[110-87-2]  · C5H8O  · 3,4-Dihydro-2H-pyran  · (MW 84.12)

(widely used OH-protecting reagent;1 applicable to alkanols, phenols, thiols; stable at high pH; labile at low pH; generally resistant to nucleophiles and organometallic reagents; resistant to hydride reductions; labile under Lewis acidic conditions)

Physical Data: mp -70 °C; bp 86 °C; fp -15 °C; d 0.922 g cm-3.

Solubility: sol water, ethanol.

Handling, Storage, and Precautions: it has been reported that the tetrahydropyranyl (THP) ethers form sensitive organic peroxides when in contact with peroxy reagents. Violent explosions have occurred during purification of these compounds. Precautions normally sufficient in isolation of such products have failed to destroy the sensitive components.2

Tetrahydropyranylation of Alcohols.

Protection of alcohol functionality as the THP ether is an often-utilized tool in organic synthesis. It must be noted that the reaction of a chiral alcohol with dihydropyran introduces an additional asymmetric center and hence a diastereomeric mixture is obtained (eq 1). This can lead to difficulties with purification, assignment of spectral features, etc., but does not prevent successful implementation.3

A variety of reaction conditions for the synthesis of THP derivatives, the majority acidic, have been proposed in the literature (eq 2). The techniques have been highly optimized and increasingly mild conditions have been developed. Mineral acids have classically been used to effect the reaction.4 Products have been obtained in 20-93% yields using these methods. However, the use of mineral acids is clearly limiting with respect to substrates containing sensitive functionality. Nevertheless, many applications in steroid5 and saccharide6 chemistry are possible using this technology. Significantly, tetrahydropyranyl ethers are not known to migrate in 1,2-diol systems.

The standard acid catalyst for effecting tetrahydropyranylation of alcohols has become p-Toluenesulfonic Acid. Reaction of even tertiary alcohols with excess dihydropyran is usually complete in 0.5-1 h at rt, although sometimes reflux temperatures are required. Yields range from 60 to 84% for tertiary alcohols.7 Catalysis by p-TsOH can give very high yields, depending on conditions and choice of solvent: p-TsOH (dioxane, 20 °C, 5 min, 71-97%).8

Tetrahydropyranylation of primary and secondary alcohols can give high yields under mild and neutral conditions using Iodotrimethylsilane (25 °C, 30 min, 80-95%). Workup is particularly convenient, consisting of evaporation of volatiles and chromatography when required. Tertiary alcohols, however, yield the corresponding iodide rather than the THP ether.9

Reaction using Boron Trifluoride Etherate (Et2O-petroleum ether, 25 °C, 47-76%) gives moderate yields with evaporation of volatiles being the only workup required.10

Pyridinium p-Toluenesulfonate (25 °C, 4 h, 94-100%) is a mild and efficient catalyst, particularly applicable to the protection of highly acid sensitive alcohols. Yields were markedly superior to procedures employing BF3.Et2O, p-TsOH, and Hydrogen Chloride.11

Tetrahydropyranylation of tertiary alcohols, while more difficult owing to the hindered nature of the substrates or competitive elimination, can be carried out using dihydropyran and Triphenylphosphine Hydrobromide (25 °C, 6-24 h, 80-96%).12 The method is applicable to even very sensitive substrates such as mevalonolactone (eq 3).

Tetrahydropyranylation of alcohols can be carried out under very mild conditions in the presence of bis(trimethylsilyl) sulfate (0 °C, 1 h, 89-100%). No rearrangement is observed even with tertiary allylic alcohols.13

Protocols have been developed which utilize an insoluble solid catalyst in combination with dihydropyran to effect the protection of alcohols as their corresponding THP ethers. These procedures are advantageous in that the catalyst may be recovered by simple filtration and the products isolated by evaporation of volatiles. In many cases the catalyst can be reused without regeneration. Reaction of alcohols with dihydropyran in the presence of Amberlyst H-15 (25 °C, 1 h, 90-98%) yields THP derivatives. Alternatively, a solution of dihydropyran and the alcohol may be passed slowly through a column of silica overlaid with Amberlyst H-15 to yield the THP ethers directly (73-97%).14 The acidic clay Montmorillonite K10 (25 °C, 15-30 min, 63-95%) is similarly applicable.15 Reillex® 425 resin (86 °C, 1.5 h, 84-98%)16 is applicable with the advantage that it does not promote the sometimes troublesome polymerization of dihydropyran.17 Polymeric derivatives of pyridinium p-toluenesulfonate are also effective. Poly(4-vinylpyridinium p-toluenesulfonate) and poly(2-vinylpyridinium p-toluenesulfonate) catalysts yield tetrahydropyranyl derivatives of primary, secondary, and tertiary alcohols (24 °C, 3-8 h, 72-95%).18

Cleavage of Tetrahydropyranyl Derivatives.

