The halogenation of aromatic and heteroaromatic compounds is one of the most valuable synthetic transformations. The halogenated derivatives can be used as bioactive compounds and lead to new pharmaceuticals entities.[1 ] They also serve as important synthetic precursors for transition-metal-catalyzed cross-couplings.[2 ] Traditional halogenation protocols rely on the usage of toxic halogen X2 (Cl2 , Br2 ) which could cause serious environmental problems. The replacement of X2 by other safe reagents is ubiquitous to solve this problem,[3 ] among which, N -halosuccinimide (NXS, X = Cl, Br, I) is quite popular and practical, which, depending on the reaction conditions, can steadily release the halide ‘cation’ (X+ ) or radical (X
•
) for the halogenation reaction. The N -bromosuccinimide (NBS) works well with some electron-rich arenes.[4 ] However, it is difficult to brominate the electron-poor arenes, and the chlorination with the less reactive N -chlorosuccinimide (NCS) is even more difficult. Therefore, the halogenations of rather electron-deficient heteroaromatics remain a formidable synthetic task. Herein, we wish to report the copper activation of NXS for both chlorination and bromination of coumarin derivatives.
Coumarin (2H -chromen-2-one) can act as a privileged medicinal scaffold, which exhibits a broad spectrum of biological activities[5 ] such as anticancer,[6 ] antioxidant,[7 ] anti-inflammatory,[8 ] and so on. Besides these pharmaceutical applications, some coumarin derivatives can be used as fluorescent labels for bioimaging[9 ] and solar cell sensitizers.[10 ] These useful chemicals can often be synthesized via the transformations of halogenated coumarins. Although halogenated coumarins can be accessed through the cyclization from halogen-containing starting materials,[11 ] the direct halogenation of coumarin itself is evidently a more straightforward and economic pathway that benefits from the abundance of commercial availability of the starting materials.
However, it is known that coumarins are usually difficult to be halogenated for their electron-deficient character. In the literature, halogenation of coumarins is often accomplished by some highly reactive reagents (Scheme [1 ], path a, b). For example, the chlorination of coumarins usually needs to use such reagents as HCl/m CPBA in DMF (path a)[12 ] or HCl with oxone (path b).[13 ] The bromination can also be accomplished using HBr/Oxone (path b).[8 ]
[13 ] However, large excess of oxidant is needed to generate reactive X+ from HX, which limited the reaction scope to substrates carrying oxidant-tolerable functional groups, and multichlorinated side products are often formed under the reaction conditions.
Scheme 1 The halogenation of coumarins from the literature and this work
There are some reports on the bromination of coumarins with electron-donating groups such as OH or NH2 , using NBS together with Brønsted acid activators or in a highly polar solvent, such as NBS in the presence of sulfonic acid functionalized silica gel,[14 ] NH4 OAc,[15 ] in molten TBABr,[16 ] or in polyethylene glycol (Scheme [1 ], path c),[17 ] etc. The successful bromination can be attributed to both the activation of NBS and the electron-rich nature of the substrates. The lack of more efficient activation method excluded the further application of these reactions to inactive coumarins, not to mention the chlorination by the less active NCS.
Recently, there are a few reports on the Lewis acid activation of N -iodosuccinimide (NIS) for the iodination of electron-rich arenes. Sutherland and coworkers[18 ] reported a silver (AgNTf2 ) catalyzed iodination; Romo’s group[19 ] and Frontier’s group[20 ] used indium(III) and gold(I) complexes, respectively, for the activation of NIS. However, the Lewis acid activation of NCS and chlorination of electron-deficient arenes is seldom reported to our knowledge. Inspired by this strategy, we set out to search for an inexpensive Lewis acid promoter to activate NCS or NBS for the halogenation of the less electron-rich coumarins.[21 ] Herein, we report a safe, convenient, and regioselective 3-halogenation protocol of coumarins promoted by CuX2 /ZnX2 with the corresponding NXS as halide source.
In the beginning, control experiment for the chlorination reaction was conducted by heating coumarin (1a ) with 5 equiv NCS in acetonitrile, but no reaction took place even after prolonged refluxing,[22 ] which indicated the NCS needed to be activated. Several Lewis acid promoters were evaluated for the chlorination of 1a using the standard protocol (Table S1 in the Supporting Information). To our delight, the chlorination of 1a could be successfully promoted by the Lewis acid catalysts investigated. Among them, the CuCl2 ·2H2 O is the most efficient and affords the 3-chloro coumarin (2a ) with 81% yield (entry 6, Table S1) based on consumed 1a with no other regioisomers or multichlorinated side products found. Other Lewis acid catalysts such as ZnCl2 , CdCl2 , or AlCl3 , etc. exhibited relatively lower catalytic activities for this chlorination. FeCl3 showed a poor regioselectivity for this reaction, which promotes the chlorination of 1a at both 3- and 4- positions with a ratio of 70:30. The reaction solvent also influenced the reaction: The yield of the desired product decreased when the chlorination was carried out in acetic acid, 1,4-dioxane, or DMF. We further optimized the dosage of NCS and CuCl2 ·2H2 O promoter (Table S2) to guarantee a complete conversion of 1a . The conversion increased when more NCS was used, and the CuCl2 ·2H2 O amount should be maintained at 1.6–2.4 times (molar ratio) that of NCS for better yields (entries 1–5, Table S2). Finally, when a molar ratio of 1:7:14 (coumarin/NCS/CuCl2 ) was used, 2a was obtained in 62% yield with full conversion of 1a (entry 7, Table S2). The CuCl2 ·2H2 O can be half replaced with ZnCl2 to complete the chlorination with similar yield of the 2a (entry 9, Table S2). Anhydrous CuCl2 can promote chlorination with the same yield as the CuCl2 ·2H2 O, but more than 99 hours reaction time is needed. The addition of extra water can accelerate the halogenation, however, the yield decreased to 46% (entries 12–14, Table S2).
