Synthesis of 5-Hydrazino-2-cyclopentenone Derivatives by a Gold(I)-Catalyzed Cycloisomerization/Hetero-Diels–Alder/Ring-Opening Tandem Reaction of Enynyl Acetates

Dina Scarpi; Nunzia Favale; Ernesto G Occhiato

doi:10.1021/acs.joc.3c00310

. 2023 May 12;88(11):7015–7025. doi: 10.1021/acs.joc.3c00310

Synthesis of 5-Hydrazino-2-cyclopentenone Derivatives by a Gold(I)-Catalyzed Cycloisomerization/Hetero-Diels–Alder/Ring-Opening Tandem Reaction of Enynyl Acetates

Dina Scarpi ¹, Nunzia Favale ¹, Ernesto G Occhiato ^1,^*

PMCID: PMC10262200 PMID: 37171055

Abstract

A highly efficient, one-pot synthesis of ring-fused 5-hydrazino-2-cyclopentenone derivatives is achieved by a gold(I)-catalyzed cycloisomerization/hetero-Diels–Alder/ring-opening tandem reaction of suitable enynyl acetates. By mixing the latter with a dialkylazodicarboxylate in the presence of a gold(I) catalyst, the 1,3-acyloxy migration/Nazarov cyclization process leads to dienyl acetate intermediates which are trapped by the heterodienophile present in situ. This provides strained intermediates which undergo highly regioselective ring opening by a retro aza-Michael reaction promoted by traces of water, eventually yielding the target compounds. Six- and seven-membered ring-fused cyclopentenones and piperidine- and tetrahydropyran-fused cyclopentenones bearing a pendant hydrazino functionality on a bridgehead carbon atom can be obtained in high yield (68–96%) by this approach.

Introduction

The 2-cyclopentenone ring is found in a variety of natural and biologically active compounds possessing a high structural diversity, many of which embed a ring-fused cyclopentenone moiety (Figure 1).¹ The importance of the 2-cyclopentenones is further enhanced by a variety of chemical transformations that can be carried out on them, which explains their popularity not only as benchmark substrates for many chemical transformations but also as starting materials in the synthesis of more complex compounds.² Thus, due to their privileged nature, many methods have been developed to access diversely functionalized 2-cyclopentenones.¹⁻³

Examples of natural and bioactive compounds containing a ring-fused 2-cyclopentenone moiety.

Among gold-mediated syntheses of 2-cyclopentenones,^1,2,4−8 those based on gold(I)-catalyzed cycloisomerization of propargyl alcohol derivatives have especially shown their efficacy in providing these valuable compounds.^1,2,9−15 We have recently contributed to this field with the synthesis of cyclopentenones fused with heterocyclic rings and their transformation into some natural compounds.¹⁶⁻¹⁹ In his pioneering work on the gold-catalyzed cycloisomerization of enynyl esters to 2-cyclopentenones,²⁰ occurring via a 1,3-acyloxy migration/Nazarov cyclization sequence,^21,22 Zhang showed that the target compounds could be obtained through the hydrolysis of the cyclopentadienyl esters formed in the process when the reaction was carried out in “wet” dichloromethane. Under anhydrous conditions, instead, the cyclopentadienyl esters could be isolated in high yield.^15,20

We have recently reported on the synthesis of ring-fused, cyclopentadienyl hydrazine derivatives 4 (Scheme 1a) by a one-pot, cascade process entailing the cycloisomerization of suitably substituted propargyl vinyl ethers 1,²³⁻²⁶ the hetero-Diels–Alder (HDA) reaction of cyclopentadiene intermediates 2 with a dialkylazodicarboxylate, and the acid-catalyzed ring opening of cycloadducts 3.²⁷ Since in the cycloisomerization of the corresponding propargyl esters 5 to 2-cyclopentenones, a cyclopentadienyl ester intermediate (6) is formed,²⁰ we were interested in evaluating whether the latter could react with a dialkylazodicarboxylate present in the reaction mixture to provide the corresponding 5-hydrazino-2-cyclopentenone derivative 8(28) bearing an N-substituted quaternary center,²⁹ through a selective C–N bond cleavage in cycloadduct 7 (Scheme 1b). In our previous work, we had demonstrated that the highly regioselective C₁–N₈ bond cleavage occurs in the presence of either the gold(I) catalyst or traces of mineral acids.²⁷ In the analogous process carried out on propargyl esters 5, the stage which is set for the C–N cleavage after the cycloaddition (i.e., intermediate 7) is different (from 3), but we nonetheless hoped for a similarly regioselective C–N cleavage by a retro aza-Michael addition upon hydrolysis of the suitably positioned ester group.

Results and Discussion

We carried out our first experiment by adding a solution of substrate 9 and diethyl azodicarboxylate (DEAD) (1 equiv) in CH₂Cl₂ (distilled over CaH₂) to a solution of the IPrAuNTf₂ (2 mol %) catalyst in the same solvent (Table 1, entry 1). Monitoring the reaction by thin layer chromatography (TLC), we found that the conversion of the starting material into reaction products was very slow as the former completely disappeared after 3 h. Gratifyingly, after an aqueous work-up, the ¹H NMR analysis of the crude reaction mixture revealed the presence of desired product 12 and the corresponding N-acetylated compound 13 in an approximately 5:1 ratio.³⁰ When we carried out the same reaction in undistilled CH₂Cl₂ (entry 2),³¹ the consumption of the starting material was still very slow, but after work-up, we recorded a very clean ¹H NMR spectrum with the signals of product 12 only, which was obtained in 86% yield after chromatography. Better results were obtained by using commercial t-Bu₃PAuNTf₂ as the catalyst, the reaction being complete in 30 min and providing 12 in 94% yield (entry 3).

Table 1. Survey of the Conditions for the Tandem Reaction Leading to 12^a.

entry	catalyst	R	solvent	time (min)	12^b	13^b
1	IPrAuNTf₂	CH₃	CH₂Cl₂^c	180	84	16
2	IPrAuNTf₂	CH₃	CH₂Cl₂^d	180	100 (86)^e
3	t-Bu₃PAuNTf₂	CH₃	CH₂Cl₂^d	30	100 (94)^e
4	t-Bu₃PAuNTf₂	CH₃	CH₂Cl₂^c	60	50	50
5	t-Bu₃PAuNTf₂	CH₃	“wet” CH₂Cl₂^f	35	100 (79)^e
6	t-Bu₃PAuNTf₂	CH₃	“wet” CH₂Cl₂^g	30	100 (95)^e
7	Ph₃PAuCl/AgNTf₂	CH₃	CH₂Cl₂^d	30	100 (94)^e
8	Ph₃PAuCl/AgOTf	CH₃	CH₂Cl₂^d	30	100 (86)^e
9	Ph₃PAuCl/AgSbF₆	CH₃	CH₂Cl₂^d	30	100 (95)^e
10	Ph₃PAuCl/AgSbF₆	CH₃	CH₂Cl₂^g	30	100 (95)^e
11	t-Bu₃PAuNTf₂	CH₃	toluene^h	420	100 (91)^e
12	t-Bu₃PAuNTf₂	CH₃	DCE^h	190	83 (74)^e
13	t-Bu₃PAuNTf₂	(CH₃)₃C	CH₂Cl₂^d	23	100 (90)^e
14ⁱ	t-Bu₃PAuNTf₂	(CH₃)₃C	CH₂Cl₂^d	40^j	100 (64)^e
15	t-Bu₃PAuNTf₂	(CH₃)₃C	CH₂Cl₂^c	30	100 (62)^e
16ⁱ	t-Bu₃PAuNTf₂	(CH₃)₃C	CH₂Cl₂^c	30^j	100 (80)^e
17	Ph₃PAuCl/AgOTf	Ph	CH₂Cl₂^d	80	100 (54)^e
18	t-Bu₃PAuNTf₂	Ph	CH₂Cl₂^d	70	100 (57)^e

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Reactions carried out by adding a 0.1 M solution of the substrate (0.2 mmol) and DEAD (1 equiv) in CH₂Cl₂ to a 0.1 M solution of the catalyst in the same solvent.

Conversion determined by ¹H NMR of the crude reaction mixture.

Distilled over CaH₂ prior to use.

Undistilled solvent (declared water content of the lot: 0.01%).

Yield after chromatography.

Prepared by adding water (0.3% v/v) to the solution of the catalyst in CH₂Cl₂ freshly distilled from CaH₂.

Prepared by adding water (0.3% v/v) to the solution of the catalyst in undistilled CH₂Cl₂.

Undistilled solvent.

ⁱ

Reaction carried out by adding DEAD after the cycloisomerization was complete.

Time taken from the addition of DEAD.

We next carried out the same experiment in CH₂Cl₂ freshly distilled from CaH₂ (entry 4). The starting material was consumed in 60 min, after which we stopped the reaction to obtain a 1:1 mixture of 12 and N-acetylated compound 13. In the next experiment (entry 5), we added water (0.3% v/v) to the reaction mixture, and similarly to the reaction carried out in undistilled CH₂Cl₂, the conversion of the starting material was complete in 35 min to provide compound 12 only (79% yield after chromatography).

The last two experiments, together with those reported in entries 1 and 2, show that water is essential to avoid the formation of the unwanted N-acetylated compound 13. Even the amount of water present in the commercial CH₂Cl₂ that we used (without prior distillation over CaH₂) seems sufficient for this (entries 2 and 3).³¹ Moreover, given the quantitative formation of product 12, the cycloaddition step must be much faster than hydrolysis of the intermediate acetate 6 which would instead lead to the corresponding unfunctionalized 2-cyclopentenone.²⁰ Given the unpredictability of the water content in the commercial solvent,³² we decided to add a measured amount of water to the reaction medium even using undistilled CH₂Cl₂ (entry 6). These conditions did not affect the reaction rate (100% conversion in 30 min) and, expectedly, provided compound 12 only (95% yield after chromatography). These were the conditions which we later used in the evaluation of the scope of the reaction.

A series of experiments with catalysts obtained by premixing Ph₃PAuCl (2 mol %) and different silver salts (entries 7–9) were also carried out in undistilled CH₂Cl₂ to evaluate other catalytic systems, and in all cases, the starting material was quickly consumed (30 min) to form the target compound in very high yield (86–95%) after chromatography. These experiments show that the presence of residual silver cations in solution does not affect the reaction outcome. The experiment with AgSbF₆ as the silver salt was repeated in “wet” CH₂Cl₂ providing the same results as in the undistilled solvent (entry 10). We also tried two other solvents: With toluene (undistilled) (entry 11), the consumption of the starting material was very slow, the starting material being consumed in 7 h, to nonetheless give 12 in 91% yield after chromatography. With dichloroethane (undistilled) (entry 12), the reaction was slow, too, reaching 83% conversion in 3 h.

