Effect of sodium acetate in atom transfer radical addition of polyhaloalkanes to olefins

Abstract

The atom transfer radical addition of polyhaloalkanes, such as bromotrichloromethane and polyfluoroalkyl iodine, to olefins smoothly proceeds in the presence of sodium acetate as an efficient auxiliary agent in dimethoxyethane. The present transition metal- and peroxide-free methodology is applicable to a broad scope of substrates.

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The atom transfer radical addition (ATRA)¹ of haloalkanes to olefins is an organic reaction used to concurrently construct carbon–halogen and carbon–carbon bonds. Especially, the Kharasch reaction² using bromotrichloromethane (BrCCl₃) and olefins can introduce both bromine and the trichloromethyl³ group into the carbon backbone, which are easily transformed into a variety of functional groups. However, the ATRA represented by the Kharasch reaction normally requires a toxic and hazardous reagent such as peroxides [(AcO)₂ or (BzO)₂],² sodium dithionite (Na₂S₂O₄)⁴ and triethylborane (Et₃B)⁵ as a radical initiator. Although the transition metal reagents⁶ (Ru,^7a,c,d,f Pd,^7b,h Ti,^7e Cu,^7g Ir^7i,j) were also adapted as radical initiators or photocatalysts in recent studies, the residue of transition metals and additional ligands might be a problematic issue. We now demonstrate the transition metal-free and safe ATRA using sodium acetate (NaOAc) as an efficient auxiliary agent for the radical pathway to furnish the various polyhalogenated products.

The acetyloxyl radical is well-known to be generated from diacetyl peroxide [(AcO)₂], which is commonly utilized in the Kharasch reaction.^2b Meanwhile, the recent research reported by Wang et al. has indicated that NaOAc also might be a short-lived acethyloxyl radical source.⁸ Although NaOAc might not be an efficient acetyloxyl radical source due to its potential anionic property as an acetate anion, we have been attracted to its safe, mild and ease in handling properties as a radical source and tried to adapt NaOAc to the ATRA (Table 1). First of all, ether type solvents were evaluated in the presence of allylbenzene (1a) as an olefin substrate, NaOAc (1.1 equiv.) and BrCCl₃ (1.1 equiv.) at 90 °C (entries 1–4), since THF has been reported to promote the Kharasch reaction.⁹ Consequently, the use of 1,2-dimethoxyethane (DME) as a solvent efficiently provided the desired halogenated product (2a) in moderate yield for 6 h (entry 4). Other solvents (e.g., c-hex, MeOH, H₂O, toluene) were totally ineffective (entries 5–8). Increment of BrCCl₃ from 1.1 equivalents to 2 equivalents dramatically improved the conversion yield (entry 9) and the prolongation of the reaction time to 24 h led the completion of the reaction to produce 2a in a good isolated yield (88%) (entry 10). Other acetates (LiOAc and KOAc), benzoate (NaOBz), alkoxide (NaOtBu) and halides (NaBr and KBr) were less efficient in the Kharasch reaction (entries 4 vs. 11–16). A significant decrement of the yield was observed without NaOAc (entry 9 vs. 17), which obviously indicated that NaOAc played an important role in the progress of the present Kharasch reaction.

Table 1 Optimization of the reaction conditions using BrCCl₃^a

Entry	Reagent	Solvent	Yield of recovered^b 1a/2a (%)
a The temperature of the external heating device.b The yield was determined by ^1H NMR using 1,4-dioxane as the internal standard.c 2.0 equiv. of BrCCl3 were used.d The reaction was carried for 24 h.e Isolated yield; DME: 1,2-dimethoxyethane.
1	NaOAc	THF	40/10
2	NaOAc	1,4-Dioxane	56/25
3	NaOAc	CPME	Complex mixture
4	NaOAc	DME	48/52
5	NaOAc	c-Hex	63/0
6	NaOAc	MeOH	46/0
7	NaOAc	H2O	65/0
8	NaOAc	Toluene	47/6
9^c	NaOAc	DME	18/81
10^c^,^d	NaOAc	DME	0/100 (88)^e
11	LiOAc	DME	Complex mixture
12	KOAc	DME	35/41
13	NaOBz	DME	18/45
14	NaOtBu	DME	43/20
15	NaBr	DME	37/7
16	KBr	DME	34/9
17^c	—	DME	56/15