Deprotection of THP ethers has been carried out using Acetic Acid (H2O-THF (3:3:2), 50 °C, 5 h, 97%),19 HOAc (H2O-THF (2:1:as required), 47 °C, 4 h, 82%),20 HOAc (THF-H2O (4:2:1), 45 °C, 3.5 h),21 aqueous Oxalic Acid (MeOH, 50-90 °C, 1-2 h),22 p-TsOH (MeOH, 25 °C, 1 h, 94%),23 pyridinium p-toluenesulfonate (EtOH, 55 °C, 3 h, 98-100%),24 bis(trimethylsilyl) sulfate (MeOH, 25 °C, 10-90 min, 93-100%).13 Cleavage with Amberlyst H-15 (MeOH, 45 °C, 0.5-2 h, 93-98%)25 is advantageous in that the acid catalyst can be recovered by filtration and no aqueous workup is required. Organotin phosphate condensates are effective in the selective cleavage of THP ethers (MeOH, reflux, 2 h, 80-90%) in the presence of MEM ethers, MOM ethers, and 1,3-dioxolanes.26 The catalyst is insoluble in the reaction medium and can be reused repeatedly.

Selective cleavage of THP ethers in the presence of t-butyldimethylsilyl ethers can be accomplished by treatment with mild Lewis acids: Dimethylaluminum Chloride (-25 °C to 25 °C, 1 h, 98%) or Methylaluminum Dichloride (-25 °C, 0.5 h, 90%).27 Selective cleavage of THP ethers of primary, secondary, and tertiary alcohols can be carried out in the presence of t-butyldimethylsilyl, acetyl, mesyl, and methoxymethyl ethers, in the presence of thiostannane catalysts: Me2Sn(SMe)2-BF3.Et2O (-20 °C or 0 °C, 3-25 h, 80-97%).28

Tetrahydropyranylation of Thiols.

Tetrahydropyranyl derivatives of thiols have been utilized for the masking of this functional group (eq 4).

Thiols react with dihydropyran in the presence of BF3.Et2O (0 °C, 0.5 h, 25 °C, 1 h) to yield (S)-2-tetrahydropyranyl hemithioacetals in satisfactory yields.29 In contrast to O-tetrahydropyranyl ethers, an S-tetrahydropyranyl ether is stable to 4 N HCl-MeOH.30 Deprotection is conveniently accomplished with Silver(I) Nitrate (0 °C, 10 min)31 or Hydrogen Bromide-Trifluoroacetic Acid (90 min)32 in quantitative yields. Oxidation to disulfides can be carried out with Iodine33 or Thiocyanogen.34

Tetrahydropyranylation of Amides.

Aromatic amides, alkyl amides, ureas, sulfonamides, and imides undergo reaction with dihydropyran-Hydrogen Chloride (benzene, reflux, 2 h, 22-73%), yielding the expected adducts.35

Tetrahydropyranylation of Amines.

Purines react with dihydropyran in the presence of a catalytic amount of p-TsOH to give the 9-tetrahydro-2-pyranyl derivatives (50-87%) (eq 5).36

Functional Group Manipulation of Tetrahydropyranyl Derivatives.

While tetrahydropyranyl derivatives are often utilized as masked equivalents of alcohols, etc., it is possible to perform functional group manipulation on such species. In these cases the tetrahydropyranyl derivatization serves to activate the alcohol rather than protect it.

Conversion of alcohols to their corresponding alkyl halides can be accomplished in two steps by conversion to the THP ethers followed by treatment with Triphenylphosphine-Carbon Tetrabromide (23 °C, 24 h, 62-87%).37 In the case of tertiary substrates, 15-25% elimination is observed. Similarly rapid conversion of tetrahydropyranyl derivatives to their corresponding bromides or iodides can be carried out with 1,2-bis(diphenylphosphino)ethane tetrahalides (0.1-4 h, 0 °C to 23 °C, 81-96%).38 Methyl esters and t-butyldimethylsilyl ethers and alkenes are unreactive under these reaction conditions. Direct conversion of alcohol tetrahydropyranyl ethers to bromides, chlorides, trifluoroacetates, methyl ethers, or nitriles can be effected with Triphenylphosphine Dibromide (25 °C, 30 min, 43-89%).39 Tetrahydropyranyl ethers may be converted to benzyl ethers, MEM ethers, benzoates, or tosylates by reaction with the appropriate electrophile in the presence of Bu3SnSMe-BF3.EtO2 (0 °C, 7-70 h, 75-78%). Oxidation of the intermediate alkoxystannane with Pyridinium Chlorochromate yields aldehydes (83%).40

Ring Opening Reactions of Dihydropyran.