A series of experiments were carried out with pivaloyl ester 10 (entries 13–16). The first experiment was carried out as usual in undistilled CH₂Cl₂, and after 23 min, we stopped the reaction to obtain cyclopentenone 12 in 90% yield after chromatography. We carried out, with this substrate, the reaction in sequence, too, by first mixing the catalyst and the substrate in CH₂Cl₂, and when the cycloisomerization was complete (10 min), we added DEAD. The TLC spot corresponding to the cycloisomerization product disappeared in 40 min, and after work-up, cyclopentenone 12 was obtained in 64% yield. Interestingly, with this ester as the substrate, the formation of the N-acylated byproduct was not observed when carrying out the reaction in anhydrous CH₂Cl₂, as after aqueous work-up, we observed the formation of 12 only (entries 15 and 16). Finally, we also tried benzoyl ester 11 as the substrate (entries 17 and 18), but the results were not as satisfactory as those with the previous esters. The cycloisomerization was complete in 10 min with both catalysts, with the formation, in the TLC plate, of a spot probably corresponding to a reaction intermediate which was completely converted into the product in about 1 h. However, ¹H NMR of the crude reaction mixture revealed the presence of two unidentified byproducts, and 12 was obtained in moderate yield (54–57%) after chromatography.

To have a clear picture of the reaction, we carried out two experiments with pivaloyl ester 10 in CD₂Cl₂ (in NMR tubes), monitoring directly by ¹H NMR (Scheme 2).

We choose 10 to have simpler NMR spectra as this ester does not form the N-acylated product in mixture with 12. In the first experiment (see the Supporting Information), we added the substrate to the solution of the catalyst (2 mol % t-Bu₃PAuNTf₂) to generate, in less than 1 min, diene 14,³⁰ and to this, we added an excess of DEAD (2 equiv) to initiate the cycloaddition step. The signals of diene 14 completely disappeared after 8 min, and at this point, the signals of two products, in a 3:1 ratio, were visible in the NMR spectrum, i.e., those that we could attribute to cycloadduct 15 (major),³⁰ as a single diastereomer, and to compound 17 (minor).³⁰ We then added D₂O (0.3% v/v) which caused the quick transformation (2 min) of cycloadduct 15 into final product 12, whereas the conversion of minor product 17 into 12 was slower and required 10 min to be completed. After this time, only the signals of our target compound 12 were present in the ¹H NMR spectrum.

In a similar experiment, we avoided the addition of deuterated water and found that the ratio between compounds 17 and 15 increased during the time, from 1:3 after 8 min to approximately 1.5:1 after 40 min. Thus, in the absence of water, cycloadduct 15 undergoes a slow cleavage of the C–N bond to generate cyclopentadienyl ester 17, and on the grounds of our previous work with propargyl vinyl ethers,²⁷ the ring-opening process leading to 17 could be promoted by the catalyst present, i.e., either by the cationic gold(I) or by the conjugated acid of its counterion (Tf₂NH). As mentioned, with the substrate we used in the present experiments, we do not observe the formation of the N-acylated byproduct under anhydrous conditions. The formation of N-acetyl derivative 13 from 9 when working in the absence of water (Table 1, entries 1 and 4) could derive from an intramolecular reaction on either 16 or 17 (when R = Me), whereas with the pivaloyl esters, N-acylation is not observed (Table 1, entries 15–16) as it could be impeded by steric hindrance.

Based on the results of the above-mentioned experiments, we may infer that when the reaction is carried out under the optimized conditions, i.e., in the presence of water, the major pathway must involve the hydrolysis of the ester group directly in the cycloadduct 15 as soon as this is formed, which triggers the regioselective cleavage of the C₁–N₈ bond by a retro aza-Michael addition driven by the formation of a conjugated system (path a, Scheme 2).

To gain insights into the role of the gold catalyst in the cycloaddition step and try to isolate the cycloadduct intermediate, we carried out an experiment on known diene 18 (Scheme 3).¹⁵ By adding DEAD to a solution of 18 in anhydrous CH₂Cl₂ and monitoring by TLC, we observed the complete disappearance of the starting material in 25 min, with the formation of cycloadduct 19,³⁰ of which we managed to record an ¹H NMR spectrum (which showed the presence of a single diastereomer) and an electrospray ionization-mass spectrometry spectrum by directly concentrating a small volume of the reaction mixture.³³ This experiment thus suggests that the gold(I) catalyst has no role in activating either the diene or the heterodienophile for the cycloaddition step. Instead, the addition of the gold catalyst to the solution of 19 caused the acid-catalyzed C–N ring cleavage to form 12 reasonably according to path b (Scheme 2) but in mixture with unidentified byproducts.

For the evaluation of the scope of the reaction, we screened a few heterodienophiles (DEAD, DIAD, and dibenzyl azodicarboxylate) and propargyl acetates bearing different substituents and distal carbo- and heterocyclic rings (Table 2). In most cases, we observed by TLC the quick disappearance (30 min) of the starting material with the concurrent formation of the desired products (obtained in 76–96% yield after chromatography) when the reaction was carried out in wet dichloromethane (DCM). In two cases only, the reaction was troublesome: (a) When using dibenzyl azodicarboxylate as the heterodienophile (with substrate 9), we noticed a fast decomposition of the heterodienophile during the reaction. This slowed the cycloaddition step, consequently allowing the hydrolysis of the intermediate acetate before the HDA process and lowering the yield of 29. (b) With phenyl-substituted substrate 22, because of a slower cycloaddition step, the hydrolysis of the intermediate acetate occurred in part, too, using both DEAD and diisopropyl azodicarboxylate (DIAD) as heterodienophiles.

Table 2. Substrate Scope of the Optimized Process.

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Reaction carried out in 1.3 mmol.

Reaction carried out in undistilled CH₂Cl₂ without addition of water.

We found that in these problematic cases, the reaction was best carried out in undistilled CH₂Cl₂ without addition of water so that final products 29 (84%) and 34–35 (68–71%) could be obtained in good yield. With substrates bearing a seven-membered ring (25–27), the tandem reaction occurred as usual in about 30 min, and the target products (39–42) were obtained in very good yield (78–88%). In these cases, however, we observed the formation of a minor diastereomer (12–15%) likely due to a lower facial selectivity in the HDA step, as previously observed with other dienophiles.²⁶

To obtain functionalized cyclopentenones fused with a piperidine and a tetrahydropyran ring, the reaction was carried out on substrates 23 and 24, respectively. With ester 23, the reaction was carried out with both DEAD and DIAD, providing products 36 and 37 in 76 and 79% yields, respectively. With this substrate, the initial gold-catalyzed rearrangement was slower (about 4 h) than that with the corresponding carbocyclic systems, whereas tetrahydropyran derivative 24 reacted much faster (both rearrangement and cycloaddition/C–N cleavage steps) and, again, with complete facial selectivity to provide 38 in 92% yield.

Finally, in view of the possible use of these cyclopentenones as intermediates in synthesis, we evaluated on two of these compounds (12 and 28, Scheme 4) the facial selectivity in reactions involving the α,β-unsaturated ketone moiety.

We choose a simple double bond reduction which was best carried out with both wet Pd/C (10%) as the catalyst in methanol and PtO₂ in acetic acid, quantitatively providing compounds 43 and 44, possessing three contiguous stereocenters, with very high facial selectivity. Nuclear Overhauser effect (NOE) studies³⁴ revealed that it is the N-protected hydrazine appendage that exerted the major hindrance as the addition of hydrogen occurred on the opposite side.

Conclusions

In conclusion, we have established a robust method for the synthesis of functionalized 2-cyclopentenones by trapping with dialkylazodicarboxylates the dienyl acetate intermediates which are formed in the gold(I)-catalyzed rearrangement of suitable propargyl acetates and the consequent highly regioselective ring opening of the HDA cycloadducts. The presence of the right amount of water is essential to promote the latter step which occurs via a retro aza-Michael reaction and to avoid the formation of the N-acylated byproduct. This tandem, one-pot process, which includes a sequence of four reactions (1,3-acyloxy migration, Nazarov cyclization, HDA, and retro aza-Michael addition), provides in high yields (68–96%) unprecedented 5-hydrazino-2-cyclopentenone derivatives with an N-substituted quaternary center. Further elaboration of these products and the extension of the methodology to different classes of propargyl esters are currently being evaluated in our laboratories.

Experimental Section

General Experimental Methods

Anhydrous solvents were prepared according to the standard techniques. Commercially available reagents were used without further purification. Melting points were recorded on a Büchi B-540 apparatus and are uncorrected. Chromatographic separations were performed under pressure on silica gel (Merck 70–230 mesh) by using flash column techniques; R_f values refer to TLC carried out on 0.25 mm silica gel plates (F₂₅₄) with the same eluent as that indicated for column chromatography. ¹H NMR (200 or 400 MHz) and ¹³C{¹H} NMR (100.4 MHz) spectra were recorded either on Varian Inova (400 MHz) or Mercury (200 or 400 MHz) spectrometers in the specified deuterated solvent at 25 °C. Solvent reference lines were set at 7.26 and 77.00 (CDCl₃) in ¹H and ¹³C{¹H} NMR spectra, respectively. Mass spectra were recorded by direct inlet of a 20 ppm solution in CH₃OH on an LCQ Fleet Ion Trap LC/MS system (Thermo Fisher Scientific) with an ESI interface in the positive ion mode. Microanalyses were carried out with a Thermo Scientific FlashSmart Elemental Analyzer CHNS/O. Acetates 9(35) and 22(12) are known.

General Procedure for the Synthesis of the Propargyl Acetates

Triflate 45 is commercially available; triflates 46,³⁶47,³⁷ and 48(38) were prepared as reported. Propargyl alcohols 49a,²³49b,²³49c,²⁶49d,³⁹49g,²³49h,²⁶ and 49i(26) are known.

STEP 1: Sonogashira Coupling

A 3:1 (v/v) solution of anhydrous THF/Et₃N (6.6 mL, 0.15 M) was added to a round-bottomed flask containing triflates 45–48 (1 mmol). The alkynol (1.0–1.1 mmol; 1.0–1.1 equiv), CuI (32 μmol, 3.2 mol %), and (Ph₃P)₂PdCl₂ (16 μmol, 1.6 mol %) were then added under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 3 h. Water (25 mL) was then added, and the product was extracted with Et₂O (3 × 20 mL). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous K₂CO₃. After filtration and evaporation of the solvent, the crude reaction mixture was purified by flash chromatography affording the corresponding intermediate propargyl alcohol 49a – i, which was used immediately in the next step.

