26LETTERS SYNLETT LETTERS
A Stereolective Synthesis of trans-1,2-Disubstituted Alkenes Bad on the Condensation of Aldehydes with Metallated 1-Phenyl-1H-tetrazol-5-yl Sulfones
Paul R. Blakemore a, William. J. Cole a, Philip J. KocieÆski*a, and Andrew Morley b
a Chemistry Department, Glasgow University, Glasgow G12 8QQ, U.K.
b Rhône-Poulen
c Rorer Ltd, Dagenham Rearch Centre, Rainham Roa
d South, Dagenham, Esx RM10 7XS, U.K.
Received 1 November 1997
Abstract: The reaction of metallated 1-phenyl-1H-tetrazol-5-yl sulfones and aldehydes gives good yields and stereolectivity of trans-1,2-disubstituted alkenes when potassium or sodium hexamethyldisilazide is ud as ba and 1,2-dimethoxyethane is ud as solvent.
In 1991 Sylvestre Julia and co-workers1 reported a new connective one-pot synthesis of alkenes involving the reaction of lithiated 2-benzothiazolyl sulfones with carbonyl compounds (Scheme 1). The reaction involves addition of carbanion 1 to the carbonyl compound to give adduct 2 which then undergoes a ries of transformations resulting in the expulsion of sulfur dioxide and the lithium derivative of 1,3-benzothiazol-2-one (5) with concomitant formation of the alkene. A detailed study of 100 examples revealed some important limitations to the method2,3: (1) high stereolectivities are only obtained in special cas; e.g. the formation of some conjugated dienes; and (2) some lithiated benzothiazolyl sulfones are unstable and undergo lf-condensation even at low temperature. This side reaction necessitated the u of "Barbier-type" reaction conditions, i.e., the addition of the ba to a mixture of sulfone and aldehyde in which ca the sulfone lithiates in situ and addition of the lithiated sulfone to the aldehyde takes place faster than lf-condensation. Unfortunately, such reaction conditions are likely to be incompatible with complex aldehyde substrates.冷热水交替
Scheme 1
Application of the Julia olefination (Note 1) to the synthesis of the conjugated diene gment of Herboxidiene A4 and the conjugated triene gment of Rapamycin5 showed that high efficiency and good stereolectivity could be cured by varying the ba and the solvent with best results being o
btained using sodium hexamethyldisilazide as ba in a non-polar solvent (Note 2). Unfortunately early attempts to extend the findings to a synthesis of simple alkenes gave poor stereolectivity (vide infra). Further improvements in carbanion stability and stereolectivity were sought by varying the heterocycle. Julia had already shown that 2-pyridyl and 2-pyrimidyl sulfones participate in the reaction though no particular advantages were noted3. We re-examined Julia's results and extended the range of heterocycles to 1-isoquinolinolyl, 1-methyl-2-imidazolyl, 4-methyl-1,2,4-triazol-3-yl, and 1-phenyl-1H-tetrazol-5-yl. Our preliminary results indicated that the 1-phenyl-1H-tetrazol-5-yl system showed sufficient promi to warrant an extended study which is the subject of this communication (Note 3).
In order to asss the influence of chain branching, ba and solvent on the stereolectivity of the reaction, four alkenes were synthesid as depicted in Tables 1-4. In each ca the performance of the 1-phenyl-1H-tetrazol-5-yl (PT) sulfones 7 and 11 (Note 4) was assd in relation to their well established benzothiazol-2-yl (BT) sulfone counterparts 6 and 10. All 96 experiments were conducted as follows. To a stirred solution of the sulfone (0.2 mmol) and dodecane (23 µl, 0.1 mmol, internal standard) in anhydrous solvent (1 ml) at –78°C (–60°C in the ca of 1,2-dimethoxyethane) under nitrogen was added dropwi the ba (0.22 mmol, Note 5) The mixture was then stirred for 3
0 min before addition of the neat aldehyde (0.3 mmol). After stirring for a further 3 h at –78°C the reaction mixture was allowed to warm slowly to rt and stirred overnight whereupon H2O (1 ml) and Et2O (2 ml) were added and the mixture shaken well. The organic layer was parated and dried over MgSO4. An aliquot of the extract was diluted 5-fold with Et2O and the resultant sample analyd by gas chromatography (Note 6). The yield and isomer ratio (Note 7) of the alkene products were ascertained in relation to the dodecane internal standard.
From the data summarid in Tables 1-4, veral trends emerge:阿长是个什么样的人
(a) The n-alkyl benzothiazolyl sulfone 6 (cf. Tables 1 and 2) often gave poor yields compared with its branched counterpart 10 (cf. Tables 3 and 4) suggesting that α-branching confers a degree of stability on the benzothiazole sulfone anions.
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(b) The n-alkyl PT sulfone 7 gave much better yields compared with its BT-substituted counterpart 6 suggesting that the PT sulfone anions are less prone to lf-condensation (cf. Tables 1 and 3).
