Facile Metal-Free Direct Transformation of N-Allyl- and tert-Butyl- Protected Arylamines to Azacycles Using Phosphoryl Chloride and TBD

A novel synthetic approach to the preparation of N-aryl substituted azacycles from N-allyl and N-tert-butyl protected arylamines is described. In this preparation, a metal free reagent system utilizing POCl3 and TBD proved to be an important contributor for reactions of N-allyland tertbutyl-protected aryamines with cyclic ethers to generate the target azacycles. This protocol provides a practical approach to high yield, direct synthesis of N-aryl substituted fivemembered and six-membered azacycles from N-allyl arylamines and N-tert-butyl arylamines.

In addition, reactions of various arylamines with cyclic ethers using metal-based reagents including activated alumina, aluminum oxide, aluminum chloride, titanium (IV) chloride, and trimethylaluminum were discovered to produce N-substituted azacycles [24][25][26][27]. Several nonmetal reagent protocols have also been developed: B(C6F5)3 and pTSA•H2O were reported as key reagents for preparation of N-substituted azacycles from primary arylamines and cyclic ethers via ring-opening of cyclic ethers followed by cyclization [29]. BF3•Et2O was also employed as an active Lewis acid to assist in ring-opening of tetrahydrofuran for synthesis of N-aryl-substituted pyrrolidines [30]. Hydrogen iodide has also been used for synthesis of Nsubstituted azacycles [31]. However, most of the reported protocols require harsh reaction conditions such as high temperature, making it difficult to expand the scope of this reaction [32]. Moreover, most of the previously reported methods employed primary arylamines (highly reactive free arylamines) as starting materials for production of N-substituted azacycles.
The allyl group is a commonly used protecting group for amines in organic and pharmaceutical syntheses as various simple methods to prepare N-allylamines have been developed. They are generally synthesized by reaction of the primary amine with allylbromide in the presence of base; several metal complexes or ion liquids have been used as efficient reagents, and microwave irradiation methods have also been employed for this purpose.
While direct transformation of N-allylamine derivatives to other useful structures would constitute an attractive strategy, to our knowledge, direct synthesis of N-substituted aryl azacycles from N-allyl protected amine derivatives have not been reported due to the low reactivity of N-allyl protected amines (secondary amines). Herein, we describe a novel, practical, metal-free, direct preparation of N-aryl substituted azacycles from N-allyl arylamine 4 derivatives. In addition, this method was applied to direct conversion of N-tert-butyl protected arylamines to azacycles.

