Triphenylphosphine-Carbon Tetrachloride1

Ph3P-CCl4
(Ph3P)

[605-35-0]  · C18H15P  · Triphenylphosphine-Carbon Tetrachloride  · (MW 262.30) (CCl4)

[56-23-5]  · CCl4  · Triphenylphosphine-Carbon Tetrachloride  · (MW 153.81)

(reagent combination for the conversion of a number of functional groups into their corresponding chlorides and for dehydrations)

Physical Data: Ph3P: mp 79-81 °C; bp 377 °C; d 1.0749 g cm-3. CCl4: mp -23 °C; bp 77 °C; d 1.594 g cm-3.

Solubility: sol CCl4, MeCN, CH2Cl2, 1,2-dichloroethane.

Preparative Method: reactive intermediates are generated in situ by reaction of Ph3P and CCl4.

Handling, Storage, and Precautions: Ph3P is an irritant; CCl4 is toxic and a cancer suspect agent; use in a fume hood. Solvents must be carefully dried because the intermediates are all susceptible to hydrolysis.

Combination of Triphenylphosphine and Carbon Tetrachloride.

This reagent combination is capable of performing a range of chlorinations and dehydrations. The reactions are typically run using the so-called two-component or three-component systems. Carbon tetrachloride can function as both the reagent and solvent. However, the rates of the reactions are highly solvent-dependent, with MeCN providing the fastest rates.1

Conversion of Alcohols to Alkyl Chlorides.

The reaction of alcohols with Triphenylphosphine and carbon tetrachloride results in the formation of alkyl chlorides.2 The mild, neutral conditions allow for the efficient conversion of even sensitive alcohols into the corresponding chlorides (eqs 1 and 2).3,4 The reaction typically proceeds with inversion of configuration.5 In eq 3, it is interesting to note that the reaction not only proceeds with inversion of configuration but also no acyloxy migration is observed.6

The conversion of an allylic alcohol to an allylic chloride occurs with no or minimal allylic rearrangement (eqs 4 and 5).7 For the synthesis of low boiling allylic alcohols, it is advantageous to substitute hexachloroacetone (HCA) for CCl4 (eq 6). The stereochemical integrity of the double bond also remains intact under these conditions.8

If the conversion of the alcohol to the chloride is attempted in refluxing MeCN, dehydration to form the alkene occurs (eqs 7 and 8).9 Occasionally the separation of the product from the triphenylphosphine oxide produced in the reaction can be problematic. This can be overcome by using a polymer-supported phosphine.10 Simple filtration and evaporation of the solvent are all that is required under these conditions. Not only is the workup facilitated, but the rate of the reaction is also increased by employing the supported reagent.10c

Conversion of Acids to Acid Chlorides.

The reaction of carboxylic acids with triphenylphosphine-CCl4 reportedly produces acid chlorides in good yield under mild conditions (eq 9).11 These conditions will allow acid sensitive functional groups to survive. Phosphoric mono- and diesters are successfully converted into the phosphoric monoester dichlorides and diester chlorides, respectively. The reaction of the diethyl ester does not produce the acid chloride. Instead, the anhydride is formed. Phosphinic acid chlorides can also be prepared from the corresponding phosphinic acid under these conditions (eq 10).12

Epoxides to cis-1,2-Dichloroalkanes.

Epoxides are converted into cis-1,2-dichlorides by the action of triphenylphosphine in refluxing CCl4.13 Cyclohexene oxide forms cis-1,2-dichlorocyclohexane (eq 11) contaminated by a trace of the trans-isomer. Cyclopentene oxide gives only the cis-isomer.

Dehydrations.

Diols may be cyclodehydrated to the corresponding cyclic ethers. The reaction is most effective for 1,4-diols (eq 12). Dehydration of 1,3- and 1,5-diols is not as successful, except in the case of the configurationally constrained 1,5-diol shown in eq 13.14 The reaction of trans-1,2-cyclohexanediol with the reagent affords trans-2-chlorocyclohexanol with none of the cis-isomer or the trans-dichloride being detected. If the reaction is performed in the presence of K2CO3 as an HCl scavenger, the epoxide is formed (eq 14).14 The yields are not as good with substituted acyclic diols.15

Dehydration of N-substituted b-amino alcohols with triphenylphosphine-CCl4 and Triethylamine produces aziridines in good yield (eq 15).16 This reaction has been successfully employed in the preparation of stable arene imines (eq 16).17 Azetidines can be obtained from the corresponding 3-aminoalkanols (eq 17).18 Additionally, reaction of 2-(3-hydroxypropyl)piperidine under these conditions yields octahydroindolizine (eq 18).

Substituted hydroxamic acids successfully cyclize to form b-lactams as long as Et3N is present (eq 19). In the absence of the base, complex mixtures are formed.19 Unsubstituted amides can be converted into nitriles via dehydration (eq 20).20 This is the reagent of choice for the transformation of the amide to the nitrile in eq 21.21

Nitriles can also be obtained from aldoximes using this reagent (eq 22).22 Ketoximes produce imidoyl chlorides via a Beckmann rearrangement under these conditions (eq 23).23 Imidoyl chlorides are also available by the reaction of monosubstituted amides with Ph3P-CCl4 in acetonitrile (eq 24).24

N,N,N-Trisubstituted ureas afford chloroformamidine derivatives (eq 25),25 while N,N-disubstituted ureas and thioureas produce carbodiimides (eq 26).26 When carbamoyl chlorides are treated with the reagent in MeCN, they are converted into isocyanates (eq 27).27 Dehydration of N-substituted formamides provides access to isocyanides (eq 28).28

Amide Formation.

