A simple and highly diasteroselective approach for the vicinal dichlorination of functional olefins

Abstract

Organocatalytic stereospecific vicinal dicholorination of a wide variety of functionalized olefins such as ketoesters, esters, ketones, carvone, cholesterol and ethyl sorbate (27 examples) was achieved using inexpensive sulfuryl chloride as well as a simple phosphine catalyst under mild reaction conditions. The products were obtained with good to excellent yields and diastereoselectivities (up to 96% yield and >25 : 1 dr).

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Of the methods to construct carbon–chlorine bonds, the direct dichlorination of alkenes is an ideal and highly desired reaction.¹ Nearly 150 years after its inception,² it remains a popular method for alkene dichlorination with molecular chlorine (Cl₂), typically producing the dichlorination product. Nevertheless, this classic method is limited because molecular chlorine is always difficult to handle due to its gaseous state as well as potential safety problems.³ Accordingly, milder and more practical organic catalytic methods based on electrophilic chlorinating agents have been developed in an attempt to address these limitations. Significant progress has been made in the area of alkene dichlorination, and a variety of milder and more practical electrophilic chlorinating agents have been developed including PhICl₂,⁴ SO₂Cl₂,⁵ Et₄NCl₃ (Mioskowski reagent),⁶ NCS–PPh₃ (Yoshimitsu reagent),⁷ H₂O₂–HCl,⁸ KMnO₄–Me₃SiCl–BnEt₃NCl (Markó-Maguire reagent),⁹ oxone–NaCl¹⁰/oxone–NH₄Cl¹¹ and (PyF)⁺BF₄⁻–Me₃SiCl–BnEt₃NCl.¹²

However, in contrast to unactivated alkenes¹¹ and 1,2-disubstituted alkenes,^11,12 the dichlorination of functionalized alkenes has lagged far behind. Recently, dichlorination of chalcone, methyl cinnamate and cinnamaldehyde were developed by Zupan¹³ and Zou,¹⁴ but the diastereoselectivity of the products was not determined or very low (dr = 1 : 1). To date, the control of the chemoselectivity during the reaction is perhaps the most challenging – particularly with terminal ethylene functionalities or highly polar substrates.^13–15 For instance, Xu and co-workers reported triphenylphosphine oxide-catalyzed stereoselective 1,2-dibromination of an unsaturated ketoester with moderate diastereoselectivities,¹⁶ but obtained 1,3-dicholorination products under the same reaction systems except halogen sources.¹⁷ Given the complexity and importance of vicinal dichloride building blocks for chlorosulfolipids synthesis,¹⁸ the development of efficient methods to dichlorinate functionalized alkenes is an important but challenging area of organic synthesis.

We sought to develop an effective method that addressed these limitations. Very recently, our group has developed an approach to organoselenium-catalyzed vicinal dichlorination of unsaturated phosphonate using sulfuryl chloride as the chloride sources.¹⁹ It is expected that the identification of suitable chloride sources to generate active dichlorinating agents and control diastereoselectivity will spur the development of dichlorination of olefins.^12–15 Herein, we describe a practical protocol for the triphenylphosphine oxide-catalyzed vicinal dichlorination of unsaturated ketoesters, esters, ketones, carvone, cholesterol and ethyl sorbate with sulfuryl chloride as the chloride sources that performed under mild conditions with no additives.

