mmol) was added dropwise to a solution of phenylhydrazine (1.39 g, 12.8 mmol) in CHCl₃ (50 mL) and Al(CH₃)₃ (6.4 mL in toluene, 2.0 M). The crude product was purified by flash column chromatography (1:2 EtOAc: Hexanes) to afford hydrazide 8 (1.12 g, 75% yield): ¹H NMR (500 MHz, CDCl₃) for major rotamer δ 7.28 (d, J = 7.6 Hz, 1H), 7.26 (app t, J = 8.2 Hz, 2H), 6.93 (app t, J = 7.4 Hz, 1H), 6.84 (app d, J = 7.8 Hz, 2H), 6.38 (dd, J = 17.6, 10.8 Hz, 1H), 6.15 (d, J = 3.7 Hz, 1H), 5.26 (d, J = 17.8 Hz, 1H), 5.11 (d, J = 10.9 Hz, 1H), 5.07 (s, 1H), 5.02 (s, 1H), 2.32-2.28 (m overlapped, 4H), 1.93(m, 2H); IR (thin film) ν_max : 3258, 1654, 1598, 1498; ¹³C NMR (125 MHz, CD₃OD) δ175.9, 150.1, 147.3, 139.9, 130.3, 121.2, 116.7, 114.2, 114.1, 34.7, 32.2, 25.7. HRMS (ES) m/z calcd. for C₁₄H₁₈N₂O [M + Na]⁺ 253.1317, found 253.1307.

6-Methylene-oct-7-enoic acid N′-phenyl-hydrazide (9)

Diene ester 7⁵ (3.26 g, 17.9 mmol) was added dropwise to a solution of phenylhydrazine (3.87 g, 35.8 mmol) in CHCl₃ (75 mL) and Al(CH₃)₃ (17.9 mL in toluene, 2.0 M). The crude product was purified by flash chromatography (1:2 EtOAc: Hexanes) to give 3.63 g hydrazine 9 (84%): ¹H NMR (500 MHz, Tol-d₈) for major rotamer δ 7.55 (d, J = 3.4 Hz, 1H), 7.12 (app t, J = 7.3 Hz, 2H), 7.00 (s, 1H), 6.80 (app t, J = 7.3 Hz, 1H), 6.75 (app d, J = 7.8 Hz, 2H), 6.33 (dd, J = 10.8, 17.6 Hz, 1H), 5.19 (d, J = 17.1 Hz, 1H), 5.1 (d, J = 10.8 Hz, 1H), 4.98 (s, 1H), 4.95 (s, 1H), 2.10 (t, J = 7.3 Hz, 2H), 1.86 (t, J = 7.3 Hz, 2H), 1.55 (m, 2H), 1.42 (m, 2H); IR (thin film) ν_max: 3265, 3087, 2933, 1655, 1602, 1495 cm⁻¹; ¹³C NMR (125 MHz, CD₃OD) δ176.0, 150.1, 147.8, 140.1, 130.3, 121.2, 116.3, 114.24, 113,47, 34.9, 32.2, 29.2, 26.88; HRMS (ES) m/z calcd. for C₁₅H₂₀N₂O [M + Na]⁺ 267.1473 found, 267.1480.

2-Benzyl-5-methylene-hept-6-enoic acid N′-phenyl-hydrazide (21)

Diene ester 20⁵ (1.98 g, 7.66 mmol) was added to a solution of phenylhydrazine (1.67 g, 15.4 mmol) in CHCl₃ (50 mL) and Al(CH₃)₃ (7.70 mL in toluene, 2.0 M). The crude product was purified by flash chromatography (1:5 EtOAc: Hexanes) to give 1.87 g hydrazide 21 (76 %): ¹H NMR (500 MHz, CDCl₃) for major rotamer δ 7.2–7.3 (m overlapped, 3H), 7.15 (app d, J = 6.5 Hz, 2H), 7.11 (s, 1H), 7.09 (app d, J = 8.0 Hz, 2H), 6.84 (app t, J = 7.2 Hz, 1H), 6.43 (app d, J = 7.8 Hz, 2H), 6.37 (dd, J = 17.6, 10.8 Hz, 1H), 5.98 (d, J = 3.6 Hz, 1H), 5.22 (d, J = 17.6 Hz, 1H), 5.09 (d, J = 10.9 Hz, 1H), 5.06 (s, 1H), 4.99 (s, 1H), 2.92 (dd, J = 13.4, 10.2 Hz, 1H), 2.81 (dd, J = 13.6, 5.0 Hz, 1H), 2.46 (m, 1H), 2.31 (m, 1H), 2.23 (m, 1H), 2.00 (m, 1H), 1.76 (m, 1H); IR (thin film) ν_max: 3248, 3027, 2928, 1667, 1601, 1495 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ 174.9, 147.8, 145.8, 139.5, 138.7, 129.1, 128.6, 126.6, 121.2, 116.3, 113.9, 113.6, 112.6, 47.7, 39.3, 31.1, 29.4. HRMS (ES) m/z calcd. for C₂₁H₂₄N₂O [M + H]⁺ 321.1967 found, 321.1972.

