Electronic Control of Product Distribution in the [5+5]-Coupling of ortho-Alkynylbenzaldehyde Derivatives and γ,δ-Unsaturated Carbene Complexes

Abstract

The coupling of highly oxygenated ortho-alkynylbenzaldehyde derivatives with γ,δ-carbene complexes was evaluated systematically. In all of the electron-rich systems investigated the exclusive product of the reaction is the dihydrophenanthrene derivative. Only the extremely electron withdrawing methanesulfonate group can prevent this process from occurring. The use of the base additive collidine resulted in a surprising yield enhancement but no other discernable effect on the course of the reaction. Dihydrophenanthrene formation was attributed to rapid dehydration after the opening of a benzo-oxanorbornene intermediate.

Introduction

Polycyclic aromatic hydrocarbons¹ have tremendous applications in materials science and medicinal chemistry. Polycyclic aromatic rings are frequently employed as organic conductors and semiconductors,² serve as the core ring structure for several medicinally-important compounds,³ and are useful as fluorescent probes for biological studies.⁴ Many polycyclic aromatics derived from combustion are carcinogenic and prevalent in the environment, and chemical derivatives are necessary for studies of their mechanisms of mutagenesis as well as that of their metabolites.⁵ Phenanthrenes are among the simplest polycyclic aromatics. The most notable medicinally-important phenanthrenoids are the phenanthroindolizidine and phenanthroquinolizidine alkaloids,⁶ the aporphine alkaloids,⁷ and abietane and kaurane diterpenoids.⁸ Phenanthrenoid ring construction⁹ is most commonly achieved using precursors where two out of the three rings are intact followed by a cyclization or annulation event. Common approaches to the construction of the phenanthrenoids include electrocyclizations of naphthylcyclobutenones,¹⁰ naphthyl Fischer carbene complex – alkyne couplings,¹¹ cyclizations of naphthylvinylketene precursors,¹² cis stilbene cyclizations,¹³ and ring closing metatheses.¹⁴ A unique approach to phenanthrenoid ring systems where two of the three rings are constructed in a single operation is the highlight of the studies in this manuscript.

The coupling of 2-alkynylbenzoyl derivatives (e.g. 1, Scheme 1) with γ,δ-unsaturated Fischer carbene complexes (2) results in the direct synthesis of phenanthrenoid ring systems (e.g. 5, 6) in a process where two of the three rings of the phenanthrene system are produced in a single reaction. ¹⁵ Hydroxyphenanthrenone 5 is formed as a single diastereomer in a complex tandem process involving the formation of an isobenzofuran (3), followed by exo-selective¹⁶ intramolecular Diels-Alder reaction (yielding benzo-oxanorbornene 4), followed by opening of the benzo-oxanorbornene ring system and hydrolysis. The Diels-Alder step is generally more successful for chromium-generated isobenzofurans compared to acid-generated isobenzofurans.¹⁷ In most of the cases examined, hydroxyphenanthrenones of general structure 5 were produced. The dihydrophenanthrenone ring systems (6) could be produced after treatment of the crude reaction mixtures with strong acid. In a recent total synthesis of antofine, a dihydrophenanthrene derivative (8) was formed directly from the coupling of carbene complex 2 and alkynylbenzoyl derivative 7.¹⁸ This compound was obtained cleanly after a single chromatography without any acid treatment. Since dihydrophenanthrene formation is likely related to the presence of the electron-donating methoxy groups, a more systematic investigation of this reaction pathway was undertaken.

Scheme 1.

