(3-Ethoxy-3-oxopropyl)iodozinc

I-Zn-(CH2)n-R
(n = 2; R = CO2Et)

[104089-16-9]  · C5H9IO2Zn  · (3-Ethoxy-3-oxopropyl)iodozinc  · (MW 293.43)

(organozinc reagents functionalized with ester, ketone, nitrile, amide, or halide functionalities, capable of C-C bond formation with a variety of organic electrophiles, e.g arylation, vinylation, ethynylation, acylation, allylation, Michael-type addition, and addition to carbonyl CO bonds)

Alternate Name: Tamaru's reagent.

Physical Data: dark powder; reagent prepared in situ (see below).

Analysis of Reagent Purity: aliquots of reactions in process can be checked by VPC or TLC after addition of 1 N HCl.1c

Preparative Methods: organozincs (1)-(5), possessing electrophilic functionality (ester, ketone, nitrile, amide, halide) in the same molecule, can be prepared in high reproducibility in mmol to mol scales by the direct reaction of the corresponding iodides and zinc metal. Four kinds of procedures have been reported. Method A:1 reaction of Zinc/Copper Couple with an iodide in benzene containing 1.5-2 equiv of DMF or DMA at 60 °C for several hours. For the preparation of zincio ketone (3), the use of HMPA in place of DMF or DMA is essential.2 For the preparation of b-zincio esters (1a-c) and b-zincio nitriles (2a-c), THF also may be used as solvent in place of benzene-DMF or DMA. Method B:3 reaction of zinc/copper couple with an iodide in benzene-DMA (2.7 equiv) under sonication at 20-35 °C for 30 min. This method is applied to the preparation of (1d), characteristically possessing an acidic amide proton. Method C:4 reaction of Zinc powder or foil, activated with 1,2-Dibromoethane (4-5%) and Chlorotrimethylsilane (3%) in THF, with a primary iodide at 35-40 °C and with a secondary iodide at 25-30 °C in the same solvent (ca. 12 h). Method D:5 reaction of zinc metal, prepared by a slow addition of Lithium Naphthalenide (2 equiv) to a THF solution of Zinc Chloride, with an alkyl bromide at rt. The zinc powders produced by this method are very reactive and react even with vinyl bromides and aryl bromides (e.g. ethyl o- and p-bromobenzoates).

Handling, Storage, and Precautions: the iodozinc reagents can be prepared and handled like Grignard reagents, and may be stored at rt for ca. one week; however, freshly prepared samples are recommended. All reactions should be conducted in a well-ventilated fume hood.

Introduction.

The title reagent is an example of a lower homolog in a series of functionalized organozinc reagents with the general structure depicted above. See Table 1 for selected examples of reagents discussed in this entry.

Reaction of Functionalized Organozincs.

As evident from their high functional group compatibility, organozincs show a very low reactivity toward most organic electrophiles. However, as discussed here, they can undergo C-C bond forming reactions with many electrophiles in the presence of an appropriate transition-metal catalyst or a Lewis acid. Some reactions of functionalized organocopper reagents,6 derived from organozincs by transmetalation with a stoichiometric amount of CuCN.2LiCl (see Copper(I) Cyanide) are discussed for comparison. For the reactions of bis(b-alkoxycarbonylethyl)zinc reagents, see Nakamura et al.7

Arylation, Vinylation, and Ethynylation.

Vinyl iodides, vinyl triflates, and aromatic iodides,2,8 as well as aromatic bromides with electron-attracting substituents,5 undergo coupling with organozincs in the presence of a catalytic amount of palladium (eqs 1-4). The vinylation (eq 3) proceeds with retention of configuration; the corresponding trans-iodide provides the trans coupling product exclusively in 71% yield.8a Arylation sometimes suffers from biaryl formation; for such cases, the use of the catalyst specified in eq 1 is recommended.8a The arylation tolerates an acidic amide proton (eq 2),3,14c and optically active phenylalanine derivatives are obtained according to this procedure.3 Organocopper reagents directly react with ethynyl iodides and bromides under mild conditions (eq 5).9

Acylation.

