Application of [Hydroxy(tosyloxy)iodo]benzene in the Wittig-Ring Expansion Sequence for the Synthesis of β-Benzocyclo-alkenones from α-Benzocycloalkenones

Abstract

The conversion of α-benzocycloalkenones to homologous β-benzocyclo-alkenones containing six, seven and eight-membered rings is reported. This was accomplished via a Wittig olefination-oxidative rearrangement sequence using [hydroxy(tosyloxy)iodo]-benzene (HTIB) is the oxidant, that enables the synthesis of regioisomeric pairs of methyl-substituted β-benzocycloalkenones. The incorporation of carbon-13 at C-1 of the β-tetralone nucleus was also demonstrated. The Wittig-HTIB approach is a useful alternative to analogous sequences in which Tl(NO₃)₃·3H₂O or the Prevost combination (AgNO₃/I₂) are employed in the oxidation step.

Introduction

Synthetic access to the β-benzocycloalkenones and their ring-substituted derivatives, 1, was facilitated by the 1977 publication of a two-step protocol involving Wittig olefination of α-benzo-cycloalkenones, 2, and oxidative ring expansion of the resulting alkenes with thallium(III) nitrate in methanol [1]. This procedure, exemplified by equation 1, enables the regiospecific placement of alkyl groups at the α-carbon atoms of the β-cycloalkenone ring, and affords dimethyl ketals when trimethyl orthoformate is employed as a co-solvent. It was later demonstrated that thallium(III) nitrate can be replaced with the Prevost combination, AgNO₃ and I₂, for two-step conversions of α-tetralones (n = 2) to β-benzosuberones [2], although the experimental procedure is a bit less convenient than the thallium nitrate method.

We have recently reported that the treatment of arylalkenes with [hydroxy(tosyloxy)iodo]benzene (3, HTIB) in 95% methanol provides a general, regiospecific synthesis of α-aryl ketones (equation 2) [3]. This oxidative rearrangement is fundamentally equivalent to the ring-expansion step depicted in eq. 1, and we now report that HTIB is an excellent alternative to Tl(NO₃)₃·3H₂O or AgNO₃/I₂ for the two-step synthesis of β-benzocycloalkenones from their lower α-benzocycloalkenone homologs. An obvious advantage of HTIB is its relatively benign character in comparison to Tl(NO₃)₃·3H₂O and AgNO₃[4].

Results and Discussion

Syntheses of the exocyclic alkenes and β-benzocycloalkenones shown in Table 1 were accomplished as indicated in equation 3. The olefination procedure was adapted from the Fitjer-Quabeck approach, wherein potassium tert-butoxide is utilized as the Wittig base in Et₂O or benzene [5]. More specifically, the α-benzocycloalkenones were added to a pre-stirred mixture of potassium tert-butoxide and the appropriate alkyltriphenylphosphonium iodide in Et₂O at room temperature. After approximately 4 h, the reaction mixtures were filtered through Celite® and concentrated. Passage of the residual material through silica gel with hexanes gave the exocyclic alkenes (characterized by ¹H‑NMR) which were used without further purification.

The oxidative ring-expansions were effected by the addition of crystalline HTIB (10 mmol) to a small excess of the alkene in 95% MeOH (mildly exothermic) at room temperature. After about 20 minutes and a preliminary aqueous workup, the resulting β-benzocycloalkenones were isolated by column chromatography in yields (from the alkenes) of 80 to 99%.

Table 1. Oxidative ring expansions of alkylidenebenzocycloalkenes to β-benzocycloalkenones with HTIB in 95% MeOH

Entry	Alkene	Alkene Yield, %	Product	Isolated Yield, %
1		26		94
2		66		99
3		91		87
4		67		82
5		62		92
6		90		80
7		60		85
8		69		91

Table 1. Oxidative ring expansions of alkylidenebenzocycloalkenes to β-benzocycloalkenones with HTIB in 95% MeOH

Entry	Alkene	Alkene Yield, %	Product	Isolated Yield, %
1		26		94
2		66		99
3		91		87
4		67		82
5		62		92
6		90		80
7		60		85
8		69		91

As indicated in Table 1 (entries 1-3), conversions of unsubstituted α-benzocycloalkenones to homologous β-benzocycloalkenones containing six, seven and eight-membered rings, via the Wittig-HTIB sequence, were demonstrated. Furthermore, as with the Tl(III)-induced rearrangements, the proper selection of substrates enables syntheses of regioisomeric pairs of methyl-substituted β-benzocycloalkenones (cf. entries 4-7). For example, the treatment of 2-methyl-1-methylideneindan with HTIB gave 3-methyl-2-tetralone (entry 4), while similar treatment of 1-ethylideneindan gave 1-methyl-2-tetralone (entry 5).

