Selective Phosphoramidation and Phosphonation of Benzoxazoles

Letter pubs.acs.org/OrgLett

Selective Phosphoramidation and Phosphonation of Benzoxazoles via Sequence Control Ling Huang,† Jiuhan Gong,† Zheng Zhu, Yufeng Wang, Shengmei Guo,* and Hu Cai* Department of Chemistry, Nanchang University, No. 999, Xuefu Road Nanchang 330031, P. R. China S Supporting Information *

ABSTRACT: A selective phosphoramidation and phosphonation of benzoxazole was developed with trialkyl phosphites in the presence of iodine under mild conditions. In the reaction, the transformation completes in 10 min at room temperature and the substrates are well tolerant, as 2-substituted azoles could afford the quaternary carboncentered products. Significantly, phosphites could be selectively introduced into the C- and N-positions of the benzoxazoles by controlling the addition sequence and the ratio of substrates. Table 1. Optimization of the Reactiona

S

elective synthesis is one of the core areas of modern organic chemistry because it not only provides valuable tools to produce a large number of useful molecules but also enhances the efficiency of reactions and reduces waste.1 Commonly, catalysts,2 ligands,3 base (acid),4 solvents,5 and even temperature6 have been applied to control the selectivity of reactions, while for the substrates possessing more than two active reaction sites the incorporation of multiple new functional groups at precise locations is considered difficult in a one-pot setup. In particular, the selectivity is challenging to achieve with the introduction of similar substituents, such as homologues, into the active position of a molecule, because of the similarity of their electronic effects and chemical features.7 Hence, a novel strategy to efficiently approach the selective introduction of homologues into the precise site of a compound is highly desirable.8 One-pot introduction of di- or multiphosphorus-containing substituents into molecules typically on the unfunctional molecules has been broadly reported.9 Among them, Stevens et al. pioneered acids promoted diphosphorylation of α,β unsaturated imines or quinolones by employing trialkyl phosphites or trimethylsilyl phosphite as phosphorus sources.10 Recently, Gao and Xu’s group reported an efficient nickelcatalyzed diphosphorylation of 1,10-phenanthroline and their analogues.11 In addition, Cui’s group enabled metal-free diphosphorylation of quinolines with HPO(OR)2.12 Despite these advances, the selective introduction of diphosphorus functionalities has been explored in a limited way. Here, we reported a metal-free selective phosphoramidation/phosphonation of benzoxazoles with trialkyl phosphites at room temperature.13 To test the reactivity of the reaction, benzoxazole and triethyl phosphite were initially selected as the model substrates. The reaction did not work when KI was used as the iodine source at 25 °C in CH3CN for 30 min (Table 1, entry 1). NIS was found to promote the reaction with a moderate yield, while I2 was found to give the best result in this formation (87% yield, entries 2 and 3). No reaction was observed when I2 was absent, indicating that iodine was important for this transformation © 2017 American Chemical Society

entry

iodine

solvent

1a/2a

1 2 3 4 5 6 7 8 9 10 11 12 13 14e

KI NIS I2

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN toluene THF xylene DCE DCM CH3CN CH3CN CH3CN

1:3 1:3 1:3 1:3 1:3 1:3 1:3 1:3 1:3 1:3 1:3 1:2 1:4 1:3

I2c I2d I2 I2 I2 I2 I2 I2 I2 I2

yieldb (%) 67 87 80 86 51 59 46 81 86 41 87 90

a Reaction conditions: benzoxazole (0.5 mmol), P(OEt)3 (1.5 mmol), [I] (150 mol %), and solvent (2 mL) at 25 °C under air conditioning for 30 min. bYield of isolated product. cI2 (100 mol %). dI2 (200 mol %). e10 min; DCE (1,2-dichloroethane).

(entry 4). Further screening was emphasized in the loading of iodine. Whether the loading of iodine was decreased or increased, the yield of the product did not improve (entries 5 and 6). The solvent effect on this reaction was significant. Toluene, THF, and xylene gave inferior yields (entries 7−9), respectively. However, the reaction performed well when DCE (1,2-dichloroethane) and DCM (dichloromethane) were used as solvents (entries 10 and 11). To further improve the yield of the reaction, we adjusted the loading of P(OEt)3 and found that Received: March 10, 2017 Published: April 21, 2017 2242