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Encouraged by the efficiency of NaOAc, the scope of the substrates was next examined (Table 2). Various terminal olefins bearing a long aliphatic side chain (1b), electron-sufficient arene (1c),¹⁰ acetoxy group (1d), epoxide (1e), benzyl ether (1f), alkyl bromide (1g) and trimethylsilane (TMS: 1h) were efficiently transformed into the corresponding products (2b–h) in good to excellent yields without fragmentation of the acetoxy group, epoxide, benzyl ether and alkyl bromide within the molecules, which were usually reactive under such radical conditions (entries 1–7). The sterically hindered 1,1-disubstituted alkene (1i) could also be converted into the desired product (2i) possessing a tertiary alkyl bromide moiety (entry 8). Meanwhile, the reaction was strongly influenced by the electronic property of the aromatic nucleus of the substrates in the case of styrene derivatives (entries 9–11). While the unsubstituted (1j) and 4-chlorinated styrenes (1k) were mainly transformed into the desired products (2j and k, entries 9 and 10), the bis-brominated product (3) was also isolated as a side-product in 26% yield in the case of 1k. The reaction using 4-methoxy styrene (1l) gave no desired product and the 1-aryl-3,3-dichloro-allylacetate derivative (4) was obtained as the sole product (entry 11).¹¹ Furthermore, trans-stilbene (1m), a 1,2-disubstituted alkene, did not undergo the Kharasch reaction (entry 12).

Table 2 Scope of substrates in ATRA using BrCCl₃^a

Entry	Substrate	Product	Yield (%)
a NR: no reaction, DME: 1,2-dimethoxyethane.
1			90
2			85
3			94
4			61
5			70
6			89
7			81
8			95
9			76
10			51
			26
11			50
12		—	NR

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The present ATRA using NaOAc in DME could be equally applied to various polyhalogenated alkanes (Tables 3 and 4). The tetrahalogenated methane having the comparatively easily cleaved C–Br bond, such as BrCCl₃ and tetrabromomethane (CBr₄), were effectively reacted with the olefin to give the corresponding desired products (2 and 5, Tables 2 and 3, entry 1), while the tetrachloromethane (CCl₄) bearing only the more stable C–Cl bond within the molecule was slightly less reactive to produce 6 in moderate yield for 48 h (entry 2). The use of bromoform (CHBr₃) could provide 7 even in low yield due to the less stable dibromomethyl radical species in comparison to the tribromomethyl radical (entry 3), Furthermore, tridecafluorohexyl iodine [CF₃(CF₂)₅I] was found to be adaptable under solvent-free conditions at 140 °C (Table 4), although the reaction under reflux conditions in DME hardly proceeded (Table 3, entry 4).¹²

Table 3 Efficiency of haloalkanes^a

Entry	Haloalkane	Product	Time (h)	Yield (%)
a NR: no reaction, DME: 1,2-dimethoxyethane.
1	CBr4		12	70
2	CCl4		48	55
3	CHBr3		24	20
4	CF3(CF2)5I		24	2

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Table 4 Scope of substrates in ATRA using CF₃(CF₂)₅I