The Wittig-HTIB sequence was also employed for incorporation of a ¹³C-label into the β-tetralone nucleus (entry 8). To this end, ¹³C-methyltriphenylphosphonium iodide was prepared from ¹³C-labeled iodomethane and utilized for the olefination of 1-indanone. Exposure of 1-(¹³C-methylidene)indan (5.0 mmol) to HTIB (4.54 mmol) in 95% MeOH (25 mL) gave 1-¹³C-2-tetralone in 91% isolated yield. The location of the label at C-1 in the β-tetralone ring was clearly revealed by NMR analysis. Thus, the singlet at δ 3.58 in the ¹H-spectrum of unlabeled β-tetralone appears as a doublet at δ 3.62 (J_CH = 128.6 Hz) in the ¹H spectrum of the ¹³C-isotopomer. A ¹³C-NMR spectrum of the labeled compound, recorded after only 16 scans, exhibits a markedly enhanced singlet at δ 45.03, while the resonances of the remaining carbons are either very weak in comparison or not perceptible.

A plausible mechanism for the HTIB-induced ring-expansions reported herein is presented in Scheme 1. It is analogous to that proposed for the oxidative rearrangement of arylalkenes to α-aryl ketones [3], and accounts for the regiochemistry of β-benzocycloalkenone formation. The similarity between iodine(III) and thallium(III) reagents in the context of oxidative rearrangements has been reviewed by Prakash [6] and almost certainly originates from their electrophilic character and capacity for reduction to the respective iodine(I) and thallium(I) oxidation states.

Scheme 1. .

Scheme 1. .

Conclusions

In summary, the Wittig-HTIB sequence is a useful method for regiospecific syntheses of β-benzocycloalkenones from α-benzocycloalkenones, and is environmentally preferable to similar protocols based on Tl(III) and Ag(I) reagents.

Experimental

General

NMR spectra were recorded on a Varian model Gemini-300 spectrometer at resonance frequencies of 300 (¹H-) and 75 (¹³C-) MHz. The NMR solvent in all cases was CDCl₃; chemical shifts are expressed relative to residual CHCl₃ (¹H spectra) or to CDCl₃ (¹³C- spectra). Multiplets in ¹H-NMR spectra are sometimes specified with a range of chemical shifts corresponding to the highest and lowest lines in the multiplet. IR spectra were recorded on a Bomem MB-100 FT-IR spectrophotometer. IR samples were neat films or a Nujol® mull (Entry 4). The elemental analysis was performed by Midwest Microlab, LTD (Indianapolis, IN). Melting points were recorded on a Thomas-Hoover Unimelt melting point apparatus and are uncorrected. 2-Methyl-1-indanone and 2-methyl-1-tetralone (used for preparation of the alkenes in entries 4 and 6) were prepared by adaptation of literature methods [7,8]. All other solvents and chemical reagents were obtained from commercial sources and used as received. Flash column chromatography was performed on a 42 mm internal diameter column packed with Kieselgel (230-400 mesh) silica gel purchased from the Aldrich Chemical Company. Thin layer chromatography (TLC) was done with glass backed 250 micron silica gel plates containing a fluorescent indicator and purchased from Alltech. The 95% methanol used as the solvent for the treatment of the substrate alkenes with [hydroxy(tosyloxy)iodo]benzene (HTIB), refers to a 95:5 (v/v) mixture of methanol and water. Consumption of the oxidant was verified prior to work-up by adding a drop of the reaction mixture to 10% KI (aq.) solution. Yields are based on the material used for the spectroscopic data presented in this paper.

