Benzyl 2,2,2-Trichloroacetimidate

[81927-55-1]  · C9H8Cl3NO  · Benzyl 2,2,2-Trichloroacetimidate  · (MW 252.53)

(reagent for protection of hydroxy groups as benzyl ethers under mildly acidic conditions1)

Alternate Name: BTCA.

Physical Data: bp 106-114 °C/0.5 mmHg; d 1.359 g cm-3

Solubility: reactions are most often carried out in a mixture of cyclohexane/dichloromethane;1 decomposition by rearrangement to N-benzyl trichloroacetamide is accelerated in more polar solvents.

Form Supplied in: colorless oil.

Purification: distillation under reduced pressure.

Handling, Storage, and Precautions: moisture sensitive.

Hydroxy Group Protection.

The benzyl ether is one of the most versatile and frequently used protecting groups in organic synthesis.2 The most common way of introducing this group is with a strong base and Benzyl Bromide using the classical Williamson ether synthesis methodology. Recently, benzyl trichloroacetimidate3 has found widespread use to protect hydroxy functionalities as their benzyl ethers under mildly acidic conditions,1,4,5a when the more conventional strong base-mediated methods either failed or gave lower yields due to side reactions and/or starting material decomposition.

The imidate can be prepared from the sodium alkoxide ion of benzyl alcohol and trichloroacetonitrile according to procedures based on those developed by Cramer3 in the late 1950s. Substituted benzyl ethers have also been prepared this way, for example using 4-methoxybenzyl trichloroacetimidate,5 3,4-dimethoxybenzyl trichloroacetimidate,6 and 2,6-dichlorobenzyl trichloroacetimidate,7 and the method has also been applied for the synthesis of allyl1b and t-butyl ethers,8 as well as for 2-phenylisopropyl esters9 for peptide synthesis. The benzyl and 4-methoxybenzyl 2,2,2-trichloroacetimidates are available commercially.

The reaction is performed in nonpolar media to prevent rearrangement of the acetimidate to N-benzyl trichloroacetamide, and as an added advantage the solid trichloroacetamide byproduct can simply be removed by filtration. These constraints limit the substrate range to those molecules soluble in this type of solvent; for example, a sugar triol which was insoluble in dichloromethane, when reacted in DMSO yielded very little of the benzylated product desired.10 It was also noted that differential (primary versus secondary) hydroxy protection in carbohydrates (eq 1) was poor,10 and the ratio of the 6-OBn to 4-OBn products was at best 2:1.

The reagent has been used widely in carbohydrate1,10-14 chemistry. The method was found to be useful in cases where O-benzoyl group migration had been observed under basic conditions (eq 2),11 and has also been applied to inositol derivatives,15 when the same problem15a was encountered.

When N-acetyl-protected sugar amines were under investigation1,12 the N-acetyl group was observed to undergo transformation to the O-benzyl imidate in competition with OH benzylation (eq 3). It appears for best yields at least 1 equiv of reagent per OH and NAc group is needed, and subsequent hydrolysis and reacetylation of the amine are necessary to obtain are the originally desired material. Similar problems were encountered with the morpholine derived lactams (eq 4),16a where mixed products were obtained, but with b-lactams16b with N-amide protection (eq 5), O-benzylation with benzyl trichloroacetimidate proceeded smoothly. BTCA has recently been used to convert diketopiperazines into their bis-benzyl imino ethers.17

Other classes of molecules which have been benzylated using this reagent include hydroxy ketones,4 hydroxy halides4,7,18 and esters19-23 such as tartrates,19 hydroxy propionates or butanoates,20 long alkyl chain hydroxy esters,21 and hydroxy lactones.4 Under basic conditions problems such as enolization, aldol reactions, elimination and epoxide formation can cause problems and when 2-substituted esters, such as ethyl (S)-lactate,22 are required as homochiral starting materials, then protection using this method circumvents the considerable risk of racemization that accompanies the use of bases (eq 6).

Under these benzylation reaction conditions, it has been shown that the N-t-butoxycarbonyl (N-Boc) (eq 7) and N-(2-trimethylsilyl)ethoxycarbonyl (N-TEOC) (eq 8) protected amino acid derivatives are converted into their N-benzyloxycarbonyl (N-Z) analogs.24 In most cases yields were moderate, but surprisingly the t-butyldimethylsilyloxy and t-butyl ester functions are relatively unaffected by the acidic conditions.