Organozinc iodides are so unreactive that they do not react smoothly even with highly reactive acid chlorides, e.g. yielding butyrophenone in 20% yield by the reaction of n-propylzinc iodide with Benzoyl Chloride in benzene-DMF at 70 °C for 4 h.10 The acylation is greatly accelerated by a palladium catalyst (eqs 6 and 7)1,2 or a stoichiometric amount of CuCN.2LiCl (eq 8).4a,5,11 The reactions in eqs 6 and 7, and the three-component connection reactions of allylic benzoates, Carbon Monoxide, and organozincs (eq 9),12 may proceed via acylpalladium intermediates.

Addition to Activated Alkenes and Alkynes.

Conjugate addition of organozincs to a,b-unsaturated aldehydes, ketones, esters, and nitro compounds takes place smoothly in the presence of Chlorotrimethylsilane (2 equiv) and either a catalytic13 or a stoichiometric amount of Copper(I) Cyanide.14 The retention of regiochemistry of the methyl substituent of (1c) (eq 11) is in contrast to the migration of the methyl group as observed for the reaction of (1c) with aldehydes (eq 18).15 The reaction is not accompanied by racemization (eq 10)13 and tolerates the acidic alkynic and amide protons (eq 12).14c Organozincs (e.g. 1a, 1e, 5) nonselectively add to conjugated iminium salts in 1,2- and 1,4-fashion (eq 13),16 while sorbaldehyde (2,4-hexadienal) undergoes a selective 1,4-addition reaction (vs. 1,2- and 1,6-additions) under the catalytic conditions shown in eq 10.13

Allylation.

Allylation of organozincs proceeds either catalytically (eqs 14 and 15)17 or stoichiometrically (eqs 16 and 17)14a with respect to CuI salts. Generally, the stoichiometric reaction shows a higher regioselectivity (SN2/SN2) and is applied to sequential double allylation reactions (eqs 16 and 17).18,19

Addition to Carbonyls.

Functionalized organozincs react smoothly with aromatic aldehydes, but not with aliphatic aldehydes, in the presence of 2 equiv of chlorotrimethylsilane to give the alcohols in good yields (eqs 18 and 19).15 Aliphatic aldehydes primarily provide the corresponding aldol products. Organocopper reagents may be sufficiently reactive toward both aromatic and aliphatic aldehydes in the presence of 2 equiv of Boron Trifluoride Etherate (eq 20).20 Organotitanium reagents, prepared by the reaction of organozincs and Chlorotitanium Triisopropoxide, are reactive toward aldehydes and ketones (eq 21).21 Dialkylzincs (e.g. bis(g-ethoxycarbonylpropyl)zinc) undergo an enantioselective addition to aldehydes in the presence of 2 equiv of Titanium Tetraisopropoxide and a catalytic amount of a chiral amide ligand.22 In the presence of trialkylsilyl chloride and at elevated temperatures, b-zincio esters intramolecularly add to the ester carbonyl to provide allyloxysiloxycyclopropanes in moderate yields (eq 22).23 These allyloxy derivatives are difficult to prepare according to Salaün's procedure.24 The isomerization of (1c) to (1b) (eq 18) may involve cyclization similar to the one shown in eq 22.

Related Reagents.

See also, for example, Ethyliodomethylzinc, Ethylzinc Iodide, 2-Iodopropane, Potassium Iodide-Zinc/Copper Couple, and entries for zinc halides (and zinc combination reagents).