Results and Discussion

The general synthetic routes to alkyne carbonyl compounds from commercially available materials are depicted below in Schemes 2–4 and involve Sonogashira coupling of trimethylsilylacetylene with a suitable benzaldehyde derivative featuring a leaving group in the ortho position as the key step. The precursor to alkyne-aldehyde 1a (iodide 10) was obtained through ortho metallation/iodination of veratraldehyde dimethyl acetal (9) (Scheme 2). Halide precursors to 1b–d were obtained from 2-iodovanillin, which was obtained from vanillin through a known multistep sequence (Scheme 3).¹⁹ Other derivatives were prepared according to the routes depicted in Scheme 4. Monomethoxy derivative 1e was prepared from commercially-available 2-hydroxy-4-methoxybenzaldehyde. Alkyne-carbonyl compounds 1f–g were prepared from commercially-available 6-bromoveratraldehyde.

Scheme 2.

Scheme 4.

Scheme 3.

The aromatic ring oxygenated alkynylbenzaldehyde and alkynylacetophenone derivatives were subjected to reaction with carbene complex 2; the results are depicted in Table 1. In all cases except for entries 2 and 4, the exclusive product after chromatographic purification was dihydrophenanthrene 16, which results from net dehydration and protiodesilylation. Exclusive formation of the silyl-retained product 17b (entry 2) was observed in the reaction employing the unprotected phenol 1b. This observation is somewhat unexpected since steric strain between the methoxy and trimethylsilyl groups is expected to be quite severe in compounds 17a–d. The reaction employing acetate-protected derivative 1c (entry 3) led primarily to the desilylated compound 16c, however in several experimental runs varying amounts of the silyl-retained compound 17c were observed. The hydroxyphenanthrenone derivative 5d (entry 4) was obtained from the reaction employing the methanesulfonyloxy derivative 1d. The yield of this latter process was significantly improved if the reaction was conducted using water as a cosolvent. The observed dihydrophenanthrene formation is likely due to activation of the C₉-O bond by the electron-donating methoxy group in the p-position and could likely involve p-quinonemethide-like intermediates during the dehydration process (see Scheme 5). Entries 1–4 represent a systematic variation in the electron-donating ability of the C₈-activating substituent. The methoxy (entry 1), hydroxyl (entry 2) and the less electron donating acetoxy groups (entry 3) all result in the dihydrophenanthrenes. Only the severely electron withdrawing methanesulfonate group²⁰ (entry 4) results in the hydroxyl-group retained product, 5d. In one case (entry 7) the crude reaction mixture was examined and a product consistent with allylsilane/enol ether 18g was observed, however all attempts to chromatographically purify this compound resulted in its conversion to the desilylated dihydrophenanthrene 16g.

Table 1.

Synthesis of dihydrophenanthrenes (16–18) through coupling of o-alkynylbenzoyl derivatives (1) with Fischer carbene complex 2.

Entry 1	Alkyne-Carbonyl Cmpd	Product(s)	Yield (%)
1	1a	16a	58
2	1b	17b	65
3	1c	16c	63a
4	1d	5d	52 (72 in 19:1 dioxane/water)
5	1e	16e	57
6	1f	16f	60
7	1g	16g	40 (92 in 9:1 dioxane:collidine)

^aIn some experimental runs variable quantities of silylated compound 17c were observed.

Scheme 5.

Interesting proton NMR properties were noted for some of the products in Table 1. For the enol ether protons of 16, a simple Pascual-Meier-Simon calculation²¹ suggests that this proton should have a chemical shift of about δ 5.6 for all of the dihydrophenanthrene examples in the Table. This proton occurs at δ 7.24 and δ 7.11 in adducts 16a and 16c respectively, however occurs at δ 6.1–6.2 in all of the other derivatives of 16 in the Table. The chemical shift of compounds 16a and 16f was calculated (DFT-B3LYP, 6–31G*) and it was found that the chemical shift of 16a is predicted to be greater by δ 0.61, perhaps due to the proximity of this hydrogen to oxygen of the bay region methoxy group (2.1 Å in the energy-minimized structure). In all of the desilylated dihydrophenanthrenes (16), the -CH₂CH₂- group appears as two triplets, each integrating for two hydrogens. However this same group in compound 17b appears as four distinct ddd patterns. This is likely due to the nonconjugated arrangement of the enol ether double bond due to due to steric interaction between the methoxy and trimethylsilyl groups, which results in a chiral compound.

