Regio- and Diastereoselective Vicinal Aminobromination of Electron Deficient Olefins via Phosphorus-Based GAP Protocol

Chemical synthesis based on Group-Assisted Purification chemistry (GAP) has been prolifically used as a powerful, greener and ecofriendly tool so far. Herein, we report hypervalent iodine (III) mediated regio- and diastereoselective aminobromination of electron-deficient olefins using group-assisted purification (GAP) method. By simply mixing the GAP auxiliary-anchored substrates with TsNH2–NBS as nitrogen/bromine sources and PhI(OAc)2 as a catalyst, a series of vicinal bromoamines with multifunctionalities were obtained in moderate to excellent yields (53–94%). The vicinal bromoamines were obtained without column chromatography and/or recrystallization simply by washing the crude mixtures with cosolvents and thus avoiding wastage of silica, solvents, time, and labor. The GAP auxiliary is recyclable and reusable.

Purification techniques such as column chromatography and recrystallization are commonly used in the above mentioned syntheses.
The development of environmentally benign and eco-friendly greener reaction protocol is ubiquitous both in academia and the pharmaceutical industry (Shi et al., 2008). GAP chemistry, recently introduced by our group, fulfills the afford-mentioned criteria of greener chemistry by avoidance of separation, workup, recrystallization, and column chromatography. The product is obtained by merely washing the reaction mixture with a combination of more polar and less polar solvents (Wang et al., 2013;Chennapuram et al., 2014;Dommaraju and Prajapati, 2015;Seifert et al., 2016;Patel et al., 2019;Li et al., 2020a;Li et al., 2020b;Li et al., 2020c). Polarity difference between the solvents plays a key role in the isolation of products, i.e., the impurities get dissolved in washing solvents and the GAPcoupled product remains insoluble clustered together. Keeping in view the greener aspect of GAP chemistry, here we report for the first time hypervalent iodine (III) mediated regio-and

