Synthesis of Substituted Tropones by Sequential Rh-Catalyzed [5+2] Cycloaddition and Elimination

Abstract

Highly substituted tropones are prepared from cycloheptatrienes derived from Rh-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and propargylic alcohols. The intermolecular [5+2] cycloaddition is highly regioselective for a variety of propargylic alcohols. Elimination of the cycloaddition products afforded various substituted tropones.

Graphical Abstract

1. Introduction

Tropone 1 and its derivatives such as tropolone 2 are non-benzenoid seven-membered aromatic compounds. The structures of tropones were first proposed 1940s.¹ To date, over two hundred of naturally occurring tropone derivatives have been identified.² They have broad pharmacological activities ranging from anti-bacterial, anti-fungal, anti-tumor to anti-viral activities.³ Many of them have complex structural architectures, such as tropone-containing natural products hainanolidol 3⁴ and harringtonolide 4⁵ (Figure 1).

Figure 1.

Tropones, tropolones and tropone-containing natural products

Numerous methods have been developed for the synthesis of tropones and their derivatives.⁶ Many of them were recently reviewed by us in the context of natural product synthesis.⁷ However, efficient synthesis of highly substituted tropones is a still challenging problem.⁸ For example, only the parent non-substituted tropone was used as the substrate in many of the cycloaddition methods involving tropones including some very recent reports.⁹

We have recently completed the first total synthesis of harringtonolide 4 via a [5+2] cycloaddition¹⁰ of oxidopyrylium ion 6 and alkene (Scheme 1).⁵ Although we were able to assemble the carbon skeleton of 4 very efficiently, it took us a number of steps to remove the extra oxygen bridge in 7 for the formation of tropone in target 4. Clearly, the development of new types of [5+2] cycloadditions is highly desirable.

Scheme 1.

Total synthesis of (±)-harringtonolide

We have recently reported intra-¹¹ and intermolecular¹² Rh-catalyzed [5+2] cycloadditions for the synthesis of highly substituted cycloheptatrienes by using 3-acyloxy-1,4-enyne as a novel 5-carbon component (Scheme 2).¹³ The high degree of unsaturation and the enol ester functionality in cycloaddition product 9 are ideally set up for the synthesis of substituted tropone 10. We herein report our efforts along this direction for the first time.

Scheme 2.

Rh-catalyzed intermolecular [5+2] cycloaddition and formation of tropones

Efforts for the conversion of cycloheptatriene product 9 directly to tropones by oxidation were fruitless. Although we were able to remove the ester group in 9 by reduction or hydrolysis, we could not convert the hydrolyzed products to tropones by oxidative reagents. During the development of the intermolecular [5+2] cycloadditions,¹² we learned that high regioselectivity could be observed when propargylic alcohols 12 were employed as the substrates (Scheme 3). With the hydroxyl group handle in product 13, we thought we might be able to prepare tropones by elimination reaction instead of oxidation reaction.

Scheme 3.

Synthesis of substituted cyclohepatrienes

Previously, we mainly used the pivalate ester of 3-hydroxy-1,4-enyne as the 5-carbon component for Rh-catalyzed [5+2] cycloadditions.¹² It generally provided higher yields of the product compared to other esters such as acetate or benzoate. We imagine that the acetate in 13 or 14 can be easily hydrolyzed under milder conditions. We first examined the scope of the Rh-catalyzed [5+2] cycloaddition using 3-acyloxy-1,4-enyne 11a and 11b with a variety of propargylic alcohols. Ester 11a was prepared in just one step from commercially available 3-methyl-1-penten-4-yn-3-ol.¹² Ester 11b is available in three steps from commercially available 1-octyn-3-ol.¹⁴

Product 13a was prepared as a single isomer (Scheme 3) in the presence of Wilkinson's catalyst. The same condition worked for most of the terminal alkynes. The addition of electron-poor phosphine can improve the yield for products 13c and 13h. When internal alkynes are employed, much better yields were obtained for products 13i and 13j/13j’ under condition b. High regioselectivity was observed for product 13i, while a ratio of 2:1 was obtained for products 13j and 13j’. The R¹ group can be methyl or other alkyl groups, such as n-pentyl in 14. When R¹ was switched phenyl group, the acetate substrate isomerized to conjugated 1,3-enyne 15¹⁵ under the reaction condition.

We next examined the possibility of synthesizing tropones by eliminating the hydroxyl group in products 13 and 14. We envisioned that conversion of allylic alcohols 13 or 14 to mesylate 17 followed by based-mediated elimination should yield tetraene intermediate 18, which could be hydrolyzed to aromatic tropone product 16 via enol intermediate 19 (Scheme 4). Indeed, a three-step sequence converted 13a to tropone 16a in a 61% isolated yield. We also tried to treat mesylate intermediate 17a with potassium carbonate in methanol to complete both elimination and hydrolysis in one step. However, the yield was much lower using the two step sequence.

