Easier Preparation of 2,6-Di-tert-butylphenyl Derivatives ^¹

Abstract

Despite steric shielding by the 2,6-di-tert-butylphenyl group (‘super-2,6-xylyl’ = xyl*), inexpensive sodium phenolate (xyl*-ONa) reacts with dimethyl sulfate to produce only xyl*-OCH₃ (94%) with complete suppression of the alternative 4-methylation. Reductive cleavage of xyl*-OCH₃ by elemental lithium with the help of an electron carrier generates xyl*-Li, which in turn yields xyl*-CO₂H (63%). The corresponding 4-methyl-derivatives of these compounds were obtained analogously. The acid chloride xyl*-COCl (77% yield) acylates HalMgCH₂R to give only xyl*-COCH₃ (86%) or xyl*-COEt (97%). These two ketones react with n-butyllithium (no carbonyl addition) and Cl-PO(OEt)₂ to furnish only the enol phosphates xyl*-C(=CH₂)OPO(OEt)₂ (84%) or xyl*-C(=CHCH₃)OPO(OEt)₂ (up to 70%), respectively. Only 1,2-elimination occurs when the latter two products are treated with tert-butyllithium, affording xyl*-C≡CH (68%) or xyl*-C≡CMe (88%), respectively.

The published syntheses^²-5 of compounds carrying a 3,4,5-unsubstituted 2,6-di-tert-butylphenyl group employ multistep routes that give yields that are not always satisfactory.⁴ Our search for a short and easy pathway with fewer side-reactions revealed that 2,6-di-tert-butyl-4-methyl­-anisole (2b; Scheme  [¹] ) had been observed in unpublished work⁶ to break ‘predominantly’ its aryl-oxygen bond (rather than O-CH₃) on treatment with elemental potassium in 1,2-dimethoxyethane (DME). Using, instead, the much safer elemental lithium together with an electron carrier, we have discovered and report here how this reductive cleavage can be used for the preparation of other 2,6-di-tert-butylphenyl-derivatives on reasonably large scales (30 mmol or more).

A first problem arose with the preparation of pure 2,6-di-tert-butylanisole (2a) as a starting material: We found that most of the published procedures^7-¹¹ for hydroxyl-methylation with iodomethane in alkaline solution, when applied to inexpensive, commercial 2,6-di-tert-butylphenol (1a), led to 2a contaminated with small but significant quantities of 2b, which could not readily be separated from 2a by physical or chemical methods [transformation of the unwanted 4-CH₃ group of 2b into 4-CO₂H (2d) or 4-CH₂CO₂H functions, with subsequent alkaline separation from 2a, were feasible but unrewarding]. In an alternative approach, the more expensive 4-bromo-2,6-di-tert-butylphenol (1c) was converted into 2c, which furnished 2a upon debromination with elemental lithium in tert-butyl alcohol.

A surprisingly simple solution to the above 4-methylation problem was found by deprotonating 1a with sodium hydride^¹² (1.5 equiv) and adding dimethyl sulfate^¹² (DMS, 1.3 equiv) instead of iodomethane, provided that the solvent diethyl ether^¹² was replaced by 1,2-dimethoxyethane (the excess of sodium hydride is stable^¹³ towards dimethyl sulfate at r.t. and provides for the scavenging of adventitious proton sources). The crude product 2a contained no 2b and was pure after distillation (yield 94%).

The reductive cleavage of 2a worked well with the blue tetrahydrofuran solution formed with elemental lithium (3.1 equiv) and 4,4¢-di-tert-butylbiphenyl (DTBB; 0.50 equiv), whereas other suggested^¹4 electron carriers (biphenyl, naphthalene, 1-dimethylaminonaphthalene^¹5) were less suitable. The successful conditions had to balance exhaustive formation of the emerging aryllithium compound 5a against its protonation to give 1,3-di-tert-butylbenzene^¹6 (6a); therefore, the blue mixture was poured onto crushed solid carbon dioxide immediately after consumption of 2a (90 min at r.t.). The best isolated yields (ca. 67%) were attained after taking into account an unusual phase transfer property: Because the sodium salt of the acid 4a is soluble in both water (to give pH ˜7) and diethyl ether, low-boiling petroleum ether was used instead of diethyl ether for the workup with aqueous sodium hydroxide so that the non-acidic components could be extracted and the expensive carrier DTBB easily recovered^¹7 (isolated yield 95%). Small amounts (up to 7%) of 2,6-di-tert-butylphenol (1a) could be detected only in the non-acidic fractions, showing that 1a was not extracted into aqueous sodium hydroxide^¹8 and indicating that a corresponding amount of the lithium phenolate 3a had been generated through the O-CH₃ cleavage of 2a. Similar treatment of 2,6-di-tert-butyl-4-methylanisole⁸ (2b) with DTBB (1 equiv) and lithium (3.2 equiv) for only one hour furnished the acid 4b (crude yield 60%) along with a non-acidic fraction containing some phenol 1b, which was derived from 3b. The solid acid chloride 7 (distilled yield 77%), which was prepared from 4a with thionyl chloride (2 equiv) and a trace of pyridine at room temperature, reacted cleanly with either methylmagnesium chloride or ethylmagnesium bromide (2 equiv in either case) at room temperature to provide ketones 8a (86%) or 8b (97%), respectively. Side-products could not be detected,^¹9 although the α-diketone 2,2′,6,6′-tetra-tert-butylbenzil might have been expected by analogy with reports in the literature.^²0,²¹ In contrast, the addition of methyllithium to 7 furnished ketone 8a along with several side-products, among which a trace of α-diketone was recognized through its two diastereotopic C(CH₃) groups, which exhibited broadened^{²0 ¹}H NMR signals (δ = 0.89 and 1.45 ppm at 80 MHz in CCl₄) that were close to coalescence. Not unexpectedly,^²² ketone 8a was not produced by treatment of 5a with acetyl chloride, which, instead, resulted in proton transfer to give 6a.

