Free radical mediated bromization of methylenecyclopropanes:

Preparation of 2,4-dibromobutenes without transition metal

Lei Yu a, Bo Chen a, Xian Huang a,b,*, Lu Ling Wu a

a Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, Chinab State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,

Chinese Academy of Sciences, Shanghai 200032, China

Received 10 July 2006

Abstract

A series of 2,4-dibromobutenes were synthesized by the reaction of methylenecyclopropanes with KBr in HOAc in the presence

of dibenzoyl peroxide, providing an environment friendly method for the synthesis of 2,4-dibromobutenes.

# 2006 Published by Elsevier B.V. on behalf of Chinese Chemical Society.

Keywords: Methylenecyclopropane; Free radical; Bromine

During the last decades, methylenecyclopropanes (MCPs), which are highly strained but readily accessible

molecules, have served as useful building blocks in organic synthesis [1]. The relief of their ring strain provides a

potent thermodynamic driving force. A variety of complex organic compounds have been synthesized via the

transformation of MCPs [2].

2,4-Dihalobutenes have attracted considerable attention because of their versatility as a building block or starting

substrate in organic and pharmaceutical synthesis [3]. During our research on MCPs, we found that 2,4-dihalobutenes

could be prepared by heating copper dihalide with MCPs in CH3CN [4]. The copper salt plays dual roles. First, it

inserts the C–C bond to open the three membered ring. Second, it acts as oxidant. However, the employment of the

double equivalents heavy metal salt does not accord to green chemistry. Thus, we tried to develop other methods to

avoid transition metal. Recently, we developed a series of MCPs’ reactions in free radical paths [5]. It is well known

that bromo radical can be generated by treating hydrobromide with peroxides. Here we wish to describe a novel

synthetic method of 2,4-dibromobutenes by the reaction of bromo radical and MCPs. This method allows to avoid the

use of heavy metal, and the reaction time is extremely short.

Heating (diphenylmethylene)cyclopropane and KBr in HOAc in the presence of dibenzoyl peroxide at 60 8C, 1,1-

diphenyl-2,4-dibromobutene was obtained in 65% yield (Table 1, entry 1). Further screening demonstrated that 80 8Cwas a better reaction temperature, and the yield of 2a was increased to 84% (Table 1, entry 2). When other free radical

initiator such as AIBN was employed, the yield of 2a was lower (Table 1, entry 4).

With these results in hand, a series of MCPs were employed to prepare the corresponding 2,4-dibromobutenes

(Table 2) [6].

www.elsevier.com/locate/cclet

Chinese Chemical Letters 18 (2007) 121–123

* Corresponding author at: Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, China.

E-mail address: huangx@mail.hz.zj.cn (X. Huang).

1001-8417/$ – see front matter # 2006 Published by Elsevier B.V. on behalf of Chinese Chemical Society.

doi:10.1016/j.cclet.2006.12.004

It was interesting that when mono substituted MCPs 1e was employed, tetrabromized product 3e could be obtained

as a side product in 10% yield at 110 8C. When 4 equivalences of KBr and 2 equivalences of dibenzoyl peroxide were

employed at this temperature, 3e could be obtained in 52% as the main product (Scheme 1).

The mechanism of this reaction was suggested as follows: the bromo radical added to the double bond of the MCP 1to form the intermediate 4, which was stabilized by the adjacent aromatic groups. Because of the high strain of the

cyclopropane ring, a b-scission of the C–C bond in the cyclopropane occurred and afforded unstable intermediate 5[7]. 5 reacted with another bromo radical to form the final product 2 (Scheme 2).

L. Yu et al. / Chinese Chemical Letters 18 (2007) 121–123122

Table 1

Reaction of MCP and HBr in the presence of radical inducers

Entry Initiator Timea (h) T (8C) Yield of 2b (%)

1 Dibenzoyl peroxide 6 60 65

2 Dibenzoyl peroxide 2 80 84

3 Dibenzoyl peroxide 1 110 71

4 AIBN 4 80 53

1a and dibenzoyl 0.3 mmol each, KBr 0.72 mmol, HOAc 2 mL.a The reaction was monitored by TLC.b Isolated yields.

Table 2

Preparation of 2,4-dibromobutenes

Compounds R1, R2 Yielda (%)

2a C6H5, C6H5 84

2b p-F-C6H5, p-F-C6H5 84

2c p-Cl-C6H5, p-Cl-C6H5 80

2d p-Me-C6H5, p-Me-C6H5 81

2e p-Br-C6H5, H 76b

a Isolated yields.b E configuration (confirmed by NOESY spectra).

Scheme 1.

In conclusion, we developed a novel synthetic method for the preparation of 2,4-dibromobutenes. This method was

more environmentally friendly, avoiding the employment of transition metal, and the reaction time is much shorter.

References

[1] For the preparation of the MCPs, see: A. Brandi, A. Goti, Chem. Rev. 98 (1998) 589, and references therein.

[2] (a) A. Brandi, S. Cicchi, F.M. Cordero, A. Goti, Chem. Rev. 103 (2003) 1213;

(b) I. Nakamura, Y. Yamamoto, Adv. Synth. Catal. 344 (2002) 111, and references therein.

[3] (a) J. Barluenga, R. Sanz, F. Fananas, Chem. Eur. J. 3 (1997) 1324;

(b) D. Sole, Y. Carcho, A. Llebaria, J. Moreto, A. Delgado, J. Org. Chem. 61 (1996) 5895;

(c) Y. Sato, T. Honda, M. Shibasaki, Tetrahedron Lett. (1992) 2593.

[4] H. Zhou, X. Huang, W. Chen, Synlett (2003) 2080.

[5] (a) H. Zhou, X. Huang, W. Chen, J. Org. Chem. 69 (2004) 5471;

(b) X. Huang, L. Yu, Synlett (2005) 2953;

(c) L. Yu, X. Huang, M. Xie, Synlett (2006) 423;

(d) L. Yu, X. Huang, Synlett (2006) 2138.

[6] Selected data: 2a 1H NMR (400 Hz, CDCl3, d, ppm): 7.19–7.33 (m, 10H), 3.62 (t, 2H, J = 7.2 Hz), 3.07 (t, 2H, J = 7.2 Hz); 13C NMR (100 Hz,

CDCl3, d, ppm): 31.0, 40.8, 123.2, 127.4, 127.6, 128.1, 128.5, 128.7, 128.8, 140.3, 142.7, 144.9; IR (KBr, y, cm�1): 2967, 1488, 1269, 1153, 699;

MS (70 eV, EI) m/z: 366 (M+, 53), 192 (100). 3e 1H NMR (400 Hz, CDCl3, d, ppm): 7.49–7.54 (m, 4H), 5.35 (s, 1H), 3.74–3.78 (m, 2H), 2.93–

3.12 (m, 2H); 13C NMR (100 Hz, CDCl3, d, ppm): 28.4, 50.7, 62.4, 72.3, 123.8, 131.2, 132.1, 135.6; IR (KBr, y, cm�1): 2922, 1587, 1486, 1218,

1109, 1074, 815; MS (70 eV, EI) m/z: 528 (M+, 3), 449 (85), 115 (100).

[7] T.G. Back, K.R. Muralidharan, J. Org. Chem. 54 (1989) 121.

L. Yu et al. / Chinese Chemical Letters 18 (2007) 121–123 123

Scheme 2.