The synthesis of an amide can be accomplished by initial reaction of an acid with Ph3P-CCl4 and then reaction of the intermediate with 2 equiv of the appropriate amine. A tertiary amine, such as Diisopropylethylamine, can be employed as the HCl scavenger in cases where one would not want to waste any of a potentially valuable amine.29 This method has been used in the construction of an amide in the synthesis of the skeleton of the lycorine alkaloids (eq 29).30

The method is effective for peptide coupling in that the yields are typically good; however, the reaction is often accompanied by racemization of the product.31 The racemization problem can be suppressed, but this involves a change in the phosphine employed32 or slightly modified reaction conditions. These modified conditions have been used successfully in the construction of a hexapeptide without racemization (eq 30).33

If amino alcohols, amino thiols, or diamines are used, the intermediate amides cyclodehydrate under the reaction conditions to form D2-oxazolines (eq 31), D2-oxazines, D2-thiazolines, or D2-imidazolines.33 The reaction requires the use of 3 equiv of the Ph3P-CCl4 reagent. The reaction is reported to fail if a commercial sample of the polymer-supported phosphine is used instead of triphenylphosphine.

1,1-Dichloroalkenes and Vinyl Chlorides.

The reaction of aldehydes produces a mixture of the 1,1-dichloroalkene and the dichloromethylene derivatives. These are the result of reaction of the in situ generated Dichloromethylenetriphenylphosphorane and Triphenylphosphine Dichloride, respectively. Benzaldehyde (eq 32) produces a 1:1 mixture of the dichloroalkene and benzal chloride in 72% yield.34

Ketones can also be used in this transformation, but sometimes enolizable ketones lead to the formation of the vinyl chloride derived from the enol. This is usually more of a problem for six-membered ring ketones than for five-membered ring ketones. Cyclopentanone yields predominantly the 1,1-dichloroalkene (eq 33), while cyclohexanone provides mainly the vinyl chloride (eq 34).35


1. (a) Appel, R. AG(E) 1975, 14, 801. (b) Appel, R.; Halstenberg, M. Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.; Academic: New York, 1979; pp 387-431.
2. (a) Lee, J. B.; Nolan, T. J. CJC 1966, 44, 1331. (b) Lee, J. B.; Downie, I. W. T 1967, 23, 359.
3. Verheyden, J. P. H.; Moffat, J. G. JOC 1972, 37, 2289.
4. Calzada, J. G.; Hooz, J. OS 1974, 54, 63.
5. Weiss, R. G.; Snyder, E. I. JOC 1970, 35, 1627.
6. Aneja, R.; Davies, A. P.; Knaggs, J. A. CC 1973, 110.
7. Snyder, E. I. JOC 1972, 37, 1466.
8. Majid, R. M.; Fruchey, O. S.; Johnson, W. L. TL 1977, 2999.
9. Appel, R.; Wihler, H.-D. CB 1976, 109, 3446.
10. (a) Harrison, C. R.; Hodge, P. CC 1975, 622. (b) Regen, S. L.; Lee, D. P. JOC 1975, 40, 1669. (c) Harrison, C. R.; Hodge, P. CC 1978, 813.
11. Lee, J. B. JACS 1966, 88, 3440.
12. Appel, R.; Einig, H. Z. Anorg. Allg. Chem. 1975, 414, 236.
13. Isaacs, N. S.; Kirkpatrick, D. TL 1972, 3869.
14. Barry, C. N.; Evans, S. A. JOC 1981, 46, 3361.
15. Barry, C. N.; Evans, S. A. TL 1983, 24, 661.
16. Appel, R.; Kleinstück, R. CB 1974, 107, 5.
17. Ittah, Y.; Shahak, I.; Blum, J. JOC 1978, 43, 397.
18. Stoilova, V.; Trifonov, L. S.; Orahovats, A. S. S 1979, 105.
19. Miller, M. J.; Mattingly, P. G.; Morrison, M. A.; Kerwin, J. F. JACS 1980, 102, 7026.
20. (a) Yamato, E.; Sugasawa, S. TL 1970, 4383. (b) Appel, R.; Kleinstück, R.; Ziehn, K.-D. CB 1971, 104, 1030.
21. Juanin, R.; Arnold, W. HCA 1973, 56, 2569.
22. Appel, R.; Kohnke, J. CB 1971, 104, 2023.
23. Appel, R.; Warning, K. CB 1975, 108, 1437.
24. Appel, R.; Warning, K.; Ziehn, K.-D. CB 1973, 106, 3450.
25. (a) Appel, R.; Warning, K.; Ziehn, K.-D. CB 1974, 107, 698. (b) Appel, R.; Warning, K.; Ziehn, K.-D. CB 1973, 106, 2093.
26. Appel, R.; Warning, K.; Ziehn, K.-D. CB 1971, 104, 1335.
27. Appel, R.; Warning, K.; Ziehn, K.-D.; Gilak, A. CB 1974, 107, 2671.
28. Appel, R.; Kleinstück, R.; Ziehn, K.-D. AG(E) 1971, 10, 132.
29. Barstow, L. E.; Hruby, V. J. JOC 1971, 36, 1305.
30. Stork, G.; Morgans, D. J. JACS 1979, 101, 7110.
31. Wieland, T.; Seeliger, A. CB 1971, 104, 3992.
32. Takeuchi, Y.; Yamada, S. CPB 1974, 22, 832.
33. Appel, R.; Bäumer, G.; Strüver, W. CB 1975, 108, 2680.
34. Rabinowitz, R.; Marcus, R. JACS 1962, 84, 1312.
35. Isaacs, N.; Kirkpatrick, D. CC 1972, 443.

Michael J. Taschner

The University of Akron, OH, USA



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