The diethyl α-(2,6-di-tert-butylphenyl)vinyl phosphate (10a) was prepared from ketone 8a in tetrahydrofuran with n-butyllithium (1.5 equiv) via enolate 9a formation and subsequent addition of ClPO(OEt)₂ (2.0 equiv), with 84% yield of pure 10a after chromatography. A similar procedure converted the ketone 8b via the enolate 9b into the pure E-isomer 10b (ca. 66%). After numerous attempts, the most suitable base for preparing the alkyne 11a from 10a was found to be tert-butyllithium (2.5-2.7 equiv) in methyl tert-butoxide. This base avoids the interfering O-P cleavage reactions and furnished spontaneously crystallizing 11a (pure yield 68%). Similarly, 10b afforded almost pure propyne 11b (‘crude’ yield 88%, no propargyl or allenyl isomer), which was also obtained from 11a in tetrahydrofuran with n-butyllithium and di­methyl sulfate.

In conclusion, steric shielding appears to account for the clean course of the above reactions with small Grignard reagents, n-BuLi, or t-BuLi.

The spectroscopic equipment was described in a previous publication.^²³

2,6-Di- tert -butylanisole (2a)

A dry Schlenk flask (1 L) was charged with a magnetic stirring bar, NaH (15.70 g, 55% in oil), and anhydrous pentane (60 mL) under a well-ventilated hood. After stirring for 10 min, the liquid was removed with a pipette and discarded, and the washed NaH powder (calcd. 360 mmol) was covered with DME (200 mL) under a blanket of dried N₂ gas. A solution of 2,6-di-tert-butylphenol (1a; 50.04 g, 242.5 mmol) in anhydrous DME (150 mL) was added dropwise with stirring during 2 h at r.t. (CARE! Brisk evolution of H₂ gas). DMS (30.1 mL, 317 mmol) was then added within 20 min to the stirred, yellow-greenish suspension, which was stirred at r.t. for a further 2.5 h.

Residual NaH was destroyed under an N₂ atmosphere through the dropwise addition of EtOH (3 mL) and then distilled H₂O (20 mL), and unconsumed DMS was hydrolyzed by stirring overnight. The colorless sediment was dissolved within the mixture by adding aq HCl (100 mL, 100 mmol), and the two phases were separated. The aqueous layer was shaken with Et₂O (3 × 80 mL), and the combined four organic layers were washed with distilled H₂O (3 × 150 mL) until neutral, dried over MgSO₄, and concentrated to yield the almost pure, golden-yellow oil 2a (54.66 g). Pure 2a distilled at 130-132 ˚C/20 Torr (Lit.^¹² 96 ˚C/0.15 Torr).

Yield: 50.02 g (94%); bright-yellow liquid.

^¹H NMR (400 MHz, CDCl₃): δ = 1.42 (s, 18 H), 3.67 (s, 3 H, OCH₃), 6.96 and 7.23 (arom. AB₂ system, ^³ J = 7.8 Hz, 3 H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 32.13 [2 × C(CH₃)₃], 35.71 [2 × C(CH₃)₃], 64.19 (OCH₃), 122.88 (C-4), 126.48 (C-3/-5), 143.63 (C-2/-6), 159.49 (C-1).

4-Bromo-2,6-di- tert -butylanisole (2c)

^¹H NMR (80 MHz, CCl₄): δ = 1.46 (s, 18 H), 3.65 (s, 3 H, OCH₃), 7.20 (s, 2 H, m-ArH).

Converted into 2a (75% yield after chromatography) with elemental Li (at least 5 equiv) in THF-t-BuOH (8 h at 70 ˚C).

3,5-Di- tert -butyl-4-methoxybenzoic Acid (2d)

The oxidation of 2b with a large excess of KMnO₄ in refluxing aq NaOH and Aliquat 336 remained incomplete after 15 h, affording the acid 2d.

Yield: 22% (crude); mp ˜191 ˚C (hexane) (Lit.^¹¹ 195-197 ˚C; Lit.^²4 192.5-194.5 ˚C).

IR (KBr): 3600-2500 (br, CO₂-H), 2966, 2873, 1692 (s), 1393, 1300, 1254, 1227, 1006 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.45 (s, 18 H), 3.73 (s, 3 H, OCH₃), 8.03 (s, 2 H, 2 × ArH).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 31.9 [2 × C(CH₃)₃], 35.9 [2 × C(CH₃)₃], 64.5 (OCH₃), 123.4 (C-1), 129.0 (C-2/-6), 144.3 (C-3/-5), 164.8 (C-4), 172.3 (CO₂H); assigned through comparison with 2a and 4a.