A likely scenario for the conversion of benzo-oxanorbornene intermediate 4 to dihydrophenanthrene derivative 16 is depicted in Scheme 5. Although no acid was deliberately added to the reaction mixture, acid is a necessary component in all of the proposed mechanisms for the conversion of benzo-oxanorbornene intermediates to the corresponding naphthalenes (see Scheme 6). In the absence of acid, coordination of the benzo-oxanorbornene oxygen to a chromium species²² could serve as a Lewis acid to initiate the ring-opening dehydration sequence. The presence of electron-donating groups para to the benzylic alcohol group is expected to facilitate the dehydration step through highly stabilized carbocation intermediates. In order to prevent the dehydration process and prevent formation of carbocation and oxonium ion intermediates, the reaction in entry 7 was examined in the presence of the weakly basic additive collidine. Surprisingly, the reaction in the presence of collidine simply resulted in an enhanced yield of the dihydrophenanthrene derivative 16g and no alteration of the reaction pathway. The role of collidine is not totally clear, however it is likely related to its ability to serve as a ligand for chromium.²³

Scheme 6.

In order to gain further insight into the reaction pathway, the conversion of the benzo-oxanorbornene intermediate to the final product was studied computationally (DFT-B3LYP, 6–31G*). The simplest adduct 4e was selected for this study to minimize times required for optimization Protonation of the benzo-oxanorbornene intermediate 4e to afford intermediate oxonium ion 20 (Scheme 6) followed by ring opening can afford either of the two carbocations 21 or 22. Minimization of initially formed oxonium ion 20 results in a product where there is significant bond lengthening of the C_4a-O bond (2.91 A) versus the C₉-O bond (1.43 A). In the neutral benzo-oxanorbornene these bonds are of nearly equal length (C_4a-O = 1.46 A; C₉-O= 1.44 A). The minimized structure of 20 has structural features similar to carbocation 21, and energy minimization results in a product of only slightly higher energy relative to 20. Carbocation 21 is heavily stabilized through resonance interaction with the enol ether methoxy group. Opening of the oxonium in the other direction to afford p-quinonemethide-like species 22 is considerably less favorable. The energetics of benzo-oxanorbornene ring opening are very similar for the cases where R= H or R = Me, however greater stabilization of a tertiary carbocation reduces the energy difference between 21 and 22.

After the ring opening process, deprotonation can afford either of conjugated dienes 23 or 24 (Scheme 7). The thermodynamically more favorable compound is isomer 23. Although 23 is more favored product of simple deprotonation, the isomerization/deconjugation product 25 is even more stable, presumably due to steric interaction of the TMS and aromatic groups in 23. This difference is even also present in the dehydration products 17g and 18g. In the conjugated isomer 17g, there is minimal overlap of the alkene group and the naphthalene ring system; the C₃-C₄-C_4a-C_4b dihedral angle is 146° in the energy minimum conformation. Compound 17g was not observed, however in one experimental run the isomerization product 18g was observed prior to chromatography. Conversion of enol ether 17g to the alkene isomer 18g is unlikely to be a thermal process, however the presence of chromium could serve as a double bond isomerization catalyst.²⁴ Based on the experimental observation and calculations, the most reasonable pathway for conversion of oxanorbornenes to aromatic systems is depicted in Scheme 8, and involves opening to the carbocation/oxonium ion species 21, followed by deprotonation to afford the hydrated naphthalene derivative 23. Water loss and energetically favorable deconjugation affords the allylsilane/enol ether.. The final product then results from protiodesilylation to afford the observed dihydrophenanthrene products.

Scheme 7.

Scheme 8.