Scheme 4.

Synthesis of substituted tropones

We then examined the scope of the three-step sequence. A variety of disubstituted tropones could be prepared from the corresponding cycloheptatrienes. Tropones 16d and 16f were obtained in lower yields from substrates bearing a benzylic or a tertiary alcohol, respectively. The TBS-protected primary alcohol in substrate 13h can be tolerated and tropone 16h was prepared in a 56% isolated yield. Trisubstituted tropone 16i was prepared from the corresponding alcohol 13i in a 63% isolated yield. Trisubstitued tropones 16j and 16j’ could be isolated in 47% and 24% yields, respectively, from a mixture of non-separable alcohols 13j and 13j’. Cycloheptriene 14 was also converted to tropone 20 under the same condition.

We further functionalized tropone products 16b, 16d, and 16e to amino-tropones 21 (Scheme 5). The amino group was introduced to the α’-position of tropones by treating them with hydrazine following literature procedures.^3a Since the α-position is blocked by methyl substituent, regioselectivity is not a concern for the amination reaction.

Scheme 5.

Amination and cycloaddition of substituted tropones

We also explored the [4+2] cycloaddition between tropone 16b and anhydride 22. Under thermal conditions, cycloaddition product 23 was obtained in high regio- and diastereoselectivity. The less substituted diene in tropone 16b selectively reacted with the dienophile and afforded only the endo-product.

In summary, we have developed an efficient sequence to convert products derived from Rh-catalyzed [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes to substituted tropones. High regioselectivity was observed for all terminal alkynes in the Rh-catalyzed [5+2] cycloaddition. For internal alkynes, high regioselectivity could also be obtained when there were two electronically differentiated substituents on the two termini of the internal alkynes. Various di- and tri-substituted tropones were synthesized efficiently from the cycloheptatriene cycloaddition product by a three-step mesylation, elimination and hydrolysis sequence.

2. Experimental section

Esters 11a and 11b were prepared from the corresponding alcohols by esterification reactions following our previously reported procedures.^12,14

General procedures for the Rh-catalyzed intermolecular [5+2] cycloaddition

Method A

To a flask containing 1,4-enyne (1 mmol) and alkyne (2 mmol) was added RhCl(PPh₃)₃ (5 mol%) and chloroform (0.4 M). The flask was flushed with argon and allowed to stir at 65 °C. The reaction was monitored by TLC until the 1,4-enyne was completely consumed (approximately 12 h). The solvent was evaporated and the resulting residue was purified via flash chromatography on silica gel using ethyl acetate and hexanes to yield [5+2] cycloaddition products.

Method B

To a flask containing 1,4-enyne (1mmol) and alkyne (2 mmol) was added [Rh(COD)Cl]₂ (5 mol%), tris[4-(trifluoromethyl)phenyl] phosphine (30 mol%) and chloroform (0.4 M). The flask was flushed with argon and allowed to stir at 65 °C. The reaction was monitored by TLC until the 1,4-enyne was completely consumed (approximately 12 h). The solvent was evaporated and the resulting residue was purified via flash chromatography on silica gel using ethyl acetate and hexanes to yield [5+2] cycloaddition products

2.1 4-(1-hydroxyethyl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13a)

Oil. Method A, 66% yield. ¹H NMR (500Mz, CDCl₃) δ 6.22 (d, J = 6.5 Hz, 1H), 6.07 (d, J = 6.5 Hz, 1H), 5.25 (t, J = 7.5 Hz, 1H), 4.44 (q, J = 6.5 Hz, 1H), 2.58-2.54 (m, 1H), 2.28-2.24 (m, 1H), 2.21 (s, 3H), 1.78 (s, 3H), 1.31 (d, J = 8.5 Hz, 3H); ¹³C NMR (100Mz, CDCl₃) δ 169.6, 151.9, 142.1, 130.8, 120.8, 119.5, 117.5, 71.1, 27.9, 23.6, 21.0, 17.9. IR (film): 2926, 1730, 1637, 1440, 1370, 1218, 1056, 830 cm⁻¹. HRMS (ESI) m/z calc. For C₁₂H₁₆O₃ (M+Na)⁺ 231.0997, found 231.0993.