2,6-Di- tert -butylbenzoic Acid (4a)

Elemental Li (975 mg, 140 mmol) was hammered to flat sheets, which were cut into smaller pieces and dropped into a dried Schlenk flask (250 mL) containing anhydrous THF (75 mL) and a magnetic stirring bar under dried argon gas. After the addition of DTBB (6.05 g, 22.7 mmol), the Schlenk flask was stoppered and sonicated in an ultrasound bath at r.t. until the mixture acquired a dark-blue color (not longer than 10 min). Pure 2,6-di-tert-butylanisole (2a; 10.00 g, 45.4 mmol) was introduced within 3 min, and the contents of the stoppered flask was stirred at r.t. for 90 min (not less than 60 min) without fading of the blue color. The mixture was poured quickly onto solid CO₂ and set aside for warming up over 30 min, whereupon the larger pieces of the unconsumed lithium were taken out. The orange-colored product mixture was dissolved in low-boiling PE (50 mL) together with aq NaOH (1 M, 100 mL). The separated aqueous layer was extracted with PE (50 mL), and the combined organic layers were then shaken with aq NaOH (2 M, 50 mL), washed with distilled H₂O (50 mL), dried over MgSO₄, and concentrated. The remaining yellow cake (7.11 g) contained mainly DTBB along with 1,3-di-tert-butylbenzene^¹6 (6a; yield 30%) and some 2,6-di-tert-butylphenol (1a; yield 7%), but no anisole 2a. This material was thoroughly mixed with MeOH, which was removed under suction, and again washed with MeOH to afford recovered pure DTBB (5.75 g, 95%).

The combined aq NaOH extracts were washed once more with PE (50 mL, to be discarded), then acidified with concd HCl and extracted with Et₂O (3 × 100 mL). The combined Et₂O extracts were washed with distilled H₂O until neutral, dried over MgSO₄, and evaporated to complete dryness, yielding the almost pure acid 4a.

Yield: 6.73 g (63%); mp 171-172 ˚C (hexane).

IR (KBr): 3600-2400 (br, CO₂-H), 3010, 1698 (s), 1295 (s), 758 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.48 (s, 18 H), 7.29 and 7.42 (arom. AB₂ system, ^³ J = 8.1 Hz, 3 H), 11.8 (br s, 1 H, CO₂H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 32.16 [2 × C(CH₃)₃], 36.81 [2 × C(CH₃)₃], 125.11 (C-3/-5), 128.83 (C-4), 130.30 (C-1), 146.90 (C-2/-6), 179.95 (CO₂H).

Anal. Calcd for C₁₅H₂₂O₂: C, 76.88; H, 9.46. Found: C, 77.19; H, 9.59.

Separation of 4a from non-acidic components was also complete after extraction with one portion of aq Na₂CO₃, but incomplete with aq NaHCO₃. The side-product 1a could not be extracted from Et₂O into either aq 2 M NaOH or Na₂CO₃.

Sodium 2,6-Di- tert -butylbenzoate

^¹H NMR (200 MHz, CDCl₃): δ = 1.34 (s, 18 H), 7.08 and 7.25 (br, arom. AB₂ system, ^³ J = ˜7.8 Hz, 3 H).

2,6-Di- tert -butyl-4-methylbenzoic Acid (4b)

Prepared as for 4a from 2b (3.00 g, 12.8 mmol) with DTBB (1 equiv) and Li (3.2 equiv) in 1 h.

Yield: 1.92 g (60%, crude); mp 182-184 ˚C (hexane).

IR (KBr): 3600-2500 (br, CO₂-H), 2968, 2916, 1697 (s), 1290 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.47 (s, 18 H), 2.34 (s, 3 H, 4-CH₃), 7.22 (s, 2 H, 3-/5-H), 12.0 (br s, 1 H, CO₂H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 21.9 (4-CH₃), 32.2 [2 × C(CH₃)₃], 36.7 [2 × C(CH₃)₃], 125.8 (C-3/-5), 127.7 (C-1), 138.0 (C-4), 146.9 (C-2/-6), 180.4 (CO₂H).

Anal. Calcd for C₁₆H₂₄O₂: C, 77.38; H, 9.74. Found: C, 77.24; H, 9.57.

2,6-Di- tert -butylbenzoyl Chloride (7)

The acid 4a (16.97 g, 72.42 mmol) was dissolved in anhydrous Et₂O (120 mL) with magnetic stirring under argon in a dried Schlenk flask (250 mL). The yellow solution became orange-colored upon the addition of SOCl₂ (10.52 mL, 144.8 mmol) and anhydrous pyridine (10 drops) as a catalyst. The flask was kept under anhydrous conditions at r.t. overnight without stirring. The brownish solution was separated by pipette from the resinous precipitate and concentrated (16.93 g, including residual SOCl₂). This material can be successfully processed further only after distillation in a wide-bore apparatus (to avoid obstruction through rapid crystallization).