Entry	Substrate	Product	Yield (%)
1			85
2			88
3			24
4			27
5			88

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Not only the unsubstituted aliphatic olefin (1b), but also the substrate having an epoxide within the molecule (1e) were efficiently converted to the corresponding polyfluorinated products (8a and b) by the solvent-free reaction in 140 °C (entries 1 and 2). Although the substrates (1h,g) possessing low boiling points (b.p. 55 °C and 128 °C, respectively) were less reactive due to their volatile nature at 140 °C (entries 3 and 4), the bromoalkene (1n) combined with the longer aliphatic chain [b.p. 150 °C (55 mmHg)] smoothly underwent the ATRA to give the desired polyfluorinated product (8e) in 88% yield. These products possessing a fluorous tag function and reactive groups, such as epoxide, bromo and iodo functionalities, can be useful in fluorous chemistry.¹³

While the reaction of trans-stilbene (1m) never proceeded (Table 2, entry 12), cis-stilbene (1o) was easily isomerized to the corresponding trans-isomer (1m) in the presence of NaOAc and BrCCl₃ in DME under reflux conditions (eq. (1)). Meanwhile, the independent use of NaOAc facilitated no isomerization (eq. (2)) and a mixture of trans- and cis-isomers was obtained using only BrCCl₃ without NaOAc (eq. (3)). These results in conjunction with Table 1, entry 15 obviously indicated that NaOAc is not a radical initiator and the reaction was initiated by the heat-induced radical cleavage (homolysis) of BrCCl₃ into the bromo and trichloromethyl radicals. The trichloromethyl radical derived from BrCCl₃ never reacted with stilbene due to the sterically hindered nature, and the less hindered bromo radical favored the radical addition to the cis-1,2-disubstituted alkene moiety of 1o to form the radical intermediate (A), which is transformed into the thermodynamically stable trans-isomer by elimination of the bromo radical. Although the real role of NaOAc¹⁴ is not clear, NaOAc plays a key role as an actual accelerator for the present radical reaction. The short-lived acetyloxyl radical might be trapped by the bromo radical to form the highly reactive acetyl hypobromite (AcOBr)¹⁵ and DME may stabilize the various radical species.¹⁶ The details of the reaction mechanism are currently under investigation.

Conclusions

We have established the efficient atom transfer radical addition (ATRA) of polyhaloalkanes to olefins in the presence of NaOAc in DME. The reaction could proceed without a transition metal and hazardous radical initiator, such as the commonly utilized peroxide, etc. Therefore, the present methodology can serve as a safe and environmentally friendly protocol generating less waste. The scope of substrates are versatile and various haloalkanes [e.g., BrCCl₃, CBr₄, CCl₄ and CF₃(CF₂)₅I] can be used to construct useful polyhalogenated products.

Acknowledgements

The Sugiyama Drugs Co., Ltd. for providing the continuation of T.I.'s university research.