2-Benzyl-6-methylene-oct-7-enoic acid N-phenyl-hydrazide (23)

Diene ester 22⁵ (0.716 g, 2.14 mmol) was added to a solution of Al(CH₃)₃ (2.14 mL in toluene, 2.0 M) and phenylhydrazine (0.463 g, 4.28 mmol). The crude product was purified by flash chromatography (1:5 EtOAc: Hexanes) to give 1.73 g hydrazine 23 (85 %): ¹H NMR (500 MHz, CDCl₃) for major rotamer δ 7.31-7.26 (m overlapped, 3H), 7.19 (app d, J = 6.0 Hz, 2H), 7.11 (app t, J = 8.2 Hz, 2H), 6.98 (s, 1H), 6.84 (app t, J = 7.4 Hz, 1H), 6.45 (app d, J = 8.2 Hz, 2H), 6.38 (dd, J = 17.7, 10.8 Hz, 1H), 5.98 (d, J = 3.6 Hz, 1H), 5.23 (d, J = 17.6 Hz, 1H), 5.09 (d, J = 10.8 Hz, 1H), 5.05 (s, 1H), 5.00 (s, 1H), 2.92 (dd, J = 13.4, 10.3 Hz, 1H), 2.79 (dd, J = 13.4, 4.9, 1H), 2.42 (m, 1H), 2.24 (t, J = 6.3 Hz, 2H), 1.83 (m, 1H), 1.65-1.50 (m, 3H); IR (thin film) 3027, 2939, 1661, 1602, 1495 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ 174.9, 147.7, 145.8, 139.4, 138.8, 129.4, 129.04, 128.7, 126.6, 121.1, 116.0, 113.4, 112.5, 48.4, 39.2, 32.9, 31.3, 26.2; HRMS (ES) m/z calcd. for C₂₂H₂₆N₂O [M + H]⁺ 335.2123 found, 335.2122.

General Procedure for the oxidation reaction of hydrazides with n-Bu₄NIO₄ followed by cycloaddition

To a cooled (0 °C) solution of a hydrazide in dry CH₂Cl₂ was added n-Bu₄NIO₄ (1.3 equiv). The reaction mixture was stirred at room temperature for 24h (TLC monitoring) and washed with 2 portions of sat Na₂SO₃. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated in vacuo.

9-Phenyl-1,9-diaza-bicyclo[4.3.1]dec-6-en-2-one (11)

To a solution of hydrazide 8 (0.20 g, 0.87 mmol) in dry CH₂Cl₂ was added n-Bu₄NIO₄ (1.3 equiv, 0.49 g, 1.13 mmol) and stirred at room temperature for 24 h. Flash column chromatography (1:2 EtOAc: Hexanes) of the crude product yielded 0.18 g (91%) of cycloadduct 11 as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.27 (m, 2H), 7.04 (app d, J = 8.7 Hz, 2H), 6.91 (app t, J = 7.3 Hz, 1H), 5.86 (br s, 1H), 4.37 (dd, J =13.8, 7.4 Hz, 1H), 4.15 (d, J = 14.8 Hz, 1H), 3.49 (d, J = 12.7 Hz, 1H), 3.23 (d, J = 14.4 Hz, 1H), 3.12 (td, J = 13.8, 3.2 Hz, 1H), 2.64 (dd, J = 12.1, 6.8 Hz, 1H), 2.55 (dt, J = 13.2, 3.1 Hz, 1H), 2.50 (td, J = 12.1, 6.1 Hz, 1H), 2.29 (m, 1H), 1.95 (m, 1H); IR (thin film) ν_max: 1702, 1597, 1492, 1342, 1163 cm⁻¹; ¹³C NMR (125 MHz, CD₂Cl₂) δ183.6, 150.9, 150.8, 129.4, 120.1, 119.2, 114.4, 51.6, 48.9, 36.8, 35.0, 33.4. HRMS (ES) m/z calcd. for C₁₄H₁₆N₂O [M + Na]⁺ 251.1160, found 251.1155.