Yield: 14.19 g (77%); mp 31.5-33 ˚C; bp 75-80 ˚C/0.1 mbar.

IR (Nujol): 1806 (COCl) cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.48 (s, 18 H), 7.29 and 7.39 (arom. AB₂ system, ^³ J = 8.0 Hz, 3 H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 32.5 [2 × C(CH₃)₃], 37.3 [2 × C(CH₃)₃], 125.9 (C-3/-5), 129.6 (C-4), 136.0 (C-1), 144.9 (C-2/-6), 173.6 (COCl).

Anal. Calcd for C₁₅H₂₁ClO: C, 71.27; H, 8.37; Cl, 14.02. Found: C, 71.33; H, 8.35; Cl, 13.11.

Note: 7 will hydrolyze to 4a within a few hours upon contact with moisture.

2,6-Di- tert -butylacetophenone (8a)

A dried Schlenk flask (250 mL) was charged with purified acid chloride 7 (14.19 g, 56.13 mmol), anhydrous Et₂O (120 mL), and a magnetic stirring bar under argon gas. The stirred, clear solution became turbid and began to boil gently on the dropwise addition of a THF solution of MeMgCl (37.4 mL, 112 mmol) at r.t. from a pressure-equalizing dropping funnel. Stirring was continued for 2.5 h, whereafter the mixture was poured into sat. aq NH₄Cl (300 mL). The aqueous layer was shaken with Et₂O (2 × 100 mL) and discarded. These three organic layers were combined, washed with distilled H₂O (3 × 80 mL), dried over MgSO₄, and evaporated to dryness, yielding the pure ketone 8a as a yellow oil that crystallized after a few minutes.

Yield: 11.24 g (86%); mp 39-41 ˚C (MeOH at -18 ˚C).

IR (KBr): 2955, 1697 (s), 1363, 1348, 1236, 750 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.38 (s, 18 H), 2.63 (s, 3 H, CH₃-α), 7.22 and 7.37 (arom. AB₂ system, ^³ J = 8.0 Hz, 3 H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 32.80 [qm, ^¹ J = 125.9 Hz, ^³ J = 4.9 Hz, 2 × C(CH₃)₃], 36.98 [m, ^² J = 3.7 Hz, 2 × C(CH₃)₃], 38.23 (sharp q, ^¹ J = 127.3 Hz, CH₃-α), 125.66 (ddd, ^¹ J = 157.3 Hz, ^³ J = 7.5 Hz, ^² J = +1.5 Hz, C-3/-5), 127.64 [app. dd, ^¹ J = 159.43 Hz, ^² J = -0.01 ( 0.03) Hz, C-4], 140.26 (tdq, ^³ J = 6.78 Hz, ⁴ J = -1.65 Hz, ^³ J = +0.89 Hz, C-1), 145.17 [dm, ^³ J = 7.40 Hz to 4-H, ^² J = +1.13 Hz to 3-H or 5-H, ⁴ J = -1.20 Hz to 5-H or 3-H, ^³ J = 3.68 Hz to 2-C(CH₃)₃ or 6-C(CH₃)₃, C-2/-6], 210.89 (qtd, ^² J = -5.57 Hz, ⁴ J = ±1.13 Hz, ⁵ J = -0.01 Hz, C=O); assigned through the following selective {^¹H} decoupling experiments: {3-/4-/5-H} → C=O as a sharp quartet with ^² J = 5.6 Hz, C-1 as a br singlet (^³ J q unresolved), C-2/-6 as a sharp decet; {CH₃-α} → C=O as a triplet with ⁴ J = 1.1 Hz, C-1 as a triple-doublet with ^³ J = 6.7 Hz and ⁴ J = 1.5 Hz; signs and values of the long-range couplings were determined through computer simulation.

Anal. Calcd for C₁₆H₂₄O: C, 82.70; H, 10.41. Found: C, 82.77; H, 10.32.

2,6-Di- tert -butylpropiophenone (8b)

Purified acid chloride 7 (1.43 g, 5.66 mmol) in anhydrous THF (24 mL) was stirred magnetically under argon gas in a dried Schlenk flask (100 mL) during the dropwise addition of a THF solution of EtMgBr (11.3 mmol, 11.3 mL) within 15 min. The darkening mixture became hot and was stirred for 2 h at r.t., then poured into iced aq NH₄Cl (50 mL) and shaken with Et₂O (3 × 25 mL). The combined organic extracts were washed with distilled H₂O (2 × 40 mL), dried over Na₂SO₄, and evaporated to dryness, affording the uncontaminated ketone 8b.

Yield: 1.36 g (97%); yellow, very viscous liquid (later a waxy solid, mp 46-48 ˚C); bp 85-90 ˚C (bath temp)/0.1 mbar.

