Aliphatic C–H azidation through a peroxydisulfate induced radical pathway

Abstract

A persulfate induced radical process to transform aliphatic tertiary C–H bonds into organic azides under transition-metal-free conditions has been developed. This method exhibits good chemo- and regioselectivity. A wide range of functional groups, including esters, halogens, azides, and dipeptides, are all tolerated well through the radical pathway, thus expanding the potential application of this method.

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The selective functionalization of isolated, aliphatic C–H bonds is a long-standing goal in organic chemistry.¹ Over the past few years, a number of strategies toward direct functionalization of selected aliphatic C–H bonds have been successfully established. Among them, C–H functionalization via a radical pathway is the earliest investigated and regarded as one of the more powerful tools in organic synthesis.^2–6 In most of those cases, pre-installed functional groups were first activated to generate heteroatom-centered radicals. Subsequent intramolecular hydrogen atom abstraction afforded carbon-centered radicals, which further coupled with other radicals to give the final products. Alternatively, the intermolecular hydrogen atom abstraction from substrates to appropriate radical abstractors also produced carbon-centered radicals directly from C–H bonds, thus avoiding pre-functionalization.^7,8 Just recently, we reported a regioselective aliphatic C–H bond oxidation using persulfate salts as the oxidant.⁹ In the reported process, the phthalimide group assisted two-step SET oxidation between substrates and sulfate radicals transformed the isolated aliphatic C–H bonds into carbocations, which further coupled with O-based nucleophiles to produce C–O bond formation products (Scheme 1, route 1). We speculated that, once the carbon-centered radicals were formed, they could be captured by appropriate reagents to forge other kinds of C–X bonds, thus preventing the subsequent oxidation step and meanwhile affording new products through direct C–H functionalization (Scheme 1, route 2).

Scheme 1 C–H functionalization via a peroxydisulfate induced radical pathway.

As we know, organic azides are versatile building blocks of great synthetic value.¹⁰ Not only are they readily converted into many other compounds such as amines, amides, imines, heterocycles, and nitrene intermediates, but they also play an irreplaceable role in “click” chemistry.¹¹ However, except for the early elegant work on weak aliphatic C–H bond azidation,¹² the direct azidation of isolated, “inactivated” aliphatic C–H bonds is still challenging, and only a few examples of isolated C–H azidation with transition-metal catalysts or under transition-metal-free conditions have been reported.^13–15 In view of the current progress and based on our recent developments in C–H oxidation chemistry, we decided to pursue the coupling between carbon-centered radicals and azidation reagents as the model reaction to fulfill our above-mentioned design (Scheme 1, route 2). When we were preparing this manuscript, Tang and coworkers reported a beautiful example to proceed the C–H azidation in the presence of a weak base.¹⁶

Our investigation began with the evaluation of several azidation reagents for the coupling reactions. At first, N-Phth-i-hexylamine 1a, sodium persulfate, and different kinds of potential azidation reagents were heated at 50 °C in acetonitrile/water mixed solvents for 4 hours (Table 1, entries 1–6). It was found that sodium azide, which was successfully applied in the Mn-catalyzed azidation system,^14b gave no azidation product under the present reaction conditions (entry 1). TMSN₃ also failed to promote the desired reaction (entry 2). The target azidation products were obtained in moderate yields when sulfonyl azides were employed as azidation reagents (entries 3–6). Among them, 3-PySO₂N₃ gave the most promising result (entry 3). Subsequent screening of radical initiators showed that potassium persulfate was the best choice for the reaction (entry 7). Further optimizations revealed that an obviously improved yield was achieved by elevating the temperature to 90 °C and increasing the persulfate loading to three equivalents (entry 11). However, other attempts such as elevating the temperature further, increasing the persulfate and 3-PySO₂N₃ loading, prolonging the reaction time, and adding base or transition-metal salts all gave negative effects (entries 10 and 12–16). It should be stated that the reaction atmosphere was crucial for the outcome of the reaction. The reaction proceeded efficiently under argon while failing in air (entry 17).