RESULTS AND DISCUSSION
Based on our prior research, we were interested in aminobromination of α,β-unsaturated cinnamic acids, which are challenging due to the formation of regio-and diastereomeric products. To develop conditions for regio-and diastereoselective transformation, we began to prepare the GAP coupled intermediate 1a-k and 2a-k in our laboratory according to the literature procedure (Rahman et al., 2020) given in supporting information. To optimize the reaction conditions, we initiated the study with the GAP anchored intermediate 1a as the test substrate, p-toluenesulfonamide (4-TsNH 2 ) and N-bromosuccinimide (NBS) as the nitrogen and bromine source respectively. To our delight, product 3a was isolated in 60% yield after 24 h with a dr value 7:1 when 1a was treated with NBS (1.5 eq) and 4-TsNH 2 (1.5 eq) in dichloromethane at room temperature without any catalyst. Lower yields were obtained with other bromine sources ( Table 1, entries 2-4). With NBS as the bromine source, a series of hypervalent iodine and transition metal catalysts were subsequently employed. The yield was significantly improved with iodobenzene diacetate (PhI(OAc) 2 ), and aminobromine product was isolated in a chemical yield of 78% with diastereoselective ratio of 7:1 (  2 | Substrate scope of aminobromination of N-(4-(diphenylphosphoryl)benzyl) cinnamates 1a-k.
Unless otherwise specified, all reactions were performed with 0.3 mmol of 1a-k, 0.6 mmol of 4-TsNH 2 , 0.6 mmol of NBS, 150 mg of MS 4Å in 3 ml of chloroform at reflux under N 2 . The dr values were determined by the analysis of 1 H NMR spectra. Isolated yields with GAP washing.
Frontiers in Chemistry | www.frontiersin.org September 2021 | Volume 9 | Article 742399 enhanced the yield up to 82% (Table 1, entry 13). An even more increase in yield was observed when 2 eq of each NBS and 4-TsNH 2 was added to the reaction medium (   entries 18-23). A yield of 67% was obtained when the catalyst loading was decreased to 10 mol%. Control experiments showed that both NBS and the 4-TsNH 2 were important for the reaction and that using activated molecular sieves 4Å generally increased the yield and selectivity.
After optimizing the conditions for aminobromination reaction, the substrate scope was subsequently explored. The results are shown in Table 2. A wide range of N-(4-(diphenylphosphoryl) benzyl) cinnamates 1a-k bearing different aryl groups with a variety of electron-donating (EDG) (such as methyl and methoxy) and electron-withdrawing groups (EWG) (floro, chloro bromo, nitro) were investigated which provided moderate to high yields (53-94%). As shown in Table 2, with regards to the EDG on the aromatic ring of cinnamic substrates 1b-1f, the addition reactions were well tolerated to produce the relevant adducts in good yields ( Table 2, 2b-2f). Both the substrates 1b and 1c with an ortho-MeC 6 H 4 and a para-MeC 6 H 4 group delivered the corresponding products 3b and 3c smoothly in 85 and 89% yields respectively. Similarly, the product 3 days with ortho-OMeC 6 H 4 was isolated in a high yield of 80%. The di-OMe and tri-OMe substituted substrates were even more effective for the reaction ( Table 2, 3e, 3f). On the other hand, substrates bearing EWG on the aromatic rings generally decreased the yield under the same conditions ( Table 2, 3g-3j). Importantly, halogen (Br or F) groups were almost consistent with the conditions, offering 3g, 3h and 3i in moderate yields. The lowest yield of 53% was obtained for 3j, which had a Cl group at the ortho-position and an NO 2 group at para-position. The substrate with a naphthyl group reduced the yield to 81% under the same conditions but enhanced the diastereoselectivity ( Table 2, 3k).
In addition to N-(4-(diphenylphosphoryl) benzyl) cinnamates, N-(4-(diphenylphosphoryl) benzyl) cinnamamides 2a-k were then exposed to aminobromination under the optimized reaction conditions for 1a-k. The reaction was applicable in the presence of 20 mol% of PhI(OAc) 2 in chloroform, substrate 2a was successfully converted in 48 h at reflux temperature to haloamine product 4a in 78% yield with a diastereoselective ratio of 18:1.
As shown in Table 3, this transformation can be extended to a variety of N-(4-(diphenylphosphoryl)benzyl) cinnamamides 2a-k to provide moderate to high yields (56-81%). The substrates with EWG and EDG display substantial variations in reaction reactivity and regioselectivity. Aminobromination was greatly facilitated by the presence of a strong EDG on the benzene ring, affording products in high yields and good to excellent diastereoselectivity ( Table 3, 4b-4e). The substrate with EWG on the aromatic ring, as expected, resulted in a lower yield ( Table 3, 4f-4j). The substrate with a naphthyl group, however, had no significant effect on the yield under the same conditions and lowered the diastereoselectivity ( Table 3, 4k).
From Table 2, 3, we further observed that EWG and EDG on the benzene ring had a significant impact on the diastereoselectivity of cinnamates and cinnamamides which is generally governed by the GAP auxiliaries. In the case of cinnamates, EDG resulted in low diastereoselectivity than EWG. For cinnamamides, however, EDG had higher diastereoselectivity than EWG. This variation in SCHEME 2 | GAP deprotection.

SCHEME 3 | A possible pathway for the synthesis of vicinal bromoamines.
Frontiers in Chemistry | www.frontiersin.org September 2021 | Volume 9 | Article 742399 5 diastereoselectivity of both derivatives could be attributed to stereoelectronic factors.
The feasibility of this procedure was studied by conducting the reaction on a gram scale for the starting materials 1a and 2a, which resulted in 85 and 73% yields for the products 3a and 4a, respectively.
In the presence of Pd/C and NaBH 4 , the GAP-tailored vicinal aminobromine was deprotected which afforded Bndpp in 93% yield (Schemes 1,2). The mixture is dissolved in a small volume of a solvent, such as ethyl acetate or DCM, and then petroleum ether is used to purify the products. The GAP auxiliary precipitates as a white solid that is filtered and treated with petroleum ether. To achieve the desired β-bromoamine as a white substance, the filtrate is evaporated under a vacuum.

