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Direct phosphorylation of benzylic C–H bonds under transition metal-free conditions forming sp3C–P bonds

Authors:	Qiang Li Chang-Qiu Zhao Tieqiao Chen Li-Biao Han

Affiliation:	College of Chemistry and Chemical Engineering, Liaocheng University, No. 1, Hunan Road, Liaocheng Shandong 252059 China.; Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island Resources, Hainan Provincial Key Lab of Fine Chem, Hainan Provincial Fine Chemical Engineering Research Center, Hainan University, Haikou 570228 China.; Zhejiang Yanfan New Materials Co., Ltd., Shangyu Zhejiang Province 312369 China

Abstract:	Direct phosphorylation of benzylic C–H bonds was achieved in a biphasic system under transition metal-free conditions. A selective radical/radical sp³C–H/P(O)–H cross coupling was proposed, and various substituted toluenes were applicable. The transformation provided a promising method for constructing sp³C–P bonds. Direct phosphorylation of benzylic C–H bonds with secondary phosphine oxides was first realized. The reaction was performed in organo/aqueous biphasic system and under transition metal-free conditions, proceeding via the cross dehydrogenative coupling. To construct C–P bonds is of great significance in modern organic synthesis,¹ because organophosphorus compounds play varied roles in medical,^2,3 materials,⁴ and synthetic chemistry fields.⁵ Traditionally, the C–P bonds were formed from P–Cl species via nucleophilic substitutions with organometallic reagents,⁶ P–OR species via Michaelis–Arbusov reactions,⁷ or P–H species via the alkylation in the present of a base or a transition metal.⁸Over the past decades, cross dehydrogenative coupling reactions (CDC reactions) have become a powerful and atom-economic methodology for constructing chemical bonds.⁹ By using this strategy, C–H bonds can couple with Z–H bonds without prefunctionalization and thus short-cut the synthetic procedures (Scheme 1a).Open in a separate window Scheme 1Cross dehydrogenative coupling reactions and direct phosphorylation of benzylic C–H bonds.A similar construction of C–P bonds via CDC was also realized.^10,11 Among these methods, the phosphorylation of sp³C–H having an adjacent N or O atom, or the carbonyl group was well-developed.¹¹ Relatively, the formation of benzylic sp³C–P bond was less reported,^11w which was mainly limited to the sp³C–H of xanthene or 8-methylquinoline (Scheme 1b).¹² In these reported processes, transition metal catalysts or photo-, electro-catalysts were usually involved,^11v and an excess of P(O)–H compounds was usually employed.^11,13 To the best of our knowledge, the phosphorylation of non-active benzylic C–H bonds has scarcely been reported.Considering both benzylic and phosphorus radicals could be generated by oxidation,¹⁴ which might subsequently couple, the phosphorylation of benzylic sp³C–H bonds would be achieved (Scheme 1c). Herein, we disclosed the construction of benzylic C–P bonds from toluene and P–H species. The reaction was carried out under transition metal-free reaction conditions,¹⁵ and exhibited high regio-selectivity. The aromatic C–H remained intact during the reaction.We began our investigation by exploring the reaction of toluene 1a and diphenylphosphine oxide 2a in the presence of an oxidant (16 Other persulfates could also be used as an oxidant albeit with decreasing yields (
Entry	Oxidant	Toluene/water (v/v)	Additive	3a yield^b (%)	3a/4^c
1	K₂S₂O₈	1 : 0	—	Trace	—
2	K₂S₂O₈	1 : 1	—	12	16 : 84
3	K₂S₂O₈	1 : 1	SDS	37	26 : 74
4	Na₂S₂O₈	1 : 1	SDS	31	27 : 73
5	(NH₄)₂S₂O₈	1 : 1	SDS	27	23 : 77
6	Oxone	1 : 1	SDS	None	—
7	—	1 : 1	SDS	None	—
8	—	1 : 1	—	None	—
9	K₂S₂O₈	1 : 1	SDBS	41	36 : 64
10	K₂S₂O₈	1 : 2	SDBS	46	28 : 72
11	K₂S₂O₈	1 : 3	SDBS	35	24 : 76
12^d	K₂S₂O₈	1 : 2	SDBS	46	32 : 68
13^e	K₂S₂O₈	1 : 2	SDBS	26	21 : 79
14^f	K₂S₂O₈	1 : 2	SDBS	29	26 : 74
15^g	K₂S₂O₈	1 : 2	SDBS	48	38 : 62
16^g^,^h	K₂S₂O₈	1 : 2	SDBS	0	—

