摘要:
1977 2353An Improved Method for the Use of Acetal-substituted Grignard Reagentsin Organic SynthesisBy Craig P. Forbes, George L. Wenteler, and Adriaan Wiechers, Department of Ch$mistry, University ofGrignard reagents derived from 2-(3-chloropropyl) -1,3-dioxolan (1 ) and 2- (3-chloropropyl) -5,5-dimethyl-l.3-dioxan (2) can be prepared in high yield without decomposition. They undergo 1 ,Z-addition to acrylaldehyde togive allylic alcohols (4a and b), which can be oxidized to give monoprotected dicarbonyl compounds.Pretoria, Pretoria 0002, South AfricaTHE reactions of acetals with Grignard reagents to pro-duce ethers after expulsion of an alkoxy-group have beenthe subject of considerable investigati0n.l The use ofnon-terminal acetal-substituted organomagnesiumhalides in organic synthesis has also been well documen-ted.1+~gJ~m*2 However, the synthetic applications ofterminal acetal-substituted organomagnesium halideshave been limited to only a few examples3j4has reported the use of the Grignard reagent (1) derivedfrom 2-(3-chloropropyl)-l,3-dioxolan in the synthesis ofdienic, trienic, and tetraenic acetals, and Corey used thesame reagent in the syntheses of (&)-porantherine.When the Grignard reagent (1) was used in excess (2.0-4.8 mol.equiv.), yields were correspondingly high. Thelow yield obtained when a molar quantity of (1) was usedwas attributed to the instability of this reagent, which waspartly consumed by ring closure to the salt of 2-cyclo-butyloxyethanol (5) . l y e J This instability apparently ne-cessitated the use of an excess of reagent in the formertwo examples.We have found that both compound (1) and the Grig-nard reagent (2) derived from 2-(3-chloropropyl)-5,5-dimethyl-1,3-dioxan give high yields of product if thereagent is prepared at a high concentration at room tem-Johnson* ( a ) E.Spath, Monatsh., 1914, 35, 319; ( b ) A. E. Tschitschi-babin, Ber., 1914, 47, 48; (c) M. F. Shostakovskii and M. R.Kulibekov, J . Gen. Chem. (U.S.S.R.), 1958, 28, 565; ( d ) C.Blomberg and A. D. Vreugdenhil, Rec. Trav. chim., 1962, 81, 238;(e) C1. Feugeas and H. Normant, Bull. SOC. chim. France, 1963,1441; (f) C1. Feugeas, ibid., pp. 2568, 2579; ( g ) C. Blomberg, A. D.Vreugdenhil, and Tj. Homsma, Rec. Trav. chim., 1963, 82, 355;( h ) M.F. Shostakovskii, A. S. Atavin, and B. A. Trofimov, J .Gen. Chem. (C.S.S.R.), 1964, 34, 2088; (i) R. A. Mallory, S.Rovinski, and I. Scheer, Proc. Chem. Soc., 1964, 416; ( j ) J.Cologne and J . Buendia, Compt. rend., 1965, 261, 1699; ( k ) R. A.Mallory, S. Rovinski, F. Kohen, and I. Scheer, J . Org. Chem.,1967, 32, 1417; (I) L. Miginiac and J. Blais, J . OrganometalZicChem., 1971, 29, 349; (m) H. Normant, Bull. SOC. chinz. France,1972, 2161; (n) G. Mousset, ibid., p. 1983; (0) G. Westera, C.Blomberg, and F. Bickelhaupt, J . Organometallic Chem., 1974, 82,291.perature, and the condensation reactions are carried outat -70 "C.We required the monoprotected oxo-aldehydes (3) forthe total synthesis of some alkaloids of the mesembraneseries5 A simple route would involve the reaction of theUGrignard reagent (1) or (2) with acrylaldehyde to give theallylic alcohol (a), and subsequent oxidation to the ketoneInitial attempts to form the Grignard reagents (1) and(2) in tetrahydrofuran in the concentration range 1 - 2 ~ ,( a ) M.Rosenberger, D. Andrews, F. DiMaria, A. J . Duggan,and G. Saucy, HeZv. Chim. Actn, 1972, 55, 249; (b) S. 2. Abbasand R. C. Poller, J.C.S. Dalton, 1974, 1769; ( c ) J . Ferard andP. F. Casals, Tetrahedron I>etters, 1974, 2483; ( d ) A. A. Ponaras,ibid., 1976, 3105.( a ) A. van der Gen, K. Wiedhaupt, J . J . Swoboda, H. C.Dunathan, and W. S. Johnson, J . Amer. Chem. Soc., 1973, 95,2656; ( b ) G. D. Abrams, W. R. Bartlett, V. A.Fung, and W. S.Johnson, Bio-organic Chem., 1971, 1, 243; (c) W. S. Johnson, K.Wiedhaup, S. F. Brady, and G. L. Olsen, J . Amer. Chem. Soc.,1974, 96, 3979.E. J . Corey and R. D. Balanson, J . Amer. Chem. Soc., 1974,96, 6516.C. P. Forbes, J. D. Michau, T. van Ree, ,4. Wiechers, and M.Woudenberg, Tetrahedron Letters, 1976, 935.(3)2354 J.C.S. Perkin Ibased on the original method of I?eugeas,lJ met withlittle success. High temperatures (>60 "C) for extendedperiods (1-3 h) were required before the starting materialdisappeared, and yields of (4) were low (25-30%). Thereaction mixtures contained large proportions of intract-able material. All previous attempts 3 9 4 to preparecompound (1) have also required reflux temperatures.Clearly, in addition to thermally induced decompositionand/or polymerization reactions, one of the major path-ways for loss of Grignard reagent is ring closure to thecyclobutyl ether (5) after work-up.We have shown thatheating a solution of Grignard reagent (1) to reflux for2 days results in complete disappearance of the Grignardreagent with the formation of (5) and polymeric materialonly.The preparations and reactions of the Grignard re-agents (1) and (2) proceeded smoothly and rapidly if theconcentration of the chloro-acetal was raised to EM andthe temperature was kept below 30 "C. These resultsare summarized in the Table. The allylic alcohols (4)Reactions of Grignard reagents (1) and (2) withacrylaldehydeGrignardreagent Product Yield (%)8589(1) ( 4 4(2) (4b)contained only very small amounts of iiiipurities and,although sensitive to low pressure distillation, werereadily purified by column chromatography.No traceof ring-closed products was detected.The allylic alcohols (4) were converted readily into thesynthons (3) by oxidation with pyridinium chlorochro-mate, in methylene chloride.EXPERIMENTAL1.r. spectra were obtained with a Unicam SP 200 aidn.m.r. spectra with a Varian HA 100 spectrometer. Massspectral (including accurate mass) measurements were madewith a DuPont 21.492 €3 spectrometer. Qualitative t.1.c.was carried out on silica gel (G254) developed with 40%ethyl acetate in light petroleum (b.p. 40-60 "C). Columnchromatography was carried out with silica gel 60 elutedwith increasing proportions of diethyl ether in pentane.AllGrignard reactions were carried out under dry nitrogen andreagents were transferred by syringe. Solvents were puri-fied and dried by standard procedures.General Procedure for the Prefiaration of the Acetals.