Reaction of a Polycyclic Diketone with Lithiated Methoxyallene: Synthesis of New Functionalized Cage Compounds

Abstract

Syntheses of several new functionalized cage compounds are described. The key steps of the reaction sequence are addition of lithiated methoxyallene 2 to cage diketone 1, preparation of dehydrated intermediate 5, and its ozonolysis leading to diester 7. Alternatively, 5 could be hydrolyzed to provide cage compound 6 with a bisenone subunit. Via diol 9 chiral crown ether 11 could be prepared in low yield. A first stereoselective epoxidation of chalcone 12 with tert-butyl hydroperoxide in the presence of 11 gave the epoxide 13 in reasonable yield, but with a low level of enantioselectivity.

methoxyallene - cage molecules - crown ether - ozonolysis - epoxidation.

References and Notes

Reviews:

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<A NAME="RG16208ST-19">19</A>

Bisallenyl Adduct 4 Methoxyallene (4.20 g, 60.0 mmol) was dissolved in dry THF (35 mL) and treated with n-BuLi (16.0 mL, 40.0 mmol, 2.5 M in hexanes) at -40 ˚C under argon atmosphere. After 5 min the solution of 2 was cooled to -78 ˚C and diketone 1 (0.522 g, 3.00 mmol, dissolved in 5 mL of THF) was added within 5 min. The reaction mixture was stirred for 2 h at
-78 ˚C and quenched with sat. aq NH₄Cl solution (25 mL). Warmup to r.t. was followed by extraction with Et₂O (3 × 30 mL) and drying (Na₂SO₄). Purification of the crude product by recrystallization (hexane-Et₂O) provided 4 (0.678 g, 74%) as a beige-colored solid, mp 148-150 ˚C. ^¹H NMR (250 MHz, CDCl₃): δ = 1.03, 1.54 (AB system, J _AB = 10.5 Hz, 2 H, CH₂), 2.25-2.46, 2.61-2.73 (2 m, 4 H each, 8 CH), 3.43 (s, 6 H, OMe), 5.46 (s, 2 H, OH), 5.48 (s, 4 H, =CH₂). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 196.6 (s, C=C=CH₂), 137.5 (s, =C=COMe), 91.8 (t, =C=CH₂), 79.1 (s, C-3, C-5), 56.6 (q, OMe), 47.8, 44.8, 40.7, 33.8 (4 d, CH), 41.4 (t, CH₂). IR (KBr): 3630-3150 (OH), 3020-2820 (=CH, CH), 1930 (C=C=C), 1650 (C=C) cm^-¹. MS (EI, 80 eV): m/z (%) = 314 (6) [M]⁺, 281 (44), 161 (46), 147 (66), 115 (70), 103 (34), 69 (65), 55 (100), 43 (38). HRMS (80 eV): m/z calcd for C₁₉H₂₂O₄: 314.1518; found: 314.1543. Anal. Calcd for C₁₉H₂₂O₄ (314.4): C, 72.59; H, 7.05. Found: C, 71.81; H, 6.97.

<A NAME="RG16208ST-20">20</A>

Compound 5
To a solution of 4 (0.205 g, 0.655 mmol) in CH₂Cl₂ (13 mL) mesyl chloride (0.082 g, 0.723 mmol, dissolved in 2 mL of CH₂Cl₂) and Et₃N (0.658 g, 6.55 mmol) were added at 0 ˚C. The solution was warmed up to r.t. and stirred for additional 2.5 h. Then, sat. aq NH₄Cl solution (5 mL) was added and the phases were separated. The organic phase was successively washed with H₂O (3 × 5 mL) and brine (1 × 5 mL) and dried (Na₂SO₄). Purification of the crude product by chromatography on alumina (hexane-EtOAc, 4:1) provided 5 (0.186 g, 96%) as an orange resin. ^¹H NMR (250 MHz, CDCl₃): δ = 1.55, 1.92 (AB system, J _AB = 10.5 Hz, 2 H, CH₂), 2.43, 2.65, 2.86, 2.93 (4 br s, 2 H each, 8 CH), 3.46 (s, 6 H, OMe), 5.51 (s, 4 H, =CH₂). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 198.7 (s, C=C=CH₂), 132.0 (s, =C=COMe), 91.1 (t, =C=CH₂), 95.1 (s, C-3, C-5), 56.4 (q, OMe), 57.3, 47.4, 44.3, 41.0 (4 d, CH), 43.3 (t, CH₂). IR (neat): 3010-2860 (CH), 1930 (C=C=C) cm^-¹. MS (EI, 80 eV): m/z (%) = 296 (100) [M]⁺, 281 (29) [M - CH₃]⁺, 265 (12) [M - OMe]⁺, 227 (15), 145 (18), 115 (15). HRMS (80 eV): m/z calcd for C₁₉H₂₀O₃: 296.1412; found: 296.1442.