2.2 4-(1-hydroxyhexyl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13b)

Oil. Method A, 71% yield. ¹H NMR (500Mz, CDCl₃) δ 6.22 (d, J = 6.5 Hz, 1H), 6.02 (d, J = 6.5 Hz, 1H), 5.22 (t, J = 7.0 Hz, 1H), 4.22-4.19 (m, 1H), 2.58-2.54 (m, 1H), 2.24-2.20 (m, 1H), 2.20 (s, 3H), 1.78 (s, 3H), 1.72 (s, 1H), 1.57-1.53 (m, 2H), 1.35-1.24 (m, 6H), 0.87 (t, J = 7.0 Hz, 3H); ¹³C NMR (100Mz, CDCl₃) δ 169.6, 151.8, 141.0, 130.7, 120.8, 119.4, 118.5, 75.5, 37.0, 31.9, 27.7, 25.7, 22.7, 21.0, 17.9, 14.2. IR (film): 2930, 1728, 1637, 1370, 1210, 1062, 834, 777 cm⁻¹. HRMS (ESI) m/z calc. For C₁₆H₂₄O₃ (M+Na)⁺ 287.1623, found 287.1618.

2.3 4-(1-hydroxy-3-phenylpropyl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13c)

Oil. Method A, 55% yield. Method B, 69% yield. ¹H NMR (400Mz, CDCl₃) δ 7.30-7.26 (m, 2H), 7.20-7.16 (m, 3H), 6.22 (d, J = 6.4 Hz, 1H), 6.05 (d, J = 6.4 Hz, 1H), 5.24 (t, J = 6.0 Hz, 1H), 4.25-4.23 (m, 1H), 2.70-2.62 (m, 2H), 2.60-2.57 (m, 1H), 2.24-2.19 (m, 4H), 1.91-1.84 (m, 2H), 1.79 (s, 3H), 1.67 (s, 1H); ¹³C NMR (100Mz, CDCl₃) δ 169.6, 152.0, 142.0, 140.5, 130.9, 128.68, 128.66, 126.1, 120.8, 119.4, 118.8, 74.8, 39.7, 32.4, 27.7, 21.0, 17.9. IR (film): 3027, 2923, 1749, 1637, 1454, 1369, 1213, 1120, 1056, 833cm⁻¹. HRMS (ESI) m/z calc. For C₁₉H₂₂O₃ (M+Na)⁺ 321.1461, found 321.1461.

2.4 4-(hydroxy(phenyl)methyl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13d)

Oil. Method A, 68% yield. ¹H NMR (400Mz, CDCl₃) δ 7.38-7.25 (m, 5H), 6.25 (s, 2H), 5.34 (s, 1H), 5.00 (t, J = 7.2 Hz, 1H), 2.41-2.36 (m, 1H), 2.28-2.23 (m, 1H), 2.18 (s, 3H), 1.73 (s, 3H); ¹³C NMR (100Mz, CDCl₃) δ 169.6, 152.0, 142.4, 140.3, 130.7, 128.6, 128.0, 126.9, 121.7, 119.3, 119.1, 77.1, 28.5, 21.0, 17.9. IR (film): 2935, 1750, 1632, 1441, 1142, 1060, 924, 770, 697 cm⁻¹. HRMS (ESI) m/z calc. For C₁₇H₁₈O₃ (M+Na)⁺ 293.1154, found 293.1151.

2.5 4-(1-hydroxy-2,2-dimethylpropyl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13e)

Oil. Method A, 73% yield. ¹H NMR (500Mz, CDCl₃) δ 6.22 (d, J = 6.5 Hz, 1H), 6.00 (d, J = 6.5 Hz, 1H), 5.26 (t, J = 7.5 Hz, 1H), 3.97 (s, 1H), 2.68-2.64 (m, 1H), 2.20-2.16 (m, 4H), 1.80 (s, 3H), 1.70 (s, 1H), 0.93 (s, 9H); ¹³C NMR (125Mz, CDCl₃) δ 169.6, 151.7, 139.0, 131.0, 121.1, 120.4, 119.5, 83.6, 36.0, 26.5, 25.6, 25.5, 21.0, 17.9. IR (film): 2981, 2874, 2341, 1747, 1637, 1480, 1266, 1005, 896. cm⁻¹. HRMS (ESI) m/z calc. For C₁₅H₂₂O₃ (M+Na)⁺ 273.1461, found 273.1460.