-4-Chlorobutan- 1-01 was oxidized with pyridinium chlorochro-mate in methylene chloride according to a standard pro-cedure.6 The crude 4-chloro$utanal was acetalized ac-cording to the procedure of Pleshakov to give 2-(3-chloro-propyl)-1,3-dioxolan,7 h.p. 55" a t 0.2 mmHg 69-70" at0.6 mmHg), vm%x. (neat) 1055, 1 160, 2 930, and 3 010 cm-l,nD27 1.4469 (lit.,7 nD20 1.4548), 6(CC1,) 1.66-2.10 (m, CH,.CH,), 3.58 (t, J 6 Hz, CH,Cl), 3.72-4.06 (m, O*CH,*CH,*O),and 4.85 [t, J 4 Hz, CH(OR),], in 67% overall yield, or 2-* Both the allylic alcohols (4) and the unsaturated ketones (3)were unstable at room temperature (t.1.c.) and so were charac-terized by high resolution mass spectrometry and not by elementalanalysis.f Despite repeated distillation this alcohol gave analyticalresults slightly outside the expected limits. Accordingly, the13C and 'H n.m.r.spectra of the acetate were also obtained.(3-chloro$vofiyZ) -5,5-dimethyl- 1,3-dioxan, b.p. 78" at 0.2mmHg, Y,, (neat) 1 150, 2 920, and 3 020 cm-l, nD27 1.4487,6(CC14) 0.73 ( s , Me), 1.20 (s, Me), 1.62-2.16 {m, CH,*CH,),3.58 (t, J 6 Hz, CH,Cl), 3.53 (ABq, .J 11 Hz, CH,*CMe,*CH,),and 4.5 [t, J 4 Hz, CH(OR),] in 7376 overall yield (Found:C, 56.0; H, 8.95; C1, 18.4%; M+ - 1, 191.0838.C,H,,-CIO,requiresC, 56.10; H, 8.9; C1, 18.4%; M - 1, 191.0838).General Procedure lor Grignard Reactions.-The chloro-acetal (20.7 mmol, 1 equiv.) mixed with dibromoethane (1.6mmol, 0.16 equiv.), in dry tetrahydrofuran (4 ml) was addedto magnesium (69.2 mmol, 2.8 equiv.). The reaction wasinitiated on slight warming and the mixture was maintainedbelow 30 "C by periodic cooling with a water-bath. After1 h no starting material remained (t.1.c.). The mixture wasdiluted with tetrahydrofuran (12 ml) and cooled to -70 "C.Acrylaldehyde (62.1 mmol, 3 equiv.) in tetrahydrofuran (5ml) was added dropwise over 20 min, and the mixture wasstirred for a further 30 niin and then quenched by dropwiseaddition of aqueous ammonium chloride.The mixturewas permitted to warm to room temperature, diluted withwater (150 ml), neutralized with glacial acetic acid (topH 6), and extracted with ether. The combined etherlayers were dried (MgSO,) and concentrated to produce theallylic alcohols * (4), which were purified by column chrom-atography to produce homogeneous oils. In this way, theGrignard reagent (1) produced 6- (1,3-dioxoZart-2-yZ) hex-l-en-3-02 (4a) (17.6 mmol, My0), v,,, (neat) 1 030, 1 130, 2 860,and 3 400 cm-l, 6(CC14) 1.4-1.78 (in, CH,*CH,*CH,), 2.10br(s, OH, D,O-exchangeable), 3.74-3.96 (m, O*CH,*CH,*O),3.90-4.18 (m, RCHOHR), 4.77 [t, J 4 Hz, CH(OR),], 4,95-5.30 (m, CH,=C), and 