Results and Discussion
In most previously reported methods, preparation of N-substituted azacycles was achieved by employment of primary arylamines. Thus, synthesis of N-substituted azacycles from N-allyl protected arylamines (secondary amines) and cyclic ethers would require two separate steps: de-allylation of N-allyl arylamine to provide the free primary amine and then reaction of the primary amine with a cyclic ether to form the azacycle. Direct preparation of azacycles from Nallyl protected arylamines (secondary amines) would provide several benefits including fewer reaction steps and reductions of cost and waste.
In this study, several types of reaction conditions were investigated to achieve direct conversion of an N-allyl protected arylamine to N-substituted azacycle. Initially, new combination reagent/base systems for synthesis of N-substituted azacycles from N-allyl 5 arylamines and cyclic ethers were investigated. The reaction was conducted in the presence of TBD as a base at 120 o C for 12 h, and N-allylaniline was used as a model substrate.
First, a variety of Lewis acids (metal-based reagents) including FeCl3, InCl2, and SnCl4 was examined to find usable conditions. However, none of these reagents led to the desired product. AlMe3, which has previously been employed for synthesis of azacycles from primary amines [28] was also examined and was found to provide the corresponding azacycle in poor yield (8%). Employment of CaBr2 and CaI2 likewise did not produce the target product. Other metal-free reagents including BF3•OEt2, PCl3, and PCl5 were investigated for the reaction, however, it provided similar negative results. It was reported that phosphoramidates can be employed as useful intermediates in preparation of several types of cyclic structures [41][42][43][44][45]. Thus, phosphorus oxychloride (POCl3) was tested in the reaction of N-allyl protected aniline to yield the N-aryl substituted azacycle, and the POCl3-mediated reaction delivered the desired product in high yield (95%). The initial reagent screening led to the promising discovery that POCl3 was an efficient reagent for direct conversion of N-allyl protected aniline to N-aryl pyrrolidine. Next, several kinds of bases were examined to find a suitable combined reagent system to prepare N-substituted azacycles. As shown in Table 2, introduction of NaOH, NaHCO3, K2CO3, and Cs2CO3 into the reactions did not afford positive results (synthetic yields were less than 10%). Liquid organic bases were also assessed for synthesis of azacycles. Employment  The effect of reaction solvent on preparation of azacycles was investigated ( Table 3).
Utilization of MeCN, DMF, or DCE solvent led to none of the azacycle, while toluene and PhCF3 gave modest synthetic yields (36% for toluene and 39% for PhCF3). However, when xylene was used as solvent, the target cyclic amine was produced in high yield, suggesting that xylene was a better solvent offor synthesis of azacycles. Next, the amounts of cyclic ether and base used for the reaction were investigated to find optimal reaction conditions ( Table 4). N-Allyl protected aniline was treated with a series of tetrahydrofuran (THF) equivalents. The yield of azacycle increased as amount of THF was increased until reaching a plateau at 25 equiv. (55% for 10 equiv., 83% for 15 equiv., 90% for 20 equiv., and 95% for 25 equiv. of THF). Next, the effect of POCl3 and TBD amounts on the reaction was examined. As shown in Table 4, several different amounts of POCl3 However, greater amounts of POCl3 or TBD in the reaction did not lead to a significant increase in synthetic yield. Reactions were carried out at several temperatures, and the target product was successfully obtained via reactions at 120 o C (see Table S1 in Supporting Information).
After determining optimized reaction conditions, the scope of this method for preparation of Naryl substituted azacycles was investigated with a variety of N-allyl protected arylamines and cyclic ethers. First, diff erent N-allyl protected arylamines were employed for the reaction with THF to give N-aryl substituted pyrrolidines. All desired products were successfully prepared in high yields via this novel synthetic method (Scheme 2). In this study, various substituents on the aromatic ring of N-allyl arylamines were examined, and reaction yields were not significantly influenced by electronic properties or position of substituents on the aromatic ring: Generation of target N-aryl-substituted azacycles in high yield was achieved with N-allyl protected arylamines bearing electron-withdrawing substituents (chloro-, fluoro-, nitrile-, and nitro-) and electron-donating substituents (methyl-, ethyl-, and methoxy-) (Scheme 2, 3b-3m).
It has been reported that reactions of six-membered cyclic ethers such as tetrahydropyran with arylamines (primary amines) yielded N-aryl substituted azacycles in low yields. However, tetrahydropyran was successfully treated with N-allyl protected aniline (secondary amine) via our synthetic method, which resulted in high yield production of the target piperidine 4e.
Several nitrogen-containing fused heterocyclic ring structures such as tetrahydroisoquinoline and isoindoline are found as important units in biologically active natural products and pharmaceuticals, which are commonly used in various medical and biological studies [46][47][48][49].
Thus, the discovery of efficient reactions of N-allyl protected arylamines with benzene fused cyclic ethers to give N-aryl substituted benzene-fused azacycles is valuable. Utilization of this POCl3/TBD mediated protocol was further expanded to direct preparation of various nitrogencontaining fused heterocyclic ring compounds from N-allyl protected arylamines. N-Allyl protected arylanilines readily reacted with phthalan or isochroman to produce the desired azacycles 4f and 4j in good yields. Of note, the yields of nitrogen-containing fused heterocyclic ring compounds from N-allyl protected arylamines were not affected by different substituents on the aryl amine, which suggests that electronic effects of substituent are not an important factor for substrate reactivity. Treatment of N-allyl protected arylamines bearing electronwithdrawing or electron-donating groups with phthalan or isochroman readily yielded the target isoindolines and tetrahydroisoquinolines in high yields (Scheme 4, 4g-4i and 4k-4m).

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The scope of this method was extended to the reaction of N-tert-butyl arylamines to produce azacycles since the tert-butyl group has been widely used for protection of amines. Several Ntert-butyl arylamines were successfully employed in reactions with several types of cyclic ethers to give the corresponding azacycles. In particular, N-tert-butyl arylamines containing either electron-donating or electron-withdrawing groups were treated with tetrahydrofuran, phthalan, or isochroman under the same reaction conditions using POCl3 and TBD, and the desired azacycles were synthesized in high yields. These results indicate that successful direct conversion of N-tert-butyl arylamines to N-aryl substituted azacycles can be achieved using the novel POCl3/TBD mediated reaction system.

Conclusion
In conclusion, a novel facile method for reaction of N-allyl and N-tert-butyl protected arylamines with cyclic ethers to give N-aryl-substituted azacycles has been reported.

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In this study, POCl3 and TBD were used as crucial reagents to convert N-allyl/N-tertbutyl protected arylamines to the corresponding azacycles. Practical utilization of this method was demonstrated from successful direct synthesis of N-aryl-substituted fiveand six-membered azacycles from reactions of various N-allylic and N-tert-butyl arylamines with a variety of cyclic ethers. Moreover, this synthetic method uses inexpensive and commercially available reagents, and reaction operation is simple.
With excellent results from a wide array of substrates, this novel synthetic method provides an approach to direct generation of various azacycles from N-allylic and Ntert-butyl arylamines.

Supporting Information
Screening of reaction conditions, experimental procedures, compound characterisation data, and 1 H and 13 C NMR spectra.