3,4-Dimethoxybenzyl Bromide

[21852-32-4]  · C9H11BrO2  · 3,4-Dimethoxybenzyl Bromide  · (MW 231.09)

(reagent for introduction of 3,4-dimethoxybenzyl protecting group, which can be cleaved selectively under conditions of benzylic oxidation1)

Alternate Name: DMBBr.

Physical Data: mp 52-53 °C.

Solubility: reactions are usually carried out in polar solvents such as THF or DMF.

Preparative Methods: synthesized from commercially available 3,4-dimethoxybenzyl alcohol and PBr32 or HBr.3

Purification: recrystallization from absolute ethanol.2

Handling, Storage, and Precautions: the reagent is quite unstable and is best prepared fresh or stored at low temperature under nitrogen. It is a lachrymator.

3,4-Dimethoxybenzyl Ethers (DMB Ethers).

The benzyl group is a frequently used protecting group4 in organic synthesis due to its acid and base stability, and its facile removal by catalytic hydrogenation or with sodium in liquid ammonia. The group is most commonly used to protect alcohol functions; however, it may not be generally applied to substrates which have other functional groups susceptible to the reductive conditions. To overcome this problem and generally to extend the range of protecting groups available, methoxy-substituted benzyl ethers have been prepared (e.g. the 3,4-dimethoxy1 and 4-methoxybenzyl5 (PMB) ethers). DMB ethers are made using the benzyl bromide (or chloride), alcohol, and base,1 or with base sensitive substrates using the trichloroacetimidate6 (see Benzyl 2,2,2-Trichloroacetimidate). PMB ethers can also made in similar fashion under either basic5 or acidic7 conditions. DMB ethers can be removed oxidatively using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)1,5 or trityl tetrafluoroborate,5b,c,6,7a and PMB ethers have also been cleaved with a variety of other methods.4,8 The products obtained are the methoxy substituted benzaldehyde and the parent alcohol (eq 1), although with an allylic alcohol there is a risk of over oxidation to give the enone (eq 2).9 Methoxybenzyl ethers with free a- or b-hydroxy groups can be converted to acid cleavable acetals with DDQ oxidation under anhydrous conditions, and further oxidized to base cleavable benzoates.10 Simple benzyl ethers and many other protecting and functional groups remain unaffected under these conditions.1,5

Each substituted benzyl ether has a different oxidation potential (1.45 V for the DMB-OR, and 1.78 V for the PMB-OR), so each methoxy substitution pattern results in different rates of ether cleavage.1,11 This means that the DMB group can be removed in the presence of a PMB ether with high selectivity (eq 3).1 It has also been shown that other methoxybenzyl ethers react at widely differing rates.11 For example, the reaction time for the DMB ether was <20 min (86% yield of alcohol), and the 2,6-dimethoxy isomer required 27.5 h (80% yield) (eq 4).11 Other substitution patterns give reaction times between these two extremes.

PMB and DMB ethers are less readily cleaved than simple benzyl ethers using catalytic hydrogenation.12 W-4 Raney Nickel gave the best selectivities (eq 5), but deprotection using Sodium-Ammonia showed no discrimination at all.12

The versatility of a combination of the substituted and unsubstituted benzyl ethers as protecting groups has been shown in the multi-step syntheses of 16-membered macrolides13 and other natural products.14,15 The DMB group alone has also been used as an alcohol protecting group in molecules ranging from the relatively simple16 to complex oligoribonucleotides,6,7a and occasionally for protection of nitrogen-containing groups.8,17

1. (a) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O. T 1986, 42, 3021. (b) Oikawa, Y.; Tanaka, T.; Horita, K.; Yoshioka, T.; Yonemitsu, O. TL 1984, 25, 5393.
2. Lakhlifi, T.; Sedqui, A.; Laude, B.; Dinh An, N.; Vebrel, J. CJC 1991, 69, 1156.
3. Coote, S. J.; Davies, S. G.; Middlemiss, D.; Naylor, A. JCS(P1) 1989, 2223.
4. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991.
5. (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. TL 1982, 23, 885. (b) Takaku, H.; Kamaike, K. CL 1982, 189. (c) Takaku, H.; Kamaike, K.; Tsuchiya, H. JOC 1984, 49, 51.
6. Takaku, H.; Ito, T.; Imai, K. CL 1986, 1005.
7. (a) Takaku, H.; Ueda, S.; Ito, T. TL 1983, 24, 5363. (b) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. TL 1988, 29, 4139.
8. Begtrup, M. BSB 1988, 97, 573.
9. Trost, B. M.; Chung, J. Y. L. JACS 1985, 107, 4586.
10. (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. TL 1982, 23, 889. (b) Nozaki, K.; Shirahama, H. CL 1988, 1847.
11. Nakajima, N.; Abe, R.; Yonemitsu, O. CPB 1988, 36, 4244.
12. Oikawa, Y.; Tanaka, T.; Horita, K.; Yonemitsu, O. TL 1984, 25, 5397.
13. (a) Nakajima, N.; Hamada, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O. JACS 1986, 108, 4645. (b) Tanaka, T.; Oikawa, Y.; Hamada, T.; Yonemitsu, O. TL 1986, 27, 3651.
14. Masamune, S. PAC 1988, 60, 1587.
15. Yadagiri, P.; Shin, D.-S.; Falck, J. R. TL 1988, 29, 5497.
16. Lebeau, L.; Oudet, P.; Mioskowski, C. HCA 1991, 74, 1697.
17. Grunder-Klotz, E.; Ehrhardt, J.-D. TL 1991, 32, 751.

Andrew N. Boa & Paul R. Jenkins

University of Leicester, UK

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