Conclusion

The coupling of γ,δ-unsaturated carbene complexes with 2-alkynylbenzaldehyde/acetophenone derivatives featuring electron-rich oxygenated aromatic ring systems leads to dihydrophenanthrenes in a net [5+5]-cycloaddition involving sequential carbene-complex alkyne coupling, isobenzofuran formation, and intramolecular Diels-Alder reaction. The net coupling process is an intermolecular one, which is inherently superior to methods based on intramolecular systems. The initially-formed benzo-oxanorbornenes undergo net dehydration and desilylation processes, which are enhanced by the presence of electron-donating groups. Electron-withdrawing methanesulfonyloxy groups suppress the dehydration pathway and result in hydroxyphenanthrenone derivative.

Experimental²⁵

General Procedure for carbene complex-alkyne coupling. To a refluxing 0.1M solution of the alkyne-aldehyde/ketone (1 eq) in dioxane (10mL/mmol) was added over a 1h period a solution of carbene complex 2 (1.2 eq) in dioxane (10 mL/mmol). After the addition, the reflux was continued for 24 h and the mixture was allowed to reach room temperature. The dioxane was removed on a rotary evaporator and the residue was suspended in hexane-ethyl acetate and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel.

Coupling of carbene complex 2 with aldehyde 1a (Table 1, entry 1). The General Procedure was followed using carbene complex 2 (348 mg, 1.20 mmol) and aldehyde 1a (265 mg, 1.00 mmol). Final purification was achieved by flash chromatography on silica gel using 4:1 hexane:ethyl acetate as eluent. Dihydrophenanthrene 16a was isolated (158 mg, 58% yield). ¹HNMR (200 MHz, CDCl₃): δ 7.53 (d, 1H, J = 8.7 Hz), 7.44 (d, 1H, J = 8.1 Hz), 7.24 (br s, 1H), 7.21 (d, 1H, J = 8.7 Hz), 7.12 (d, 1H, J = 8.1 Hz), 3.98 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 2.99 (t, 2H, J = 6.7 Hz), 2.44 (t, 2H, J = 6.7 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 159.6, 149.8, 144.9, 130.2, 129.5, 125.5, 125.1, 124.8, 124.6, 124.5, 113.6, 96.3, 61.0, 56.8, 54.6, 30.1, 26.5; MS (EI): 270 (M⁺, 100), 255 (52), 240 (12), 224 (16), 212 (33); HRMS (EI): Calcd for C₁₇H₁₈O₃ 270.1256, Found 270.1265.

Coupling of carbene complex 2 with aldehyde 1b (Table 1, entry 2). The General Procedure was followed using carbene complex 2 (346 mg, 1.20 mmol) and aldehyde 1b (248 mg, 1.00 mmol). Final purification was achieved by flash chromatography on silica gel using 4:1 hexane:ethyl acetate as eluent. Dihydrophenanthrene 17b was isolated (214 mg, 65% yield). ¹HNMR (400 MHz, CDCl₃): δ 7.50 (d, 2H, J = 8.0 Hz), 7.18 (d, 1H, J = 8.0 Hz), 7.14 (d, 2H, J = 8.0 Hz), 5.98 (s, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 2.85 (ddd, 1H, J = 15.0, 14.7, 6.3 Hz), 2.74 (ddd, 1H, J = 15.0, 6.3, 2.0 Hz), 2.53 (ddd, 1H, J = 15.0, 5.3, 2.0 Hz), 2.21 (ddd, 1H, J = 15.0, 14.7, 5.3 Hz), 0.02 (s, 9H); ¹³C NMR (CDCl₃): δ 165.8, 145.4, 140.5, 134.4, 131.6, 129.8, 125.2, 125.1, 123.4, 116.9, 115.5, 60.6, 55.8, 30.6, 22.9, 1.2; HRMS (ESI): Calcd for C₁₈H₂₅O₃Si (M+H) 329.1573, Found 329.1573