IR (film): 2970, 1708 (s), 1474, 1457, 1364, 1203, 945, 741 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.16 (t, ^³ J = 7.0 Hz, 3 H, CH₃-β), 1.33 (s, 18 H), 2.85 (q, ^³ J = 7.0 Hz, 2 H, CH₂-α), 7.22 and 7.35 (arom. AB₂ system, ^³ J = 8.0 Hz, 3 H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 7.16 (qt, ^¹ J = 127.4 Hz, ^² J = 3.7 Hz, CH₃-β), 32.74 [qsept, ^¹ J = 126.1 Hz, ^³ J = 4.9 Hz, 2 × C(CH₃)₃], 37.11 [m, ^² J = 3.7 Hz, 2 × C(CH₃)₃], 42.73 (tq, ^¹ J = 124.1 Hz, ^² J = 4.4 Hz, CH₂-α), 125.73 (dd, ^¹ J = 158.0 Hz, ^³ J = 7.4 Hz, C-3/-5), 127.56 (dm, ^¹ J = 160.6 Hz, C-4), 139.76 (td, ^³ J = 6.6 Hz, ⁴ J = 1.5 Hz, C-1), 145.40 (m, ^³ J = 3.7 Hz, C-2/-6), 212.31 (m, ^³ J = ˜ ^² J = 4.9 Hz, C=O); assigned through the following selective {^¹H} decoupling experiments: {3-/4-/5-H} → C=O as a sextet with ^³ J = ˜ ^² J = 4.8 Hz, C-1 as a singlet with linewidth = 1.2 Hz (œ^³ Jœ < 0.3 Hz unresolved); {CH₂-α} → CH₃-β as a sharp quartet with ^¹ J = 127 Hz; {CH₃-β} → CH₂-α as a sharp triplet with ^¹ J = 124.1 Hz, C=O as a triple-triplet with ^² J = 4.8 Hz and ⁴ J = ˜1.1 Hz.

Anal. Calcd for C₁₇H₂₆O: C, 82.87; H, 10.64. Found: C, 82.98; H, 10.84.

Diethyl α-(2,6-Di- tert -butylphenyl)vinyl Phosphate (10a)

2,6-Di-tert-butyl acetophenone (8a; 11.24 g, 48.37 mmol) in anhydrous THF (225 mL) was stirred magnetically in a dry Schlenk flask (500 mL) under argon gas and cooled to -60 ˚C. The yellow solution turned red and the internal temperature rose to -30 ˚C on addition of n-BuLi (2.4 M in hexane, 30.25 mL, 72.6 mmol) within 5 min. After further stirring for 5 min, ClPO(OEt)₂ (13.94 mL, 96.68 mmol) was added at -30 ˚C. The mixture was warmed to r.t. and poured into aq NaOH (1 M, 200 mL). The aqueous layer was shaken with Et₂O (2 × 100 mL) and the combined three organic layers were washed with distilled H₂O (3 × 50 mL), dried over MgSO₄, and concentrated to give a yellow liquid containing 10a and residual ClPO(OEt)₂. Chromatography in a column (diameter 35 mm) of silica gel (63-200 mesh; 60 Å; 200 g) with low-boiling PE (500 mL) and then PE-Et₂O (4:1, 300 mL) removed part of the contamination. The elution rate had to be decreased very much on increasing the Et₂O concentration, so as to avoid heating and breaking of the silica gel column. The almost pure product 10a (14.90 g, 84%) was eluted with the next 100-mL portions of PE-Et₂O (4:1, then 2:1) and Et₂O, followed by other byproducts with additional Et₂O. The analytically pure sample was obtained as a colorless oil through rechromatography.

IR (film): 2967, 2912, 1647, 1364, 1274, 1256, 1056, 1033, 993 (vs), 807 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.35 [td, ^³ J _HH = 7.0 Hz, ⁴ J _PH = 1.1 Hz, 6 H, 2 × POC(CH ₃)], 1.49 (s, 18 H), ˜4.19 and ˜4.23 (2 × m, 4 H, diastereotopic H of 2 × POCH₂ groups, including ^³ J _PH), 4.80 (dd, ^² J _HH = 2.8 Hz, ⁴ J _PH = 1.7 Hz, 1 H, 1 β-H syn to aryl), 5.42 (dd, ^² J _HH = 2.8 Hz, ⁴ J _PH = 0.5 Hz, 1 H, 1 β-H anti to aryl), 7.23 and 7.42 (arom. AB₂ system, ^³ J = 8.0 Hz, 3 H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 16.08 (qtd, ^¹ J _CH = 127.5 Hz, ^² J _CH = 2.7 Hz, ^³ J _CP = 7.2 Hz, 2 × POCCH₃), 33.0 [qsept, ^¹ J _CH = 126 Hz, ^³ J _CH = 4.8 Hz, 2 × C(CH₃)₃], 37.51 [m, ^² J _CH = 3.8 Hz, 2 × C(CH₃)₃], 64.26 (tqd, ^¹ J _CH = 148.5 Hz, ^² J _CH = 4.5 Hz, ^² J _CP = 6.2 Hz, 2 × POCH₂), 104.04 (td, ^¹ J _CH = 161.5 Hz, ^³ J _CP = 2.2 Hz, olefinic CH₂-β), 125.34 (dm, ^¹ J _CH = ˜158 Hz, C-3/-5), 128.46 (dm, ^¹ J _CH = ˜159 Hz, C-4), 133.62 (m from ^³ J _CP = 10.6 Hz and several differing ^³ J _CH, C-1), 150.36 (app. octet, ^³ J _CH = 3.6 Hz, C-2/-6), 151.94 (td, ^² J _CH = 6.0 Hz, ^² J _CP = 8.9 Hz, C-α).

