Phosphorylation of 2-Aryl Quinoxaline Derivatives via C-H/P-H Cross Coupling under Transition-Metal-Free Conditions

Abstract In this study, we have developed an efficient protocol for synthesis of phosphorus-substituted heterocycles through reaction between 2-Aryl quinoxalines and dialkyl phosphites under transition-metal-free conditions. Here, K2S2O8 has been used as the sole oxidant for the facile synthesis of phosphorus substituted derivates. A variety of heteroaryl phosphonate derivatives have been synthesized under optimized conditions in good to excellent yields with this facile and environment friendly protocol.


Introduction
Organophosphorus based molecules are highly important in organic chemistry due to their wide spectrum biological properties and synthetic applications. [1][2][3][4][5][6][7][8][9][10] These compounds have been used as bioactive molecules in medicinal chemistry, [3][4][5] as priveleged ligands for transition-metal catalysis and organocatalysts, [6][7][8] as building block in organic synthesis 2 and also employed as additives or flame-retardants in polymer sciences. In light of their importance, development of efficient synthetic methods for construction of the carbon-phosphorus bond has been a recurring research focus since many years. The classical strategies for C À P bond construction commonly rely on the transition-metal catalyzed cross-coupling reaction and these reactions involve coupling between carbon nucleophiles such as organometallic reagents with an electrophilic P-reagent. [11][12][13][14][15][16] More recently, methods for the construction of C-P bonds through the addition of P-centered radicals to unsaturated systems leading to synthesis of organophosphorus compounds has grown in interest [17][18][19][20] Generally, P-centered radicals are obtained from radical initiators such as peroxides, azo compounds, manganese salts, R 3 B/O 2 , Ag/K 2 S 2 O 8 , etc. [21][22][23][24][25][26][27][28] Phosphorus-substituted heterocycles are class of compounds found in many biologically active molecules and advanced functional materials. [29][30][31][32] Recently, Cui and coworkers reported an approach for the direct phosphonation of quinoxalin-2(1H)-ones under the metal-free condition by using K 2 S 2 O 8 as an oxidant to generate a phosphorous-centered radical 33 As a continuation of our interest in reactions through such a radical pathway, 34-36 herein, we have described the synthesis of 3-phosphonated quinoxalines with K 2 S 2 O 8 as an oxidant between various 2-aryl quinoxalines and dialkyl H-phosphonates in PhCl at 80 C (Scheme 1).

Results and discussion
Initially the reaction of 2-phenylquinoxaline 1a with dimethyl phosphite 2a was carried out in the presence K 2 S 2 O 8 as an oxidant in chlorobenzene under ambient atmosphere (Table 1). Dimethyl (3-phenylquinoxalin-2-yl)phosphonate 3a was obtained in 14% yield at room temperature for 3 h. Then we performed a series of screening reactions for increasing the yield of the desired product 3a (entry 1). Therefore, The effect of different parameters such as oxidants, reaction solvents, and reaction temperature were investigated. The corresponding product was obtained in 63% and 88% yield at 50 C and 80 C respectively (entries 2 and 3). Elevation in temperature (100 C and 120 C) led to reduction in product yield. (entry 4 and 5). By increasing amount of K 2 S 2 O 8 to 3 eq. or 4 eq., no improvement was observed and even a slight decrease in yield (84% and 82%) was observed (entry 6 and 7). Reaction was carried out in presence of different solvents like DCE, CH 3 [14][15][16]. In addition, the effect of reagent stoichiometry was examined by varying the ratio of Quinoxaline 1a/dimethyl phosphite 2 from 1:3 to 1:4 (entries 17 and 18). These results indicated no effect of additional phosphite on reaction turnover. The original 2.5 equiv. dimethyl phosphite was found to be the best choice to give the desired product in 88% yield (entry 3). As expected, in the absence of K 2 S 2 O 8 (entry 19), formation of 3a was not detected and this indicated the importance of K 2 S 2 O 8 for this reaction.
With optimized reaction conditions in hand, the substrate scope of coupling of various 2-aryl quinoxalines with dialkyl H-phosphonates was then investigated. The results are summarized in Scheme 2. A variety of 2-aryl quinoxalines bearing electron-rich (H, Me and OMe) and electronwithdrawing (Cl) moities at different position of the aryl ring were reacted with dimethyl phosphite and diethyl phosphite to afford the corresponding products 3a-f and 3 h-l in good to Scheme 2. Substrate scope for C-H phosphonation under transition-metal-free conditions excellent yields. In addition, 1-naphthyl substituted quinoxaline was tolerated under the optimal conditions, which provided the product 3 g in 75% yield.
According to the proposed mechanism, firstly heat catalyzes the homolytical cleavage of persulfate to form two highly oxidizing sulfate radicals 4. These can perform H-atom abstraction on the weak P-H bond 2 to form the phosphine centered radical 5. The phosphine centered radical can then add into a transiently protonated heterocycle to form a Minisci type intermediate 6.
Then, a subsequent H-atom abstraction/deprotonation sequence can result in the desired phosphonated product 3a-l.

Conclusions
In summary, we have described the synthesis of 3-phosphonated quinoxalines by using 2-aryl quinoxaline derivatives and commercially available dialkyl phosphite as a P-radical precursor. Various 3phosphonated quinoxalines were prepared with good to excellent yields. The K 2 S 2 O 8 was employed as the sole oxidant for the formation of C(sp 2 )-P bonds under transition-metal-free conditions.

Disclosure statement
No potential conflict of interest was reported by the authors.