2.6 4-(2-hydroxypropan-2-yl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13f)

Oil. Method A, 62% yield. ¹H NMR (400Mz, CDCl₃) δ 6.25 (d, J = 6.8 Hz, 1H), 6.17 (d, J = 6.4 Hz, 1H), 5.26 (t, J = 7.2 Hz, 1H), 2.42 (d, J = 7.6 Hz, 2H), 2.21 (s, 3H), 1.78 (s, 3H), 1.41 (s, 6H); ¹³C NMR (100Mz, CDCl₃) δ 169.7, 151.4, 145.4, 130.6, 120.9, 119.7, 115.5, 73.0, 30.0, 29.9, 21.0, 17.8. IR (film): 3450, 2979, 1740, 1637, 1438, 1367, 1215, 1115, 1062, 957. cm⁻¹. HRMS (ESI) m/z calc. For C₁₃H₁₈O₃ (M+Na)⁺ 245.1148, found 245.1153.

2.7 4-(1-hydroxy-2-methylpentyl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13g)

Oil. Method A, 64% yield (dr 1:1). ¹H NMR (500Mz, CDCl₃) δ 6.23 (dd, J = 9.0, 6.0 Hz, 1H), 6.02 (dd, J = 15.0, 6.0 Hz, 1H), 5.23-5.21 (m, 1H), 4.01 (dd, J = 45.5, 6.0 Hz, 1H), 2.48-2.44 (m, 1H), 2.30-2.27 (m, 1H), 2.21 (s, 3H), 1.78 (s, 3H), 1.67-1.65 (m, 1H), 1.34-1.25 (m, 4H), 1.10-1.07 (m, 1H), 0.92-0.85 (m, 5H), 0.79 (d, J = 7.0 Hz, 1H); ¹³C NMR (100Mz, CDCl₃) δ 169.6, 166.6, 151.8, 151.6, 140.3, 140.2, 130.9, 130.8, 121.0, 120.7, 119.8, 119.5, 119.4, 119.1, 80.4, 79.2, 37.6, 37.3, 36.1, 34.2, 27.9, 21.0, 20.5, 20.4, 17.907, 17.899, 16.7, 14.6, 14.5, 14.3. IR (film): 3426, 2922, 1727, 1456, 1371, 1216, 1123, 1037, 924 cm⁻¹. HRMS (ESI) m/z calc. For C₁₆H₂₄O₃ (M+Na)⁺ 287.1617, found 287.1615.

2.8 4-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13h)

Oil. Method B, 90% yield. ¹H NMR (500Mz, CDCl₃) δ 6.26 (d, J = 6.5 Hz, 1H), 6.14 (d, J = 6.5 Hz, 1H), 5.21 (t, J = 7.0 Hz, 1H), 4.30 (d, J = 8.5 Hz, 1H), 3.63 (dd, J = 10.0, 3.5 Hz, 1H), 3.39 (dd, J = 10.0, 8.5 Hz, 1H), 2.76 (d, J = 2.5 Hz, 1H), 2.59-2.55 (m, 1H), 2.21 (s, 3H), 2.17-2.13 (m, 1H), 1.78 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H); ¹³C NMR (125Mz, CDCl₃) δ 169.6, 152.1, 135.6, 131.0, 119.8, 119.7, 119.6, 75.2, 67.3, 28.0, 26.1, 21.0, 18.5, 17.9, −5.0, −5.1. IR (film): 2970, 2858, 2349, 1738, 1436, 1374, 1110, 1060, 834 cm⁻¹. HRMS (ESI) m/z calc. For C₁₈H₃₀O₄Si (M+Na)⁺ 361.1805, found 361.1802.

2.9 4-(hydroxymethyl)-3,7-dimethylcyclohepta-1,3,6-trien-1-yl acetate (13i)

Oil. Method B, 76% yield. ¹H NMR (500Mz, CDCl₃) δ 6.18 (s, 1H), 5.40 (t, J = 9.0 Hz, 1H), 4.23 (s, 2H), 2.44 (d, J = 7.5 Hz, 2H), 2.20 (s, 3H), 2.06-2.01 (m, 1H), 1.87 (s, 3H), 1.76 (s, 3H); ¹³C NMR (100Mz, CDCl₃) δ 169.5, 151.0, 130.2, 129.9, 127.4, 124.7, 122.3, 62.8, 30.4, 20.9, 17.8, 17.6. IR (film): 3405, 2950, 1752, 1637, 1321, 1131, 1061, 1016, 873 cm⁻¹. HRMS (ESI) m/z calc. For C₁₂H₁₆O₃ (M+Na)⁺ 231.0991, found 231.0989.