With the optimized chlorination conditions in hand, we extended this reaction to a series of coumarins substituted by methyl, methoxy, hydroxyl, chlorine, bromine, acetoxy, and dimethylamino groups. This method can also be applied to the bromination of these substrates using NBS, which is promoted by CuBr2 . The results of these halogenation reactions are summarized in Table [1 ]. For detailed reaction conditions including the ratios of reactants, reaction temperature and time, see Tables S3 and S4 in the Supporting Information.
Table 1 The 3-Halogenation of Substituted Coumarinsa
Entry
Substrate
Product
Yield (%)
1
2a , X = Cl, 62b
3a , X = Br, 61c
3
2b , X = Cl, 45b
3b , X = Br, 49c
5
2c , X = Cl, 84b
3c , X = Br, NRc
7
2d , X = Cl, 71b
3d , X = Br, 77c
9
2e , X = Cl, NRb
3e , X = Br, NRc
11
2f , X = Cl, 74b
3f , X = Br, 77c
13
2g , X = Cl, 84b
3g , X = Br, 66c
15
2h , X = Cl, 95b
3h , X = Br, 99c
17
2i , X = Cl, 68b
3i , X = Br, 73c
19
2j , X = Cl, 76b
3j , X = Br, 85c
21
2k , X = Cl, 58b
3k , X = Br, 61c
a Isolated yield. NR = no reaction.
b Chlorination conditions: The materials were refluxing in 20 mL MeCN (ca. 82 ℃) until the coumarin is consumed. For 2a –e : A mixture of coumarin (1.0 mmol), NCS (7.0 mmol), CuCl2 ·2H2 O (7.0 mmol), and ZnCl2 (7.0 mmol) is used; for 2f –j : coumarin (1.0 mmol), NCS (1.0 mmol), CuCl2 ·2H2 O (2.0 mmol), and ZnCl2 (2.0 mmol) is used; for 2k : coumarin (1.0 mmol), NCS (1.0 mmol), and CuCl2 ·2H2 O (1.6 mmol) are used and reacts at RT (room temperature).
c Bromination conditions: The starting materials were refluxed in 20 mL MeCN (ca. 82 ℃) until the coumarin is consumed. For 3a –c : A mixture of coumarin (1.0 mmol), NBS (5.0 mmol), and CuBr2 (10 mmol) is used; for 3d ,e ,h –j : Coumarin (1.0 mmol), NBS (2.0 mmol), and CuBr2 (3.2 mmol) is used; for 3f ,g : coumarin (1.0 mmol), NBS (1.5 mmol), and CuBr2 (2.4 mmol) are used and reacts at RT, for 3k : coumarin (1.0 mmol), NBS (1.0 mmol), and CuBr2 (1.6 mmol) are used and reacts at RT.
As illustrated in Table [1 ], the amount of NCS is varied from 1 to 7 equiv, depending on the electronic properties of the substituents: it costs only one or two equivalents of NCS to chlorinate the activated coumarins (2f –k ), but 7 equiv of NCS are needed to complete the chlorination of the substrates with electron-withdrawing or weakly electron-donating groups (2a –d ). Less amount of NBS (1–5 equiv) was needed to complete the bromination reaction. Some halogenation reactions can be achieved at room temperature (2k , 3f ,g ,k ). Notably, the complete bromination of 1k to afford 3k can be achieved in less than one minute at room temperature, which otherwise would take 72 hours to complete when NH4 OAc was used as the activation reagent.[15 ] In regard to the halogenation yield, the halogenation of the active substrates gives good to excellent yields (2f –k , 3f –k ), and even the less active coumarins gives the 3-halo coumarins (2a –d ; 3a–d ) in moderate to good yields (49–84%). In the case of 4-hydroxyl coumarin, no anticipated 3-halo products (2e , 3e ) were found, possibly owing to the lower reactivity of the C=C double bond, caused by chelating of copper with 4-hydroxyl group, which decreases the electron density. The bromination of 4-chloro coumarin (1c ) and the halogenation of 4-bromo coumarin gives no anticipated products, obviously due to the steric hindrance of the 4-halogen atom.