STEP 2: Acetylation

Propargyl alcohol 49a – i (1 mmol) was dissolved in anhydrous DCM (10 mL, 0.1 M), and freshly distilled Et₃N (3.0 mmol, 3.0 equiv) and a catalytic amount of 4-dimethylaminopyridine (0.05 mmol, 0.05 equiv) were added. After cooling at 0 °C (ice bath), Ac₂O (2.0 mmol, 2.0 equiv) was dropwise added. After 10 min, the ice bath was removed, and the reaction mixture was left under stirring at 25 °C (external bath) overnight. Aqueous saturated NaHCO₃ (10 mL) was added, and the product was extracted with DCM (2 × 10 mL); the combined organic extracts were dried over anhydrous K₂CO₃. After filtration and evaporation of the solvent, the crude reaction mixture was purified by flash column chromatography to give the pure propargyl acetate which was stored at 4 °C as a solution in the eluent containing 1% Et₃N. The solution of the propargyl acetate in the eluent was concentrated and dried under vacuum just prior to use.

2,2-Dimethylpropionic Acid 3-Cyclohex-1-enyl-1-methylprop-2-ynyl Ester (10)

Compound 10 was prepared starting from propargyl alcohol 49a (207 mg, 1.4 mmol) and following the general acetylation procedure but using pivaloyl chloride (204 μL, 1.7 mmol) as the acylating agent and an excess of Et₃N (1.9 mL, 14 mmol). Purification by flash chromatography (n-hexane/EtOAc, 30:1 + 1% Et₃N; R_f = 0.29) afforded pure 10 as a colorless oil (277 mg, 86%). ¹H NMR (400 MHz, CDCl₃): δ 6.11–6.09 (m, 1H), 5.55 (q, J = 6.8 Hz, 1H), 2.12–2.04 (m, 4H), 1.64–1.53 (m, 4H), 1.46 (d, J = 6.4 Hz, 3H), 1.20 (s, 9H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃): δ 177.3, 135.5, 120.0, 86.0, 85.0, 60.7, 38.6, 29.0, 27.0 (3 C), 25.6, 22.2, 21.5, 21.4. MS (ESI) m/z (%): 257 ([M + Na]⁺, 100). IR (CHCl₃): 3026, 2975, 2938, 2862, 2225, 1734, 1723, 1281, 1158 cm^–1. Anal. Calcd for C₁₅H₂₂O₂: C, 76.88; H, 9.46. Found: C, 76.65; H, 9.45.

Acetic Acid 3-Cyclohex-1-enyl-1-butylprop-2-ynyl Ester (20)

Propargyl alcohol 49b was prepared as reported.²³ Acetylation of compound 49b (143 mg, 0.75 mmol) afforded 20, which was purified by flash chromatography (n-hexane/EtOAc, 30:1 + 1% Et₃N; R_f = 0.43). Pure 20 was obtained as a colorless oil (153 mg, 88%). ¹H NMR (400 MHz, CDCl₃): δ 6.11–6.09 (m, 1H), 5.46 (t, J = 6.4 Hz, 1H), 2.11–2.04 (m, 4H), 2.05 (s, 3H), 1.77–1.70 (m, 2H), 1.60–1.55 (m, 4H), 1.41–1.29 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃): δ 169.9, 135.7, 119.9, 86.9, 83.8, 64.6, 34.7, 29.0, 27.1, 25.5, 22.2, 22.1, 21.4, 21.0, 13.9. MS (ESI) m/z (%): 257 ([M + Na]⁺, 100). Anal. Calcd for C₁₅H₂₂O₂: C, 76.88; H, 9.46. Found: C, 76.95; H, 9.41.

Acetic Acid 3-Cyclohex-1-enyl-1-isopropylprop-2-ynyl Ester (21)

Propargyl alcohol 49c was prepared as reported.²⁶ Acetylation of propargyl alcohol 49c (133 mg, 0.74 mmol) afforded 21, which was purified by flash chromatography (n-hexane/EtOAc, 40:1 + 1% Et₃N; R_f = 0.17). Pure 21 was obtained as a colorless oil (112 mg, 69%). ¹H NMR (400 MHz, CDCl₃): δ 6.13–6.09 (m, 1H), 5.32 (d, J = 5.2 Hz, 1H), 2.12–2.03 (m, 4H), 2.06 (s, 3H), 2.01–1.93 (m, 1H), 1.63–1.53 (m, 4H), 0.99 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃): δ 170.0, 135.7, 119.9, 87.6, 82.4, 69.5, 32.5, 29.0, 25.5, 22.1, 21.4, 21.0, 18.2, 17.5. MS (ESI) m/z (%): 243 ([M + Na]⁺, 100). IR (CHCl₃): 3027, 2933, 2876, 2223, 1734, 1373, 1242 cm^–1. Anal. Calcd for C₁₄H₂₀O₂: C, 76.33; H, 9.15. Found: C, 76.51; H, 9.30.

Acetic Acid 1-Methyl-3-(1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)-prop-2-ynyl Ester (23)

Compound 49e was obtained by Sonogashira coupling of 47 (1.13 g, 2.9 mmol) and (±)-3-butyn-2-ol (230 μL, 2.9 mmol). Purification of the crude by flash chromatography (n-hexane/EtOAc, 2:1 + 1% Et₃N; R_f = 0.13) afforded pure propargyl alcohol 49e which was used immediately in the next step. ¹H NMR (400 MHz, CDCl₃): δ 7.66 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.94–5.92 (m, 1H), 4.61 (q, J = 6.8 Hz, 1H), 3.65–3.62 (m, 2H), 3.16 (t, J = 5.6 Hz, 2H), 2.43 (s, 3H), 2.32–2.28 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H). Acetylation of compound 49e afforded 23, which was purified by flash chromatography (n-hexane/EtOAc, 4:1 + 1% Et₃N; R_f = 0.29). Pure 23 was obtained as a thick yellow oil (572 mg, 56% over 2 steps from 47). ¹H NMR (400 MHz, CDCl₃): δ 7.63 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.95–5.93 (m, 1H), 5.50 (q, J = 6.8 Hz, 1H), 3.62–3.59 (m, 2H), 3.14 (t, J = 6.0 Hz, 2H), 2.41 (s, 3H), 2.30–2.26 (m, 2H), 2.04 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃): δ 169.7, 143.7, 132.9, 129.7 (2 C), 129.4, 127.6 (2 C), 118.5, 87.1, 83.7, 60.5, 44.8, 42.3, 29.1, 21.4, 21.3, 21.0. MS (ESI) m/z (%): 370 ([M + Na]⁺, 100). IR (CHCl₃): 3028, 3014, 2940, 2858, 2232, 1734, 1343, 1230 cm^–1. Anal. Calcd for C₁₈H₂₁NO₄S: C, 62.23; H, 6.09; N, 4.03; S, 9.23. Found: C, 62.15; H, 6.19; N, 3.80; S, 8.90.

Acetic Acid 3-(3,6-Dihydro-2H-pyran-4-yl)-1-methylprop-2-ynyl Ester (24)

Compound 49f was obtained by Sonogashira coupling of 48 (2.0 mmol) and (±)-3-butyn-1-ol (157 μL, 2.0 mmol). Purification of the crude by flash chromatography (n-hexane/EtOAc, 3:1 + 1% Et₃N; R_f = 0.22) afforded pure propargyl alcohol 49f which was used immediately in the next step. ¹H NMR (200 MHz, CDCl₃): δ 6.07–6.04 (m, 1H), 4.65 (q, J = 6.8 Hz, 1H), 4.21–4.18 (m, 2H), 3.77 (t, J = 5.4 Hz, 2H), 2.27–2.19 (m, 2H), 1.47 (d, J = 6.4 Hz, 3H). Acetylation of compound 49f afforded 24, which was purified by flash chromatography (n-hexane/EtOAc, 30:1 + 1% Et₃N; R_f = 0.24). Pure 24 was obtained as a colorless oil (266 mg, 69% over 2 steps from S7). ¹H NMR (400 MHz, CDCl₃): δ 6.13–6.06 (m, 1H), 5.57 (q, J = 6.8 Hz, 1H), 4.22–4.12 (m, 2H), 3.76 (t, J = 5.6 Hz, 2H), 2.26–2.16 (m, 2H), 2.07 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃): δ 169.8, 133.3, 117.6, 86.4, 84.2, 65.2, 63.7, 60.6, 28.9, 21.4, 21.0. MS (ESI) m/z (%): 217 ([M + Na]⁺, 100). IR (CHCl₃): 3028, 2937, 2863, 2832, 2230, 1734, 1238 cm^–1. Anal. Calcd for C₁₁H₁₄O₃: C, 68.02; H, 7.27. Found: C, 67.95; H, 7.35.

Acetic Acid 3-Cyclohept-1-enyl-1-methylprop-2-ynyl Ester (25)

Propargyl alcohol 49g was prepared as reported.²³ Acetylation of compound 49g (63 mg, 0.38 mmol) afforded 25, which was purified by flash chromatography (n-hexane/EtOAc, 40:1 + 1% Et₃N; R_f = 0.29). Pure 25 was obtained as a colorless oil (54 mg, 69%). ¹H NMR (400 MHz, CDCl₃): δ 6.31 (t, J = 6.4 Hz, 1H), 5.58 (q, J = 6.4 Hz, 1H), 2.32–2.29 (m, 2H), 2.19–2.15 (m, 2H), 2.07 (s, 3H), 1.76–1.69 (m, 2H), 1.58–1.52 (m, 3H), 1.51–1.47 (m, 2H), 1.48 (d, J = 6.4 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃): δ 169.9, 141.0, 125.9, 88.0, 84.5, 61.0, 34.0, 32.0, 29.1, 26.5, 26.4, 21.6, 21.1. MS (ESI) m/z (%): 229 ([M + Na]⁺, 100). IR (CHCl₃): 3020, 2927, 2853, 2221, 1733, 1449, 1372, 1233 cm^–1. Anal. Calcd for C₁₃H₁₈O₂: C, 75.69; H, 8.80. Found: C, 75.70; H, 8.80.

Acetic Acid 3-Cyclohept-1-enyl-1-isopropylprop-2-ynyl Ester (26)

Propargyl alcohol 49h was prepared as reported.²⁶ Acetylation of compound 49h (260 mg, 1.35 mmol) afforded 26, which was purified by flash chromatography (n-hexane/EtOAc, 30:1 + 1% Et₃N; R_f = 0.28). Pure 26 was obtained as a pale-yellow oil (297 mg, 94%). ¹H NMR (400 MHz, CDCl₃): δ 6.30 (t, J = 6.4 Hz, 1H), 5.35 (d, J = 5.6 Hz, 1H), 2.33–2.29 (m, 2H), 2.19–2.14 (m, 2H), 2.08 (s, 3H), 2.03–1.94 (m, 1H), 1.76–1.69 (m, 2H), 1.58–1.47 (m, 4H), 1.01 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃): δ 170.0, 140.7, 126.0, 89.2, 82.2, 69.6, 34.0, 32.6, 32.0, 29.1, 26.44, 26.37, 21.0, 18.2, 17.5. MS (ESI) m/z (%): 257 ([M + Na]⁺, 100). IR (CHCl₃): 3032, 2969, 2927, 2854, 2213, 1733, 1448, 1372, 1236 cm^–1. Anal. Calcd for C₁₅H₂₂O₂: C, 76.88; H, 9.46. Found: C, 76.90; H, 9.46.