(c) In the BT ries, the stereolectivity of the reaction is not markedly
nsitive to changes in ba counterion whereas in the PT ries, an D o w n l o a d e d b y : U n i v e r s i t y o f I l l i n o i s . C o p y r i g h t e d m a t e r i a l.
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increa in E:Z ratio is generally obrved as one travers the ries Li→Na→K.
青春的风(d) The prence of α-alkyl branching in either the sulfone or aldehyde component does not result in a significant increa in stereolectivity (Note 8).
(e) As the polarity and coordinating ability of the solvent increas (DME > THF > Et2O > PhMe), the trans lectivity of the reaction increas. Indeed, in the phenyltetrazole ries, a combination of potassium hexamethyldisilazide as ba and DME as solvent results in high trans lectivity albeit with a sacrifice in yield compared with lithium or sodium hexamethyldisilazide as ba. When the sacrifice in yield is unacceptable (cf. Tables 3 and 4), the u of sodium hexamethyldisilazide in DME provides optimum yield and stereolectivity.
In order to establish the preparative potential of the method, we synthesid (E)-1-cyclohexyl-1-hexene (9)6 according to the following procedure. To a stirred solution of sulfone 7 (2.80 g, 10.0 mm
ol) in anhydrous DME (40 ml) under nitrogen at –55°C was added dropwi via cannula a solution of potassium hexamethyldisilazide (2.74 g, 80% by weight, 11.0 mmol) in DME (20 ml) over 10 min. The yellow-orange solution was stirred for 70 min during which time the solution became dark brown. Neat cyclohexanecarboxaldehyde (1.67 g, 15.0 mmol) was added dropwi over 5 min. and the mixture stirred at –55°C for 1 h during which time the colour changed to light yellow. The cooling bath was removed and the mixture stirred at ambient temperature overnight whereupon H2O (5 ml) was added and stirring continued for 1 h. The mixture was diluted with Et2O (150 ml) and then extracted with H2O (200 ml). The aqueous pha was extracted with Et2O (3 x 30 ml) and the combined organic layers washed with H2O (3 x 50 ml) and brine (50 ml). After drying over MgSO4, the solvent was removed in vacuo to yield a pale yellow oil (2.74 g) which was purified by column chromatography (SiO2, hexanes) to give alkene 9 (1.18 g, 7.1 mmol, 71%) as a colourless oil after kugelrohr distillation (bp 180°C/15 mmHg). 13C NMR analysis (90 MHz, CDCl3) revealed a single trans isomer: δ = 136.6 (CH), 127.9 (CH), 41.0 (CH), 33.5 (2C, CH2), 32.6 (CH2), 32.1 (CH2), 26.5 (CH2), 26.4 (2C, CH2), 22.4 (CH2), 14.2 (CH3
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In conclusion, the synthesis of simple alkenes using the one-pot Julia olefination is both more efficient and more stereolective using phenyltetrazolyl sulfones as coupling partners. We have shown that yield and stereolectivity of the reaction can be optimid by varying the solvent and ba with sodium or potassium hexamethyldisilazide in DME being generally the most effective. Furthermore, the enhanced stability of the PT sulfone anions allows the metallation step to take place prior to the addition of the aldehyde component thereby extending the scope of the reaction to ba-nsitive substrates. We predict that the one-pot variant of the Julia olefination will become one of the premiere fragment linkage reactions in the construction of functionally complex targets and no doubt further enhancements in stereolectivity and efficiency will be discovered in due cour.Notes
1.The one-pot olefination of Sylvestre Julia is operationally simpler and more amenable to scaleup than the classical 3/4-step variant originally reported by Marc Julia 7,8.
2. A recent synthesis of 1,2-disubstituted alkenes using the one-pot Julia olefination showed that the
stereochemistry of the reaction was dependent on the ba and solvent 9.
3.All of the other heterocycles examined gave the desired alkene products but the yields and/or stereolectivity were generally inferior to the benzothiazolyl system.
我作文500字4.The BT sulfones 6 and 10 and the PT sulfones 7 and 11 were prepared from the commercially available (Aldrich) benzothiazole-2-thiol and 1-phenyl-1H -tetrazole-5-thiol (14) as illustrated in the
following example:
6 δH (200 MHz, CDCl 3) 8.21 (1H, dm, J 8.0), 8.02 (1H, dm, J 7.0),7.69-7.53 (2H, m), 3.54-3.45 (2H, m), 1.97-1.79 (2H, m), 1.50-1.22(4H, m), 0.86 (3H, t, J 7.0); δC (50 MHz, CDCl 3) 165.9 (C), 152.8 (C),136.8 (C), 128.1 (CH), 127.
7 (CH), 125.5 (CH), 122.5 (CH) 54.