Coupling of carbene complex 2 with aldehyde 1c (Table 1, entry 3). The General Procedure was followed using carbene complex 2 (348 mg, 1.20 mmol) and aldehyde 1c (277 mg, 1.00 mmol). Final purification was achieved by flash chromatography on silica gel using 4:1 then 2:1 hexane:ethyl acetate as eluent. Compound 16c was isolated (188 mg, 63%). ¹HNMR (400 MHz, CDCl₃): δ 7.54 (d, 1H, J = 8.8 Hz), 7.49 (d, 1H, J = 8.2 Hz), 7.23 (d, 1H, J = 8.2 Hz), 7.11 (d, 1H, J = 8.8 Hz), 7.09 (br s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.00 (t, 2H, J = 7.6 Hz), 2.44 (t, 2H, J = 7.6 Hz), 2.40 (s, 3H); ¹³C NMR: (100 MHz, CDCl₃): δ 169.3, 160.3, 148.2, 141.2, 133.7, 130.8, 130.6, 126.5, 125.4, 124.3, 124.2, 120.6, 96.0, 61.6, 54.7, 30.0, 26.5, 20.8; IR (neat): 1764 cm⁻¹; HRMS (ESI): Calcd for C₁₈H₁₉O₄ (M+H) 299.1278, Found 299.1288.

Coupling of carbene complex 2 with aldehyde 1d (Table 1, entry 4). The General Procedure was followed using carbene complex 2 (290 mg, 1.00 mmol) and aldehyde 1d (326 mg, 1.00 mmol) in 19:1 dioxane:water (10 mL). Final purification was achieved by flash chromatography on silica gel using 4:1 followed by 1:1 hexane:ethyl acetate as eluent. Compound 5d was isolated (300 mg, 72%). ¹HNMR (400 MHz, CDCl₃): δ 7.30 (d, 1H, J = 8.1 Hz), 7.08 (d, 1H, J = 8.1 Hz), 4.93 (t, 1H, J = 6.6 Hz), 3.63 (s, 3H), 3.30 (s, 3H), 2.60-2.50 (m, 2H), 2.34 (ddd, 1H, 17.0, 13.8, 4.3 Hz), 2.26 (ddd, 1H, J = 12.9, 8.8, 4.3 Hz), 2.17 (ddd, 1H, J = 13.8, 9.6, 3.8 Hz), 2.02-1.90 (m, 2H), 1.85 (br s, 1H), 0.06 (s, 9H); ¹³C NMR (100 MHz, CDCl₃): δ 203.2, 160.3, 149.7, 142.4, 142.0, 141.4, 132.4, 125.0, 122.6, 69.0, 60.7, 39.2, 37.8, 37.6, 36.4, 31.4, 0.0; IR (neat): 3409, 1645 cm⁻¹; Mass Spec (FAB): 433 (M+Na, 16), 411 (M+H, 16), 395 (100); HRMS: Calcd for C₁₉H₂₇O₆SSi (M+H) 411.1298, Found 411.1282.

Coupling of carbene complex 2 with aldehyde 1e (Table 1, entry 5). The General Procedure was followed using carbene complex 2 (221 mg, 0.76 mmol) and aldehyde 1e (161 mg, 0.69 mmol). Final purification was achieved by flash chromatography on silica gel using 4:1 hexane:ethyl acetate as eluent. Compound 16e was isolated (95 mg, 57%). ¹HNMR (200 MHz, CDCl₃): δ 7.72 (d, 1H, J = 8.8 Hz), 7.50 (d, 1H, J = 8.2 Hz), 7.32 (d, 1H, J = 2.2 Hz), 7.16 (d, 1H, J = 8.2 Hz), 7.13 (dd, 1H, J = 8.8, 2.4 Hz), 6.17 (s, 1H), 3.98 (s, 3H), 3.88 (s, 3H), 3.05 (t, 2H, J = 8.2 Hz), 2.52 (t, 2H, J = 8.2 Hz); ¹³C NMR (50 MHz, CDCl₃): δ 161.0, 157.46, 130.1, 130.0, 129.4, 129.2, 128.5, 124.1, 116.7, 101.8, 91.6, 55.3, 54.8, 29.6, 29.5, 27.5; IR (neat): 1657 (s), 1621 (s) cm⁻¹; Mass Spec (EI): 240 (M, 100), 225 (45); HRMS (EI): Calcd for C₁₆H₁₆O₂ 240.1150, Found 240.1148.