Acetic Acid 3-Cyclohept-1-enyl-1-butylprop-2-ynyl Ester (27)

Propargyl alcohol 49i was prepared as reported.²⁶ Acetylation of compound 49i (323 mg, 1.57 mmol) afforded 27, which was purified by flash chromatography (n-hexane/EtOAc, 30:1 + 1% Et₃N; R_f = 0.45). Pure 27 was obtained as a colorless oil (366 mg, 94%). ¹H NMR (400 MHz, CDCl₃): δ 6.30 (t, J = 6.8 Hz, 1H), 5.48 (t, J = 6.8 Hz, 1H), 2.32–2.28 (m, 2H), 2.19–2.14 (m, 2H), 1.78–1.69 (m, 4H), 1.57–1.46 (m, 4H), 1.42–1.31 (m, 4H), 0.91 (t, J = 6.4 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃): δ 170.0, 140.8, 126.0, 88.6, 83.7, 64.7, 34.7, 34.0, 32.0, 29.1, 27.2, 26.42, 26.35, 22.2, 21.1, 13.9. MS (ESI) m/z (%): 519 ([2 M + Na]⁺, 42), 271 ([M + Na]⁺, 100). IR (CHCl₃): 3027, 2929, 2855, 2216, 1734, 1457, 1374, 1230 cm^–1. Anal. Calcd for C₁₆H₂₄O₂: C, 77.38; H, 9.74. Found: C, 77.40; H, 9.79.

General Procedure for the Gold(I)-Catalyzed Cycloisomerization/Hetero-Diels–Alder/Ring-Opening Tandem Reaction

The solution of propargyl acetates 9 and 20–27 in the eluent used for chromatography was concentrated and dried under vacuum just prior to use. Water (0.7 mmol, 3.5 equiv) was added to a solution of commercially available gold(I) complex ^tBu₃PAuNTf₂ (4.0 μmol, 2 mol %) in DCM (2 mL) and stirred at 25 °C under a nitrogen atmosphere, followed by the addition of a solution of propargyl acetate (0.2 mmol) and the dienophile (0.2 mmol, 1.0 equiv) in DCM (2 mL; final concentration of the acetate: 0.05 M). The reaction mixture was stirred at 25 °C until complete consumption of the starting material (TLC monitoring; usually 0.5–4 h). Aqueous saturated NaHCO₃ (4 mL) was added, and the reaction mixture was vigorously stirred at 25 °C for 20 min; after separation of the phases, the product was extracted with DCM (5 mL), and the combined organic extracts were dried over anhydrous Na₂SO₄. After filtration and evaporation of the solvent, the oily residue was purified by flash chromatography.

Diethyl (3aS,7aR)-1-(1-Methyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (12)

Compound 12 was prepared following the general procedure, starting from acetate 9 (52 mg, 0.27 mmol) and DEAD. The reaction was complete in 30 min. Purification by flash chromatography (EtOAc/n-hexane, 1:2; R_f = 0.20) afforded 12 (83 mg, 95%) as a white solid. mp 98.9–100.1 °C. ¹H NMR (400 MHz, CDCl₃) (3.3 : 1 mixture of rotamers): δ 6.70 (br s, 1H, major), 6.47 (br s, 1H, minor), 5.98 (br s, 1H), 4.29–4.19 (m, 2H), 4.18–4.06 (m, 2H), 3.40 (br s, 1H, major), 3.33 (br s, 1H, minor), 2.09 (s, 3H), 2.01–1.91 (m, 3H), 1.64–1.56 (m, 1H), 1.53–1.42 (m, 2H), 1.39–1.25 (m, 1H), 1.30 (t, J = 6.8 Hz, 3H), 1.19 (t, J = 6.8 Hz, 3H), 1.14–1.06 (m, 1H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 206.6 and 206.2, 176.8 and 176.2, 156.8 and 156.6, 154.8 and 154.7, 127.6 and 127.3, 68.6, 62.4 and 62.2, 62.0, 48.1 and 47.8, 29.2 and 29.0, 21.7 and 21.6, 20.3 and 20.1, 20.0 and 19.8, 17.3, 14.42 and 14.36, 14.3 and 14.1. MS (ESI) m/z (%): 671 ([2M+ Na]⁺, 70), 347 ([M + Na]⁺, 100). IR (CHCl₃): 3393, 3027, 2943, 1749, 1714, 1617, 1379, 1229, 1203 cm^–1. Anal. Calcd for C₁₆H₂₄N₂O₅: C, 59.24; H, 7.46; N, 8.64. Found: C, 59.53; H, 7.66; N, 8.36. On carrying out the reaction under the conditions reported in Table 1 entry 4 (see text), a 1:1 mixture of compounds 12 and 13 was obtained. A small amount of compound 13 could be isolated by flash chromatography (eluent: EtOAc/n-hexane, 1:4 + 1% Et₃N; R_f = 0.24) and spectroscopically characterized. 13: ¹H NMR (400 MHz, CDCl₃) (3:1 mixture of rotamers): δ 6.00 (m, 1H, minor), 5.97 (m, 1H, major), 4.37–4.01 (m, 4H), 3.36 (br s, 1H, major), 3.28 (br s, 1H, minor), 2.57 (s, 3H, minor), 2.50 (s, 3H, major), 2.09 (s, 3H, major), 2.07 (s, 3H, minor), 2.04–1.93 (m, 1H), 1.87–1.82 (m, 1H), 1.74–1.65 (m, 2H), 1.55–1.46 (m, 1H), 1.43–1.36 (m, 3H), 1.30–1.22 (m, 2H), 1.20–1.08 (m, 4H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers, major rotamer reported): δ 205.1, 179.7, 171.6, 153.7, 153.4, 129.1, 69.8, 64.0, 62.5, 49.7, 27.2, 24.4, 21.2, 17.6, 17.4, 17.3, 14.4, 14.1. MS (ESI) m/z (%): 755 ([2 M + Na]⁺, 100), 389 ([M + Na]⁺, 33), 367 ([M + 1]⁺, 2). IR (CHCl₃): 3033, 2985, 2943, 1717, 1623, 1377, 1336, 1259 cm^–1. Compound 12 was also synthesized on a larger scale, starting from acetate 9 (250 mg, 1.3 mmol) and affording, after purification by flash chromatography, pure 12 (404 mg, 96%) as a white solid.

Diisopropyl (3aS,7aR)-1-(1-Methyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (28)

Compound 28 was prepared following the general procedure, starting from acetate 9 (53 mg, 0.27 mmol) and DIAD. The reaction was complete in 30 min. Purification by flash chromatography (EtOAc/n-hexane, 1:3; R_f = 0.14) afforded 28 (90 mg, 95%) as a white solid. mp 132.6–134.0 °C. ¹H NMR (400 MHz, CDCl₃) (2.9 : 1 mixture of rotamers): δ 6.66 (br s, 1H, major), 6.48 (br s, 1H, minor), 5.99 (s, 1H, minor), 5.97 (s, 1H, major), 5.04–4.91 (m, 1H), 4.87–4.80 (m, 1H), 3.39 (br s, 1H, major), 3.31 (br s, 1H, minor), 2.07 (s, 3H), 1.98–1.92 (m, 3H), 1.61–1.56 (m, 1H), 1.50–1.40 (m, 2H), 1.32–1.25 (m, 1H), 1.28 (d, J = 6.0 Hz, 3H), 1.27 (d, J = 6.0 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H), 1.11–1.06 (m, 1H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 206.7, 176.8 and 176.2, 156.6, 154.4, 127.8 and 127.4, 70.4 and 70.2, 69.9, 68.7 and 68.4, 48.3 and 47.9, 29.3 and 29.0, 21.95 (2 C), 21.89, 21.86, 21.7, 20.3, 20.1, 17.3. MS (ESI) m/z (%): 727 ([2 M + Na]⁺, 100), 375 ([M + Na]⁺, 39). IR (CHCl₃): 3397, 3031, 2985, 2941, 1734, 1710, 1376, 1240 cm^–1. Anal. Calcd for C₁₈H₂₈N₂O₅: C, 61.34; H, 8.01; N, 7.95. Found: C, 61.39; H, 8.08; N, 7.47.

Dibenzyl (3aS,7aR)-1-(1-Methyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (29)

The solution of propargyl acetate 9 in EtOAc/n-hexane and 1:20 + 1% Et₃N was concentrated and dried under vacuum just prior to use. Gold(I) complex IPrAuSbF₆ was generated in situ by mixing IPrAuCl (2.4 mg, 4.9 μmol, 2 mol %) and AgSbF₆ (1.7 mg, 4.9 μmol, 2 mol %) in DCM (2.5 mL) and leaving the mixture under stirring for 5 min at 25 °C before adding the substrates. In a round bottom flask containing acetate 9 (47 mg, 0.24 mmol) and dibenzyl azodicarboxylate (80 mg, 0.27 mmol), DCM (2.4 mL) was added, and the resulting solution was immediately transferred into the flask containing the gold(I) complex. The reaction mixture was stirred until complete consumption of the starting material (1.75 h). Aqueous saturated NaHCO₃ (5 mL) was added, and the reaction mixture was vigorously stirred at 25 °C for 20 min; after separation of the phases, the product was extracted with DCM (5 mL), and the combined organic extracts were dried over anhydrous Na₂SO₄. After filtration and evaporation of the solvent, the oily residue was purified by flash chromatography (eluent: EtOAc/n-hexane, 1:2; R_f = 0.32), affording pure 29 (90 mg, 84%) as a white foam. ¹H NMR (400 MHz, CDCl₃) (2.5 : 1 mixture of rotamers): δ 7.32–7.29 (m, 8H), 7.24–7.21 (m, 2H), 6.96 (br s, 1H, major), 6.71 (br s, 1H, minor), 5.95 (s, 1H), 5.19–4.96 (m, 4H), 3.41 (m, 1H, major), 3.17 (m, 1H, minor), 2.04 (s, 3H, major), 1.97–1.93 (m, 3H and 3H minor), 1.61–1.56 (m, 1H), 1.51–1.37 (m, 2H), 1.32–1.26 (m, 1H), 1.14–1.04 (m, 1H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 206.5 and 206.3, 177.1 and 176.6, 156.7 and 156.4, 154.7 and 154.6, 135.6 and 135.4 (2 C), 128.5 (2 C), 128.32 (2 C), 128.29 (2 C), 128.0 (2 C), 127.8 (2 C), 127.4, 68.9 and 68.8, 68.1 and 68.0, 67.7 and 67.6, 48.1 and 47.7, 29.2 and 28.9, 21.7 and 21.3, 20.3, 20.0 and 19.6, 17.3. MS (ESI) m/z (%): 919 ([2 M + Na]⁺, 100), 471 ([M + Na]⁺, 45), 449 ([M + 1]⁺, 25). IR (CHCl₃): 3395, 3029, 2945, 1749, 1717, 1617, 1233 cm^–1. Anal. Calcd for C₂₆H₂₈N₂O₅: C, 69.63; H, 6.29; N, 6.25. Found: C, 69.56; H, 6.31; N, 6.28.