Notes and references

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2. (a) M. S. Kharasch, E. V. Jensen and W. H. Urry, Science, 1945, 102, 128; (b) M. S. Kharasch, E. V. Jensen and W. H. Urry, J. Am. Chem. Soc., 1946, 68, 154–155; (c) M. S. Kharasch, E. V. Jensen and W. H. Urry, J. Am. Chem. Soc., 1947, 69, 1100–1105; (d) M. S. Kharasch, O. Reinmuth and W. H. Urry, J. Am. Chem. Soc., 1947, 67, 1105–1100.
3. The trichloromethyl group is easily hydrolyzed to the corresponding carboxylic acid and can be efficiently transformed into the gem-dichloromethyl functionality as an useful equivalent of the aldehyde. We have also developed the Pt/C-catalyzed chemoselective hydrogenation method of the trichloromethyl group to prepare the gem-dichloromethyl functionality. The related references are cited in the following paper, see: T. Imanishi, Y. Fujiwara, Y. Sawama, Y. Monguchi and H. Sajiki, Adv. Synth. Catal., 2012, 354, 771–776.
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7. For the recent selected reports using the transition metals, see: (a) F. Simal, S. Sebille, A. Demonceau, A. F. Noels, R. Nuňez, M. Abad, F. Teixidor and C. Viňas, Tetrahedron Lett., 2000, 41, 5347–5351; (b) D. Motoda, H. Kinoshita, H. Shinokubo and K. Oshima, Adv. Synth. Catal., 2002, 344, 261–265; (c) L. Quebatte, R. Scopelliti and K. Severin, Angew. Chem., Int. Ed., 2004, 43, 1520–1524; (d) A. E. Díaz-Álvarez, P. Crochet, M. Zablocka, C. Duhayon, V. Cadierno and J.-P. Majoral, Eur. J. Inorg. Chem., 2008, 786–794; (e) L. Cao and C. Li, Tetrahedron Lett., 2008, 49, 7380–7382; (f) K. Parkhomenko, L. Barloy, J.-B. Sortais, J.-P. Djukic and M. Pfeffer, Tetrahedron Lett., 2010, 51, 822–825; (g) W. T. Eckenhoff and T. Pintauer, Dalton Trans., 2011, 40, 4909–4917; (h) J. R. Khusnutdinova, N. P. Rath and L. M. Mirica, Angew. Chem., Int. Ed., 2011, 50, 5532–5536; (i) J. D. Nguyen, J. W. Tucker, M. D. Konieczynska and C. R. J. Stephenson, J. Am. Chem. Soc., 2011, 133, 4160–4163; (j) C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner and C. R. J. Stephenson, J. Am. Chem. Soc., 2012, 134, 8875–8884.
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9. M. Heintz, G. Leny and J. Y. Nedelec, Tetrahedron Lett., 1984, 25, 5767–5768.
10. The reaction of 1c under light-shielding conditions provided the same yield along with that under optimized conditions, which clearly pointed out that the present Kharasch reaction was significantly facilitated by both heating and the addition of NaOAc.
11. After the generation of the desired product (2l), the bromine is eliminated by the electron-donating property of the methoxy group to form the cation intermediate (B) and the subsequent nucleophilic attack by an acetate anion produces the intermediate C. The following elimination of the hydrochloride affords 4. Alternatively, B can be transformed into D in association with dehydrochlorination and the subsequent addition of the acetate anion to D affords 4
    .
12. The detail of the optimization was depicted in ESI.†.
13. J. A. Gladysz, D. P. Curran and I. T. Horvath, Handbook of Fluorous Chemistry, Wiley-VCH, Weinheim, 2004.
14. The elemental iron and copper metals were also known to facilitate the ATRA of CCl₄ and CCl₃Br to olefins. See: F. Bellesia, L. Forti, F. Ghelfi and U. M. Pagnoni, Synth. Commun., 1997, 27, 961–971 . The present reactions could be promoted by the use of the various combinations of polyhalomethanes, olefins, NaOAc and DMA each purchased from variety of suppliers (e.g., Aldrich, Wako Pure Chemical Industries, Tokyo Chemical Industry etc.), although the promotion by the trace of metal impurities cannot be perfectly ruled out.
15. Acyl hypobromite plays the role as a good radical initiator, see: P. S. Skell and D. D. May, J. Am. Chem. Soc., 1983, 105, 3999–4008.
16. 1,2-Dimethoxyethane and its related compounds, which can form bidentate metal complexes are known to be transformed into various radical species. Sodium cation complex derived from NaOAc and 1,2-dimethoxyethane might facilitate the formation of various radical species and the following ATRA of polyhaloalkanes to olefins, see: (a) R. Thissen, C. Alcaraz, O. Dutuit, P. Mourgues, J. Chamot-Rooke and H. E. Audier, J. Phys. Chem. A, 1999, 103, 5049–5054; (b) H. Liu, J. Sun and S. Yang, J. Phys. Chem. A, 2003, 107, 5681–5691.

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Footnote

† Electronic supplementary information (ESI) available: The typical procedure and the spectroscopic data of products such as ¹H and ¹³C NMR, IR and elemental analysis were depicted. See DOI: 10.1039/c3ra47457g

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