Anal. Calcd for C₂₀H₃₃PO₄: C, 65.20; H, 9.03. Found: C, 65.00; H, 8.87.

Diethyl 1-(2,6-Di- tert -butylphenyl)-1-propenyl Phosphate (10b)

In a procedure similar to that used for 10a, 2,6-di-tert-butylpropiophenone (8b) was treated with n-BuLi (1.9 equiv) and ClPO(OEt)₂ (2 equiv) to give the enol phosphate 10b (63-70% after chromatography as above).

^¹H NMR (400 MHz, CDCl₃): δ = 1.33 (d, ^³ J _HH = 7.1 Hz, 3 H, CH₃-γ), 1.34 [td, ^³ J _HH = 7.1 Hz, ⁴ J _PH = 1.1 Hz, 6 H, 2 × POC(CH ₃)], 1.45 (s, 18 H), ˜4.18 and ˜4.21 (2 m, 4 H, diastereotopic H of 2 × POCH₂ groups, including ^³ J _PH), 5.60 (qd, ^³ J _HH = 7.1 Hz, ⁴ J _PH = 0.7 Hz,^²5 1 H, 1 β-H anti to aryl), 7.24 and 7.43 (arom. AB₂ system, ^³ J = 8.0 Hz, 3 H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 15.39 (qd, ^¹ J _CH = 127.3 Hz, ^² J _CH = 1.4 Hz, CH₃-γ), 16.11 (qtd, ^¹ J _CH = 127.3 Hz, ^² J _CH = 2.6 Hz, ^³ J _CP = 7.2 Hz, 2 × POCCH₃), 33.00 [qsept, ^¹ J _CH = 126 Hz, ^³ J _CH = 4.9 Hz, 2 × C(CH₃)₃], 37.70 [m, ^² J _CH = ˜3.7 Hz, 2 × C(CH₃)₃]), 64.07 (tqd, ^¹ J _CH = 148 Hz, ^² J _CH = 4.5 Hz, ^² J _CP = 6.2 Hz, 2 × POCH₂), 111.32 (dqd, ^¹ J _CH = 154.1 Hz, ^² J _CH = 7.1 Hz, ^³ J _CP = 2.2 Hz, olefinic CH-β), 125.81 (dm, ^¹ J _CH = ˜157 Hz, C-3/-5), 128.34 (dm, ^¹ J _CH = ˜158 Hz, C-4), 130.80 (m from ^³ J _CP = 10.6 Hz and several differing ^³ J _CH, C-1), 146.39 (unresolved, includes d, ^² J _CH = 6.0 Hz and d, ^² J _CP = 9.4 Hz, C-α), 150.73 (unresolved, includes d, ^³ J _CH = 7.0 Hz to 4-H, C-2/-6); assigned through selective {^¹H} decoupling experiments as follows: {3-/4-/5-H} → C-1 as a dd of ^³ J _CP and ^³ J _CH = 6.2 Hz;^²5 {all CH₃} → CH-β as a dd (^¹ J _CH, ^³ J _CP), C-α as a dd (^² J _CH = 6.0 Hz, ^² J _CP), C-2/-6 as a d (^³ J _CH = 7.0 Hz), and POCH₂ as a td (^¹ J _CH, ^² J _CP).

Anal. Calcd for C₂₁H₃₅PO₄: C, 65.95; H, 9.22. Found: C, 66.21; H, 9.23.

2,6-Di- tert -butylphenylacetylene (11a)

Anhydrous t-BuOMe (50 mL) in a dried Schlenk flask (500 mL) under argon gas was stirred magnetically during the addition of the sticky oil 10a (14.49 g, 39.32 mmol) together with further t-BuOMe (150 mL). After complete dissolution and subsequent cooling to -70 ˚C, t-BuLi (1.7 M in hexane, 62.5 mL, 106.2 mmol) was added dropwise with stirring. The resulting red solution was stirred for 10 min at -70 ˚C and for 15 min at r.t., then poured onto iced H₂O (500 mL). The aqueous layer was shaken with Et₂O (2 × 200 mL), and the combined organic layers were washed with distilled H₂O until neutral, dried over MgSO₄, and evaporated to give a reddish-brown liquid (8.16 g) that was purified by chromatography on a column (diameter 35 mm) of silica gel (63-200 mesh; 60 Å; 92 g) with low-boiling PE: The first 200 mL eluted part of the hydrocarbon contaminations, followed by 220 mL with the pure product 11a that crystallized immediately after concentration.

Yield: 5.73 g (68%); mp 39-40.5 ˚C (EtOH).