Acetylazobenzene (13a)

To a solution of hydrazide 12a (0.21 g, 1.40 mmol) in dry CH₂Cl₂ was added n-Bu₄NIO₄ (1.3 equiv, 0.788 g, 1.81 mmol) and stirred at room temperature for 5 h (TLC monitoring). Flash column chromatography (1:2 EtOAc: Hexanes) of the crude product yielded 0.15 g (72%) of N-acyl azo 13a as a red oil. ¹H NMR (500 MHz, CDCl₃) δ 7.9 (m, 2H), 7.56 (m, 3H), 2.44 (s, 3H); IR (thin film) ν_max: 1743, 1565, 1479 cm⁻1; ¹³C NMR (125 MHz, CDCl₃) δ 188.7, 151.7, 133.7, 129.5, 123.8, 21.4. HRMS (ES) m/z calcd. For C₈H₈N₂O [M + Na]⁺ 171.0534, found 171.0540.

Isobutyrylazobenzene (13b)

To a solution of hydrazide 12b¹⁴ (0.34 g, 1.91 mmol) in dry CH₂Cl₂ was added n-Bu₄NIO₄ (1.3 equiv, 1.07 g, 2.47 mmol) and stirred at room temperature for 5 h (TLC monitoring). Flash column chromatography (1:2 EtOAc: Hexanes) of the crude product yielded 0.31 g (91%) of N-acyl azo 13b as a red oil.¹H NMR (500 MHz, CDCl₃) δ 7.89 (m, 2H), 7.56 (m, 3H), 3.14 (m, 1H), 1.31 (d, J = 7.3 Hz, 6H); IR (thin film) ν_max: 1736, 1501, 1453 cm⁻¹; ¹³C NMR (500 MHz, CD₂Cl₂) δ 195.4, 152.4, 133.7, 133.7, 129.9, 123.7, 34.9, 18.3; HRMS (ES) m/z calcd. for C₁₀H₁₂N₂O [M + H]⁺ 177.0950 found, 177.9038.

Ethyl(phenyl)azocarboxylate (13c)

To a solution of hydrazide 12c¹⁵ (0.15 g, 0.832 mmol) in dryCH₂Cl₂ was added n-Bu₄NIO₄ (1.3 equiv, 0.469 g, 1.08 mmol) and stirred at room temperature for 5h (TLC monitoring). Flash column chromatography (1:2 EtOAc: Hexanes) of the crude product yielded 0.14 g (95%) of N-acyl azo 13c as a red oil.¹H NMR (400 MHz, CDCl₃) δ 7.94 (m, 2H), 7.56 (m, 3H), 4.53 (q, 2H), 1.48 (t, J = 7.1 Hz, 3H); IR (thin film) 2986, 1755, 1503; ¹³C NMR (500 MHz, CDCl₃) δ 162.4, 151.8, 134.0, 129.5, 123.9, 64.7, 14.4; HRMS (ES) m/z calcd. For C₉H₁₀N₂O₂ [M + Na] 201.0640, found 201.0639.