Diethyl (3aS,7aR)-1-(1-Butyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (30)

Compound 30 was prepared following the general procedure, starting from acetate 20 (42 mg, 0.18 mmol) and DEAD. The reaction was complete in 30 min. Purification by flash chromatography (EtOAc/n-hexane, 1:2; R_f = 0.29) afforded 30 (60 mg, 91%) as a white solid. mp 70.5–73.0 °C. ¹H NMR (400 MHz, CDCl₃) (3.1 : 1 mixture of rotamers): δ 7.04 (br s, 1H, major), 6.81 (br s, 1H, minor), 5.93 (s, 1H), 4.22–4.13 (m, 2H), 4.11–3.99 (m, 2H), 3.39 (br s, 1H, major), 3.32 (br s, 1H, minor), 2.39–2.22 (m, 2H), 1.98–1.86 (m, 3H), 1.60–1.48 (m, 3H), 1.48–1.30 (m, 5H), 1.26 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 6.8 Hz, 3H), 1.10–0.99 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 206.8 and 206.5, 181.0 and 180.4, 156.9 and 156.7, 154.8, 125.7 and 125.5, 68.6, 62.4, 62.0, 47.2 and 46.9, 30.7, 29.3 and 29.1, 28.6, 22.4, 21.9 and 21.8, 20.5 and 20.3, 20.2 and 20.0, 14.4, 14.1, 13.7. MS (ESI) m/z (%): 755 ([2 M + Na]⁺, 100), 389 ([M + Na]⁺, 64). IR (CHCl₃): 3398, 3027, 2939, 2874, 1749, 1715, 1379, 1230 cm^–1. Anal. Calcd for C₁₉H₃₀N₂O₅: C, 62.27; H, 8.25; N, 7.64. Found: C, 62.27; H, 8.34; N, 7.37.

Diisopropyl (3aS,7aR)-1-(1-Butyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (31)

Compound 31 was prepared following the general procedure, starting from acetate 20 (43 mg, 0.18 mmol) and DIAD. The reaction was complete in 30 min. Purification by flash chromatography (EtOAc/n-hexane, 1:2; R_f = 0.33) afforded 31 (67 mg, 92%) as a white solid. mp 82.7–84.5 °C. ¹H NMR (400 MHz, CDCl₃) (2.9 : 1 mixture of rotamers): δ 6.59 (br s, 1H, major), 6.38 (br s, 1H, minor), 5.99 (s, 1H, minor), 5.96 (s, 1H, major), 5.03–4.94 (m, 1H), 4.89–4.83 (m, 1H), 3.43 (br s, 1H, major), 3.36 (br s, 1H, minor), 2.42–2.26 (m, 2H), 2.01–1.93 (m, 3H), 1.65–1.55 (m, 3H), 1.49–1.35 (m, 5H), 1.293 (d, J = 6.4 Hz, 3H), 1.288 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 1.12–1.07 (m, 1H), 0.94 (t, J = 7.6 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 206.8, 180.8 and 180.3, 156.7 and 156.5, 154.5, 125.9 and 125.6, 70.4 and 70.2, 69.9, 68.4, 47.4 and 47.1, 30.7, 29.5, 28.7, 22.6, 22.0 (2 C), 21.9, 21.7 and 21.6 (2 C), 20.6, 20.4, 13.8. MS (ESI) m/z (%): 811 ([2 M + Na]⁺, 72), 417 ([M + Na]⁺, 100). IR (CHCl₃): 3397, 3015, 2985, 2939, 2875, 1748, 1707, 1385, 1240 cm^–1. Anal. Calcd for C₂₁H₃₄N₂O₅: C, 63.93; H, 8.69; N, 7.10. Found: C, 63.90; H, 7.25; N, 8.74.

Diethyl (3aS,7aR)-1-(1-Isopropyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (32)

Compound 32 was prepared following the general procedure, starting from acetate 21 (41 mg, 0.19 mmol) and DEAD. The reaction was complete in 30 min. Purification by flash chromatography (EtOAc/n-hexane, 1:2; R_f = 0.23) afforded 32 (56 mg, 85%) as a white solid. mp 118.5–122.7 °C. ¹H NMR (400 MHz, CDCl₃) (4.6 : 1 mixture of rotamers): δ 6.75 (br s, 1H, major), 6.53 (br s, 1H, minor), 5.97 (s, 1H, minor), 5.95 (s, 1H, major), 4.27–4.17 (m, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.51 (m, 1H, major), 3.45 (m, 1H, minor), 2.59 (quint, J = 6.8 Hz, 1H), 2.02–1.91 (m, 3H), 1.63–1.57 (m, 1H), 1.53–1.42 (m, 2H), 1.40–1.32 (m, 1H), 1.30 (t, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H), 1.18–1.12 (m, 1H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 207.1 and 206.7, 186.2 and 185.6, 157.0 and 156.7, 154.9, 124.0 and 123.7, 69.0 and 68.9, 62.4 and 62.3, 62.2 and 62.0, 46.2 and 45.8, 29.6 and 29.3, 29.1 and 29.0, 21.9 and 21.8, 21.0, 20.5 and 20.4, 20.2, 20.1 and 19.9, 14.45 and 14.38, 14.3 and 14.2. MS (ESI) m/z (%): 727 ([2M + Na]⁺, 100), 375 ([M + Na]⁺, 22). IR (CHCl₃): 3395, 3031, 2942, 2874, 1749, 1715, 1339, 1233 cm^–1. Anal. Calcd for C₁₈H₂₈N₂O₅: C, 61.34; H, 8.01; N, 7.95. Found: C, 61.32; H, 8.04; N, 7.91.

Diisopropyl (3aS,7aR)-1-(1-Isopropyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (33)

Compound 33 was prepared following the general procedure, starting from acetate 21 (43 mg, 0.19 mmol) and DIAD. The reaction was complete in 60 min. Purification by flash chromatography (EtOAc/n-hexane, 1:4; R_f = 0.28) afforded 33 (61 mg, 83%) as a white solid. mp 131.0–133.8 °C. ¹H NMR (400 MHz, CDCl₃) (3.2 : 1 mixture of rotamers): δ 6.62 (br s, 1H, major), 6.41 (br s, 1H, minor), 5.97 (s, 1H, minor), 5.94 (s, 1H, major), 5.00–4.94 (m, 1H), 4.88–4.82 (m, 1H), 3.51 (br s, 1H, major), 3.44 (br s, 1H, minor), 2.62–2.56 (m, 1H), 2.05–1.88 (m, 3H), 1.63–1.58 (m, 1H), 1.50–1.43 (m, 2H), 1.41–1.33 (m, 1H), 1.29 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.0 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.18–1.14 (m, 9H), 1.13–1.05 (m, 1H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 207.0, 185.8 and 185.4, 156.7, 154.4, 124.2 and 123.7, 70.4, 69.8, 68.8, 46.3 and 46.0, 29.5, 29.0, 22.0, 21.92 (2 C), 21.86, 21.7, 21.0, 20.6, 20.3, 20.1. MS (ESI) m/z (%): 783 ([2M+ Na]⁺, 100), 403 ([M + Na]⁺, 38). IR (CHCl₃): 3393, 3031, 2984, 2941, 2876, 1746, 1712, 1385, 1233 cm^–1. Anal. Calcd for C₂₀H₃₂N₂O₅: C, 63.13; H, 8.48; N, 7.36. Found: C, 63.06; H, 8.59; N, 7.66.

Diethyl (3aS,7aR)-1-(1-Phenyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (34)

Compound 34 was prepared following the general procedure, starting from acetate 22 (53 mg, 0.21 mmol) and DEAD, without water addition. The reaction was complete in 50 min. Purification by flash chromatography (EtOAc/n-hexane, 1:2; R_f = 0.24) afforded 34 (55 mg, 68%) as a white foam. ¹H NMR (400 MHz, CDCl₃) (2.8 : 1 mixture of rotamers): δ 7.52–7.46 (m, 2H), 7.44–7.39 (m, 3H), 7.01 (br s, 1H, major), 6.87 (br s, 1H, minor), 6.42–6.38 (m, 1H), 4.30–4.16 (m, 2H), 4.09 (q, J = 7.2 Hz, 2H), 4.06 (br s, 1H, major), 3.90 (br s, 1H, minor), 2.08–1.96 (m, 2H), 1.94–1.85 (m, 1H), 1.68–1.61 (m, 1H), 1.47–1.37 (m, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.17–1.12 (m, 3H), 1.08–1.02 (m, 1H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 206.9, 175.8, 157.0, 154.9, 134.0, 130.3, 128.7 (2 C), 127.4 (2 C), 126.9, 69.0, 62.6, 62.1, 46.5 and 46.0, 28.7 and 28.5, 22.3 and 22.1, 18.5, 18.2 and 18.1, 14.5, 14.4 and 14.2. MS (ESI) m/z (%): 795 ([2M + Na]⁺, 100), 409 ([M + Na]⁺, 30). IR (CHCl₃): 3400, 3027, 3015, 2946, 2873, 1748, 1707, 1337 cm^–1. Anal. Calcd for C₂₁H₂₆N₂O₅: C, 65.27; H, 6.78; N, 7.25. Found: C, 65.29; H, 7.13; N, 7.20.

