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

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. This journal is © The Royal Society of Chemistry.

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.[8]

Over 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).

Scheme 1

Cross 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,[11] 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,[11] 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 (Table 1). When 2a was stirred in toluene at 120 °C for 3 h in the presence of 2 equiv. potassium persulfates, a trace amount of diphenylbenzylphosphine oxide 3a (<1%) was detected (entry 1). In a mixed solvent of toluene/water (1 : 1), the yield of 3a was increased to 12% (entry 2). It should be noted that the homocoupled product 1,2-diphenylethane 4 was formed in 16 : 84 ratio (3a/4). Further addition of 1 equiv. phase transfer reagent (sodium dodecyl sulfate, SDS) led to produce 3a in 37% yield (entry 3).[16] Other persulfates could also be used as an oxidant albeit with decreasing yields (Table 1, entries 4 and 5). No desired products were detected when the reaction was carried out with oxone or in the absence of oxidants (entries 6–8). By using sodium 4-dodecylbenzenesulfonate (SDBS) instead of SDS as the phase transfer reagent, a higher yield was afforded (entry 9). A higher percent of water (toluene/water = 1 : 2) gave 3a in 46% yield. However, further increasing the percent of water led to a decrease of the yield (entries 10 and 11). The yield was not changed with a decreased load of SDBS to 50 mol%. Further reducing the amount of SDBS to 20 mol% resulted in a poorer yield (entries 12 and 13). At lower temperature, the yield of 3a was also decreased to 29% (entry 14). Worth noting is that the reaction could be complete within 15 min when 3 equiv. of K2S2O8 was used, producing 3a in 48% yield (entry 15).

Optimization of the reaction conditionsa

Entry	Oxidant	Toluene/water (v/v)	Additive	3a yieldb (%)	3a/4c
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
12d	K2S2O8	1 : 2	SDBS	46	32 : 68
13e	K2S2O8	1 : 2	SDBS	26	21 : 79
14f	K2S2O8	1 : 2	SDBS	29	26 : 74
15g	K2S2O8	1 : 2	SDBS	48	38 : 62
16g,h	K2S2O8	1 : 2	SDBS	0	—

Reaction condition: 1a (1 mL), 2a (0.2 mmol), oxidant (2 equiv.), additive (1 equiv.) and H2O, 120 °C, 3 h. under N2.

GC yields using n-dodecane as an internal standard.

The ratio of 3a/4 was determined by GC analysis.

50 mol% SDBS was used.

20 mol% SDBS was used.

At 100 °C.

1 (0.8 mL) and H2O (1.6 mL), 3 equiv. K2S2O8 was used, 120 °C for 15 min.

3 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 (Table 2). Toluene and variously substituted toluene reacted with secondary phosphine oxides to afford corresponding 3. The phosphorylation of sp2C–H was not detected, and only mono-phosphorylation product was formed, which exhibited excellent chemo- and regioselectivity.

Transition-metal-free benzylic C–H phosphorylationa

Reaction 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.

1 mmol scale, 30 min.

130 °C.

100 °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 Table 1. In most cases, 1,2-diphenylethane 4 was detected, which showed benzyl radical 5 should be involved.[17]

We 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).

Scheme 2

Proposed mechanism for the direct phosphorylation of benzylic C–H bonds under transition metal-free reaction conditions.

Conclusions

In summary, we have achieved the first direct phosphorylation of benzylic C–H bonds with secondary phosphine oxides in a biphasic system under the transition metal-free reaction conditions via radical/radical sp3C–H/P(O)–H cross coupling. This transformation is applicable to various toluene derivatives, affording a new atom-economic protocol for sp3C–P bond formation. Compared with the previous reports, this novel process based on a readily available reaction system exhibits exclusive chemo- and regioselectivity.

Conflicts of interest

There are no conflicts to declare.