3-Benzyl-9-phenyl-1,9-diaza-bicyclo[4.3.1]dec-6-en-2-one (24)

To a cooled (0 °C) solution of hydrazide 21 (0.24 g, 0.75 mmol) in CH₂Cl₂ was added n-Bu₄NIO₄ (1.3 equiv, 0.42 g, 97 mmol) and stirred at 25 °C. After 24h (TLC monitoring), the reaction mixture was diluted with CH₂Cl₂ (10 mL) and washed with sat Na₂SO₃ (2 × 10 mL). The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated in vacuo. Flash column chromatography (1:3 EtOAc: Hexanes) of the crude product afforded cycloadduct 24 (0.22 g, 91%) as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.24 (m, 7H), 6.95 (app d, J = 7.9 Hz, 2H), 6.87 (app t, J = 7.3 Hz, 1H), 5.83 (br s, 1H), 4.33 (dd, J =13.8, 7.3 Hz, 1H), 4.20 (d, J = 14.7, 1H), 3.49 (d, J = 14.5 Hz, 1H), 3.40 (m, 1H), 3.22-3.17 (m, 2H), 2.61 (dd, J = 14.1, 7.7 Hz, 1H), 2.53 (dd, J = 12.3, 6.9 Hz, 1H), 2.39 (m, 1H), 2.17 (d, J = 11.7 Hz, 1H), 1.74 (m, 1H); IR (thin film) 2930, 1694, 1598,1495 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ 184.7, 150.7, 149.9, 140.5, 129.7, 129.4, 128.8, 126.7, 120.48, 119.7, 114.9, 51.0, 49.3, 46.6, 39.5, 38.9, 34.6. HRMS (ES) m/z calcd. for C₂₁H₂₂N₂O [M + H]⁺ 319.1810 found 319.1810.

General Procedure for the preparation of N-acyl azo dienophiles with NBS.¹⁶

To a solution of a hydrazide in CH₂Cl₂ was added pyridine (1 equiv). The reaction mixture was cooled to 0° C and N-bromosuccinimide (1 equiv) was added to the solution. After 2h, the orange reaction mixture was poured into H₂O. The layers were separated and the aqueous layer was extracted with 3 portions of CH₂Cl₂ The combined organic layers were washed with 5% HCl, 10% K₂CO_3, brine, and dried over Na₂SO₄. The organic layer was concentrated in vacuo.

6-Methylene-oct-7-enoic acid azobenzene (14)

To a solution of hydrazide 9 (0.101 g, 0.413 mmol) in CH₂Cl₂ (5 mL) was added pyridine (0.033 g, 0.417 mmol). The reaction mixture was cooled to 0° C and N-bromosuccinimide (0.074g, 0.416 mmoles) was added to the solution. The organic layer was concentrated in vacuo to give 0.096 g of N-azo dienophile 14 in 96% yield and was used without further purification: ¹H NMR (500 MHz, CDCl₃) δ 7.89 (app d, J = 7.1 Hz, 2H), 7.60-7.51 (m overlapped, 3H), 6.37 (dd, J = 17.6, 10.8 Hz, 1H), 5.23 (d, J = 17.6 Hz, 1H), 5.08 (d, J = 10.8 Hz, 1H), 5.4 (s, 1H), 5.2 (s, 1H) 2.77 (t, J = 7.3 Hz, 2H), 2.27 (t, J = 7.7 Hz, 2H), 1.82 (m, 2H), 1.63 (m, 2H); IR (thin film) ν_max: 2941, 1743, 1499 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ191.5, 151.7, 145.9, 138.9, 133.5, 129.4, 123.6, 116.1, 113.4, 34.2, 31.2, 27.7, 23.4. HRMS (ES) m/z calcd. for C₁₅H₁₈N₂O [M + Na]⁺ 265.1317 found, 265.1324.

2-Benzyl-6-methylene-oct-7-enoic acid azobenzene (29)

To a solution of hydrazide 23 (0.023 g, 0.069 mmol) in CH₂Cl₂ (2 mL) was added pyridine (0.0054 g, 0.0687 mmol). The reaction mixture was cooled to 0 °C and N-bromosuccinimide (0.0122g, 0.0688 mmoles) was added to the solution. The organic layer was concentrated under vacuo to give N-acylazo dienophile 29 (0.0215 g) in 94% yield and used without further purification: ¹H NMR (500 MHz, CD₂Cl₂) δ 7.82 (app d, J = 7.5 Hz, 2H), 7.58-7.55 (m overlapped, 3H), 7.28-7.20 (m, 5H), 6.35 (dd, J = 17.6, 10.8 Hz, 1H), 5.20 (d, J = 17.6 Hz, 1H), 5.05 (d, J = 10.9 Hz, 1H), 4.98 (s, 1H), 4.95 (s, 1H), 3.31 (m, 1H), 3.12 (dd, J = 13.8, 7.7 Hz, 1H), 2.88 (dd, J = 13.8, 6.7, 1H), 2.18 (m, 2H), 1.83 (m, 1H), 1.65-1.53 (m, 3H); IR (thin film) ν_max: 2941, 1735, 1594, 1498; ¹³C NMR (125 MHz, CD₂Cl₂) δ 193.0, 151.7, 145.9, 139.0, 138.7, 133.3, 129.3, 129.0, 128.3, 126.4, 123.3, 115.7, 113.1, 47.1, 37.1, 31.1, 30.6, 25.5; HRMS (ES) m/z calcd. for C₂₂H₂₄N₂O [M + Na]⁺ 355.1786 found, 355.1785.