The most frequently employed acid catalyst is TfOH (Trifluoromethanesulfonic Acid, or triflic acid), but others that have been used include BF3.OEt2,4,8 TMSOTf,4,16 p-TsOH,6 and TFA.23,16 Camphorsulfonic acid, pyridinium p-toluenesulfonate, and trityl perchlorate have also been investigated in conjunction with the more reactive 4-methoxybenzyl trichloroacetimidate.5a

Functional groups sometimes sensitive to acidic conditions such as simple esters,1,19-23 lactones,4,5d acetals,1,5a,15 epoxides,5a,13 2-methoxyethyloxymethyl (MEM) groups,6 t-butyldimethylsilyl ethers,14,24-27 and orthoformates15b are generally unaffected by the catalytic amounts of acid used, although some tertiary alcohols4 and 1-trimethylsilylalkynes4 have been noted to give poor yields.

Related Reagents.

Benzyl Bromide; Benzyl Chloride; Benzyl Iodide; Benzyl Trifluoromethanesulfonate; 3,4-Dimethoxybenzyl Bromide; 4-Methoxybenzyl 2,2,2-Trichloroacetimidate.

1. (a) Wessel, H.-P.; Iversen, T.; Bundle, D. R. JCS(P1) 1985, 2247. (b) Iversen, T.; Bundle, D. R. CC 1981, 1240.
2. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991.
3. (a) Cramer, F.; Pawelzik, K.; Baldauf, H. J. CB 1958, 91, 1049. (b) Cramer, F.; Hennrich, N. CB 1961, 94, 976.
4. Eckenberg, P.; Groth, U.; Huhn, T.; Richter, N.; Schmeck, C. T 1993, 49, 1619.
5. (a) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. TL 1988, 29, 4139. (b) Takaku, H.; Ueda, S.; Ito, T. TL 1983, 24, 5363. (c) Romo, D.; Johnson, D. D.; Plamondon, L.; Miwa, T.; Schreiber, S. L. JOC 1992, 57, 5060. (d) Adams, E.; Hiegemann, M.; Duddeck, H.; Welzel, P. T 1990, 46, 5975.
6. Takaku, H.; Ito, T.; Imai, K. CL 1986, 1005.
7. Amouroux, R.; Gerin, B.; Chastrette, M. T 1985, 41, 5321.
8. Armstrong, A.; Brackenridge, I.; Jackson, R. F. W.; Kirk, J. M. TL 1988, 29, 2483.
9. Yue, C.; Thierry, J.; Potier, P. TL 1993, 34, 323.
10. Bovin, N. V.; Musina, L. Y.; Khorlin, A. Y. BAU 1986, 35, 614.
11. Yasumori, T.; Sato, K.; Hashimoto, H.; Yoshimura, J. BCJ 1984, 57, 2538.
12. (a) Kusumoto, S.; Yamamoto, M.; Shiba, T. TL 1984, 25, 3727. (b) Imoto, M.; Yoshimura, H.; Yamamoto, M.; Shimamoto, T.; Kusumoto, S.; Shiba, T. TL 1984, 25, 2667.
13. Schubert, J.; Schwesinger, R.; Knothe, L.; Prinzbach, H. LA 1986, 2009.
14. Takahashi, S.; Terayama, H.; Kuzuhara, H. TL 1992, 33, 7565.
15. (a) Ozaki, S.; Kondo, Y.; Nakahira, H.; Yamaoka, S.; Watanabe, Y. TL 1987, 28, 4691. (b) Baudin, G.; Glanzer, B. I.; Swaminathan, K. S.; Vasella, A.; HCA 1988, 71, 1367. (c) Estevez, V. A.; Prestwich, G. D. TL 1991, 32, 1623.
16. (a) Danklmaier, J.; Honig, H. LA 1989, 665. (b) Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S.; Sasaki, A.; Sunagawa, M. T 1988, 44, 2149.
17. Groth, U.; Schmeck, C.; Schöllkopf, U. LA 1993, 321.
18. Voss, G.; Gerlach, H. HCA 1983, 66, 2294.
19. Hansson, T. G.; Kihlberg, J. O. JOC 1986, 51, 4490.
20. (a) White, J. D.; Kawasaki, M. JOC 1992, 57, 5292. (b) Keck, G. E.; Murry, J. A. JOC 1991, 56, 6606.
21. (a) Imoto, M.; Yoshimura, H.; Yamamoto, M.; Shimamoto, T.; Kusumoto, S.; Shiba, T. BCJ 1987, 60, 2197. (b) Widmer, U. S 1987, 568.
22. Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima, S. T 1989, 45, 5767.
23. Keck, G. E.; Andrus, M. B.; Romer, D. R.; JOC 1991, 56, 417.
24. Barrett, A. G. M.; Pilipauskas, D. JOC 1990, 55, 5170.
25. Hong, C. Y.; Kishi, Y.; JACS 1992, 114, 7001.
26. Lawrence, N. J.; Fleming, I. TL 1990, 31, 3645.
27. Danishefsky, S. J.; Deninno, S.; Lartey, P. JACS 1987, 109, 2082.

Andrew N. Boa & Paul R. Jenkins

Leicester University, UK

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