Preparation of Hypervalent Iodine Reagents

Typical Synthesis of (Diacetoxyiodo)benzene

A solution of 32% (w/v) peracetic acid (100 mL, 421 mmol) in acetic acid was added dropwise with mechanical stirring to a cooled flask (15 ^oC) containing iodobenzene (65.28 g, 320.0 mmol), over a period of 1 hour. The rate of addition was adjusted to keep the temperature of the reaction mixture between 25-30 ^oC. Mechanical stirring was continued for 4 hours during which time a white precipitate separated. Water (100 mL) was added to facilitate precipitation and to dilute any remaining oxidant. The solid was isolated by vacuum filtration, washed with water (2 x 100 mL) and ether (150 mL), dried over P₂O₅ in a vacuum dessicator overnight and identified as (diacetoxyiodo)benzene; yield 94.86 g (92%); mp 160-161 °C (lit. [9] mp 159-161 °C).

Typical Synthesis of [Hydroxy(tosyloxy)iodo]benzene (HTIB, 3)

A solution of (diacetoxyiodo)benzene (40.26 g 125.0 mmol) in boiling acetonitrile (120 mL) was added at once to a solution of p-toluenesulfonic acid monohydrate (24.72 g, 130.0 mmol) in boiling acetonitrile (80 mL), with magnetic stirring, to give a yellow-green solution. The solution was allowed to cool to room temperature, and the crystalline [hydroxy(tosyloxy)iodo]benzene that separated was isolated by vacuum filtration and washed with acetonitrile (100 mL) and ether (100 mL); yield, 45.39 g (93%); mp 136-7 ^oC, dec. (lit.[10] mp 136-138.5 ^oC).

Representative Procedure - Reaction of HTIB with 1-Methylideneindan (4) (Entry 1).

Crystalline HTIB (3.92 g, 10.0 mmol) was added to a stirred solution of 1-methylideneindan (1.43 g, 11.0 mmol) in 95% methanol (40 mL). The solid dissolved rapidly (~15 sec) with the evolution of heat (41 ^oC) to give a colorless solution. The solution was stirred at room temperature for 20 minutes and the solvent was removed in vacuo to give an oily mixture. This mixture was partitioned between CH₂Cl₂ (40 mL) and H₂O (25 mL) and transferred to a separatory funnel. The organic layer was separated, washed with H₂O (2 x 25 mL) and brine (1 x 30 mL), dried over MgSO₄, and concentrated in vacuo to a bright yellow oil (1.51 g), which was subjected to flash column chromatography on silica gel (hexanes; 5 % ethyl acetate/hexanes) to give β-tetralone (5) as a light yellow oil (R_f = 0.29, 5 % ethyl acetate/hexanes); yield, 1.38 g (94 %); ¹H-NMR δ 2.54 (t, J = 6.6, 2H), 3.06 (t, J = 6.6, 2H), 3.58 (s, 2H), 7.11-7.15 (m, 1H), 7.20-7.24 (m, 3H); ¹³C-NMR δ 28.13, 37.95, 44.91, 126.80, 126.87, 127.58, 128.19, 133.28, 136.71, 210.71; IR (C=O) 1719 cm^-1.

Summary of Purification, Yield and Spectral Data for β-benzocycloalkenones (Entries 2-7)

Conversion of Alkene 6 to Ketone 7 (Entry 2)

Flash column chromatography of the oil on silica gel (petroleum ether; 10% ethyl acetate/petroleum ether) gave 2-benzosuberone (7) as a colorless oil; yield, 1.58 g (99%); ¹H-NMR δ 1.99 (m, 2H), 2.57 (dd, J = 6.9, 6.9, 2H), 2.95 (m, 2H), 3.73 (s, 2H), 7.14-7.22 (m, 4H); ¹³C-NMR δ 26.11, 32.85, 43.56, 50.04, 127.14, 127.59, 129.24, 129.60, 133.61, 140.51, 208.90; IR (C=O) 1710 cm^-1; 2,4-dinitro- phenylhydrazone, mp 174-176 °C (lit. [11] mp 169-170 °C).