General Procedure for the T2IMDA reaction with N-acylazo dienophiles catalyzed by ZnCl₂

To a cooled solution (− 78 °C) of N-acylazo dienophile (0.01M) in CH₂Cl₂ was added ZnCl₂ (10 mol %) as a solid in one portion. After 2h, the reaction mixture gradually allowed to warm to 25 °C and was completed after 3h (monitored by TLC). The solution was diluted with CH₂Cl₂ and poured in H₂O. The layers were separated and the aqueous layer was extracted with 3 portions of CH₂Cl₂. The combined organic layers were washed with NaHCO₃, brine and dried over Na₂SO₄. The organic layer was concentrated in vacuo.

10-Phenyl-1,10-diaza-bicyclo[5.3.1]undec-7-en-2-one (15)

To a solution of N-acylazo dienophile 14 (0.0960 g, 0.396 mmol) in CH₂Cl₂ (10 mL) was added ZnCl₂ (0.0054 g, 0.0396 mmol). Purification of the crude product by column chromatrography (1:3 EtOAc: Hexanes) afforded cycloadduct 15 (0.075 g, 78% yield) as a pale yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.26 (app t, J = 7.8 Hz, 2H), 6.90 (app d, J = 8.7 Hz, 2H), 6.81 (app t, J = 7.3 Hz, 1H), 5.55 (br s, 1H), 4.20 (d, J = 5.2 1H), 4.15 (d, J = 15.5 Hz, 1H), 3.96 (br d, J = 15.7, 1H), 3.56 (br d, J = 15.8 Hz, 1H), 2.62 (dd, J = 13.1, 9.3, 1H), 2.52 (m, 1H), 2.41 (t, J = 11.5, 1H), 2.15-2.10 (m, 3H), 1.90 (m, 1H), 1.44 (m, 1H); IR (thin film) ν_max: 2932, 1656, 1599, 1497 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ 180.5, 148.7, 141.7, 129.2, 121.9, 118.7, 112.0, 47.5, 47.1, 37.6, 33.7, 27.2, 24.4. HRMS (ES) m/z calcd. for C₁₅H₁₈N₂O [M + Na]⁺ 265.1317 found, 265.1308.

3-Benzyl-10-phenyl-1,10-diaza-bicyclo[5.3.1]undec-7-en-2-one (30)

To a solution of N-acylazo dienophile 29 (0.087 g, 0.26 mmol) in CH₂Cl₂ (7 mL) was added ZnCl₂ (0.0036 g, 0.011 mmol). Purification of the crude product by column chromatrography (1:4 EtOAc: Hexanes) to afford cycloadduct 30 (0.062 g, 71% yield) as a pale yellow oil: ¹H NMR (500 MHz, CDCl₃) δ. δ 7.31-7.18 (m overlapped, 7H), 6.76 (app t, J = 7.3 Hz, 1H), 6.64 (app d, J = 8.8 Hz, 2H), 5.66 (br s, 1H), 4.24 (d, J =15.6, 1H), 4.13 (dd, J = 15.5, 5.1, 1H), 3.98 (dt, J = 15.6, 2.1 Hz, 1H), 3.55 (br d, J = 15.6, 1H), 3.20 (dd, J = 13.5, 8.5, 1H), 2.76 (m, 1H), 2.66 (dd, J = 13.5, 6.4 Hz, 1H), 2.49 (br m, 1H), 2.17-2.05 (m, 2H), 1.87 (m, 2H), 1.4 (m, 1H); IR (thin film) ν_max: 2930, 1698, 1598, 1497 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ181.9, 148.3, 140.8, 140.1, 129.4, 128.9, 128.3, 126.2, 122.4, 118.3, 111.6, 48.5, 47.6, 46.7, 40.6, 33.9, 31.4, 27.0; HRMS (ES) m/z calcd. for C₂₂H₂₄N₂O [M + H]⁺ 333.1967 found, 333.1963.