8 (CH 2),30.3 (CH 2), 22.1 (CH 2), 22.0 (CH 2), 13.8 (CH 3). 7 δH (200 MHz,CDCl 3) 7.75-7.54 (5H, m), 3.78-3.68 (2H, m), 2.02-1.87 (2H, m), 1.57-1.32 (4H, m), 0.92 (3H, t, J 7.0); δC (50 MHz, CDCl 3) 153.6 (C), 133.2(C), 131.6 (CH), 129.8 (CH), 125.2 (CH), 56.1 (CH 2), 30.3 (CH 2), 22.2(CH 2), 21.8 (CH 2), 13.8 (CH 3). 10 δH (270 MHz, CDCl 3) 8.18 (1H, dm,J 7.5), 7.9
9 (1H, dm, J 7.3), 7.62 (1H, t, J 6.4), 7.56 (1H, t, J 7.3), 3.55(1H, dd, J 14.3, 4.6), 3.33 (1H, dd, J 14.3, 7.9), 2.40-2.15 (1H, m), 1.55-1.10 (8H, m), 1.12 (3H, d, J . 6.8), 0.81 (3H, d, J 6.8); δC (67.5 MHz,CDCl 3) 166.8 (C), 152.7 (C), 136.8 (C), 128.1 (CH), 127.7 (CH), 125.4(CH), 122.4 (CH), 60.8 (CH 2), 36.6 (CH 2), 31.6 (CH 2), 28.6 (CH), 26.0(CH 2), 22.5 (CH 2), 19.9 (CH 3), 14.0 (CH 3). 11 δH (270 MHz, CDCl 3)7.70-7.54 (5H, m), 3.81 (1H, dd, J 14.5, 4.6), 3.58 (1H, dd, J 14.5, 7.9),
2.40-2.24 (1H, m), 1.60-1.20 (8H, m), 1.15 (3H, d, J 6.8), 0.88 (3H, t, J 6.6); δC (67.5 MHz, CDCl 3) 154.2 (C), 13
3.2 (C), 131.5 (CH), 129.8(CH), 125.3 (CH), 62.0 (CH 2), 36.6 (CH 2), 31.7 (CH 2), 28.4 (CH), 26.1(CH 2), 22.6 (CH 2), 19.8 (CH 3), 1
4.1 (CH 3).
5.Stock solutions of lithium hexamethyldisilazide (LiHMDS, 0.45M in hexanes), NaHMDS (0.54 M in toluene) and KHMDS (0.44 M in toluene) were dispend.月球的英文
6.The isomer ratio of alkene 8 was determined by GC analysis using a DB-225 fud silica capillary column (50% cyanopropylphenyl silicone, 30 m x 0.32 mm x 0.25 µm) at 50 → 90°C; helium carrier gas 1.5 ml min –1; make-up gas 25 ml min –1; split ratio 300:1. The isomer ratio of alkenes 9, 12 and 13 was determined with an SGE HT5 capillary column (5% phenyl equivalent polysiloxane-carborane, 12 m x 0.22 mm x 0.1 µm); helium carrier gas 1.4 ml min –1; make-up gas 25 ml min –1;split ratio 75:1. A flame ionisation detector (FID) was ud throughout.The identity of each alkene isomer was verified by GC-MS.
辣椒传入中国7.Authentic samples of the isomeric alkenes rich in the (Z )-isomer were obtained via the Schlosr modification of the Wittig reaction 10. 8.In the classical Julia olefination bad on the reductive elimination of β-acyloxy sulfones, chain branching dramatically improves the stereolectivity of the reaction 11,12.
Acknowledgements . We thank the EPSRC and Rhône-Poulenc Rorer for a CASE studentship (PRB).References (1)Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.1991, 32, 1175.
(2)Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim.Fr. 1993, 130, 336.
(3)Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull.Soc. Chim. Fr. 1993, 130, 856.
(4)
Smith, N. D.; Kocie Æski, P. J.; Street, S. D. A. Synthesis 1996,652.
(5)Bellingham, R.; Jarowicki, K.; Kocie Æski, P.; Martin, V. Synthesis 1996, 285.
(6)Campbell, J. B.; Molander, G. A. J. Organomet. Chem. 1978, 156,71.
(7)Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 4833.
(8)Kocienski, P. In Comprehensive Organic Synthesis ; B. M. Trost and I. Fleming, Ed.; Pergamon: Oxford, 1991; Vol. 6; pp 975.(9)
Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327.
(10)Schlosr, M.; Schaub, B.; de Oliveira-Neto, J.; Jeganathan, S.
Chimia 1986, 40, 244.(11)Kocie Æski, P.; Lythgoe, B.; Ruston, S. R. J. Chem. Soc., Perkin
Trans. 1 1978, 829.(12)Kocie Æski, P.; Lythgoe, B.; Waterhou, I. J. Chem. Soc., Perkin
Trans. 1 1980, 1045.
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