Table 1 Optimization conditions for the C–H azidation^a

Entry	M2S2O8 (equiv.)	[N3] (equiv.)	Condition	Yield^b (%)
a 1a (0.10 mmol), initiator, azide reagent, water (0.5 mL), acetonitrile (1.0 mL), Ar, in a sealed tube. b GC yields. c Isolated yield. d K2CO3 (1.0 equiv.) was added. e Fe(OAc)2 (0.1 equiv.) was added. f The reaction was performed under air. Phth = phthalyol. TPS = 2,4,6-triisopropyl-phenylsulfonyl.
1	Na2S2O8 (2.0)	NaN3 (2.0)	50 °C, 4 h	nd
2	Na2S2O8 (2.0)	TMSN3 (2.0)	50 °C, 4 h	nd
3	Na2S2O8 (2.0)	3-PySO2N3 (2.0)	50 °C, 4 h	45
4	Na2S2O8 (2.0)	C12H25SO2N3 (2.0)	50 °C, 4 h	33
5	Na2S2O8 (2.0)	TPS-N3 (2.0)	50 °C, 4 h	23
6	Na2S2O8 (2.0)	TsN3 (2.0)	50 °C, 4 h	37
7	K2S2O8 (2.0)	3-PySO2N3 (2.0)	50 °C, 4 h	54
8	(NH4)2S2O8 (2.0)	3-PySO2N3 (2.0)	50 °C, 4 h	42
9	K2S2O8 (2.0)	3-PySO2N3 (2.0)	90 °C, 4 h	75
10	K2S2O8 (2.0)	3-PySO2N3 (2.0)	100 °C, 4 h	72
11	K2S2O8 (3.0)	3-PySO2N3 (2.0)	90 °C, 4 h	87 (71^c)
12	K2S2O8 (4.0)	3-PySO2N3 (2.0)	90 °C, 4 h	78
13	K2S2O8 (3.0)	3-PySO2N3 (3.0)	90 °C, 4 h	88
14	K2S2O8 (3.0)	3-PySO2N3 (2.0)	90 °C, 6 h	80
15^d	K2S2O8 (3.0)	3-PySO2N3 (2.0)	90 °C, 4 h	42
16^e	K2S2O8 (3.0)	3-PySO2N3 (2.0)	90 °C, 4 h	79
17^f	K2S2O8 (3.0)	3-PySO2N3 (2.0)	90 °C, 4 h	nd

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With the optimized reaction conditions in hand, we next evaluated the substrate scope and the selectivity of the reaction. As illustrated in Scheme 2, a wide variety of N-Phth-amines with different alkyl side chains were transformed into azide compounds with good yields and excellent selectivity. These data showed that the length of the alkyl side chains did not affect the efficiency of the reaction very much (2a–2d), while suitable electronic features were essential for both the chemo- and regioselectivity of this reaction. Because tertiary C–H bonds are more electron-rich than secondary and primary ones, this azidation reaction exhibited an overwhelming bias toward tertiary C–H bonds no matter where they are located (2b–2n). When secondary C–H bonds and tertiary C–H bonds were at the same distance from an electron-withdrawing group (PhthN–), the azidation took place only at the more electron-rich tertiary C–H bonds, leaving the secondary ones intact (2i, 2j and 2m). Moreover, due to the inductive effects resulting in electronic distinctions between two inequivalent tertiary C–H bonds, this reaction also showed a good remote regioselectivity. The azidation preferred to occur at more electron-rich, remote tertiary C–H bonds, giving remote functionalized products as the major regioisomers (2j–2l). Besides linear alkyl side chains, the C–H azidation also proceeded well on substrates with cyclic carbon backbones. For example, methylcyclohexylamines exhibited good reactivity toward sulfonyl azide and gave satisfactory yields (2m and 2n). In contrast with the tertiary C–H bonds, secondary bonds exhibited rather lower reactivity and poorer regioselectivity toward azidation under the standard reaction conditions, affording a mixture of regioisomers in modest yield (2o).