Diisopropyl (3aS,7aR)-1-(1-Phenyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (35)

Compound 35 was prepared following the general procedure, starting from acetate 22 (68 mg, 0.27 mmol) and DIAD, without water addition. The reaction was complete in 30 min. Purification by flash chromatography (EtOAc/n-hexane, 1:3; R_f = 0.23) afforded 35 (79 mg, 71%) as a white foam. ¹H NMR (400 MHz, CDCl₃) (4.5 : 1 mixture of rotamers): δ 7.51–7.49 (m, 2H), 7.43–7.41 (m, 3H), 6.73 (br s, 1H, major), 6.52 (br s, 1H, minor), 6.42 (s, 1H, minor), 6.39 (s, 1H, major), 5.06–4.95 (m, 1H), 4.89–4.83 (m, 1H), 4.00 (m, 1H, major), 3.90 (m, 1H, minor), 2.08–1.96 (m, 2H), 1.94–1.85 (m, 1H), 1.66–1.60 (m, 1H), 1.48–1.38 (m, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.4 Hz, 3H), 1.19–1.14 (m, 6H), 1.08–1.02 (m, 1H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 206.8, 175.6 and 175.0, 156.8 and 156.4, 154.5, 134.3, 130.3, 128.7 (2 C), 127.4 (2 C), 126.9, 70.6, 70.2 and 70.0, 69.0 and 68.8, 46.6 and 46.2, 28.8 and 28.5, 22.1, 22.0, 21.9 (2 C), 21.7, 18.5, 18.3. MS (ESI) m/z (%): 851 ([2M + Na]⁺, 100), 437 ([M + Na]⁺, 47). IR (CHCl₃): 3400, 3026, 2985, 2942, 2874, 1746, 1707, 1376, 1244 cm^–1. Anal. Calcd for C₂₃H₃₀N₂O₅: C, 66.65; H, 7.30; N, 6.76. Found: C, 66.38; H, 7.30; N, 6.61.

Diethyl (4aS,7aR)-1-(7-Methyl-5-oxo-2-tosyl-1,2,3,4,5,7a-hexahydro-[2]pyrindin-4a-yl)-hydrazine 1,2-Dicarboxylate (36)

Compound 36 was prepared following the general procedure, starting from acetate 23 (48 mg, 0.14 mmol) and DEAD. The reaction was complete in 4 h. Purification by flash chromatography (EtOAc/n-hexane, 1:1; R_f = 0.29) afforded 36 (51 mg, 76%) as a white solid. mp 210.4–211.7 °C. ¹H NMR (400 MHz, CDCl₃) (2.8 : 1 mixture of rotamers): δ 7.61 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.05 (br s, 1H, major), 6.74 (br s, 1H, minor), 6.02 (s, 1H), 4.11–3.87 (m, 5H), 3.72–3.62 (m, 1H, minor), 3.44–3.34 (m, 2H), 2.93 (dd, J = 12.4, 3.2 Hz, 1H, major), 2.71 (br d, J = 12.4 Hz, 1H, minor), 2.39 (s, 3H), 2.43–2.34 (m, 1H), 2.19 (s, 3H), 2.03–1.97 (m, 1H), 1.86–1.79 (m, 1H), 1.14–1.06 (m, 6H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 204.0, 175.3, 156.8, 154.6, 143.5, 132.9, 129.6 (2 C), 127.8, 127.5 (2 C), 66.4 and 66.1, 62.8 and 62.6, 62.2, 48.5 and 48.1, 42.2, 42.0, 28.9, 21.4, 17.2, 14.2, 14.1. MS (ESI) m/z (%): 981 ([2M + Na]⁺, 100), 502 ([M + Na]⁺, 32), 480 ([M + 1]⁺, 8). IR (CHCl₃): 3392, 3032, 2985, 2873, 1748, 1717, 1328, 1233 cm^–1. Anal. Calcd for C₂₂H₂₉N₃O₇S: C, 55.10; H, 6.10; N, 8.76; S, 6.69. Found: C, 55.02; H, 6.13; N, 8.74; S, 6.68.

Diisopropyl (4aS,7aR)1-(7-Methyl-5-oxo-2-tosyl-1,2,3,4,5,7a-hexahydro-[2]pyrindin-4a-yl)-hydrazine 1,2-Dicarboxylate (37)

Compound 37 was prepared following the general procedure, starting from acetate 23 (190 mg, 0.55 mmol) and DIAD. The reaction was complete in 4.5 h. Purification by flash chromatography (EtOAc/n-hexane, 1:2; R_f = 0.05) afforded 37 (220 mg, 79%) as a white solid. mp 200.1–201.5 °C. ¹H NMR (400 MHz, CDCl₃) (6 : 1 mixture of rotamers): δ 7.61 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.71 (br s, 1H, major), 6.47 (br s, 1H, minor), 6.05 (s, 1H, minor), 6.02 (s, 1H, major), 4.83–4.77 (m, 1H), 4.64–4.58 (m, 1H), 4.02 (d, J = 12.8 Hz, 1H), 3.48–3.33 (m, 2H), 2.91 (dd, J = 12.8, 4.0 Hz, 1H, major), 2.81 (dd, J = 12.4, 4.4 Hz, 1H, minor), 2.58–2.50 (m, 1H, minor), 2.39 (s, 3H), 2.35–2.28 (m, 1H), 2.20 (s, 3H), 2.03–1.97 (m, 1H), 1.88–1.80 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.0 Hz, 3H), 0.74 (d, J = 6.0 Hz, 3H, minor). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 203.8, 174.9, 156.3, 154.2, 143.9 and 143.5, 132.9, 129.9 and 129.6 (2 C), 127.7, 127.5 and 127.4 (2 C), 71.0, 70.5 and 70.3, 65.8, 48.4, 42.5 and 42.1, 42.3 and 41.9, 29.1 and 28.9, 21.9 and 21.8, 21.7, 21.6, 21.4 and 21.3 (2 C), 17.2. MS (ESI) m/z (%): 1037 ([2M + Na]⁺, 100), 530 ([M + Na]⁺, 87). IR (CHCl₃): 3394, 3031, 2985, 1746, 1717, 1623, 1246 cm^–1. Anal. Calcd for C₂₄H₃₃N₃O₇S: C, 56.79; H, 6.55; N, 8.28; S, 6.32. Found: C, 56.83; H, 6.59; N, 8.18; S, 6.30.

Diethyl (4aS,7aR)-1-(7-Methyl-5-oxo-3,4,5,7a-tetrahydro-1H-cyclopenta[c]pyran-4a-yl)-hydrazine 1,2-Dicarboxylate (38)

Compound 38 was prepared following the general procedure, starting from acetate 24 (81 mg, 0.42 mmol) and DEAD. The reaction was complete in 60 min. Purification by flash chromatography (EtOAc/n-hexane, 1:1; R_f = 0.39) afforded 38 (125 mg, 92%) as a white solid. mp 41.7–46.5 °C. ¹H NMR (400 MHz, CDCl₃) (5.8 : 1 mixture of rotamers): δ 6.81 (br s, 1H, major), 6.59 (br s, 1H, minor), 6.04 (s, 1H), 4.30–4.19 (m, 3H), 4.17–4.08 (m, 2H), 3.99 (dd, J = 12.8, 4.0 Hz, 1H, major), 3.86 (dd, J = 12.4, 4.0 Hz, 1H, minor), 3.77–3.72 (m, 1H), 3.36 (td, J = 11.2, 2.0 Hz, 1H), 3.21 (m, 1H, major), 3.17 (m, 1H, minor), 2.17 (s, 3H), 2.06–1.98 (m, 1H), 1.84–1.76 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 205.1 and 204.8, 175.1 and 174.4, 157.0 and 156.5, 154.8, 127.7 and 127.4, 65.9 and 65.8, 63.5, 63.3 and 63.1, 62.7, 62.4 and 62.3, 48.2 and 47.9, 29.3 and 29.0, 17.2, 14.4 and 14.3, 14.2 and 14.1. MS (ESI) m/z (%): 675 ([2M + Na]⁺, 100), 349 ([M + Na]⁺, 25), 327 ([M + 1]⁺, 2). IR (CHCl₃): 3393, 3028, 3014, 2985, 2878, 1749, 1718, 1379, 1239 cm^–1. Anal. Calcd for C₁₅H₂₂N₂O₆: C, 55.21; H, 6.79; N, 8.58. Found: C, 55.20; H, 6.80; N, 8.56.

Diethyl (3aS,8aR)-1-(1-Methyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (39)

Compound 39 was prepared following the general procedure, starting from acetate 25 (46 mg, 0.22 mmol) and DEAD, without water addition. The reaction was complete in 2 h. Purification by flash chromatography (EtOAc/n-hexane, 1:3; R_f = 0.13) afforded 39 (64 mg, 85%) as a white solid. mp 130.8–132.3 °C. ¹H NMR (400 MHz, CDCl₃) (9 : 1 mixture of diastereoisomers; major diastereoisomer as a 4.3 : 1 mixture of rotamers): δ 6.62 (br s, 1H major rotamer), 6.55 (br s, 1H, minor diastereoisomer), 6.39 (br s, 1H minor rotamer), 6.12 (s, 1H, both rotamers), 6.02 (s, 1H, minor diastereoisomer), 4.28–4.13 (m, 2H), 4.11–3.99 (m, 2H), 3.69 (m, 1H, minor diastereoisomer), 3.48 (m, 1H, major rotamer), 3.33 (m, 1H, minor rotamer), 2.17–2.08 (m, 1H), 2.10 (s, 3H), 2.02–1.96 (m, 1H), 1.91–1.82 (m, 1H), 1.71–1.58 (m, 4H), 1.30 (t, J = 6.8 Hz, 3H), 1.22–1.14 (m, 1H), 1.16 (t, J = 6.8 Hz, 3H), 1.12–1.04 (m, 1H), 1.03–0.93 (m, 1H), 0.90–0.80 (m, 2H, minor rotamer). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of diastereoisomers and rotamers; major rotamer of the major diastereoisomer reported): δ 207.5, 179.6, 156.8, 154.7, 130.4, 72.6, 62.4, 62.1, 54.2, 35.0, 31.5, 31.0, 25.4, 22.6, 17.6, 14.4, 14.0. MS (ESI) m/z (%): 699 ([2M+ Na]⁺, 100), 361 ([M + Na]⁺, 51). IR (CHCl₃): 3406, 3027, 2932, 2859, 1747, 1714, 1379, 1236 cm^–1. Anal. Calcd for C₁₇H₂₆N₂O₅: C, 60.34; H, 7.74; N, 8.28. Found: C, 60.42; H, 7.77; N, 7.96.