General Procedure for the hydrogenation of the bridgehead alkene

To a solution of a cycloadduct in EtOH was added 10% Pd/C. The reaction mixture was stirred under 1 atmosphere or 50 psi of H₂ for 5 h. The catalyst was filtered through celite and the filtrate was concentrated in vacuo.

9-Phenyl-1,9-diaza-bicyclo[4.3.1]decan-2-one (16)

To a solution of cycloadduct 11 (0.025, 0.011 mmol) in EtOH (5 mL) was added 10% Pd/C (0.003 g). The reaction mixture was stirred under 1 atmosphere of H₂ for 5 h. The clear oil was purified by column chromatography (1:1 EtOAc: Hexanes) to afford 16 (0.023 g, 92% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.26 (m, 2H), 6.91-6.89 (m, 3H), 3.8 (ddd, J = 9.7, 9.7, 5.3 Hz, 1H), 3.7 (d, J = 14.9 Hz, 1H), 3.24-3.18 (m, 2H), 2.92 (m, 1H), 2.59 (dt, J = 13.7, 4.4 Hz, 1H), 2.18 (m, 1H), 1.98-1.80 (m, 5H), 1.69-1.64 (m, 1H), ¹³C NMR (125 MHz, CDCl₃) δ178.7, 149.3, 129.2, 120.3, 114.1, 49.2, 45.7, 35.4, 31.0, 30.6, 22.9, 19.7; IR (thin film) ν_max : 2933, 1682, 1599, 1495 cm⁻¹; HRMS (ES) m/z calcd. for C₁₄H₁₈N₂O [M + H]⁺ 231.1497, found 231. 1498.

10-Phenyl-1,10-diaza-bicyclo[5.3.1]undecan-2-one (18)

To a solution of cycloadduct 15 (0.041, 0.17 mmol) in EtOH (5 mL) was added 10% Pd/C (0.004 g). The reaction mixture was stirred under 1 atmosphere of H₂ for 5 h. The clear oil was purified by column chromatography (1:1 EtOAc: Hexanes) to afford 18 (0.036 g, 89% yield): ¹H NMR (500 MHz, CDCl₃) δ 7.246 (m, 2H), 6.88-6.82 (m, 3H), 3.97 (d, J = 14.4 Hz, 1H), 3.79-3.74 (m, 2H), 3.39 (d, J = 14.3 Hz, 1H), 2.63 (td, J = 13.1, 3.2 Hz, 1H), 2.55 (m, 1H), 2.15-2.05 (m, 2H), 1.99-1.94 (m, 4H), 1.57-1.47 (m, 2H), 1.33-1.25 (m, 1H) ¹³C NMR (125 MHz, CD₃OD) δ176.1, 146.9, 129.5, 119.7, 113.9, 46.4, 40.6, 35.3, 34.7, 30.7, 28.0, 26.0, 25.1. HRMS (ES) m/z calcd. for C₁₅H₂₀N₂O [M + Na]⁺ 267.1473, found 267.1468.

3-Benzyl-9-phenyl-1,9-diaza-bicyclo[4.3.1]decan-2-one (25)

To a solution of cycloadduct 24 (0.037, 0.12 mmol) in EtOH (5 mL) was added 10% Pd/C (0.004 g). The reaction mixture was stirred under high pressure H₂ (50 psi) for 5 h. The clear oil was purified by column chromatography (1:2 EtOAc: Hexanes) to afford 25 (0.032 g, 86% yield): ¹H NMR (500 MHz, CDCl₃) δ 7.33-7.25 (m, 7H), 6.89-6.85 (m, 3H), 3.83-3.78 (m, 2H), 3.32 (dd, J = 14.1, 5.6 Hz, 1H), 3.23-3.17 (m, 3H), 2.67 (dd, J = 14.1, 8.3 Hz, 1H), 2.14 (br s, 1H), 1.92 (m, 1H), 1.83-1.65 (m, 5H); IR (thin film) 2922, 1686, 1599, 1497. ¹³C NMR (125 MHz, CDCl₃) δ 179.8, 149.4, 140.6, 129.6, 129.1, 128.5, 126.3, 120.1, 113.9, 48.7, 45.7, 44.9, 38.2, 31.5, 30.1, 26.2, 22.9. HRMS (ES) m/z calcd. for C₂₁H₂₄N₂O [M + H]⁺ 321.1967, found 321.1960.