5.65-6.03 (m, -C=CH-) (Found: M-'-- 1, 171.1021. C9H1,03 requires M - 1, 171.1025); andthe Grignard reagent (2) produced 6-( 5,5-dimethyZ- 1,3-dioxan-2-yZ)h,ex-l-enz-3-02 (4b) (18.4 mmol, 89%), Y,, (neat)915, 1009, 1 117, 2 828, 2 940, and 3 410 cm-l, 6(CC14) 0.70(s, Me), 1.15 (s, Me), 1.26-1.70 (m, CH,CH,*CH,), 2.25br (s,OH, D,O-exchangeable), 3.43 (ABq, J 11 Hz, OCH,.CMe2*CH,0), 3.53-3.80 [m, RCH(OH)R], 4.46 [t, J 4.5 Hz,RCH(OR),], 4.95-5.28 (m, CH,=C), and 5.64-6.00 (m,-C=CH-) (Found: Mf, 214.1555; M+ -.1, 213.1485.CI2H2,O3 requires M , 214.2568; M - 1, 213.1490).2-CyclobutyZoxyethano2 (5) .-The Grignard reagent ( l ) , pre-pared as before, was diluted to 1 . 5 ~ with tetrahydrofuranand refluxed under nitrogen for 48 h. Quenching withaqueous ammonium chloride and work-up produceda thick oil which, upon distillation, afforded the homo-geneous alcohol ( 5 ) , b.p.70" at 1 mmHg, vmax (neat)1 110, 1 138, 2 850, and 3 350 cm-l, 6H(CC14) 1.24-2.38(6 H, m, cyclobutyl), 3.22-3.72 (m, A,B,, ROCH,CH,O),3.78 ( s , OH, D,O-exchangeable), and 3.78-4.12 (quintet,C, t, CH,*CH,*CHO), 61.88 (1 C, t, OCH,CH,OH), 69.08 (1 C,t, O*CH,-CH,*OH), and 73.76 ( 1 C, d, [CH,],CHO), in 32%yield. This alcohol, on treatment with acetic anhydride-pyridine, afforded the acetate quantitatively, 6(CC14) 1.2-2.3 (9 H, m, cyclobutyl, OAc), 3.35-3.50 (2 H, t, CH,OCO),3.70-4.05 ( 1 H, quintet, R,CHOR), and 4.05-4.20 (2 H,t, ROCH,R).General Oxidation Procedure.-The oxidations were carriedout with pyridinium chlorochromate according to a generalmethod for acid-labile compounds.6 Compound (4a)6 E.J . Corey and K. W. Suggs, Tetrahedron Letters, 1975,2647.7 M. G. Pleshakov, A. E. Vasil'ev, I. K. Sarycheva, and N. A.Preobrazhenskii, J. Gen. Chem. ( U . S . S . R . ) , 1961,31, 1433.R,CHOR), 6c(CDCl3) 12.59 (1 C, t. CH,[CH,],), 30.45 (2The residue was an intractable tar1977 2355yielded, after distillation (120" and 0.3 inmHg), the Iioino-gerieous 6-( 1,3-dioxoZan-2-yZ)hex-l-en-3-one (3a), v1,,..,. (neat)1 135, 1456, 1679, and 2 890 cm-l, a(CC1,) 1.48-1.88 (m,CH,CH,), 2.50-2.70 (m, RCH,CO), 3.67-4.00 (m, OCH,-CH,O), 4.77 [t, J 4 Hz, RCH(OR),], and 5.60-6.50 (ABX,CH,=CH-COK) (Found: M+ - 1, 160.0853. C,H140 re-quires M - 1, 169.0864), in 66% yield; and compound (4b)after distillation (l6O3 and 0.3 mmHg), yielded the homo-geneous 6-( 5,5-dirnethyZ- 1,3-dioxan-2-yZ) hex- 1-en-3-one (3b),vmax. (neat) 1 133, 1405, 1 679, 2 800, and 2 920 cm-l, a(CC1,)0.67 (s, Nlej, 1.15 (s, Me), 1.41-1.86 (in, CH,.CH,), 2.46-2.64(m, RCH,CO), 3.42 (ABq, J 11 Hz, CH,.Chle,CH,), 4.34it, J 4.5 Hz, RCH(OR),], and 5.62-6.48 (ARX, CH,=CH-COR) (Found: M+, 212.1427. CI,H,,O, requires M ,212.1412), in 46% yield.We thank Dr. N. Vernieulen, Department of Biochemistry,University of Pretoria, for high resolution mass spectra. Wethank the C.S.I.R., Pretoria, for financial support.[7/614 Received, 7th A f i r i l , 1977
ISSN:1472-7781
DOI:10.1039/P19770002353
出版商:RSC
年代:1977
数据来源: RSC