Our initial investigations employed β,γ-unsaturated α-ketoesters derivatives. This offers two possibilities for the addition of chloride: 1,2-dichlorination or 1,3-dichlorination (eqn (1)).¹⁷ Thus, this was explored as a good substrate in dichlorination of functionalized alkenes systems. An inexpensive sulfuryl chloride (SO₂Cl₂) – a surrogate of chlorine gas – is a good electrophilic chlorinating reagent reported by Brown⁵ and Kobayashi.²⁰ Based on this concept, initial experiments were performed with β,γ-unsaturated α-ketoesters 1a and sulfuryl chloride in dichloromethane at room temperature. The desired 1,2-dichlorination product was obtained in 85% isolated yield in one hour, but the diastereoselectivity was very poor (3 : 1) (Table 1, entry 1). Thus, improving the diastereoselectivity was our next aim. We wondered if we could boost the diastereoselectivity by adding catalyst. Recently, Denton²¹ and Xu¹⁷ reported Ph₃PO-catalyzed dichlorination of epoxides and alkene using oxalyl chloride as the “Cl” sources, respectively. Inspired by these results, we then tried to use Ph₃PO (5 mol%) as the catalyst in this system. To our delight, the results showed exclusive chemoselectivity with the 1,2-dichlorination (2a) being the only product with excellent yield (94%) and diastereoselectivity (20 : 1) (Table 1, entry 2). The 1,3-dichlorination product in eqn (1) was not detected. Next, different solvents such as CH₃CN, THF, toluene, CHCl₃ and DCE were evaluated (Table 1, entries 3–7), and the best yield (96%) and diastereoselectivity (>25 : 1) were obtained with CHCl₃ as the solvent (Table 1, entry 5). Notably, with no catalyst (Table 1, entry 8), the conversion was also completed in CHCl₃, but with poor diastereoselectivity. Some other “Cl” sources such as SOCl₂, NCS, CH₃COCl and POCl₃ were applied in this reaction, but only produced trace amount of 2a and no reaction, respectively (Table 1, entries 9–12). Furthermore, when the catalyst loading was reduced to 2.5 mol%, there was no significant change in diastereoselectivities (>25 : 1) but lower yields (89%) were obtained (Table 1, entry 13). Finally, the use of PPh₃ rather than Ph₃PO afforded a small change in yield (94%) but poor diastereoselectivity (6 : 1) (Table 1, entry 14). When decreasing the reaction temperature, i.e., from 10 °C to −10 °C (Table 1, entries 15–20), the yields of product were better than the case of no Ph₃PO.

Table 1 Screening of the reaction conditions^a

Entry	Solvent	“Cl” sources (eq.)	Catalyst	Yield^b (%)	dr (anti/syn)^c
a Reactions were carried out with 1a (0.2 mmol, 1 eq.), “Cl” sources, catalyst (5 mol%) and solvent (1.0 mL) at room temperature for 1 h.b Isolated yields.c Determined by ^1H NMR spectroscopic analysis of the crude reaction mixture.d DCE = 1,2-dichloroethane.e n.d. = not determined.f 2.5 mol% Ph3PO was used.g 10 °C.h The yield parentheses was determined by ^1H NMR spectroscopy by using 1,2-dichloroethane as an internal standard.i 0 °C, 4 h.j −10 °C, 4 h.
1	DCM	SO2Cl2 (1.05)	—	85	3 : 1
2	DCM	SO2Cl2 (1.05)	Ph3PO	94	20 : 1
3	MeCN	SO2Cl2 (1.05)	Ph3PO	93	14 : 1
4	Toluene	SO2Cl2 (1.05)	Ph3PO	90	20 : 1
5	CHCl3	SO2Cl2 (1.05)	Ph3PO	96	>25 : 1
6	THF	SO2Cl2 (1.05)	Ph3PO	89	17 : 1
7	DCE^d	SO2Cl2 (1.05)	Ph3PO	92	>25 : 1
8	CHCl3	SO2Cl2 (1.05)	—	95	3.5 : 1
9	CHCl3	SOCl2 (1.05)	Ph3PO	Trace	n.d.^e
10	CHCl3	NCS (2.1)	Ph3PO	—	—
11	CHCl3	CH3COCl (2.1)	Ph3PO	—	—
12	CHCl3	POCl3 (0.7)	Ph3PO	—	—
13^f	CHCl3	SO2Cl2 (1.05)	Ph3PO	89	>25 : 1
14	CHCl3	SO2Cl2 (1.05)	PPh3	94	6 : 1
15^g	CHCl3	SO2Cl2 (1.05)	—	83^h	4 : 1
16^g	CHCl3	SO2Cl2 (1.05)	Ph3PO	88^h	>25 : 1
17^i	CHCl3	SO2Cl2 (1.05)	—	51^h	7 : 1
18^i	CHCl3	SO2Cl2 (1.05)	Ph3PO	63^h	>25 : 1
19^j	CHCl3	SO2Cl2 (1.05)	—	2^h	—
20^j	CHCl3	SO2Cl2 (1.05)	Ph3PO	25^h	>25 : 1

