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

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-benzocycloalkenones, 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, AgNO 3 and I 2 , 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. MeOH, RT (1) 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(NO 3 ) 3 ·3H 2 O or AgNO 3 /I 2 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(NO 3 ) 3 ·3H 2 O and AgNO 3 [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 Et 2 O 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 Et 2 O 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 1 H-NMR) which were used without further purification.
The Wittig-HTIB sequence was also employed for incorporation of a 13 C-label into the β-tetralone nucleus (entry 8). To this end, 13 C-methyltriphenylphosphonium iodide was prepared from 13 C-labeled iodomethane and utilized for the olefination of 1-indanone. Exposure of 1-( 13 C-methylidene)indan (5.0 mmol) to HTIB (4.54 mmol) in 95% MeOH (25 mL) gave 1-13 C-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 1 H-spectrum of unlabeled β-tetralone appears as a doublet at δ 3.62 (J CH = 128.6 Hz) in the 1 H spectrum of the 13 C-isotopomer. A 13 C-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.

Conclusions
In summary, the Wittig-HTIB sequence is a useful method for regiospecific syntheses of βbenzocycloalkenones 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 ( 1 H-) and 75 ( 13 C-) MHz. The NMR solvent in all cases was CDCl 3 ; chemical shifts are expressed relative to residual CHCl 3 ( 1 H spectra) or to CDCl 3 ( 13 C-spectra). Multiplets in 1 H-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 o C) 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 o C. 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 P 2 O 5 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).

Preparation of 13 C-Methyltriphenylphosphonium Iodide
A solution of 13 C-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 13 C-methyltriphenylphosphonium iodide; yield, 12.60 (97%); melting point, 182-184 °C (lit. [17] mp 183-184 °C). (18) Potassium tert-butoxide (1.35 g, 12.0 mmol) was added at once under argon to a mechanically stirred mixture of 13 C-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-( 13 Cmethylidene)indan (18) as a colorless oil; yield, 0.91 g (69%); 1 H-NMR δ 2.97 (m, 2H), 3.14 (m, 2H)