Coupling of carbene complex 2 with aldehyde 1f. The General Procedure was followed using carbene complex 2 (450 mg, 1.55 mmol) and aldehyde 1f (375 mg, 1.29 mmol). Final purification was achieved by flash chromatography on silica gel using 4:1 hexane:ethyl acetate as eluent. Compound 16f was isolated (242 mg, 60%). ¹HNMR (200 MHz, CDCl₃): δ 7.38 (d, 1H, J = 8.1 Hz), 7.24 (s, 1H), 7.12 (s, 1H, J = 8.1 Hz), 7.07 (s, 1H), 6.10 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H), 3.81 (s, 3H), 3.00 (t, 2H, J = 8.8 Hz), 2.47 (t, 2H, J = 8.8 Hz); ¹³C NMR (50 MHz, CDCl₃): δ 161.2, 149.3, 148.8, 129.2, 128.8, 127.4, 124.7, 122.9, 107.2, 101.9, 91.8, 55.9, 55.8, 54.9, 29.6, 27.7; MS (EI): 270 (M, 100), 255 (38), 227 (27); HRMS (EI): Calcd for C₁₇H₁₈O₃ 270.1256, Found 270.1251.

Coupling of carbene complex 2 with ketone 1g. The General Procedure was followed using carbene complex 2 (300 mg, 1.03 mmol) and ketone 1g (280 mg, 1.00 mmol). Final purification was achieved by flash chromatography on silica gel using 4:1 followed by 3:2 hexane:ethyl acetate as eluent. Compound 16g was isolated (115 mg, 40%). ¹HNMR (200 MHz, CDCl₃): δ 7.30 (s, 1H), 7.18 (s, 1H), 7.03 (s, 1H), 6.11 (s, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 3.86 (s, 3H), 2.98 (t, 2H, J = 8.8 Hz), 2.60 (s, 3H), 2.48 (t, 2H, J = 8.8 Hz); ¹³C NMR (50 MHz, CDCl₃): δ 160.5, 148.9, 148.5, 128.8, 127.6, 127.4, 127.2, 126.0, 124.8, 103.7, 102.5, 91.8, 55.9, 55.7, 54.8, 29.5, 27.7, 19.6; MS (EI): 284 (M, 100), 269 (54), 241 (30); HRMS (EI): Calcd for C₁₈H₂₀O₃ 284.1412, found 284.1407. If one omits the chromatography step a different product consistent with 18g was obtained in greater than 90% purity: ¹H NMR (200 MHz, CDCl₃): δ 7.21 (s, 1H), 7.19 (s, 1H), 7.03 (s, 3H), 4.79 (br d, 1H, J = 4.0 Hz), 4.03 (s, 6H), 3.65 (s, 3H), 3.65-3.30 (m, 3H), 2.89 (s, 3H), 0.03 (s, 9H).

Coupling of carbene complex 2 with ketone 1g in 10:1 dioxane: collidine. A modification of the General Procedure was followed using carbene complex 2 (430 mg, 1.50 mmol) and ketone 1g (280 mg, 1.00 mmol) in collidine (1 mL) and dioxane (10 mL) at 80°C. After a 24h period at 80 °C, the mixture was cooled to room temperature and filtered through a thin layer of Celite and the solvent was removed on a rotary evaporator. The residue was dissolved in dichloromethane and washed with saturated aqueous ammonium chloride solution and then dried over sodium sulfate. The solution was concentrated under reduced pressure and then purified by flash chromatography on silica gel using 14:1 hexane:ethyl acetate as an eluent to afford compound 16g (260 mg, 92%).