2.10 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(hydroxymethyl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13j and 13j’)

Oil. Method B, 79% yield (2:1) mixture. Major ¹H NMR (500Mz, CDCl₃) δ 6.29 (s, 1H), 5.34 (t, J = 7.5 Hz, 1H), 4.36-4.34 (m, 2H), 4.30-4.26 (m, 2H), 2.40 (s, 2H), 2.20 (s, 3H), 1.77 (s, 3H), 0.89 (s, 9H), 0.08 (s, 6H); Major ¹³C NMR (100Mz, CDCl₃) δ 169.5, 151.7, 131.8, 130.2, 122.3, 120.1, 63.7, 63.5, 31.7, 26.0, 21.0, 18.5, 17.6, −5.0. IR (film): 2930, 2858, 1728, 1472, 1370, 1135, 1062, 834 cm⁻¹. HRMS (ESI) m/z calc. For C₁₈H₃₀O₄Si (M+Na)⁺ 361.1805, found 361.1808.

2.11 4-(hydroxymethyl)-7-pentylcyclohepta-1,3,6-trien-1-yl acetate (14)

Oil. Method A, 62% yield. ¹H NMR (500Mz, CDCl₃) δ 6.26 (d, J = 6.0 Hz, 1H), 6.06 (d, J = 6.5 Hz, 1H), 5.28 (t, J = 7.0 Hz, 1H), 4.24 (s, 2H), 2.42 (d, J = 7.5 Hz, 2H), 2.19 (s, 3H), 2.08 (t, J = 8.0 Hz, 2H), 1.68 (s, 1H), 1.38-1.32 (m, 2H), 1.29-1.24 (m, 2H), 1.20-1.16 (m, 2H), 0.85 (t, J = 7.5 Hz, 3H); ¹³C NMR (125Mz, CDCl₃) δ 169.7, 151.6, 137.9, 135.5, 120.24, 120.15, 118.3, 66.2, 32.2, 31.7, 29.1, 29.0, 22.6, 21.0, 14.2. IR (film): 3431, 2928, 1750, 1436, 1364, 1122, 1020, 928 cm⁻¹. HRMS (ESI) m/z calc. For C₁₅H₂₂O₃ (M+Na)⁺ 273.1467, found 273.1471.

General procedures for the synthesis of tropones from cyclohepatrienes

To a solution of the cycloheptatriene substrate (0.2 mmol) in dry dichloromethane (4 ml) was added triethylamine (85 μL) and MsCl (31 μL) at −78 C. The reaction was warmed to room temperature and stirred for 1h. The solution was quenched with saturated aqueous NaHCO₃ (10 mL) solution and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried with Na₂SO₄, concentrated under vacuum to give the crude mesylation product.

To a solution of the crude mesylation product in dry THF (4 mL) was added DBU (44 μL) at room temperature. After stirring at this temperature for 10-30 min, it was concentrated to give the crude tetraene product. To a solution of this crude product in MeOH (4 mL) was added K₂CO₃ (13 mg) at room temperature. After stirring at this temperature for 5-10 min, the product was concentrated under vacuum. The residue was purified by flash chromatography on silica gel using ethyl acetate and hexanes to give the final tropone product.

2.12 5-ethyl-2-methylcyclohepta-2,4,6-trienone (16a)

Oil. 18 mg, 61% yield. ¹H NMR (500Mz, CDCl₃) δ 7.25 (d, J = 9.5 Hz, 1H), 7.04 (s, 2H), 6.78 (d, J = 9.5 Hz, 1H), 2.55 (q, J = 7.5 Hz, 2H), 2.25 (s, 3H), 1.21 (t, J = 7.5 Hz, 3H); ¹³C NMR (100Mz, CDCl₃) δ 187.2, 150.1, 149.4, 139.6, 138.5, 136.0, 131.2, 33.0, 22.7, 15.3. IR (film): 3417, 3055, 2854, 1728, 1573, 1266, 1080, 957cm⁻¹. HRMS (ESI) m/z calc. For C₁₀H₁₂O (M+Na)⁺ 171.0780, found 171.0779.

2.13 5-hexyl-2-methylcyclohepta-2,4,6-trienone (16b)

Oil. 28 mg, 67% yield. ¹H NMR (500Mz, CDCl₃) δ 7.24 (d, J = 9.0 Hz, 1H), 7.03 (s, 2H), 6.76 (d, J = 9.0 Hz, 1H), 2.49 (t, J = 7.5 Hz, 2H), 2.25 (s, 3H), 1.57-1.55 (m, 2H), 1.34-1.27 (m, 6H), 0.88 (t, J = 7.0 Hz, 3H); ¹³C NMR (100Mz, CDCl₃) δ 187.2, 150.1, 148.2, 139.5, 138.7, 135.9, 132.0, 40.0, 31.8, 31.0, 29.0, 22.8, 22.7, 14.3. IR (film): 3040, 2925, 1737, 1581, 1664, 1360, 1220, 962 cm⁻¹. HRMS (ESI) m/z calc. For C₁₄H₂₀O (M+Na)⁺ 227.1412, found 227.1416.

