Crotyl Chloride

[591-97-9]  · C4H7Cl  · Crotyl Chloride  · (MW 90.55)

(butenylating agent via Grignard and other organometallic reagents,1,2 organoborane compounds,3 other nucleophiles,4 and organosilane compounds5)

Alternate Name: 1-chloro-2-butene.

Physical Data: (E) isomer: bp 84.8 °C/752 mmHg; nD20 1.4350; d420 0.9295 g cm-3; (Z) isomer: bp 84.1 °C/758 mmHg; nD20 1.4390; d420 0.9426 g cm-3.

Solubility: (Z) isomer: insol H2O; sol alcohol, acetone, and chloroform; (E) isomer: insol H2O; sol acetone and chloroform.

Form Supplied in: clear liquid; widely available in 70% purity, predominantly (E) isomer. Main impurity: 3-chloro-1-butene.

Preparative Methods: pure isomers can be prepared by chloride displacement of corresponding alcohols via Ph3P in various solvents,7 and other chlorinating agents.8

Handling, Storage, and Precautions: flammable and corrosive; incompatible with strong oxidizing agents and strong bases; store in a cool dry place. Use in a fume hood.

Electrophilic Reactions.

Crotyl chloride, like other allylic chlorides, acts as an electrophile to undergo nucleophilic substitution with organometallic agents1,9 which include Grignard reagents,1,10 organolithium11 and organocuprate reagents.12 Extensive mechanistic studies suggest that these transformations proceed via concerted SN2 (which gives a-substituted product) and SN2 (which gives g-substituted product) reactions.

In reactions with a given nucleophile, (E) and (Z) isomers often afford different ratios of a- and g-substituted products. In the case of phenyllithium,11 (E)-crotyl chloride gives an a/g ratio of 75/25, whereas the (Z) isomer gives an a/g ratio of 25/75.

The regioselectivity of a- vs. g-substitution is enhanced in reaction with alkyl cuprates, e.g. Lithium Di-n-butylcuprate gives an a/g ratio of 96/4. When combined with an alkylcopper in the presence of a Lewis acid, e.g. with n-BuCu/BF3, regioselectivity is reversed to afford an a/g ratio of 2/98.9b However, the Lewis acid does not significantly increase the regioselectivity with PhCu (the a/g ratio remains the same at 16/84 in presence of Boron Trifluoride Etherate).9b Higher regioselectivity for a-phenyl substitution can be achieved by converting crotyl chloride to crotyl triethylsilyloxy ether, then combining it with Phenylmagnesium Bromide in the presence of a catalytic amount of Dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) (PdCl2(dppf)). This gives a a/g ratio of 96/4.2,10 When NiCl2(dppf) is used as the catalyst, g-substitution is the major pathway with a/g of 12/88. High g-substitution (95-100%) regioselectivity is observed when crotyl chloride reacts with alkyl(aryl)zinc chlorides mediated by CuCN.2LiBr (see Copper(I) Cyanide).12

In addition to reaction with organometallic reagents, crotyl chloride also undergoes substitution with other nucleophiles. For example, when reacted with sodium benzenethiosulfonate in ethanol at 50 °C, it gives crotyl thiosulfonates. This can then be followed by reaction with vinylalanates to generate crotyl vinyl sulfides (eq 1),4a which readily undergo thio-Claisen rearrangement when heated in a mixture of dimethoxyethane and water.

Another example of such nucleophilic substitution is the regioselective cross-coupling with organoboranes. Crotyl chloride can be cross-coupled with alkyl-9-BBN mediated by Methylcopper to give mainly the 1,4-diene g-substitution products (eq 2).3,13 The 1,5-diene a-substitution products can be obtained by reacting crotyl chloride with lithium alkylthioallyl borates.14

Upon deprotonation with a strong base (e.g. Lithium Diisopropylamide) at -78 °C, a crotyl chloride carbanion is formed.6 This carbanion then reacts with Chlorotrimethylsilane to generate a-chlorocrotyltrimethylsilane. Like other substituted allylsilanes, it reacts with a variety of electrophiles when activated by Lewis acids (e.g. BF3.OEt2, Titanium(IV) Chloride) to afford vinyl chlorides with (Z) selectivity (eq 3).