IR (KBr): 3264 (sharp, ≡C-H), 2963, 2912, 2870, 1584 (w), 1463, 1362, 1258, 754 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.56 (s, 18 H), 3.81 (s, 1 H, ≡CH), 7.20 and 7.29 (arom. AB₂ system, ^³ J = 8.0 Hz, 3 H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 30.32 [qsept, ^¹ J = 126 Hz, ^³ J = 4.8 Hz, 2 × C(CH₃)₃], 36.32 [m, ^² J = 3.8 Hz, 2 × C(CH₃)₃], 85.91 (d, ^² J = 48.8 Hz, C≡CH), 92.47 (d, ^¹ J = 250.0 Hz, C≡CH), 119.43 (m, C-1), 123.60 (sharp dd, X-part of AA′X, ^¹ J = 159.1 Hz, ^³ J = 7.6 Hz, C-3/-5), 128.03 (sharp d, ^¹ J = 159.8 Hz, C-4), 154.54 (m, C-2/-6).

Anal. Calcd for C₁₆H₂₂: C, 89.66; H, 10.35. Found: C, 89.50; H, 10.35.

1-(2,6-Di- tert -butylphenyl)-1-propyne (11b)

The pure enol phosphate 10b (1.61 g, 4.21 mmol) dissolved very slowly in anhydrous t-BuOMe (30 mL) on magnetic stirring in a Schlenk flask (100 mL) under argon gas. The pale-yellow solution was cooled to -70 ˚C with stirring and turned dark-red during the dropwise addition of t-BuLi (1.7 M in hexane, 6.20 mL, 10.5 mmol). After further stirring for 15 min at -70 ˚C and for 15 min at r.t., the contents of the flask were poured onto iced H₂O (100 mL) and Et₂O (30 mL). The aqueous layer was shaken with Et₂O (2 × 50 mL), and the combined organic extracts were washed with distilled H₂O until neutral, dried over MgSO₄, and evaporated to dryness, affording propyne 11b (849 mg, 88%; mp 83-88.5 ˚C). The analytically pure sample (white needles) had mp 90-92 ˚C (2 from MeOH); bp 85-90 ˚C (bath temp)/0.15 mbar.

IR (KBr): 2959, 2912, 2870, 1481 (w), 1416, 1362, 1256, 760 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.53 (s, 18 H), 2.12 (s, 3 H, CH₃-γ), 7.13 and 7.26 (arom. AB₂ system, ^³ J = 8.0 Hz, 3 H).

^¹³C NMR (100.6 MHz, CDCl₃): δ = 4.90 (sharp q, ^¹ J = 130.8 Hz, CH₃-γ), 30.23 [qsept, ^¹ J = 125.6 Hz, ^³ J = 4.9 Hz, 2 × C(CH₃)₃], 36.27 [m, ^² J = 3.7 Hz, 2 × C(CH₃)₃], 82.17 (q, ^³ J = 4.8 Hz,^²6,²7 C≡CCH₃), 99.69 (sharp q, ^² J = 10.8 Hz,^²6,²7 C≡CCH₃), 121.25 (tdq, ^³ J = 7.5 Hz, ⁴ J = 1.5 Hz, ⁴ J = 1.9 Hz, C-1), 123.43 (dd, ^¹ J = 158.5 Hz, ^³ J = 7.5 Hz, C-3/-5), 126.72 (sharp d, ^¹ J = 160.0 Hz, C-4), 153.16 (unresolved m, containing d ^³ J = 7.3 Hz, C-2/-6); assigned through the following selective {^¹H} decoupling experiments: {3-/4-/5-H} → C-1 as a quartet (⁴ J = 1.9 Hz to CH₃-γ); {C(CH ₃)₃} → C-2/-6 as a doublet (^³ J = 7.3 Hz to 4-H), C(CH₃)₃ as the X-part of AA′X with |^³ J+⁵ J| = 3.8 Hz to 3-H and 5-H; {CH₃-γ} → C-α as a singlet, C-β as a singlet, C-1 as a triple doublet (^³ J to 3-/5-H and ⁴ J = 1.5 Hz to 4-H).

Anal. Calcd for C₁₇H₂₄: C, 89.41; H, 10.59. Found: C, 89.52; H, 10.87.

Acknowledgment

Financial support by the Deutsche Forschungsgemeinschaft is gratefully­ acknowledged.

References

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• 9 For the general phase-transfer setup with MeI and aq NaOH, see: Klages CP. Voß J. Chem. Ber.  1980,  113:  2255 
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• 10 Loupy A. Sansoulet J. Vaziri-Zand F. Bull. Soc. Chim. Fr.  1987,  1027 
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  CrossrefSearch in Google Scholar
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• 14 Maercker A. Angew. Chem., Int. Ed. Engl.  1987,  26:  972 ; Angew. Chem. 1987, 99, 1002
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• 18 For 1a, pK _a = 14.22 in EtOH-H₂O (1:1), or ˜11.7 in H₂O, according to: Cohen LA. Jones WM. J. Am. Chem. Soc.  1963,  85:  3397 
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• 19 In accordance with the preparation of 2,4,6-tri-tert-butylpropiophenone from EtMgBr, see: Leibfritz D. Chem. Ber.  1975,  108:  3014 
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  CrossrefSearch in Google Scholar
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• 22 de Jong P. Recl. Trav. Chim. Pays-Bas  1942,  61:  539 
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• 23 Knorr R. Menke T. Ferchland K. Mehlstäubl J. Stephenson DS. J. Am. Chem. Soc.  2008,  130:  14179 
  CrossrefSearch in Google Scholar
• 24 Cohen LA. Jones WM. J. Am. Chem. Soc.  1962,  84:  1625 
  CrossrefSearch in Google Scholar
• 26 In agreement with q ^³ J = 4.7 Hz and q ^² J = -10.4 Hz for propyne, see: Hayamizu K. Yamamoto O. Org. Magn. Reson.  1980,  13:  460 
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• 27 In accordance with q ^³ J = 4.5 Hz and q ^² J = (-)10.5 Hz for 1-phenylpropyne, see: Wesdemiotis Ch. Schwarz H. Levsen K. Borchers F. Justus Liebigs Ann. Chem.  1976,  1889 
  Crossref

Sterically Congested Molecules, Part 21. Part 20 is ref. 23.