Treatment of dihydropyran with n-pentylsodium,41 or n-Butyllithium42 yields trans-1-hydroxy-4-nonene (73%) (eq 6).

Cleavage of dihydropyran with HCl(aq) (30 min, 25 °C) constitutes a convenient preparation of 5-hydroxypentanal (eq 7).43

Tetrahydropyranyl ethers are unstable to reduction with Lithium Aluminum Hydride-Aluminum Chloride (eq 8). Cleavage occurs in the tetrahydropyranyl ring or exocyclicly.44 The reaction is seldom useful synthetically since the two modes are competitive. In marked contrast, tetrahydropyranyl derivatives of thiols are cleaved selectively at the ring carbon-oxygen bond, giving hydroxyalkyl thioethers (58-82%) (eq 9).45

Tetrahydropyranyl derivatives of amines are hydrogenolized by LiAlH4 in the absence of any Lewis acid (eq 10).46

Dihydropyran is a convenient starting material for the preparation of (E)-4-hexen-1-ol, in three steps (eq 11).47

Anion Chemistry.

Dihydropyran and derivatives can be quantitatively deprotonated with t-Butyllithium (-78 °C to 5 °C, 0.5 h, THF) (eq 12). The resulting anion reacts with electrophiles such as ketones and alkyl halides in good yields. Cuprates derived from this anion add smoothly in conjugate fashion to a,b-enones in excellent (91%) yields (eq 13).48

Electrophilic Addition to Dihydropyran.

Electrophilic addition of acetals and orthoesters to dihydropyran occurs in the presence of mild catalyst systems such as Chlorotrimethylsilane-Tin(II) Chloride (0 °C, 2 h, 55-84%) (eq 14).49 The synthetic utility of the reaction is however limited by the lack of stereocontrol.

Specific Applications.

The THP protecting group has been widely applied in the field of organic synthesis and no attempt can be made to comprehensively review its use in these pages. However, several specific applications may be of interest.

Introduction of the trans-CH=CHCH2OH moiety may be conveniently accomplished using a mixed Gilman cuprate reagent bearing a terminal THP-protected ether (eq 15).50 The transformation is of considerable utility in several fields of synthesis, including prostaglandin chemistry.

The tetrahydropyranyl derivative of propargyl alcohol, tetrahydro-2-(2-propynyloxy)-2H-pyran, can be converted to methyl 4-hydroxy-2-butynoate in four steps.51 Diethyl [(2-tetrahydropyranyloxy)methyl]phosphonate is a convenient Wadsworth-Emmons reagent.52 Tetrahydropyranyl esters of a-bromo acids can be used in the Reformatsky reaction for the preparation of b-hydroxy acids.53 Elimination of a tetrahydropyranyloxy moiety from butyne-1,4-diols with lithium hydride constitutes an efficient method for the synthesis of allenic alcohols.54

Related Reagents.

2-Chloroethyl Chloromethyl Ether; Dimethoxymethane; Ethyl Vinyl Ether; p-Methoxybenzyl Chloride; (p-Methoxybenzyloxy)methyl Chloride; 2-Methoxyethoxymethyl Chloride.