Conversion of Alkene 8 to Ketone 9 (Entry 3)

Flash column chromatography of the oil on silica gel (hexanes; 5% ethyl acetate/hexanes) gave 7,8,9,10-tetrahydro-5H-benzocyclooctan-6-one (9) as a colorless oil (R_f = 0.32, 5% ethyl acetate/ hexanes); yield, 1.51 g (87%); ¹H-NMR δ 1.76 (m, 2H), 1.87 (m, 2H), 2.35 (m, 2H), δ 2.84 (m, 2H), 3.82 (s, 2H), 7.14-7.30 (m, 3H) [12]; ¹³C-NMR δ 24.63, 31.14, 32.98, 40.87, 48.58, 126.73, 127.99, 129.98, 130.27, 133.66, 141.13, 212.05; IR (C=O) 1700 cm^-1; oxime, mp 128-129 °C (lit.[13] mp 130-131 °C).

Conversion of Alkene 10 to Ketone 11 (Entry 4)

Flash column chromatography on silica gel (5% ethyl acetate/hexanes; 10% ethyl acetate/hexanes) gave a yellow oil (R_f = 0.78, 10% ethyl acetate in hexanes). Kugelrohr distillation of this oil gave 3-methyl-2-tetralone (11) as white rosettes; yield, 1.31 g (82%); mp 38-40 ^oC (lit. [14] mp 37-40 °C); ¹H‑NMR δ 1.20 (d, J = 6.9, 3H), 2.54 (m, 1H), 2.84 (dd, J = 15.4, 11.0, 1H), 3.08 (dd, J = 15.4, 5.8, 1H), 3.61 (s, 2H), 7.12-7.26 (m, 4H); ¹³C-NMR δ 14.89, δ 36.73, δ 42.31, δ 44.07, δ 126.76, δ 126.87, δ 127.80, δ 128.13, δ 133.51, δ 136.24, δ 212.28; IR (C=O) 1722 cm^-1.

Conversion of Alkene 12 to Ketone 13 (Entry 5)

Flash column chromatography of the oil on silica gel (hexanes; 5% ethyl acetate/hexanes) gave 1‑methyl-2-tetralone (13) as a colorless oil (R_f = 0.24, 5% ethyl acetate/hexanes); yield, 1.48 g (92%); ¹H‑ NMR δ 1.48 (d, J = 6.9, 3H), 2.43-2.69 (overlapping m’s, 2H), 3.08 (m, 2H), 3.54 (quartet, J = 6.9, 1H), 7.21-7.29 (m, 4H); ¹³C-NMR δ 13.74, 27.70, 36.82, 47.12, 125.72, 126.36, 126.73, 127.18, 136.56, 137.63, 211.83; IR (C=O) 1714 cm^-1; Anal. Calcd. for C₁₁H₁₂O: C: 82.46%, H: 7.55 %, Found: C 82.35 %, H 7.60%.

Conversion of Alkene 14 to Ketone 15 (Entry 6)

Flash column chromatography of the oil on silica gel (hexanes; 5% ethyl acetate/hexanes) gave 3‑methyl-2-benzosuberone (15) as a colorless oil (R_f = 0.27, 5% ethyl acetate/hexanes); yield, 1.40 g (80%); ¹H-NMR δ 1.03 (d, J = 6.3, 3H), 1.56 (m, 1H), 2.13 (m, 1H), 2.80 (m, 1H), 2.92 (m, 2H), 3.72 (AB doublet pair, J = 54.9, 15.4, 2H), 7.14-7.26 (m, 4H); ¹³C-NMR δ 10.80, 27.94, 30.75, 41.69, 45.15, 122.57, 122.98, 124.46, 125.00, 129.39, 136.17, 206.11; IR (C=O) 1708 cm^-1.