Scheme 2 Substrate scope for the C–H azidation. Reaction conditions: N-Phth-protected amines (0.10 mmol), K₂S₂O₈ (0.30 mmol), 3-PySO₂N₃ (0.20 mmol), water (0.5 mL), acetonitrile (1.0 mL), Ar, 90 °C, 4 h. Isolated yields. ^a C3 : C2 > 20 : 1.^b C3 : C2 = 14 : 1. ^c C7 : C3 = 3 : 1.

After accomplishing the reactivity and selectivity studies, the functional group compatibility was investigated. As shown in Scheme 3, a broad array of functional groups were tolerated very well in this C–H azidation reaction. For instance, amino acid esters (2p and 2q), as well as protected alcohol groups such as benzoate and mesylate (2r–2t) all coupled with 3-PySO₂N₃ readily, affording moderate to good yields. It should be mentioned that halogens, specifically iodine, which are variably tolerated in radical processes, all survived well under the reaction conditions. Good efficiency and yields were obtained in the cases of chloro- and bromo-substituted substrates (2u and 2v). Although an iodo-substituted substrate reacted with 3-PySO₂N₃ sluggishly under the standard conditions, a 49% yield with 47% starting material recovered showed that a good mass balance was obtained (2w). Besides, a pre-installed azide group was also compatible with the reaction, producing the di-azide compound 2x. This azidation protocol could also be extended to the modification of synthetic peptides (2y and 2z). The electron-rich, remote tertiary C–H bond selectivity was maintained very well, and good yields were obtained. When there were two inequivalent tertiary C–H bonds existing in a dipeptide, for example, N-Phth-Leu-Val-OMe, the more remote and electron-rich tertiary C–H bond in the leucine residue was tagged with an azide group preferentially (2z).

Scheme 3 Functional group compatibility for the C–H azidation. Reaction conditions: N-Phth-protected amino compounds (0.10 mmol), K₂S₂O₈ (0.30 mmol), 3-PySO₂N₃ (0.20 mmol), water (0.5 mL), acetonitrile (1.0 mL), Ar, 90 °C, 4 h. Isolated yields. ^a 47% of starting material was recovered. ^b 1.5 equiv. 3-PySO₂N₃ was used.^c Di-azidation product was isolated in 12% yield.

A plausible mechanism is outlined in Scheme 4. At first, sulfate radical anions are generated by the pyrolysis of persulfate salts. The sulfate radicals abstract the hydrogen atoms from the most electron-rich positions of the substrates to afford carbon radicals II. Subsequently, the radicals II attack the terminal nitrogen atoms of sulfonyl azides to form intermediates III,¹⁷ which then decompose into the final azidation products IV and sulfonyl radicals V. The latter are further oxidized by remaining sulfate radicals to sulfonyl cations and subsequently react with O-based nucleophiles such as water to form pyridine-3-sulfonic acids.¹⁸ As shown in Scheme 1, once the carbon radicals II form, there are two competing reaction pathways, i.e. radical trapping by the sulfonyl azides and further oxidation by the persulfates. The ¹H-NMR figures of crude products clearly showed that under the standard reaction conditions, the azidation products were obtained overwhelmingly more than the oxidation products,¹⁹ indicating that the radical trapping reaction is more faster than the second oxidation.

Scheme 4 Proposed mechanism.

Conclusions

In conclusion, an efficient and practical C–H azidation method has been developed. This radical process proceeded in an aqueous solvent without a transition-metal catalyst, exhibiting good remote tertiary C–H bond selectivity and broad functional group compatibility. Tertiary C–H bonds in a series of substrates, including dipeptides, can be easily transformed into organic azides in good yields. Many functional groups, including halogens, can be tolerated under the radical conditions.

Acknowledgements

We gratefully acknowledge the financial support from the National Basic Research Program of China (973 Program) (Grant No. 2015CB856600) and the National Nature Science Foundation of China (Grant No. 21332001).

Notes and references

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18. After the reaction, pyridine-3-sulfonic acid was detected by LC-MS.
19. Azidation products/oxidation products >33/1, see the ESI† for details.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00237d

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