Open in a separate window^aReaction condition: 1a (1 mL), 2a (0.2 mmol), oxidant (2 equiv.), additive (1 equiv.) and H₂O, 120 °C, 3 h. under N₂.^bGC yields using n-dodecane as an internal standard.^cThe ratio of 3a/4 was determined by GC analysis.^d50 mol% SDBS was used.^e20 mol% SDBS was used.^fAt 100 °C.^g1 (0.8 mL) and H₂O (1.6 mL), 3 equiv. K₂S₂O₈ was used, 120 °C for 15 min.^h3 equiv. TEMPO was added.Based on the above results, we can easily find that a serious amount of 1,2-diphenylethane 4 was formed. These results suggest that the homocoupling rate of 1a was very quick. Thus, the choice of the phase transfer reagent and oxidant is the key to cross-coupling of toluene and diphenylphosphine oxide in this biphasic solvent system.Excessive P–H species were usually employed in reported CDC reactions to form C–P bonds, because of their facile oxidation.¹³ In our procedure, toluene was excessive, thus the yields were calculated based on 2a. The yields looked like low, which did not indicate the poorer conversion rate of P–H species. With the optimized conditions in hand, the substrate scope of the CDC reactions was explored (

Open in a separate window^aReaction conditions: 1 (0.8 mL), 2 (0.2 mmol), K₂S₂O₈ (3 equiv.), SDBS (50%) and H₂O (1.6 mL), 120 °C, under N₂, the reactions were monitored by TLC and/or GC until 2 work out.^b1 mmol scale, 30 min.^c130 °C.^d100 °C.In addition to toluene, o-xylene, m-xylene, p-xylene, mesitylene, and 1,2,4,5-tetramethylbenzene all coupled with 2a to give the expected 3b–f in moderate yields. Methoxy substituted toluene gave relatively lower yields of 3g and 3h. para-Halo substituted toluene exhibited good reactivity, furnishing the coupling products 3i and 3j in moderate yields. Comparing to toluene, a decreasing order of reactivity was observed for ethyl benzene (3l, 30% yield), isobutyl benzene (3m, 27% yield), isopropyl benzene (3n, <10% yield), and diphenyl methane (3o, trace). The order was probably controlled by the steric hindrance around the benzylic carbon. 1-Methylnaphthalene and 2-methylnaphthalene also gave low yields (3p and 3q). However, 2-methylquinoline served well and coupled with 2a, affording the product 3r in 49% yield, which could be ascribed to the activation of the nitrogen atom. Besides of 2a, diaryl phosphine oxides having methyl, F, and Cl substituents could also be employed as the substrate, producing 3s–3u in moderate yields under similar reaction conditions.Although the mechanism of the direct phosphorylation of benzyl C–H bond in aqueous solution is not quite clear, some aspects could be grasped based on experimental results. Firstly, the desired product 3a was not detected when the 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added, implying that a radical pathway might be possible in this reaction (entry 16). Secondly, the reaction only occurred in aqueous phase, and relied on the presence of PTC (phase transfer catalyst), as seen in that 3a was difficultly formed in entries 1 and 2 of 17We supposed 1 is converted to benzyl radical 5 by SO₄⁻ radical that is generated via hemolytic cleavage of potassium persulfates.¹⁸ Meanwhile, phosphorus radical 6 is similarly formed from 2. Because potassium persulfate was water soluble, both 1 and 2 had to be transferred into aqueous solution to react with potassium persulfates.¹⁹ This proposal is also in accord with the experimental results that no products of sp²C–H phosphorylation are detected, which are the main products in the previous radical systems.²⁰ Finally, cross couplings between 5 and 6 produce 3 (Scheme 2).Open in a separate window Scheme 2Proposed mechanism for the direct phosphorylation of benzylic C–H bonds under transition metal-free reaction conditions. Keywords:

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