3-Benzyl-10-phenyl-1,10-diaza-bicyclo[5.3.1]undecan-2-one (31)

To a solution of cycloadduct 30 (0.040, 0.12 mmol) in EtOH (5 mL) was added 10% Pd/C (0.004 g). The reaction mixture was stirred under high pressure H₂ (psi) for 5 h. The clear oil was purified by column chromatography (1:2 EtOAc: Hexanes) to aff ord 31 (0.036 g, 86% yield): ¹H NMR (500 MHz, CDCl₃) δ 7.28-7.25 (m overlapped, 5H), 7.13 (app t, J = 7.3 Hz, 2H), 6.75 (app t, J = 7.3 Hz, 1H), 6.54 (app d, J = 7.8 Hz, 2H), 4.07 (br d, J = 14.4 Hz, 1H), 3.77-3.70 (m, 2H), 3.27-3.20 (m, 2H), 2.91 (m, 1H), 2.66 (dd, J = 13.4, 5.3 Hz, 1H), 2.08-2.03 (m, 2H), 1.94-1.90 (m, 2H), 185-1.75 (m, 2H), 1.54-1.45 (m, 2H), 1.32 (br d, J = 13.4 Hz, 1H); IR (thin film) ν_max: 2921, 1677, 1597, 1497 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ 177.8, 147.1, 140.5, 129.6, 129.4, 128.5, 126.3, 119.4, 113.4, 46.9, 46.2, 39.8, 39.6, 37.6, 35.3, 27.7, 26.9, 24.6. HRMS (ES) m/z calcd. for C₂₂H₂₆N₂O [M + H]⁺ 335.2123 found, 335.2121.

General Procedure for the reductive N-N bond cleavage with Raney-Ni

A solution of saturated cycloadducts in EtOH and Raney nickel was stirred under 1 atmosphere of H₂. After 6 h, the reaction mixture was stirred at r.t or refluxed over night. The catalyst was filtered through a pad of celite. The filtrate was concentrate under vacuo and chromatographed.

6-(2-Phenylamino-ethyl)-azepan-2-one (17)

To a solution of 16 (0.020g, 0.087 mmol) in EtOH (5 mL) was added Raney nickel and stirred under 1 atmosphere of H₂. After 6 h, the reaction mixture was refluxed over night. Purification of the crude product by column chromatography (1:1 EtOAc: CHCl₃) to afford 6-substituted caprolactam 17 (0.016 g, 80%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.19 (app t, J = 7.4 Hz, 2H), 6.72 (app t, J = 7.3 Hz, 1H), 6.61 (app d, J = 8.6 Hz, 2H), 6.02 (br s, 1H), 3.59 (br s, 1H), 3.20-310 (m, 4H), 2.48 (dd, J = 6.9, 4.8 Hz, 2H), 1.97 (m, 1H), 1.85 (m, 1H), 1.75 (br m, 1H), 1.69-1.47 (m, 4H and H₂O); IR (thin film) ν_max: 3369, 2920, 1654 cm⁻¹ ; ¹³C NMR (125 MHz, CDCl₃) δ 178.7, 148.3, 129.5, 117.7, 112.9, 47.5, 41.8, 36.9, 36.6, 36.5, 32.8, 21.7; HRMS (ES) m/z calcd. for C₁₄H₂₀N₂O [M + Na]⁺ 255.1473 found, 255.1473.