2.14 2-methyl-5-(3-phenylpropyl)cyclohepta-2,4,6-trienone (16c)

Oil. 29 mg, 60% yield. ¹H NMR (400Mz, CDCl₃) δ 7.31-7.29 (m, 2H), 7.24-7.21 (m, 2H), 7.19-7.16 (m, 2H), 7.02 (s, 2H), 6.76 (d, J = 9.2 Hz, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2.53 (t, J = 9.5 Hz, 2H), 2.27 (s, 3H), 1.96-1.88 (m, 2H); ¹³C NMR (100Mz, CDCl₃) δ 187.2, 150.4, 147.5, 141.7, 139.6, 138.5, 135.7, 132.2, 128.7, 128.6, 126.3, 39.4, 35.4, 32.5, 22.7. IR (film): 3053, 2927, 2858, 1730, 1573, 1456, 1265, 1097, 733, 700 cm⁻¹. HRMS (ESI) m/z calc. For C₁₇H₁₈O (M+H)⁺ 239.1430, found 239.1436.

2.15 5-benzyl-2-methylcyclohepta-2,4,6-trienone (16d)

Oil. 21 mg, 51% yield. ¹H NMR (500Mz, CDCl₃) δ 7.33-7.30 (m, 3H), 7.26-7.24 (m, 1H), 7.17-7.15 (m, 2H), 6.99 (s, 2H), 6.81 (d, J = 9.0 Hz, 1H), 3.85 (s, 2H), 2.25 (s, 3H); ¹³C NMR (100Mz, CDCl₃) δ 187.1, 150.6, 146.0, 139.5, 139.1, 138.5, 135.6, 132.7, 129.2, 129.1, 127.1, 45.5, 22.7. IR (film): 3055, 2987, 2361, 1726, 1575, 1422, 1265, 896. cm⁻¹. HRMS (ESI) m/z calc. For C₁₅H₁₄O (M+Na)⁺ 233.0937, found 233.0945.

2.16 2-methyl-5-neopentylcyclohepta-2,4,6-trienone (16e)

Oil. 28 mg, 72% yield. ¹H NMR (500Mz, CDCl₃) δ 7.26 (d, J = 9.0 Hz, 1H), 7.00 (s, 2H), 6.72 (d, J = 9.5 Hz, 1H), 2.41 (s, 2H), 2.27 (s, 3H), 0.93 (s, 9H); ¹³C NMR (100Mz, CDCl₃) δ 187.2, 150.5, 145.5, 140.5, 138.3, 135.4, 134.3, 53.6, 32.8, 29.6, 22.7. IR (film): 3060, 2964, 1730, 1587, 1403, 1264, 1080, 1026 cm⁻¹. HRMS (ESI) m/z calc. For C₁₃H₁₈O (M+Na)⁺ 213.1255, found 213.1259

2.17 5-isopropyl-2-methylcyclohepta-2,4,6-trienone (16f)

Oil. 14 mg, 42% yield. All spectra data are in accordance with literature.¹⁶

2.18 2-methyl-5-(2-methylpentyl)cyclohepta-2,4,6-trienone (16g)

Oil. 31 mg, 75% yield. ¹H NMR (400Mz, CDCl₃) δ 7.24 (d, J = 9.2 Hz, 1H), 7.05-6.98 (m, 2H), 6.73 (d, J = 9.2 Hz, 1H), 2.55-2.51 (m, 1H), 2.25 (s, 3H), 2.25-2.20 (m, 1H), 1.72-1.67 (m, 1H), 1.41-1.25 (m, 3H), 1.19-1.13 (m, 1H), 0.90-0.85 (m, 6H); ¹³C NMR (100Mz, CDCl₃) δ 187.2, 150.2, 147.1, 139.2, 139.0, 135.7, 133.0, 47.6, 39.1, 34.5, 22.7, 20.3, 19.4, 14.5. IR (film): 2455, 2360, 2254, 1737, 1625, 1565, 1421, 1230, 1095, 904. cm⁻¹. HRMS (ESI) m/z calc. For C₁₄H₂₀O (M+Na)⁺ 227.1406, found 227.1409

2.19 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methylcyclohepta-2,4,6-trienone (16h)