Conversion of Alkene 16 to Ketone 17 (Entry 7)

Flash column chromatography of the oil on silica gel (hexanes; 5% ethyl acetate/hexanes; 10% ethyl acetate/hexanes) gave 1-methyl-2-benzosuberone (17) as a colorless oil (R_f = 0.26, 5% ethyl acetate/hexanes); yield, 1.47 g (85%); ¹H-NMR δ 1.45 (d, J = 7.1, 3H), 1.92 (m, 1H), 2.08 (m, 1H), 2.47 (m, 1H), 2.66 (m, 1H), 2.79 (m, 1H), 2.95 (m, 1H), 3.88 (quartet, 6.9, 1H), 7.12-7.26 (m, 4H); ¹³C‑NMR δ 14.50, 27.07, 32.33, 42.21, 50.80, 127.12, 127.16, 127.21, 129.40, 138.61, 139.65, 211.89; IR (C=O) 1709 cm^-1; 2,4-dinitrophenylhydrazone, mp 144-146 °C (lit. [15] mp 150-151 °C).

Preparation of 13C-Methyltriphenylphosphonium Iodide

A solution of ¹³C-labeled iodomethane [16] (5.00 g, 35.0 mmol) in benzene (20 mL) was added dropwise to a cooled (-4 to 0 °C) solution of triphenylphosphine (8.39 g, 32.0 mmol) in benzene (50 mL) over one hour. A white solid began to separate after 40 minutes. This mixture was allowed to warm to room temperature and stirred for a period of 4 hours. The white solid was collected by vacuum filtration and identified by melting point as ¹³C-methyltriphenylphosphonium iodide; yield, 12.60 (97%); melting point, 182-184 °C (lit. [17] mp 183-184 °C).

Preparation of ¹³C-Methylideneindan (18)

Potassium tert-butoxide (1.35 g, 12.0 mmol) was added at once under argon to a mechanically stirred mixture of ¹³C-methyltriphenylphosphonium iodide (4.86 g, 12.0 mmol) in dry ether (50 mL) to give a canary yellow mixture. This mixture was vigorously stirred for 30 minutes. A solution of 1‑indanone (1.32 g, 10.0 mmol) in dry ether (20 mL) was added to the mixture over a period of 5 minutes. The color of the mixture gradually became a vivid blue as it was stirred overnight (14 hours). The resulting mixture was filtered through Celite® (10 g), and the filtrate was concentrated in vacuo to give a light yellow oil. The oil was eluted with hexanes through a pad of silica gel (30 g) on a sintered glass funnel under aspirator vacuum. The eluant was concentrated in vacuo to give 1-(¹³C-methylidene)indan (18) as a colorless oil; yield, 0.91 g (69%); ¹H-NMR δ 2.97 (m, 2H), 3.14 (m, 2H), 5.16 (dt, J_HH = 2.1, J_HC = 127.20, 1H), 5.68 (dt, J_HH = 2.1, J_HC = 125.4, 1H), 7.34-7.44 (m, 3H), 7.66 (d, J = 6.9, 1H); ¹³C-NMR δ 12.93, 30.01, 31.10, 102.73 (enhanced), 120.50, 120.53, 125.24, 126.31, 128.13, 128.15; IR (¹²C=¹³C) 1715 cm^-1.

Reaction of ¹³C Labeled Methylideneindan with HTIB (Entry 8)

Crystalline HTIB (1.78 g, 4.54 mmol) was added to a stirred solution of 1-(¹³C-methylidene)indan (18, 0.66 g, 5.0 mmol) in 95% methanol (25 mL). The solid dissolved rapidly with the evolution of heat to give a colorless solution. The solution was stirred at room temperature for 20 minutes, and the solvent was removed in vacuo to give an oily mixture. This mixture was partitioned between CH₂Cl₂ (25 mL) and H₂O (25 mL). The organic layer was washed with H₂O (2 x 25 mL) and brine (1 x 20 mL), dried over MgSO₄, and concentrated in vacuo to give a bright yellow oil (0.79 g). Flash column chromatography of the oil on silica gel (hexanes; 5 % ethyl acetate/ hexanes) gave 1-¹³C-β-tetralone (19) as a light yellow oil (R_f = 0.30, 5 % ethyl acetate/hexanes); yield, 0.61 g (91 %); ¹H-NMR δ 2.58 (t, J = 6.6, 2H), δ 3.10 (t, J = 6.6, 2H), δ 3.62 (d, J_HC = 128.6, 2H), δ 7.15-7.19 (m, 4H); ¹³C-NMR, (16 transients) δ 45.03; IR (C=O) 1718 cm^-1.