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With the optimized reaction conditions in hand, the scope of this dichlorination addition reaction was surveyed (Table 2). In general, all reactions were completed in one hour to give the corresponding products in high yields and moderate to excellent diastereoselectivities. Different esters groups were examined and the results revealed that diversified esters could be tolerated in this reaction system (products 2a–2g), except strong electron-donating-isopropyl (2c), -sec-butyl (2d) and 2-methoxyethyl (2f) groups, these resulted in moderate diastereoselectivities. Electron-donating or electron-withdrawing substituents at the para- or meta-position on the aromatic ring as well as 2-naphthyl were tolerated to afford the desired products in excellent yields and diastereoselectivities (products 2i–2l and 2m–2p). The substrate with –Me at the para-position gave yield at the same level, albeit with moderate diastereoselectivity (product 2h). However, the substrates with heteroaryl (such as 2-thienyl and 2-furanyl) rather than phenyl led to no product (products 2q–2r). The 1q and 1r were collapsed into other compounds as shown by GC/MS, and we tried to isolate some products but with failure. Reaction of substrate 1t under identical reaction conditions was unsuccessful (product 2t), the mixture compounds (such as 1,2-addition and 1,4-addition) were detected in ¹H NMR spectrum. Furthermore, aliphatic groups, such as cyclohexyl-substituted ketoester was not tolerated when using our optimized reaction conditions (product 2s). Notably, when gram-scale reaction of 1a gives 2a in comparable yield and excellent stereoselectivity (product 2a–2d), the Ph₃PO was recovered in 91% yield. The trans-dichloride products of 2o and 2p were determined with X-ray crystallographic analysis (Fig. 1).

Table 2 Scope of ketoesters^a

a Reactions were carried out with 1 (0.2 mmol), SO₂Cl₂ (0.21 mmol), Ph₃PO (5 mol%) and CHCl₃ (1.0 mL) at room temperature for 1 h.b Isolated yields.c Determined by ¹H NMR spectroscopic analysis of the crude reaction mixture.d Ketoester 1 (1.15 g, 6.0 mmol) and Ph₃PO (84 mg, 0.3 mmol) were dissolved in CHCl₃ (10.0 mL), after SO₂Cl₂ (0.9 g, 6.6 mmol) in CHCl₃ (4.0 mL) was added over 0.5 h, then the mixture stirred vigorously at room temperature for 2 h. Finally, the Ph₃PO was recovered in 91% yield.e NR = no reaction.

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Fig. 1 X-ray crystallographic structures of 2o and 2p.

To further extend the substrate scope of the dichlorination reaction, a series of α,β-unsaturated compounds and trisubstituted alkenes were explored (Table 3). To our delight, all tested substrates could give moderate to excellent yields. The activities and the diastereselectivities have a significant relationship with the length and the steric hindrance of the aliphatic chain on the ester side (products 4a–4e). Increasing the length and the steric hindrance of the aliphatic chain would decrease the yields (from 92% to 75%) and diastereselectivities (from >25 : 1 to 3.3 : 1) (products 4f–4h). The trisubstituted alkenes, such as carvone and cholesterol, were efficiently converted in 75–91% yield (products 4i–4j). And the trans-dichloride product (4j) was determined by X-ray structural analysis.

Table 3 Scope of esters and ketones^a

a Reactions were carried out with 3 (0.2 mmol), SO₂Cl₂ (0.21 mmol), Ph₃PO (5 mol%) and CHCl₃ (1.0 mL) at room temperature for 1 h.b Isolated yields.c Determined by ¹H NMR spectroscopic analysis of the crude reaction mixture.

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With these results in hand, the applicability of this methodology to dichlorination of α,β,γ,δ-unsaturated ester ethyl sorbate was evaluated. Interestingly, vicinal dichlorination product 5 was obtained in good yield and excellent diastereselectivity as well as regioselectivity compared to the literature (Scheme 1(I)),^6,18a which was the important synthon for chlorosulfolipids synthesis. Intriguingly, the dichlorination products of unsaturated compounds could undergo further transformations under simple conditions. For example, the ketoester carbon–oxygen double bond of 2a could be reduced to give diol 6 (Scheme 1(II)), bearing a core structure in chlorosulfolipids as well.^18b,c

Scheme 1 Synthetic study.

In conclusion, we have developed an efficient and novel route for the direct vicinal dichlorination of unsaturated ketoesters, esters, ketones, carvone, cholesterol and ethyl sorbate using Ph₃PO as catalyst. These processes gave dichlorination products in excellent yields and high diastereoselectivities (up to 96% yield and >25 : 1 dr). The transformation offers a practical and facile synthetic tool for useful compounds such as chlorosulfolipids. Further studies to expand the scope of this reaction to other alkenes (such as tetrasubstituted alkenes) and asymmetric synthesis are ongoing in our laboratory. This will extend the utility of this new strategy for catalytic alkenes dichlorination.

Acknowledgements

We are grateful for the financial support from the Start-up Grant from Jiaxing University (No. 70513022), Jiaxing Science Project (No. 2015AY11014), the National Natural Science Foundation of China (21371078, 21472029).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental section, crystallography, the NMR datum of products, copies of ¹H and ¹³C NMR spectra of products. CCDC 1417743, 1417744 and 1495828. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra20101f

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