Mechanism
The outcomes of various experimentation within our research team, as well as other Wei et al., 2001;Wang and Wu, 2007;Chen et al., 2009a), lead to the conclusion that NBS may react with 4-TsNH 2 to generate N-bromo-ptoluenesulfonamide (4-TsNHBr) 6 (Scheme 3), which would be oxidized by PhI(OAc) 2 to generate intermediate Int-I that may either follow cycle A or cycle B. In cycle A, the Int-I will form aziridinium Int-II with a double bond of 1a or 2a, which is then stereoselectively attacked by the dissociated bromide from the Int-I at the more electrophilic carbon (beta to carbonyl carbon) to yield compound Int-III. Int-III and 16 eventually provide the ultimate bromoamine substance 3a or 4a and restore Int-I. When the fragile N-I bond of Int-I is broken, N-acetoxy-N-halo-p-toluenesulfonamide Int-IV can form, which could then be the active intermediate for cycle B. Int-IV that forms an equilibrium with nitrenium ion Int-V (Kikugawa et al., 2003;Murata et al., 2008) could react with olefin 1a or 2a to afford aziridinium Int-VI which would lead to Int-VII following an S N 2 nucleophilic attack by the nearby bromide. Finally, the reaction of the intermediate Int-VII with 6 gives the final product and regenerates Int-IV.
Benefiting from the present methodology and this mechanism analysis, the utilizations of GAP chemistry for aminohalogenation and diamination of a broader scope of substrates (Chen et al., 2003b;Chen et al., 2004), in search for new chirality (Wu et al., 2019a;Wu et al., 2019b;Liu et al., 2020) and on multi-component reactions will be further conducted in our labs (Jiang et al., 2012a;Jiang et al., 2012b).

EXPERIMENTAL SECTION
Aminobromination of 4-(Diphenylphosphoryl) Benzyl Cinnamates 1a-k and N-(4-(Diphenylphosphoryl) Benzyl) Cinnamamides 2a-k Typical procedure: Into a dry vial was added 1a or 2a (1 mmol, 1 eq), NBS (356 mg, 2 mmol, 2 eq), 4-TsNH 2 (342 mg, 2 mmol, 2 eq), PhI(OAc) 2 (64 mg, 20 mol%) and freshly activated 4 Å molecular sieves (500 mg) and capped under nitrogen protection. CHCl 3 (3 ml) was added via a syringe and the reaction mixture was allowed to reflux for 48 h. After completion (monitored by TLC), the reaction was quenched with dropwise addition of saturated aqueous Na 2 SO 3 solution (2 ml) and DCM (3 × 10 ml) was added to extract the product. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was redissolved in the minimal amount of solvents like ethyl acetate or DCM, and then petroleum ether was added. The GAP auxiliary precipitated in the form of a white solid which was filtered and washed with petroleum ether. The filtrate is evaporated under a vacuum to obtain the desired β-aminobromine as a white product.
General Procedure for Deprotection of Group-Assisted Purification Auxiliary BnDpp.
To a 10 ml round bottom flask was added 4a (0.2 g, 0.32 mmol), 10 wt% Pd/C (20 mg) 2 ml MeOH and NaBH 4 (15.2 mg, 2 equiv.). To prevent the loss of produced hydrogen and overpressure in the flask, it was sealed with a rubber septum and a deflated balloon. the reaction mixture was drained through a Celite after 2 h and the filtrate was concentrated under reduced pressure before being redissolved in EtOAc. After that, KHSO 4 was used to neutralize the reaction mixture. The organic layer was separated, dried over anhydrous Na 2 SO 4 and evaporated to dryness to afford crude GAP auxiliary, which was easily purified using the GAP washing method.

CONCLUSION
In conclusion, we have demonstrated a new method for the preparation of vicinal aminobrominated products of electrondeficient olefins coupled with GAP auxiliaries dppBnOH and dppBnNH 2 . Good yields and diastereoselectivities were obtained in a clean and eco-friendly reaction condition comprising the catalyst PhI(OAc) 2 with NBS and 4-TsNH 2 as the bromine and nitrogen sources. The Group-Assisted Purification (GAP) chemistry was successfully applied and the compounds were obtained as precipitates without column chromatography and recrystallization by merely adding ethyl acetate and petroleum ether. Besides, the GAP auxiliary can be recovered for reuse.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

AUTHOR CONTRIBUTIONS
GL, AA and AR designed the project. AR, NZ, IK and FF performed the experiments. AA and AR analyzed the data and wrote the manuscript. GL supervised, funded and critically reviewed manuscript.