Oil. 32 mg, 56% yield. ¹H NMR (500Mz, CDCl₃) δ 7.27 (d, J = 9.5 Hz, 1H), 7.19-7.03 (m, 2H), 6.83 (d, J = 9.0 Hz, 1H), 3.83 (t, J = 6.0 Hz, 2H), 2.71 (t, J = 6.5 Hz, 2H), 2.28 (s, 3H), 0.86 (s, 9H), 0.01 (s, 6H); ¹³C NMR (100Mz, CDCl₃) δ 187.1, 150.7, 145.0, 139.20, 139.18, 135.6, 133.4, 63.6, 43.1, 26.1, 22.7, 18.5, −5.2. IR (film): 2953, 2895, 1730, 1631, 1577, 1374, 1254, 1095. cm⁻¹. HRMS (ESI) m/z calc. For C₁₆H₂₆O₂Si (M+Na)⁺ 301.1594, found 301.1597

2.20 2,5,6-trimethylcyclohepta-2,4,6-trienone (16i)

Oil. 19 mg, 63% yield. ¹H NMR (500Mz, CDCl₃) δ 7.14-7.11 (m, 2H), 6.81 (d, J = 9.5 Hz, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H); ¹³C NMR (100Mz, CDCl₃) δ 186.3, 149.0, 147.1, 144.1, 140.2, 134.9, 132.1, 26.0, 25.5, 22.1. IR (film): 2923, 2855, 1738, 1566, 1372, 1216, 950, 894, 713 cm⁻¹. HRMS (ESI) m/z calc. For C₁₀H₁₂O (M+H)⁺ 149.0960, found 149.0966

2.21 6-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylcyclohepta-2,4,6-trienone (16j)

Oil. 27 mg, 47% yield. ¹H NMR (500Mz, CDCl₃) δ 7.28 (d, J = 9.5 Hz, 1H), 7.14 (d, J = 10.0 Hz, 1H), 7.07 (s, 1H), 4.53 (s, 2H), 2.25 (s, 6H), 0.94 (s, 9H), 0.11 (s, 6H); ¹³C NMR (100Mz, CDCl₃) δ 186.5, 150.0, 145.3, 145.0, 140.8, 134.9, 129.1, 65.2, 26.15, 26.11, 23.2, 22.3, 18.6, −5.1. IR (film): 3055, 2955, 1729, 1626, 1265, 1063, 1017, 838. cm⁻¹. HRMS (ESI) m/z calc. For C₁₆H₂₆O₂Si (M+Na)⁺ 301.1594, found 301.1600

2.22 5-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylcyclohepta-2,4,6-trienone (16j’)

Oil. 13 mg, 24% yield. ¹H NMR (500Mz, CDCl₃) δ 7.36 (s, 1H), 7.14 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 9.5 Hz, 1H), 4.53 (s, 2H), 2.24 (s, 6H), 0.93 (s, 9H), 0.11 (s, 6H); ¹³C NMR (100Mz, CDCl₃) δ 187.1, 149.4, 147.8, 142.0, 136.5, 134.8, 132.9, 66.5, 26.1, 22.7, 22.1, 18.6, −5.0. IR (film): 3055, 2954, 2858, 1738, 1625, 1265, 1177, 1060, 940. cm⁻¹. HRMS (ESI) m/z calc. For C₁₆H₂₆O₂Si (M+Na)⁺ 301.1594, found 301.1601

2.23 5-methyl-2-pentylcyclohepta-2,4,6-trienone (20)

Oil. 23 mg, 60% yield. ¹H NMR (400Mz, CDCl₃) δ 7.12 (d, J = 9.2 Hz, 1H), 6.99 (s, 2H), 6.80 (d, J = 9.2 Hz, 1H), 2.62-2,58 (m, 2H), 2.30 (s, 3H), 1.56-1.50 (m, 2H), 1.36-1.31 (m, 4H), 0.88 (t, J = 6.8 Hz, 3H); ¹³C NMR (100Mz, CDCl₃) δ 186.8, 153.9, 143.3, 139.7, 139.0, 135.3, 132.3, 35.4, 32.0, 28.8, 25.8, 22.8, 14.2. IR (film): 2955, 2925, 1729, 1633, 1574, 1462, 1190, 1040, 844. cm⁻¹. HRMS (ESI) m/z calc. For C₁₃H₁₈O (M+Na)⁺ 213.1249, found 213.1256

General procedures for the amination of tropones

To a solution of α-methyl-tropone (0.1 mmol) in EtOH (0.5 ml) was added 65% hydrazine monohydrate (0.12 mL). The solution was allowed to stir at 60°C until all starting material was consumed by monitoring the reaction by TLC (~2h). The reaction was concentrated under vacuum and then taken up in EtOAc (4 mL) and washed with H₂O (3×4 ml). The organic layer was then washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel using ethyl acetate and hexanes to provide the desired α-amino-tropones.