<A NAME="RG16208ST-21">21</A> Hoff S. Brandsma L. Arens JF. Recl. Trav. Chim. Pays-Bas  1968,  87:  1179 

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<A NAME="RG16208ST-23">23</A> The diester 7 was recently obtained by a one-pot reaction of 1 with dimethoxycarbene in moist toluene in 19% yield, see: Romański J. Mlostoń G. Heimgartner H. Helv. Chim. Acta  2007,  90:  1279 

<A NAME="RG16208ST-24">24</A>

Ozonolysis of Bisallenyl-Substituted Compound 5
To a solution of 5 (0.37 g, 1.25 mmol) in MeOH (30 mL) argon was bubbled for 5 min with cooling to -78 ˚C. Then, the solution was treated with ozone until the solution remained blue for 20 min, followed by oxygen for 5 min. The reaction mixture was allowed to warm to r.t. within 1 h and the solvent was evaporated in vacuo. Purification of the crude product by chromatography (alumina, hexane-EtOAc, 4:1, 1:1 to 0:1) afforded diester 7 (0.080 g, 23%) as colorless crystals and methyl ketone 8 (0.033 g, 10%) as a pale yellow oil.
Diester 7: mp 134-136 ˚C. ^¹H NMR (250 MHz, CDCl₃): δ = 1.66, 2.04 (AB system, J _AB = 11 Hz, 2 H, CH₂), 2.60-2.88, 3.00-3.15 (2 m, 4 H each, 8 CH), 3.80 (s, 6 H, CO₂Me). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 43.2 (t, CH₂), 42.1, 45.2, 49.2, 58.6 (4 d, CH), 52.2 (q, OMe), 94.7 (s, C-3, C-5), 170.7 (s, CO₂Me). IR (KBr): 2990-2840 (CH), 1720 (C=O) cm^-¹. MS (EI, 80 eV): m/z (%) = 276 (2) [M]⁺, 245 (4) [M - OMe]⁺, 218 (15), 217 (100) [M - CO₂Me]⁺. HRMS (80 eV): m/z calcd for C₁₅H₁₆O₅: 276.0998; found: 276.0978.
Methyl ketone 8: ^¹H NMR (250 MHz, CDCl₃): δ = 1.52, 1.89 (AB system, J _AB = 11 Hz, 2 H, CH₂), 2.27 (s, 3 H, Me), 2.32 (m_c, 1 H, CH), 2.62-2.67, 2.71-2.76 (2 m, 2 H, 1 H, 3 CH), 2.77-2.81, 2.84-2.88, 2.94-2.99, 3.08-3.13 (4 m, 1 H each, CH), 3.27, 3.32 (2 s, 3 H each, OMe), 3.73 (s, 3 H, CO₂Me). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 28.2 (q, Me), 43.1 (t, CH₂), 41.6, 42.1, 44.7, 45.6, 46.0, 49.0, 55.9, 58.9 (8 d, CH), 51.4, 51.7, 52.0 (3 q, OMe), 94.2, 98.7, 102.8 [3 s, C(OMe)₂, C-3, C-5], 171.5 (s, CO₂Me), 205.9 (s, COMe). MS (FAB⁺, 80 eV): m/z (%) = 357 (4) [M + Na]⁺, 335 (3) [MH]⁺, 304 (18), 303 (85), 291 (100) [M - MeCO]⁺, 154 (17), 137 (25), 136 (19), 105 (21), 81 (26), 69 (34), 55 (49), 43 (47).

