2-Methoxyethoxymethyl Chloride1

[3970-21-6]  · C4H9ClO2  · 2-Methoxyethoxymethyl Chloride  · (MW 124.58)

(protection of alcohols,2 phenols,15 and carboxylic acids;20 functionalized one-carbon synthon23)

Alternate Name: MEMCl.

Physical Data: bp 50-52 °C/13 mmHg; d 1.094 g cm-3.

Handling, Storage, and Precautions: moisture sensitive; a lachrymator and possible carcinogen.

Protection of Alcohols.

The 2-methoxyethylmethyl (MEM) group was developed as a protective group that can be introduced with the ease of the methoxymethyl (MOM) group but can be cleaved under milder conditions, thus affording another level of selectivity in deprotection.2 The most common method for its introduction is occasioned with MEMCl and Diisopropylethylamine (CH2Cl2, 25 °C, 3 h, quant.). Introduction of the MEM group is also faster than the formation of the related MOM derivative, which may be the result of anchimeric assistance. Alternatively the salt, MEMNEt3+ Cl- (MeCN, reflux, 30 min, >90% yield) may be used for its introduction, but this procedure has not seen extensive use. An alkoxide prepared from Sodium Hydride or Potassium Hydride, when treated with MEMCl (THF or DME, 0 °C, 10-60 min, >95% yield), affords the MEM ether. The reaction of tributyltin ethers in the presence of Cesium Fluoride, DMF, and MEMCl has also been used to prepare MEM ethers, but this method is primarily used as part of a scheme for the interconversion of protective groups.3 For example, the reaction of THP ethers with Bu3SnSMe/BF3.Et2O gives the corresponding tin ethers. Since the MEM group is of low steric demand, little selectivity is expected when protecting two similar alcohols, but electronic effects can be used to advantage to achieve modest selectivity (eq 1).4

The original method devised to effect deprotection is to treat the MEM derivative with Zinc Bromide (CH2Cl2, 25 °C, 2-10 h, 90% yield)1 or Titanium(IV) Chloride (CH2Cl2, 0 °C, 20 min, 95% yield)1 to form a chelate, which upon further reaction reconstitutes the alcohol. Since then a number of other cleavage methods have been developed which rely on the fact that the MEM group can be viewed as an acetal or ether. Reagents such as Bromodimethylborane (CH2Cl2, -78 °C, NaHCO3, H2O, 87-95% yield),5 Ph2BBr (CH2Cl2, -78 °C, 71% yield),6 (-SCH2CH2S-)BBr,7 (i-PrS)2BBr (DMAP, K2CO3, H2O),8 and 2-bromo-1,3,2-benzodioxaborole9 cleave ethers like BBr3. Me2BBr cleaves MTM and MOM ethers and acetals, but (i-PrS)2BBr converts the MEM group to the i-PrSCH2- ether which can be cleaved using the same conditions used to cleave the MTM ether. The cyclic thio derivative appears to be sterically sensitive (eq 2). It does not cleave benzyl, allyl, methyl, THP, TBDMS, and TBDPS ethers, whereas the related oxygen analog (2-bromo-1,3,2-benzodioxaborole) is a much more powerful reagent and cleaves the following groups in the order: MOMOR &AApprox; MEMOR > t-Boc > Cbz > t-BuOR > BnOR > allylOR > t-BuO2CR &AApprox; secondary alkylOR > BnO2CR > primary alkylOR >> alkylO2CR. The t-butyldimethylsilyl group is stable to this reagent.

Protic acids such as Pyridinium p-Toluenesulfonate (t-BuOH, or 2-butanone, heat, 80-99% yield)10 and Tetrafluoroboric Acid (CH2Cl2, 0 °C, 3 h, 50-60% yield)11 can also be used to cleave the MEM ethers. The former also cleaves the MOM ether and has the advantage that it cleanly cleaves allylic ethers which can not be cleaved by Corey's original procedure. The MEM group is reasonably stable to CF3CO2H/CH2Cl2 (1:1), which is used to cleave Boc groups, and to 0.2 N HCl, but it is not stable to 2.0 N HCl or HBr-AcOH.12 Iodotrimethylsilane has long been known as a powerful reagent for the cleavage of ethers, esters, carbamates, etc., and thus it is no surprise that it will cleave the MEM ether as well. It does tend to form iodides when cleaving allylic and benzylic ethers, but this is somewhat suppressed when the reagent is prepared in situ (Me3SiCl, NaI, MeCN, -20 °C, 79%).13 In a synthesis of tirandamycin, deprotection of a MEM ether was unsuccessful using conventional methods and an entirely new method was developed which oxidizes the methylene (n-BuLi, THF; then Hg(OAc)2, H2O, THF, 81% yield) (eq 3).14

Protection of Phenols.