According to previous reports,[23 ] Lewis acid catalyzed halogenation reactions might proceed through either copper(III) mechanism or electrophilic aromatic substitution (EAS) mechanism. As described above, the reaction conditions and yields are greatly affected by the substituents: electron-donating substituents favor the halogenation, while electron-withdrawing substituents impede the halogenation, which is in agreement with an EAS mechanism. A control experiment shows the chlorination reaction under O2 atmosphere or argon protection gave similar results, this further supports the EAS mechanism.[23c ] A plausible mechanism is illustrated in Scheme [2 ] with the chlorination of coumarin (1a ) by NCS/CuCl2 as an example.
Scheme 2 The proposed halogenation mechanism
The chlorination proceeds via the highly reactive chlorine ‘cation’ (Cl+ ) generated in situ. Firstly, copper chlorides coordinate with the carbonyls of NCS (A ). This complexation in A substantially increased the electron-withdrawing power of the carbonyls, leading to the heterolytic cleavage of the N–Cl bond to expel a chlorine cation (Cl+ ) as shown in B and C . The highly electrophilic Cl+ regioselectively added to the 3-position of the coumarin ring to give a more stable benzyl carbocation D . Subsequent proton transfer from D to the N atom in C yields 3-chloro coumarin 2a as the chlorinated product and succinimide, which is still coordinating with copper (NHS-Cu ). This mechanism necessitates the use of two equivalents of copper chloride relative to NCS. Electron-donating substituents increase the electron density of the coumarin to facilitate the electrophilic attack of the positive halogen and render a higher stability of the carbocation intermediate D , thus leading to higher halogenation efficiency. As a result, the halogenation of 7-methoxy coumarin gave the 3-halocoumarins (Table [1 ], 2h , 3h ) quantitively, while the coumarins with chlorine groups (2b ,c , 3c ) gave relative lower yields.
Table 2 The Halogenation of Heteroarenesa
Entry
Substrate
Product
Yield (%)
1
5a X = Cl, 99b
6a X = Br, 98c
3
5b X = Cl, 69b
6b X = Br, 96c
5
5c X = Cl, 72b
6c X = Br, 86c
7
5d X = Cl, 98b
6d X = Br, 98c
a Isolated yield.
b Chlorination conditions: The materials were refluxing in 20 mL MeCN (ca. 82 ℃) until the heteroarene was consumed. For 5a ,c : Heteroarene (1.0 mmol), NCS (7.0 mmol), and CuCl2 ·2H2 O (14.0 mmol) are used. For 5b : Naphthoquinone (1.0 mmol), NCS (10.0 mmol), and CuCl2 ·2H2 O (20.0 mmol) are used. For 5d : Methoxysalen (1.0 mmol), NCS (2.0 mmol), and CuCl2 ·2H2O (4.0 mmol) are used and reacts at RT.
c Bromination conditions: For 6a ,b : Naphthoquinone (1.0 mmol), NBS (5.0 mmol), and CuBr2 (10 mmol) are used. For 6c ,d : Heteroarene (1.0 mmol), NBS (1 mmol) and CuBr2 (1.6 mmol) are used, and 6d is prepared at RT.
We also tested the halogenation of other heteroarenes using this copper activation strategy (Table [2 ]) to access their valuable halo derivatives. For example, the selective halogenation of the naphthoquinones would provide an important platform for further derivatization of this important quinone.[24 ] The halogenation of naphthoquinones (4a ,b ) can regioselectively afford the monohalogenated products (5a , 6a ,b ) in quantitative yields, except the chlorination of 2-methyl-1,4-naphthoquinone (5b , 69%). There was an early report of the bromination of 2-methyl flavone (4c ) using NBS alone gave the methyl brominated product.[25 ] Interestingly, upon using copper activation, a selective 3-bromination takes place on the heteroaromatic ring (5c , 6c ), which also supports the EAS mechanism. The halogenation of 8-methoxypsoralen (4d ) also affords quantitative yields of monohalogenated products (5d , 6d ).
In conclusion, we developed a CuX2 /ZnX2 promoted regioselective halogenation of coumarins by NCS or NBS with moderate to excellent yields.[26 ] The NXS dosage depends on the electronic properties of the substituent groups and varies from 1–7 equiv of the substrates, and the metal halide needs to be used in an amount 1.6–2 times that of NXS. Due to the usage of inexpensive reagents, the reaction can be scaled up although excess NXS, and metal halides are often needed to complete the conversion for some relatively electron-deficient coumarins without electron-donating substituents or even with electron-withdrawing substituents. This methodology can be applied to other less electron-rich or rather electron-deficient heterocyclic compounds such as 1,4-naphthoquinones, flavone, and methoxypsoralen to give monohalogenated derivatives. Therefore, this protocol provides an alternative approach to the halogenation of heteroaromatic compounds using copper activation of NXS with safe workup. We believe this concise procedure may also be applied to the halogenation of other aromatic compounds.