Nucleophilic Reactions.

As an allylic chloride, crotyl chloride can be easily converted into a wide variety of crotyl organometallic reagents5b and crotylsilane compounds.15 The reagents serve as nucleophiles for addition to various carbonyl compounds, imines, oxime silyl ethers, and other electrophiles to generate homoallylic alcohols, amines, and hydroxylamines. Crotyl chloride forms organometallic reagents with a wide range of metals including lithium, potassium, magnesium, barium, tin, zinc, copper, boron, aluminum, titanium, zirconium, chromium, etc. An extensive review on the use of crotyl organometallic and other allylic organometallic compounds has appeared.5b

Crotylmagnesium chloride (see Crotylmagnesium Bromide), easily prepared by stirring crotyl chloride with excess magnesium in ether at rt,15a has recently been used to generate nitrones or N,N-disubstituted hydroxylamines by reaction with aliphatic nitro compounds.16 More commonly, however, crotylmagnesium chloride is used for nucleophilic addition to carbonyl groups to yield homoallylic alcohols. The regioselectivity and yields of these reactions are often enhanced by addition of other metals and/or metal salts, e.g. Mn, Cerium(III) Chloride, TiCl4, etc.16,17

Related Reagents.

Allyl Chloride; 3-Chloro-1-butene; Methallyl Chloride.

1. Magid, R. M. T 1980, 36, 1901.
2. Hayashi, T.; Konishi, M.; Yokota, K.; Kumada, M. JOM 1985, 285, 359.
3. Yatagai, H., JOC 1980, 45, 1640.
4. (a) Kozikowski, A. P.; Ames, A.; Wetter H. JOM 1979, 164, C33. (b) Fang, J.; Chen, C. C. JCS(P1) 1990, 3365.
5. (a) Aoki, S.; Mikami, K.; Terada, M.; Nakai, T. T 1993, 49, 1783. (b) Yamamoto, Y.; Asao, N. CRV 1993, 93, 2207.
6. Hosomi, A.; Ando, M. Sakurai, H. CL 1984, 1385.
7. (a) Magid, R. M.; Fruchey, O. S.; Johnson, W. L.; Allen, T. G. JOC 1979, 44, 359. (b) Snyder, E. I. JOC 1972, 37, 1466. (c) Magid, R. M.; Fruchey, O. S.; Johnson, W. L. TL 1977, 35, 2999. (d) Anderson, A. G.; Owen, N. E. T.; Freenor, F. J.; Erickson, D. S 1976, 6, 398.
8. Munyemana, F.; Frisque-Hesbain, A. M.; Devos, A.; Ghosez, L. TL 1989, 30, 3077.
9. (a) Maruyama, K.; Yamamoto, Y. JACS 1977, 99, 8068. (b) Maruyama, K.; Yamamoto, S.; Yatagai, H.; Maruyama, K. JACS 1980, 102, 2318.
10. Hayashi, T.; Konishi, M.; Yokota, K.; Kumada, M. CC 1981, 313.
11. Wawzonek, S.; Studnicka, B. J.; Zigman, A. R. JOC 1969, 34, 1316.
12. Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. JOC 1991, 56, 1445.
13. Yamamoto, Y.; Yatagai, H.; Sonoda, A.; Murahashi, S. CC 1976, 452.
14. Yamamoto, Y.; Yatagai, H.; Maruyama, K. CC 1979, 157.
15. (a) Sakurai, H.; Kudo, Y.; Miyoshi, H. BCJ 1976, 49, 1433. (b) Kira, M.; Hino, T.; Sakurai, H. TL 1989, 30, 1099.
16. Bartoli, G.; Marcantoni, E.; Petrini M. CC 1993, 1373.
17. (a) Cahiez, G.; Chavant, P. TL 1989, 30, 7373. (b) Pons, J-M; Santelli, M. TL 1986, 27, 4153.

Lihong L. D'Angelo

The Coca-Cola Company, Atlanta, GA, USA

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