Methoxyethoxymethyl chloride can also be used to protect phenols. The conditions for its introduction are similar to those used for alcohols (NaH, THF, 0 °C; MeOCH2CH2OCH2Cl, 0 °C -> 25 °C, 2 h, 75% yield).15,16 In contrast to the alcohol derivatives, phenolic MEM ethers can be cleaved with Trifluoroacetic Acid (CH2Cl2, 23 °C, 1 h, 74% yield).17 1 M HCl (THF, 5 h, 60 °C)18 and HBr/EtOH19 will also effect cleavage. In general, the cleavage conditions used for alcohols are also effective with the phenolic derivatives. During an examination of the asymmetric reduction of an acetophenone derivative with (+)-B-Chlorodiisopinocampheylborane, it was found that a phenolic MEM ether was slowly cleaved (eq 4).16

Protection of Acids.

Carboxylic acids are converted to MEM esters using conditions similar to those used for alcohol protection (MEMCl, i-Pr2EtN, CH2Cl2, 0 °C, 2 h).20 Deprotection of this ester is effected with 3 M HCl (THF, 40 °C, 12 h) or with ZnBr221 or MgBr2.22

Miscellaneous Uses.

Outside of the protective group arena, MEMCl has been used to alkylate enolates23 and aryllithium reagents in the presence of Ph2TlBr.24 MEM ethers have also proven to be a good one-carbon source for the preparation of isochromans (eq 5)25 and other oxygen heterocycles (eq 6).26

Guaiacolmethyl chloride (GUMCl) (1) is a reagent similar to MEMCl, but it produces derivatives that are somewhat more acid sensitive. In fact the GUM group can be removed in the presence of a MEM group. It is a more sterically demanding reagent, and thus it is possible to introduce this group selectively onto a primary alcohol in the presence of a secondary alcohol. Because of its similarity to a p-methoxyphenyl group, it should be possible to remove it oxidatively. Cleavage is effected with ZnBr2 in CH2Cl2 just as with the MEM group.27

Related Reagents.

Chloromethyl Methyl Ether.

1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991.
2. Corey, E. J.; Gras, J.-L.; Ulrich, P. TL 1976, 809.
3. Sato, T.; Otera, J.; Nozaki, H. JOC 1990, 55, 4770.
4. Posner, G. H.; Haces, A.; Harrison, W.; Kinter, C. M. JOC 1987, 52, 4836.
5. Quindon, Y.; Morton, H. E.; Yoakim, C. TL 1983, 24, 3969.
6. Shibasaki, M.; Ishida, Y.; Okabe, N. TL 1985, 26, 2217.
7. Williams, D. R.; Sakdarat, S. TL 1983, 24, 3965.
8. Corey, E. J.; Hua, D. H.; Seitz, S. P. TL 1984, 25, 3.
9. Boeckman, R. K., Jr.; Potenza, J. C. TL 1985, 26, 1411.
10. Monti, H.; Léandri, G.; Klos-Ringuet, M.; Corriol, C. SC 1983, 13, 1021.
11. Ikota, N.; Ganem, B. CC 1978, 869.
12. Vadolas, D.; Germann, H. P.; Thakur, S.; Keller, W.; Heidemann, E. Int. J. Pept. Protein Res. 1985, 25, 554.
13. Rigby, J. H.; Wilson, J. Z. TL 1984, 25, 1429.
14. Ireland, R. E.; Wuts, P. G. M.; Ernst, B. JACS 1981, 103, 3205.
15. Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.; Keck, G. E.; Gras, J.-L. JACS 1978, 100, 8031.
16. Everhart, E. T.; Graig, J. C. JCS(P1) 1991, 1701.
17. Mayrargue, J.; Essamkaoui, M.; Moskowitz, H. TL 1989, 30, 6867.
18. Brade, W.; Vasella, A. HCA 1989, 72, 1649.
19. Fujita, V.; Ishiguro, M.; Onishi, T.; Nishida, T. S 1981, 469.
20. Meyers, A. I.; Reider, P. J. JACS 1979, 101, 2501.
21. Posner, G. H.; Weitzberg, M.; Hemal, T. G.; Asiruatham, E.; Cun-Heng, H. T 1986, 42, 2919.
22. Kim, S.; Park, Y. H.; Kee, I. S. TL 1991, 32, 3099.
23. Hlasta, D. J.; Casey, F. B.; Ferguson, E. W.; Gangell, S. J.; Heimann, M. R.; Jaeger, E. P.; Kullnig, R. K.; Gordon, R. J. JMC 1991, 34, 1560. Topgi, R. S. JOC 1989, 54, 6125. Laredo, G. C.; Maldonado, L. A. H 1987, 25, 179. Onaka, M.; Matsuoka, Y.; Mukaiyama, T. CL 1981, 531.
24. Marko, I. E.; Kantam, M. L. TL 1991, 32, 2255.
25. Mohler, D. L.; Thompson, D. W. TL 1987, 28, 2567.
26. Blumenkopf, T. A.; Look, G. C.; Overman, L. E. JACS 1990, 112, 4399.
27. Loubinoux, B.; Coudert, G.; Guillaumet, G. TL 1981, 22, 1973.

Peter G. M. Wuts

The Upjohn Co., Kalamazoo, MI, USA

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