Schemes 20 and 23 in ref. 14.

This supports the E-configuration.

References

• 2 Rundel W. Chem. Ber.  1968,  101:  2956 
  CrossrefSearch in Google Scholar
• 3 DeKoning AJ. Recl. Trav. Chim. Pays-Bas  1981,  100:  421 
  Search in Google Scholar
• 4 Yoshifuji M. Niitsu T. Shiomi D. Inamoto N. Tetrahedron Lett.  1989,  30:  5433 
  CrossrefSearch in Google Scholar
• 5 Kawasaki S. Nakamura A. Toyota K. Yoshifuji M. Bull. Chem. Soc. Jpn.  2005,  78:  1110 
  CrossrefSearch in Google Scholar
• 7 Kornblum N. Seltzer R. J. Am. Chem. Soc.  1961,  83:  3668 
  CrossrefSearch in Google Scholar
• 8 Stoochnoff BA. Benoiton NL. Tetrahedron Lett.  1973,  14:  21 
  CrossrefSearch in Google Scholar
• 9 For the general phase-transfer setup with MeI and aq NaOH, see: Klages CP. Voß J. Chem. Ber.  1980,  113:  2255 
  CrossrefSearch in Google Scholar
• 10 Loupy A. Sansoulet J. Vaziri-Zand F. Bull. Soc. Chim. Fr.  1987,  1027 
• 11 Schuster II. Parvez M. Freyer AJ. J. Org. Chem.  1988,  53:  5819 
  CrossrefSearch in Google Scholar
• 12 Jackman LM. DeBrosse CW. J. Am. Chem. Soc.  1983,  105:  4177 
  CrossrefSearch in Google Scholar
• 13 Knorr R. Mehlstäubl J. Böhrer P. Chem. Ber.  1989,  122:  1791 
  CrossrefSearch in Google Scholar
• 14 Maercker A. Angew. Chem., Int. Ed. Engl.  1987,  26:  972 ; Angew. Chem. 1987, 99, 1002
  CrossrefSearch in Google Scholar
• 15 Cohen T. Sherbine JP. Matz JR. Hutchins RR. McHenry BM. Willey PR. J. Am. Chem. Soc.  1984,  106:  3245 
  CrossrefSearch in Google Scholar
• 16 For ^¹H NMR analysis, see: Edler R. Voß J. Chem. Ber.  1989,  122:  187 
  CrossrefSearch in Google Scholar
• 17 Adam W. Richter M. Chem. Ber.  1992,  125:  243 
  CrossrefSearch in Google Scholar
• 18 For 1a, pK _a = 14.22 in EtOH-H₂O (1:1), or ˜11.7 in H₂O, according to: Cohen LA. Jones WM. J. Am. Chem. Soc.  1963,  85:  3397 
  CrossrefSearch in Google Scholar
• 19 In accordance with the preparation of 2,4,6-tri-tert-butylpropiophenone from EtMgBr, see: Leibfritz D. Chem. Ber.  1975,  108:  3014 
  CrossrefSearch in Google Scholar
• 20 Lauer D. Staab HA. Chem. Ber.  1969,  102:  1631 
  CrossrefSearch in Google Scholar
• 21 Ditto SR. Card RJ. Davis PD. Neckers DC. J. Org. Chem.  1979,  44:  894 
  CrossrefSearch in Google Scholar
• 22 de Jong P. Recl. Trav. Chim. Pays-Bas  1942,  61:  539 
  Search in Google Scholar
• 23 Knorr R. Menke T. Ferchland K. Mehlstäubl J. Stephenson DS. J. Am. Chem. Soc.  2008,  130:  14179 
  CrossrefSearch in Google Scholar
• 24 Cohen LA. Jones WM. J. Am. Chem. Soc.  1962,  84:  1625 
  CrossrefSearch in Google Scholar
• 26 In agreement with q ^³ J = 4.7 Hz and q ^² J = -10.4 Hz for propyne, see: Hayamizu K. Yamamoto O. Org. Magn. Reson.  1980,  13:  460 
  CrossrefSearch in Google Scholar
• 27 In accordance with q ^³ J = 4.5 Hz and q ^² J = (-)10.5 Hz for 1-phenylpropyne, see: Wesdemiotis Ch. Schwarz H. Levsen K. Borchers F. Justus Liebigs Ann. Chem.  1976,  1889 
  Crossref

Sterically Congested Molecules, Part 21. Part 20 is ref. 23.

Schemes 20 and 23 in ref. 14.

This supports the E-configuration.