1. Greene, T. W. Protective Groups in Organic Synthesis; Wiley: New York, 1981.
2. Meyers, A. I.; Schwartzman, S.; Olson, G. L.; Cheung, H.-C. TL 1976, 2417.
3. Corey, E. J.; Wollenberg, R. H.; Williams, D. R. TL 1977, 2243.
4. (a) Paul, R. BCF 1934, 1, 971. (b) Woods, G. F.; Kramer, D. N. JACS 1947, 69, 2246. (c) Parham, W. E.; Anderson, E. L. JACS 1948, 70, 4187. (d) Jones, R. G.; Mann, M. J. JACS 1953, 75, 4048.
5. (a) Loewenthal, H. J. E. T 1959, 6, 269. (b) Dauben, W. G.; Bradlow, H. L. JACS 1952, 74, 559. (c) Ott, A. C.; Murray, M. F.; Pederson, R. L. JACS 1952, 74, 1239.
6. (a) Straus, D. B.; Fresco, J. R. JACS 1965, 87, 1364. (b) Griffin, B. E.; Jarman, M.; Reese, C. B. T 1968, 24, 639.
7. Robertson, D. N. JOC 1960, 25, 931.
8. van Boom, J. H.; Herschied, J. D. M.; Reese, C. B. S 1973, 169.
9. Olah, G. A.; Husain, A.; Singh, B. P. S 1985, 703.
10. Alper, H.; Dinkes, L. S 1972, 81.
11. Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. JOC 1977, 42, 3772.
12. Bolitt, V.; Mioskowski, C.; Shin, D.-S.; Falck, J. R. TL 1988, 4583.
13. Morizawa, Y.; Mori, I.; Hiyama, T.; Nozaki, H. S 1981, 899.
14. Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S. S 1979, 618.
15. Hoyer, S.; Laszlo, P.; Orlovic, M.; Polla, E. S 1986, 655.
16. Johnston, R. D.; Marston, C. R.; Krieger, P. E.; Goe, G. L. S 1988, 393.
17. Olah, G. A.; Husain, A.; Singh, B. P. S 1983, 892.
18. Menger, F. M.; Chu, C. H. JOC 1981, 46, 5044.
19. Corey, E. J.; Nicolaou, K. C.; Melvin Jr., L. S. JACS 1975, 97, 654.
20. Corey, E. J.; Schaaf, T. K.; Huber, W., Koelliker, U.; Weinshenker, N. M. JACS 1970, 92, 397.
21. Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J. JOC 1979, 44, 1438.
22. Grant, H. N.; Prelog, V.; Sneeden, R. P. A. HCA 1963, 46, 415.
23. Corey, E. J.; Niwa, H.; Knolle, J. JACS 1978, 100, 1942.
24. Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. JOC 1977, 42, 3772.
25. Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S. S 1979, 618.
26. Otera, J.; Niibo, Y.; Chikada, S.; Nozaki, H. S 1988, 328.
27. Ogawa, Y.; Shibasaki, M. TL 1984, 663.
28. Sato, T.; Otera, J.; Nozaki, H. JOC 1990, 55, 4770.
29. (a) Hiskey, R. G.; Tucker, W. P. JACS 1962, 84, 4789. (b) Holland, G. F.; Cohen, L. A. JACS 1958, 80, 3765.
30. Griffin, B. E.; Jarman, M.; Reese, C. B. T 1968, 24, 639.
31. Holland, G. F.; Cohen, L. A. JACS 1958, 80, 3765.
32. Hammerström, K.; Lunkenheimer, W.; Zahn, H. Macromol. Chem., 1970, 133, 41.
33. Holland, G. F.; Cohen, L. A. JACS 1958, 80, 3765.
34. Hiskey, R. G.; Tucker, W. P. JACS 1962, 84, 4794.
35. Speziale, A. J.; Ratts, K. W.; Marco, G. J. JOC 1961, 26, 4311.
36. Robins, R. K.; Godefroi, E. F.; Taylor, E. C.; Lewis, L. R.; Jackson, A. JACS 1961, 83, 2574.
37. Wagner, A.; Heitz, M.-P.; Mioskowski, C. TL 1989, 557.
38. Schmidt, S. P.; Brooks, D. W. TL 1987, 767.
39. Sonnet, P. E. SC 1976, 6, 21.
40. Sato, R.; Otera, J.; Nozaki, H. JOC 1990, 55, 4770.
41. Paul, R.; Tchelitcheff, S. BCF 1952, 808.
42. Pattison, F. L. M.; Dear, R. E. A. CJC 1963, 41, 2600.
43. (a) Woods, Jr., G. F. OSC 1955, 3, 470. (b) Paul, R. BCF 1934, 1, 976.
44. Eliel, E. L.; Nowak, B. E.; Daignault, R. A.; Badding, V. G. JOC 1965, 30, 2441.
45. Eliel, E. L.; Nowak, B. E.; Daignault, R. A. JOC 1965, 30, 2448.
46. Eliel, E. L.; Daignault, R. A. JOC 1965, 30, 2450.
47. Paul, R.; Riobé, O.; Maumy, M. OSC 1988, 6, 675.
48. Boeckman Jr., R. K.; Bruza, K. J. TL 1977, 4187.
49. Mukaiyama, T.; Wariishi, K.; Saito, Y.; Hayashi, M.; Kobayashi, S. CL 1988, 1101.
50. Corey, E. J.; Wollenberg, R. H. JOC 1975, 40, 2265.
51. Earl, R. A.; Townsend, L. B. OS 1981, 60, 81.
52. (a) Kluge, A. F. OS 1984, 64, 80. (b) Kluge, A. F.; Clousdale, I. S. JOC 1979, 44, 4847.
53. Bogavac, M.; Arsenijevic, L.; Arsenijevic, V. BCF 1980, 145.
54. (a) Cowie, J. S.; Landor, P. D.; Landor, S. R. CC 1969, 541. (b) Cowie, J. S.; Landor, P. D.; Landor, S. R. JCS(P1) 1973, 720.

Paul Ch. Kierkus

BASF Corporation, Wyandotte, MI, USA

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