<A NAME="RG16208ST-25">25</A> Hormuth S. Reissig H.-U. Dorsch D. Liebigs Ann. Chem.  1994,  121 

<A NAME="RG16208ST-26A">26a</A> For a mechanistic discussion of the ozonolysis of allenes, see: Langler RF. Raheja RK. Schank K. Beck H. Helv. Chim. Acta  2001,  84:  1943 ; and references therein

<A NAME="RG16208ST-26B">26b</A>

The formation of diester 7 can be rationalized by single-electron transfers via intermediates A to D, whereas the formation of the methyl ketone 8 is more speculative. Therefore, a single-electron transfer to intermediate C by O₂ ^- and conversion of the carbonyl group into an acetal moiety by the solvent methanol may lead to this side product (Scheme  [²] ).

For epoxidations using chiral crown ethers, see:

<A NAME="RG16208ST-27A">27a</A> Bakó P. Bakó T. Mészáros A. Keglevich G. Szőllősy A. Bodor S. Makó A. Tőke L. Synlett  2004,  643 

<A NAME="RG16208ST-27B">27b</A> Hori K. Tamura M. Tani K. Nishiwaki N. Ariga M. Tohda Y. Tetrahedron Lett.  2006,  47:  3115 ; and references cited therein

<A NAME="RG16208ST-28">28</A> Stock HT. Kellogg RM. J. Org. Chem.  1996,  61:  3093 

<A NAME="RG16208ST-29">29</A>

It should be noted that the yield of 11 may be enhanced by a template-directed reaction of 9 and 10 (e.g., by the use of a Cs salt). See also ref. 15.

<A NAME="RG16208ST-30">30</A>

Reaction of 9 and 10
To a suspension of NaH (4 mg, 0.16 mmol) in THF (1 mL) were added a solution of 9 (18 mg, 0.08 mmol, dissolved in 5 mL of THF) and a solution of 10 (43 mg, 0.08 mmol, dissolved in 10 mL of THF) over a period of 30 min. The reaction mixture was refluxed for 84 h and after cooling to r.t. H₂O (10 mL) was added, and the phases were separated. The aqueous phase was extracted with CH₂Cl₂ (3 × 20 mL) and the combined organic phases were dried with MgSO₄. Purification of the crude product by chromatography (SiO₂, hexane-EtOAc, 4:1, 1:1, then 1:3) gave product 11 (3 mg, 7%) as a pale yellow resin and starting material 10 (5 mg, 12%).
Product 11: [α]_D = 6.7 (c 0.08, CHCl₃). ^¹H NMR (250 MHz, CDCl₃): δ = 0.83, 0.87 (2 d, J = 10 Hz, 1 H each, CH₂), 0.99-1.80 (m, 8 H, CH), 3.25-4.55 (m, 12 H, OCH₂), 7.05-7.35 (m, 6 H, Ar), 7.40 (d, J = 8 Hz, 2 H, Ar), 7.85 (d, J = 2 Hz, 2 H, Ar), 7.97 (d, J = 2 Hz, 2 H, Ar). MS (EI, 80 eV, 240 ˚C): m/z (%) = 558 (6) [M]⁺, 356 (10), 327 (10), 284 (13), 269 (18), 268 (14), 239 (14), 129 (12), 123 (23), 113 (10), 111 (16), 109 (12), 105 (10), 99 (14), 97 (24), 96 (18), 91 (35), 85 (24), 83 (30), 82 (18), 74 (29), 72 (35), 55 (53), 44 (23), 43 (100) [MeCO]⁺, 41 (47), 26 (43). HRMS (80 eV): m/z calcd for C₃₇H₃₄O₅: 558.24060; found: 558.24255.

For chiral recognition of racemic primary amines by BINOL-containing crown ethers, see:

<A NAME="RG16208ST-31A">31a</A> Kyba EP. Koga K. Sousa LR. Siegel MG. Cram DJ. J. Am. Chem. Soc.  1973,  95:  2692 

<A NAME="RG16208ST-31B">31b</A> Cram DJ. Science  1974,  183:  803 

<A NAME="RG16208ST-31C">31c</A> Yamamoto K. Yunioka H. Okamoto Y. Chikamatsu H. J. Chem. Soc., Chem. Commun.  1987,  168 

<A NAME="RG16208ST-31D">31d</A> Galán A. Andreu D. Echavarren AM. Prados P. de Mendoza J. J. Am. Chem. Soc.  1992,  114:  1511 ; see also refs. 15 and 16