Diethyl (3aS,8aR)-1-(1-Isopropyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (40)

Compound 40 was prepared following the general procedure, starting from acetate 26 (61 mg, 0.26 mmol) and DEAD. The reaction was complete in 40 min. Purification by flash chromatography (EtOAc/n-hexane, 1:3; R_f = 0.22) afforded 40 (74 mg, 78%) as a white solid. mp 129.9–132.2 °C. ¹H NMR (400 MHz, CDCl₃) (4.5 : 1 mixture of diastereoisomers; major diastereoisomer as a 3 : 1 mixture of rotamers): δ 6.63 (br s, 1H major rotamer), 6.54 (br s, 1H, minor diastereoisomer), 6.38 (br s, 1H minor rotamer), 6.11 (s, 1H, both rotamers), 6.03 (s, 1H, minor diastereoisomer), 4.32–4.13 (m, 2H), 4.12–3.98 (m, 2H), 3.91 (m, 1H, minor diastereoisomer), 3.64–3.62 (m, 1H, major rotamer), 3.50 (m, 1H, minor rotamer), 2.62–2.51 (m, 1H), 2.19–2.08 (m, 1H), 2.01–1.83 (m, 2H), 1.71–1.58 (m, 4H), 1.30 (t, J = 6.8 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H), 1.22–1.18 (m, 1H), 1.17–1.14 (m, 6H), 1.07–0.94 (m, 2H), 0.91–0.79 (m, 2H, minor rotamer). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of diastereoisomers and rotamers; major rotamer of the major diastereoisomer reported): δ 208.0, 189.3, 157.0, 154.7, 126.6, 72.8, 62.4, 62.1, 51.6, 35.1, 31.1, 29.2, 25.7, 25.6, 22.3, 21.2, 19.9, 14.5, 14.3. MS (ESI) m/z (%): 755 ([2M + Na]⁺, 100), 389 ([M + Na]⁺, 25). IR (CHCl₃): 3420, 3026, 2971, 2932, 2859, 1747, 1710, 1378, 1236 cm^–1. Anal. Calcd for C₁₉H₃₀N₂O₅: C, 62.27; H, 8.25; N, 7.64. Found: C, 62.30; H, 8.27; N, 7.59.

Diisopropyl (3aS,8aR)-1-(1-Isopropyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (41)

Compound 41 was prepared following the general procedure, starting from acetate 26 (69 mg, 0.30 mmol) and DIAD. The reaction was complete in 30 min. Purification by flash chromatography (EtOAc/n-hexane, 1:4; R_f = 0.15) afforded 41 (92 mg, 79%) as a white solid. mp 154.0–158.4 °C. ¹H NMR (400 MHz, CDCl₃) (6.5 : 1 mixture of diastereoisomers; major diastereoisomer as a 4 : 1 mixture of rotamers): δ 6.50 (br s, 1H major rotamer), 6.43 (br s, 1H, minor diastereoisomer), 6.29 (br s, 1H minor rotamer), 6.11 (s, 1H, both rotamers), 6.02 (s, 1H, minor diastereoisomer), 4.99–4.90 (m, 1H), 4.85–4.76 (m, 1H), 3.94 (m, 1H, minor diastereoisomer), 3.63 (d, J = 5.6 Hz, 1H, major rotamer), 3.50 (d, J = 5.6 Hz, 1H, minor rotamer), 2.60–2.51 (m, 1H), 2.15–2.07 (m, 1H), 1.99–1.88 (m, 2H), 1.88–1.81 (m, 1H, major), 1.76–1.58 (m, 4H), 1.33–1.23 (m, 9H), 1.20–1.13 (m, 9H), 1.07–0.93 (m, 2H), 0.91–0.79 (m, 1H, major). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of diastereoisomers and rotamers; major rotamer of the major diastereoisomer reported): δ 208.0, 188.9, 156.7, 154.2, 126.7, 72.7, 70.4, 69.9, 51.6, 35.2, 31.2, 29.2, 25.73, 25.71, 22.2, 22.1, 22.0, 21.8, 21.7, 21.2, 19.9. MS (ESI) m/z (%): 811 ([2M+ Na]⁺, 100), 417 ([M + Na]⁺, 26). IR (CHCl₃): 3404, 3027, 2984, 2933, 2859, 1740, 1706, 1376, 1239 cm^–1. Anal. Calcd for C₂₁H₃₄N₂O₅: C, 63.93; H, 8.69; N, 7.10. Found: C, 63.95; H, 8.70; N, 7.11.

Diethyl (3aS,8aR)-1-(1-Butyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (42)

Compound 42 was prepared following the general procedure, starting from acetate 27 (69 mg, 0.28 mmol) and DEAD. The reaction was complete in 30 min. Purification by flash chromatography (EtOAc/n-hexane, 1:3; R_f = 0.24) afforded 42 (94 mg, 88%) as a white solid. mp 84.2–87.3 °C. ¹H NMR (400 MHz, CDCl₃) (4.7 : 1 mixture of diastereoisomers; major diastereoisomer as a 3.2 : 1 mixture of rotamers): δ 6.81 (br s, 1H major rotamer), 6.63 (br s, 1H, minor diastereoisomer), 6.56 (br s, 1H minor rotamer), 6.11 (s, 1H, both rotamers), 6.01 (s, 1H, minor diastereoisomer), 4.21–3.96 (m, 4H), 3.75 (m, 1H, minor diastereoisomer), 3.50 (m, 1H, major rotamer), 3.35 (m, 1H, minor rotamer), 2.59–2.53 (m, 1H, minor diastereoisomer), 2.44–2.36 (m, 1H), 2.29–2.21 (m, 1H), 2.16–2.05 (m, 1H), 2.02–1.77 (m, 3H), 1.72–1.48 (m, 5H), 1.42–1.34 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.23–1.16 (m, 1H), 1.14 (t, J = 6.8 Hz, 3H), 1.08–0.92 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of diastereoisomers and rotamers; major rotamer of the major diastereoisomer reported): δ 207.7, 183.9, 156.9, 154.7, 128.6, 72.5, 62.4, 62.1, 53.0, 35.0, 31.1, 31.0, 28.9, 25.7, 25.5, 22.5, 22.2, 14.5, 14.2, 13.8. MS (ESI) m/z (%): 783 ([2M+ Na]⁺, 100), 403 ([M + Na]⁺, 61), 381 ([M + 1]⁺, 5). IR (CHCl₃): 3406, 3014, 2933, 2861, 1747, 1711, 1334, 1236 cm^–1. Anal. Calcd for C₂₀H₃₂N₂O₅: C, 63.13; H, 8.48; N, 7.36. Found: C, 63.15; H, 8.48; N, 7.41.

Diethyl (1S,3aS,7aR*)-1-(1-Methyl-3-oxo-octahydroinden-3a-yl)-hydrazine 1,2-Dicarboxylate (43)

To a solution of 12 (160 mg, 0.49 mmol) in MeOH (9.0 mL), 10% Pd/C wet (107 mg, 0.045 mmol) was added under a nitrogen atmosphere. The resulting suspension was first flushed with hydrogen under vigorous stirring and then maintained under a hydrogen atmosphere (balloon) at room temperature. After 2 h, the mixture was filtered over a Celite pad, and the residual solution was evaporated under reduced pressure. The foamy residue was purified by flash chromatography (eluent: EtOAc/n-hexane, 1:4; R_f = 0.18), and pure compound 43 (158 mg, 99%) was obtained as a white foam. ¹H NMR (400 MHz, CDCl₃) (4.1 : 1 mixture of rotamers): δ 6.68–6.45 (m, 1H, major), 6.48–6.44 (m, 1H, minor), 4.29–4.16 (m, 2H), 4.14–4.07 (m, 2H), 2.57–2.48 (m, 2H), 2.25–2.11 (m, 2H), 1.99–1.89 (m, 1H), 1.84–1.65 (m, 2H and 1H major), 1.62–1.48 (m, 2H), 1.40–1.28 (m, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 1.12 (d, J = 6.0 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 215.8 and 215.4, 156.7 and 156.6, 155.3 and 155.2, 69.9 and 69.8, 62.5 and 62.4, 62.2 and 61.9, 44.9 and 44.7, 42.9 and 42.8, 27.9 and 27.8, 26.3 and 26.1, 21.4 and 21.3, 20.3 and 20.2, 19.4 and 19.3, 18.7, 14.5 and 14.4, 14.3 and 14.2. MS (ESI) m/z (%): 675 ([2M+ Na]⁺, 100), 349 ([M + Na]⁺, 27), 327 ([M + 1]⁺, 2). IR (CHCl₃): 3385, 2959, 2937, 1748, 1705, 1379, 1339, 1317, 1234 cm^–1. Anal. Calcd for C₁₆H₂₆N₂O₅: C, 58.88; H, 8.03; N, 8.58. Found: C, 58.91; H, 8.10; N, 8.60.

Diisopropyl (1S,3aS,7aR*)-1-(1-Methyl-3-oxo-octahydroinden-3a-yl)-hydrazine 1,2-Dicarboxylate (44)

It was prepared in the same way as reported for 43, starting from 28 (82 mg, 0.23 mmol) and obtaining, after flash chromatography purification (eluent: EtOAc/n-hexane, 1:4; R_f = 0.21), compound 44 (81 mg, 99%) as a white foam. ¹H NMR (400 MHz, CDCl₃) (3.5 : 1 mixture of rotamers): δ 6.54 (br s, 1H, major), 6.35 (br s, 1H, minor), 5.06–4.94 (m, 1H), 4.88–4.82 (m, 1H), 2.58–2.48 (m, 2H), 2.26–2.12 (m, 2H), 1.96–1.92 (m, 1H, major), 1.87–1.77 (m, 1H, minor), 1.76–1.65 (m, 2H), 1.61–1.47 (m, 2H), 1.34–1.26 (m, 9H), 1.23–1.19 (m, 6H), 1.12 (d, J = 6.4 Hz, 3H). ¹³C{¹H} NMR (100.4 MHz, CDCl₃) (mixture of rotamers): δ 215.53 and 215.50, 156.5 and 156.4, 155.0 and 154.8, 70.5 and 70.4, 70.1 and 70.0, 69.7, 45.0 and 44.7, 42.9 and 42.8, 27.9 and 27.8, 26.5 and 26.1, 22.0, 21.9, 21.86, 21.8, 21.4 and 21.1, 20.3 and 20.2, 19.4, 18.8. MS (ESI) m/z (%): 731 ([2M+ Na]⁺, 51), 377 ([M + Na]⁺, 100), 355 ([M + 1]⁺, 13). IR (CHCl₃): 3393, 2985, 2938, 1748, 1700, 1387, 1375, 1314, 1239 cm^–1. Anal. Calcd for C₁₈H₃₀N₂O₅: C, 61.00; H, 8.53; N, 7.90. Found: C, 60.98; H, 8.57; N, 7.85.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c00310.

Structure assignment by NMR studies; proton NMR experiment carried out in CD₂Cl₂; copies of ¹H and ¹³C{¹H} NMR spectra for all new compounds; ¹H NMR spectra (enlarged view) of compound 12 recorded at variable temperatures (PDF)

The authors declare no competing financial interest.