2.24 2-amino-4-hexyl-7-methylcyclohepta-2,4,6-trienone (21a)

Oil. 17 mg, 79% yield. ¹H NMR (500Mz, CDCl₃) δ 7.37 (d, J = 9.5 Hz, 1H), 6.80 (s, 1H), 6.57 (d, J = 10.0 Hz, 1H), 5.80 (bs, 2H), 2.54-2.51 (m, 2H), 2.40 (s, 3H), 1.62-1.57 (m, 2H), 1.35-1.25 (m, 6H), 0.89 (t, J = 6.5 Hz, 3H); ¹³C NMR (125Mz, CDCl₃) δ 175.2, 154.1, 150.5, 139.0, 137.5, 123.9, 115.3, 41.2, 32.1, 31.9, 29.1, 23.4, 22.8, 14.3. IR (film): 3055, 2987, 1730, 1530, 1422, 1265, 839. cm⁻¹. HRMS (ESI) m/z calc. For C₁₄H₂₁NO (M+Na)⁺ 242.1515, found 242.1584.

2.25 2-amino-4-benzyl-7-methylcyclohepta-2,4,6-trienone (21b)

Oil. 19 mg, 85% yield. ¹H NMR (500Mz, CDCl₃) δ 7.39 (d, J = 10.0 Hz, 1H), 7.32-7.29 (m, 2H), 7.24-7.22 (m, 1H), 7.18 (d, J = 7.0 Hz, 2H), 6.76 (s, 1H), 6.62 (d, J = 10.0 Hz, 1H), 5.76 (bs, 2H), 3.90 (s, 2H), 2.39 (s, 3H); ¹³C NMR (125Mz, CDCl₃) δ 175.5, 153.9, 148.0, 140.3, 139.5, 137.4, 129.1, 128.9, 126.9, 124.5, 115.3, 46.5, 23.4. IR (film): 3319, 3282, 2382, 1728, 1609, 1521, 1276, 969, 740. cm⁻¹. HRMS (ESI) m/z calc. For C₁₅H₁₅NO (M+Na)⁺ 248.1045, found 248.1048.

2.26 2-amino-4-(tert-butyl)-7-methylcyclohepta-2,4,6-trienone (21c)

Oil. 16 mg, 79% yield. ¹H NMR (500Mz, CDCl₃) δ 7.37 (d, J = 10.0 Hz, 1H), 6.76 (s, 1H), 6.52 (d, J = 10.0 Hz, 1H), 5.79 (bs, 2H), 2.46 (s, 2H), 2.41 (s, 3H), 0.94 (s, 9H); ¹³C NMR (125Mz, CDCl₃) δ 175.2, 153.3, 147.3, 139.2, 136.8, 126.0, 117.3, 54.8, 32.8, 29.8, 23.4. IR (film): 3419, 3281, 2952, 1730, 1605, 1524, 1424, 1363, 1163, 962, 829 cm⁻¹. HRMS (ESI) m/z calc. For C₁₃H₁₉NO (M+Na)⁺ 228.1358, found 228.1365.

Procedure for the synthesis of 23 via [4+2] cycloaddition

To a solution of tropone 16b (0.06 mmol) in xylene (0.3 mL) was added furan-2,5-dione (29.5 mg). The solution was allowed to stir at 120 °C overnight. The reaction was concentrated under vacuum and purified by flash column chromatography on silica gel using ethyl acetate and hexanes to provide the desired cycloaddition product in 65% yield.

2.27 9-hexyl-6-methyl-3a,4,8,8a-tetrahydro-1H-4,8-ethenocyclohepta[c]furan-1,3,5-trione (23)

Oil. 12 mg, 65% yield. ¹H NMR (400Mz, CDCl₃) δ 6.98 (d, J = 6.8 Hz, 1H), 5.79 (d, J = 6.0 Hz, 1H), 3.99 (dd, J = 6.0, 1.2 Hz, 1H), 3.69 (dd, J = 7.2, 2.0 Hz, 1H), 3.60-3.58 (m, 1H), 3.53 (dd, J = 7.2, 1.2 Hz, 1H) 2.12-2.08 (m, 2H), 1.76 (s, 3H), 1.37-1.33 (m, 2H), 1.30-1.23 (m, 6H), 0.87 (t, J = 9.6 Hz, 3H); ¹³C NMR (125Mz, CDCl₃) δ 193.4, 171.0, 152.5, 144.2, 137.7, 118.1, 53.9, 47.9, 43.1, 42.2, 36.7, 31.7, 28.9, 26.8, 22.8, 18.4, 14.3. IR (film): 3055, 2930, 2359, 1785, 1674, 1265, 1076, 928, 832 cm⁻¹. HRMS (ESI) m/z calc. For C₁₈H₂₂O₄ (M+Na)⁺ 325.1410, found 325.1424.