7-(2-Phenylamino-ethyl)-azocan-2-one (19)

To a solution of 18 (0.025g, 0.102 mmol) in EtOH (5 mL) was added Raney nickel and stirred under 1 atmosphere of H₂. After 6 h, the reaction mixture was refluxed over night. The catalyst was filtered through a pad of celite. The filtrate was concentrate in vacuo and purified by column chromatography (1:1 EtOAc: CHCl₃) to afford enantholactam 19 (0.022 g, 87%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.18 (app t, J = 7.4 Hz, 2H), 6.73 (app t, J = 7.3 Hz, 1H), 6.61 (app d, J = 7.6 Hz, 2H), 5.92 (br s, 1H), 3.70 (br s, 1H), 3.43 (ddd, J = 9.3, 7.1, 3.8 Hz, 1H), 3.20-3.11 (m, 3H), 2.43 (ddd, J= 8.1, 5.5, 2.9, 2H), 1.85-1.30 (m, 9H); IR (thin film) ν_max: 3346, 2925, 1661 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ 177.8, 148.3, 129.5, 117.7, 112.9, 45.7, 42.0, 39.4, 33.1, 32.4, 29.9, 28.5, 23.7; HRMS (ES) m/z calcd. for C₁₅H₂₂N₂O [M + H]⁺ 247.1810, found 247.1811.

3-Benzyl-6-(2-phenylamino-ethyl)-azepan-2-one (28)

To a solution of 25 (0.018 g, 0.056 mmol) in EtOH (5 mL) was added Raney nickel and NaOH (0.2 mL, 1N) stirred under 1 atmosphere of H₂. After 6 h, the H₂ balloon was removed and stirred for 48 h. Purification by column chromatography (1:1 EtOAc: Hexanes) afforded cis-3,6-substituted caprolactam 28 (0.013 g, 72%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 7.29 -7.16 (m overlapped, 7H), 6.71 (app t, J = 7.3 Hz, 1H), 6.60 (app d, J = 7.9 Hz, 2H), 5.94 (br s, 1H), 3.49 (dd, J = 15.1, 5.6 Hz, 1H), 3.24 (dd, J = 14.1, 5.1 Hz, 1H), 3.11 (m, 3H), 2.71 (m, 1H), 2.57 (dd, J = 14.1, 9.3 Hz, 1H), 1.90-1.50 (m, 8H); IR (thin film) ν_max: 3326, 3046, 1643 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ 179.2, 148.2, 140.6, 129.5, 129.4, 128.5, 126.2, 117.8, 113.0, 45.5, 45.3, 42.1, 37.3, 33.8, 33.5, 29.9, 29.3; HRMS (ES) m/z calcd. for C₂₁H₂₆N₂O [M + H]⁺ 323.2123, found 323.2129.

3-Benzyl-7-(2-phenylamino-ethyl)-azocan-2-one (32)

To a solution of 31 (0.021 g, 0.063 mmol) in EtOH (5 mL) was added Raney nickel and NaOH (0.2 mL, 1N) stirred under 1 atmosphere of H₂. After 6 h, the H₂ balloon was removed and stirred for 48 h. Purification by column chromatography (2:1 EtOAc: Hexanes) afforded cis-3,7-disubstituted enantholactam 32 (0.016 g, 77%) as a clear oil: ¹H NMR (500 MHz, CDCl₃) δ 7.25-7.15 (m overlapped, 7H), 6.73-6.63 (m overlapped, 3H), 5.75 (br s, 1H), 3.70 (br m, 2H), 3.15-3.05 (m, 4H), 2.91 (m, 1H), 2.66 (dd, J = 13.8, 6.7 Hz, 1H), 1.78 (m, 2H), 1.65 (m, 2H), 1.51 (br s, 2H), 1.36 (m, 2H); IR (thin film) ν_max: 3312, 2932, 1651 cm⁻¹; ¹³C NMR (125 MHz, CDCl₃) δ 178.9, 148.3, 140.7, 129.6,129.4, 128.6, 126.3, 117.8, 113.0, 44.5, 42.1, 38.9, 38.6, 35.6, 31.7, 30.2, 29.9, 22.9. HRMS (ES) m/z calcd. for C₂₂H₂₈N₂O [M + H]⁺ 337.2280 found, 337.2280.

Scheme 12.

Catalytic Hydrogenation and N-N bond cleavage of cycloadduct 24.

Scheme 13.

Diastereoselective T2IMDA reaction of hydrazide 23.