DOI: 10.1021/acs.orglett.7b00726 Org. Lett. 2017, 19, 2242−2245

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afforded the corresponding product in 95% yield (3l) when the benzothiazole was used as a substrate. Meanwhile, benzothiazoles that were electron-rich or electron-deficient on the phenyl rings provided the desired products in excellent yields (3m,n). In addition to benzoxazoles, 2-phenyl-1,3,4-oxadiazole led to 3o in 44% yield. More importantly, 5-chloro-2-methylbenzoxazole, which could produce quaternary carbon-centered molecules, worked well and gave 3p in 64% yield. In addition, a series of phosphite esters, such as P(OiPr)3, P(OnBu)3, and P(OMe)3, showed high reactivities under the standard conditions (3q−s). unfortunately, P(OPh)3 did not work in this reaction, which was most likely because of the difficulty of the iodo- attacking phenyl (3t). Additionally, the substrates with bromo- on the phenyl could be toleranted this reaction and gave good product yields (3u,v). Notably, the reaction proceeds well on a gram scale. We conducted several control experiments to gain insight into the reaction mechanism. Initially, radical scavengers such as BHT or 1,1-diphenylene were employed in the reaction under the standard conditions, and no drops of the product yields were observed (see the Supporting Information), suggesting that no radical procedure was involved in this transformation. Then, 3a was not obtained when 2iodobenzoxazole instead of benzoxazole was used as the substrate with P(OEt)3 without I2, indicating that the iodination procedure of benzoxazole does not occur during the reaction process (see the Supporting Information). The results of 31P NMR experiments suggest that iodine reacts with P(OR)3 completely and affords the species of IPO(OEt)2 (see the Supporting Information). To further investigate the reaction pathway, we used 1HNMR to study the C6D6 solutions of benzoxazole and P(OEt)3 mixed with iodine, respectively (Figure 1). We found that a signal appeared at 7.22 (C2-H)

neither smaller nor larger amounts of P(OEt)3 had positive effects on the reaction (entries 12 and 13). Screening of the reaction time revealed that the reaction could complete with 90% yield within 10 min (entry 14). Under the optimized reaction conditions, the substrate scope and reaction limitation were explored, and the results are summarized in Scheme 1. The reactions of 5-, 6-, and 7Scheme 1. Scope of the Reaction

Figure 1. Control experiments of the reaction.

chlorobenzoxazoles with P(OEt)3 proceeded smoothly and obtained the desired 3b, 3c, and 3d with 92−95% yields. Other halogen-substituted benzoxazoles, such as 5-fluorobenzoxazole, were also tolerant in this reaction under the standard conditions, affording the corresponding product in 84% yield (3e). Furthermore, a range of benzoxazoles bearing electrondonating groups on the phenyl ring participated in this reaction to provide 3f, 3g, 3h, and 3i in excellent yields. We found that substrates with electron-withdrawing groups, such as 5nitrobenzoxazole and 5-sulfonamidebenzoxazole, were not highly reactive substrates in this reaction (3j,k), probably due to the electronic deficiency of N-3. Furthermore, the reaction

ppm when benzoxazole was in C6D6, while the 1H spectrum showed that the signal of 7.22 ppm shifted to 7.69 ppm after the C6D6 solution of P(OEt)3-mixed iodine was added to the benzoxazole solution. This implied that the IPO(OEt)2 species reacted with the benzoxazole and produced an new intermediate. We then added the C6D6 solution of P(OEt)3 into the above mixtures, the signals at 7.69 ppm and at 7.60 ppm disappeared, and new signals appeared, showing the desired product formed. 2243

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corresponding product was isolated in 60% yield (4g). The other phosphites with benzoxazole could also be achieved with satisfying results. For example, P(OiPr)3/P(OEt)3 and P(OnBu)3 /P(OEt)3 partners were used in the reactions, and the yields of products were 93% and 81%, respectively (4h,i). In conclusion, we have successfully described a one-pot phosphoramidation/phosphonation of benzoxazoles with phosphites. This reaction, a part of P(OR)3 reacts with iodine to form phosphoriodidate intermediate, followed by a reaction with azoles, subsequently with P(OR)3, completes very quickly in excellent yields under room temperature. 2-Substituted benzoxazoles can also participate in this reaction, which affords a quaternary carbon-centered product. Furthermore, a strategy of selective phosphonate functionalities into the C-2 and N-3 positions is provided by controlling the adding ratio and sequence of the substrates. Additionally, gram-scale synthesis of this reaction is successful.

On the basis of mechanistic studies and previous literature reports,11,14 a plausible reaction pathway of the selective phosphoramidation/phosphonation of benzoxazoles is depicted in Scheme 2. Initially, I2 reacts with trialkylphosphites to form Scheme 2. Plausible Mechanism of the Reaction

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dialkyl phosphoriodidates A and byproduct RI.9a Then the nitrogen lone pair electron of benzoxazole attacks phosphorus of A, furnishing iodine salt B. Subsequently, nucleophile addition of B generates ylide C in the presence of trialkyl phosphites. Finally, a Michaelis−Arbuzov-like procedure affords the desired product, as well as RI. After studying the reaction mechanism, we wondered whether two different phosphites could be introduced by a one-pot approach to azoles by feeding the substrates in sequence and controlling the ratio of I2 and phosphites. Thus, we realized the selective phosphonation/phosphoramidation of azoles, and the results are shown in Scheme 3. When P(OMe)3

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00726. Procedures and analytical data (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected].

Scheme 3. Selective Reaction of Benzoxazoles

ORCID

Shengmei Guo: 0000-0002-4120-286X Author Contributions †

L.H. and J.G. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the financial support for this work from the National Science Foundation of China (21302084, 21571094), The National Basic Research Program of MOST of China (2012CBA01204), and the Jiangxi Province Science Foundation (20151BAB213007).

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