1. (a) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Tsubaki, K.; Yoshida, Z. TL 1985, 26, 5559. (b) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. OS 1989, 67, 98. (c) OSC 1993, 8, 274.
2. Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. AG(E) 1987, 26, 1157.
3. (a) Jackson, R. F. W.; Wythes, M. J.; Wood, A. TL 1989, 30, 5941. (b) Jackson, R. F. W.; James, K.; Wythes, M. J.; Wood, A. CC 1989, 644. (c) Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.; Wythes, M. J. JOC 1992, 57, 3397; See also (d) Dunn, M. J.; Jackson, R. F. W.; Pietruszka, J.; Wishart, N.; Ellis, D.; Wythes, M. J. SL 1993, 499. (e) Jackson, R. F. W.; Wishart, N.; Wythes, M. J. SL 1993, 219.
4. (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. JOC 1988, 53, 2390. (b) Jubert, C.; Knochel, P. JOC 1992, 57, 5452.
5. Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. JOC 1991, 56, 1445.
6. Knochel, P.; Rozema, M. J.; Tucker, C. E.; Retherford, C.; Furlong, M.; AchyuthaRao, S. PAC 1992, 64, 361.
7. Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. JACS 1987, 109, 8056.
8. (a) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. TL 1986, 27, 955. (b) Sakamoto, T.; Nishimura, S.; Kondo, Y.; Yamanaka, H. S 1988, 485. (c) For the palladium catalyzed coupling reaction of alkylzincs and vinyl iodides, see: Negishi, E.; Valente, L. F.; Kobayashi, M. JACS 1980, 102, 3298.
9. (a) Yeh, M. C. P.; Knochel, P. TL 1989, 30, 4799. (b) Sörensen, H.; Greene, A. E. TL 1990, 31, 7597.
10. Tamaru, Y.; Ochiai, H.; Sanda, F.; Yoshida, Z. TL 1985, 26, 5529.
11. Majid, T. N.; Yeh, M. C. P.; Knochel, P. TL 1989, 30, 5069.
12. Tamaru, Y.; Yasui, K.; Takanabe, H.; Tanaka, S.; Fugami, K. AG(E) 1992, 31, 645.
13. Tamaru, Y.; Tanigawa, H.; Yamamoto, T.; Yoshida, Z. AG(E) 1989, 28, 351.
14. (a) Yeh, M. C. P.; Knochel, P. TL 1988, 29, 2395. (b) Retherford, C.; Yeh, M. C. P.; Schipor, I.; Chen, H. G.; Knochel, P. JOC 1989, 54, 5200. (c) Knoess, H. P.; Furlong, M. T.; Rozema, M. J.; Knochel, P. JOC 1991, 56, 5974. (d) Retherford, C.; Knochel, P. TL 1991, 32, 441. (e) Sidduri, A.-R.; Knochel, P. JACS 1992, 114, 7579.
15. Tamaru, Y.; Nakamura, T.; Sakaguchi, M.; Ochiai, H.; Yoshida, Z. CC 1988, 610.
16. (a) Comins, D. L.; O'Conner, S. TL 1987, 28, 1843. (b) Comins, D. L.; Foley, M. A. TL 1988, 29, 6711.
17. Ochiai, H.; Tamaru, Y.; Tsubaki, K.; Yoshida, Z. JOC 1987, 52, 4418.
18. Zhu, L.; Rieke, R. D. TL 1991, 32, 2865.
19. Chen, H. G.; Gage, J. L.; Barrett, S. D.; Knochel, P. TL 1990, 31, 1829.
20. Yeh, M. C. P.; Knochel, P.; Santa, L. E. TL 1988, 29, 3887.
21. Ochiai, H.; Nishihara, T.; Tamaru, Y.; Yoshida, Z. JOC 1988, 53, 1343.
22. (a) Rozema, M. J.; Sidduri, A.-R.; Knochel, P. JOC 1992, 57, 1956. (b) Yoshioka, M.; Kawakita, T.; Ohno, M. TL 1989, 30, 1657. (c) Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M. TL 1989, 30, 7095.
23. Yasui, K.; Fugami, K.; Tanaka, S.; Ii, A.; Yoshida, Z.; Saidi, M. R.; Tamaru, Y. TL 1992, 33, 785.
24. (a) Salaün, J.; Marguerite, J. OS 1984, 63, 147; (b) OSC 1990, 7, 131.

Yoshinao Tamaru

Nagasaki University, Japan



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.