Supplementary Material

jo3c00310_si_001.pdf^{(5.2MB, pdf)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

jo3c00310_si_001.pdf^{(5.2MB, pdf)}

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

[ref1] Simeonov S. P.; Nunes J. P. M.; Guerra K.; Kurteva V. B.; Afonso C. A. M. Synthesis of Chiral Cyclopentenones. Chem. Rev. 2016, 116, 5744–5893. 10.1021/cr500504w. [DOI] [PubMed] [Google Scholar]

[ref2] Aitken D. J.; Eijsberg H.; Frongia A.; Ollivier J.; Piras P. P. Recent Progress in the Synthetic Assembly of 2-Cyclopentenones. Synthesis 2013, 46, 1–24. 10.1055/s-0033-1340414. [DOI] [Google Scholar]

[ref3] Gibson S. E.; Lewis S. E.; Mainolfi N. Transition metal-mediated routes to cyclopentenones. J. Organomet. Chem. 2004, 689, 3873–3890. 10.1016/j.jorganchem.2004.04.045. [DOI] [Google Scholar]

[ref4] Zhou W.; Voituriez A. Synthesis of Cyclopentenones with C4-Quaternary Stereocenters via Stereospecific [3,3]-Sigmatropic Rearrangement and Applications in Total Synthesis of Sesquiterpenoids. J. Am. Chem. Soc. 2021, 143, 17348–17353. 10.1021/jacs.1c07966. [DOI] [PubMed] [Google Scholar]

[ref5] Wang Y.; Zarca M.; Gong L.-Z.; Zhang L. A C–H Insertion Approach to Functionalized Cyclopentenones. J. Am. Chem. Soc. 2016, 138, 7516–7519. 10.1021/jacs.6b04297. [DOI] [PubMed] [Google Scholar]

[ref6] Matsuda T.; Sakurai Y. Gold(I)-Catalyzed Ring-Expanding Spiroannulation of Cyclopropenones with Enynes. J. Org. Chem. 2014, 79, 2739–2745. 10.1021/jo500045n. [DOI] [PubMed] [Google Scholar]

[ref7] Basmadjian C.; Zhao Q.; Désaubry L. Exploratory studies toward a synthesis of flavaglines. A novel access to a highly substituted cyclopentenone intermediate. Tetrahedron Lett. 2015, 56, 727–730. 10.1016/j.tetlet.2014.12.093. [DOI] [Google Scholar]

[ref8] Zi W.; Toste F. D. Gold(I)-Catalyzed Enantioselective Carboalkoxylation of Alkynes. J. Am. Chem. Soc. 2013, 135, 12600–12603. 10.1021/ja407150h. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref9] Meng F.-T.; Qin X.-Y.; Li J.; Zhang T.-S.; Tu S.-J.; Jiang B.; Hao W.-J. Gold Self-Relay Catalysis Enabling [3,3]-Sigmatropic Rearrangement/Nazarov Cyclization and Allylic Alkylation Cascade for Constructing All-Carbon Quaternary Stereocenters. Chin. J. Chem. 2022, 40, 687–692. 10.1002/cjoc.202100734. [DOI] [Google Scholar]

[ref10] Meng F.-T.; Chen J.-L.; Qin X.-Y.; Zhang T.-S.; Tu S.-J.; Jiang B.; Hao W.-J. Gold self-relay catalysis for accessing functionalized cyclopentenones bearing an all-carbon quaternary stereocenter. Org. Chem. Front. 2022, 9, 140–146. 10.1039/d1qo01313k. [DOI] [Google Scholar]

[ref11] Zhou Y.; Chen X.; Yin D.-L.; Ling Y.; Wang S.-F.; Zhang X.; Rao W.-D. Gold-Catalyzed Cycloisomerization-Halogenation Sequence of 1,3-Enyne Esters with NXS: Efficient Synthesis of 5-Bromo/Iodocyclo-pentenones. Eur. J. Org. Chem. 2019, 2019, 999–1007. 10.1002/ejoc.201801530. [DOI] [Google Scholar]

[ref12] Chen X.; Zhou Y.; Hong M.; Ling Y.; Yin D.; Wang S.; Zhang X.; Rao W. Gold (I)-Catalyzed Tandem Cycloisomerization and Fluorination of 1,3(4)-Enyne Esters with NFSI: One-Pot Assembly of 5-Fluoro-Cyclopentenones. Adv. Synth. Catal. 2018, 360, 3700–3708. 10.1002/adsc.201800701. [DOI] [Google Scholar]

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PERMALINK

Synthesis of 5-Hydrazino-2-cyclopentenone Derivatives by a Gold(I)-Catalyzed Cycloisomerization/Hetero-Diels–Alder/Ring-Opening Tandem Reaction of Enynyl Acetates

Dina Scarpi

Nunzia Favale

Ernesto G Occhiato

Abstract

Introduction

Figure 1.

Scheme 1. Previous (a) and Current Studies (b) on Cycloisomerization/HDA/Ring-Opening Tandem Reactions.

Results and Discussion

Table 1. Survey of the Conditions for the Tandem Reaction Leading to 12a.

Scheme 2. Experiments on Ester 10 in CD2Cl2 for Direct Monitoring by 1H NMR.

Scheme 3. Isolation of the Cycloadduct Intermediate.

Table 2. Substrate Scope of the Optimized Process.

Scheme 4. Hydrogenation of Compounds 12 and 28.

Conclusions

Experimental Section

General Experimental Methods

General Procedure for the Synthesis of the Propargyl Acetates

STEP 1: Sonogashira Coupling

STEP 2: Acetylation

2,2-Dimethylpropionic Acid 3-Cyclohex-1-enyl-1-methylprop-2-ynyl Ester (10)

Acetic Acid 3-Cyclohex-1-enyl-1-butylprop-2-ynyl Ester (20)

Acetic Acid 3-Cyclohex-1-enyl-1-isopropylprop-2-ynyl Ester (21)

Acetic Acid 1-Methyl-3-(1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)-prop-2-ynyl Ester (23)

Acetic Acid 3-(3,6-Dihydro-2H-pyran-4-yl)-1-methylprop-2-ynyl Ester (24)

Acetic Acid 3-Cyclohept-1-enyl-1-methylprop-2-ynyl Ester (25)

Acetic Acid 3-Cyclohept-1-enyl-1-isopropylprop-2-ynyl Ester (26)

Acetic Acid 3-Cyclohept-1-enyl-1-butylprop-2-ynyl Ester (27)

General Procedure for the Gold(I)-Catalyzed Cycloisomerization/Hetero-Diels–Alder/Ring-Opening Tandem Reaction

Diethyl (3aS*,7aR*)-1-(1-Methyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (12)

Diisopropyl (3aS*,7aR*)-1-(1-Methyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (28)

Dibenzyl (3aS*,7aR*)-1-(1-Methyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (29)

Diethyl (3aS*,7aR*)-1-(1-Butyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (30)

Diisopropyl (3aS*,7aR*)-1-(1-Butyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (31)

Diethyl (3aS*,7aR*)-1-(1-Isopropyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (32)

Diisopropyl (3aS*,7aR*)-1-(1-Isopropyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (33)

Diethyl (3aS*,7aR*)-1-(1-Phenyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (34)

Diisopropyl (3aS*,7aR*)-1-(1-Phenyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (35)

Diethyl (4aS*,7aR*)-1-(7-Methyl-5-oxo-2-tosyl-1,2,3,4,5,7a-hexahydro-[2]pyrindin-4a-yl)-hydrazine 1,2-Dicarboxylate (36)

Diisopropyl (4aS*,7aR*)1-(7-Methyl-5-oxo-2-tosyl-1,2,3,4,5,7a-hexahydro-[2]pyrindin-4a-yl)-hydrazine 1,2-Dicarboxylate (37)

Diethyl (4aS*,7aR*)-1-(7-Methyl-5-oxo-3,4,5,7a-tetrahydro-1H-cyclopenta[c]pyran-4a-yl)-hydrazine 1,2-Dicarboxylate (38)

Diethyl (3aS*,8aR*)-1-(1-Methyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (39)

Diethyl (3aS*,8aR*)-1-(1-Isopropyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (40)

Diisopropyl (3aS*,8aR*)-1-(1-Isopropyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (41)

Diethyl (3aS*,8aR*)-1-(1-Butyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (42)

Diethyl (1S*,3aS*,7aR*)-1-(1-Methyl-3-oxo-octahydroinden-3a-yl)-hydrazine 1,2-Dicarboxylate (43)

Diisopropyl (1S*,3aS*,7aR*)-1-(1-Methyl-3-oxo-octahydroinden-3a-yl)-hydrazine 1,2-Dicarboxylate (44)

Data Availability Statement

Supporting Information Available

Supplementary Material

References

Associated Data

Supplementary Materials

Data Availability Statement

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Table 1. Survey of the Conditions for the Tandem Reaction Leading to 12^a.

Scheme 2. Experiments on Ester 10 in CD₂Cl₂ for Direct Monitoring by ¹H NMR.

Diethyl (3aS,7aR)-1-(1-Methyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (12)

Diisopropyl (3aS,7aR)-1-(1-Methyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (28)

Dibenzyl (3aS,7aR)-1-(1-Methyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (29)

Diethyl (3aS,7aR)-1-(1-Butyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (30)

Diisopropyl (3aS,7aR)-1-(1-Butyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (31)

Diethyl (3aS,7aR)-1-(1-Isopropyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (32)

Diisopropyl (3aS,7aR)-1-(1-Isopropyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (33)

Diethyl (3aS,7aR)-1-(1-Phenyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (34)

Diisopropyl (3aS,7aR)-1-(1-Phenyl-3-oxo-3,4,5,6,7,7a-hexahydro-3aH-inden-3a-yl)-hydrazine 1,2-Dicarboxylate (35)

Diethyl (4aS,7aR)-1-(7-Methyl-5-oxo-2-tosyl-1,2,3,4,5,7a-hexahydro-[2]pyrindin-4a-yl)-hydrazine 1,2-Dicarboxylate (36)

Diisopropyl (4aS,7aR)1-(7-Methyl-5-oxo-2-tosyl-1,2,3,4,5,7a-hexahydro-[2]pyrindin-4a-yl)-hydrazine 1,2-Dicarboxylate (37)

Diethyl (4aS,7aR)-1-(7-Methyl-5-oxo-3,4,5,7a-tetrahydro-1H-cyclopenta[c]pyran-4a-yl)-hydrazine 1,2-Dicarboxylate (38)

Diethyl (3aS,8aR)-1-(1-Methyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (39)

Diethyl (3aS,8aR)-1-(1-Isopropyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (40)

Diisopropyl (3aS,8aR)-1-(1-Isopropyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (41)

Diethyl (3aS,8aR)-1-(1-Butyl-3-oxo-4,5,6,7,8,8a-hexahydro-3H-azulen-3a-yl)-hydrazine 1,2-Dicarboxylate (42)

Diethyl (1S,3aS,7aR*)-1-(1-Methyl-3-oxo-octahydroinden-3a-yl)-hydrazine 1,2-Dicarboxylate (43)

Diisopropyl (1S,3aS,7aR*)-1-(1-Methyl-3-oxo-octahydroinden-3a-yl)-hydrazine 1,2-Dicarboxylate (44)