Triflamidation of Allyl-Containing Substances:Unusual Dehydrobromination vs. Intramolecular Heterocyclization

Allyl halides with triflamide under oxidative conditions form halogen-substituted amidines. Allyl cyanide reacts with triflamide in acetonitrile or THF solutions in the presence of NBS to give the products of bromotriflamidation with a solvent interception, whereas in CH2Cl2 two regioisomers of the bromotriflamidation product without a solvent interception were obtained. The formed products undergo base-induced dehydrobromination to give linear isomers with the new C=C bond conjugated either with the nitrile group or the amidine moiety or alkoxy group. Under the same conditions, the reaction of allyl alcohol with triflamide gives rise to amidine, which was prepared earlier by the reaction of diallyl formal with triflamide. Unlike their iodo-substituted analogs, bromo-substituted amidines successfully transform into imidazolidines under the action of potassium carbonate.


Introduction
Oxidative sulfonamidation of unsaturated compounds is a convenient method for the formation of the C-N bond and an expedient route to the synthesis of various linear and cyclic compounds capable of further functionalization. The course of the reaction and the structure of products strongly depend on the reagent, oxidant, and reaction conditions [1][2][3][4].
Allylic substrates differ from their vinylic analogs in the possibility of migration of the double bond upon nucleophilic or electrophilic attack of the terminal olefinic carbon atom, which is impossible in vinylic substrates. In the literature, there are not so many examples of the reactions of oxidative sulfonamidation with the participation of allyl-containing substrates. Thus, in the presence of mild oxidant Cu(OAc) 2 and Cs 2 CO 3 as a base, Narylsulfonyl-ortho-allylanilines undergo oxidative cyclization to afford the products with four fused rings [5]. Homoallylic aromatic sulfonamides ArSO 2 NHCH(R)CH 2 CH=CH 2 are intramolecularly oxidized by PhI(OAc) 2 in the presence of KBr with cyclization to 4-bromopyrrolidines to give a mixture of the cis and trans isomers in high yield [6]. N-Bromosuccininide (NBS) induced enantioselective cyclization of allyl-N-tosylcarbamates catalyzed by a complex of Sc(OTf) 3 with chiral phosphine was reported [7]; the yield of the target products, substituted oxazolidinones, reached 71-90%. The latter was easily recyclized to the oxymethyl-substituted aziridines (Scheme 1).
Intramolecular bromoamination of O-allyl-N-hydroxytosylamides via 5-endo-tet-cyclization with bromoacetamide proceeds trans-diastereoselectively leading to isoxazolidines in good Analytically pure compounds were isolated by column chromatography. The structure of compounds 4 and 5 was proved by NMR and IR spectroscopy, as well as elemental analysis data. In particular, the IR spectrum of 4 contains absorption bands at 3334 (ν NH ), 1556 (ν C=N ), and 663 cm -1 (ν C-Br ). The 1 H NMR spectrum shows a broadened singlet of the NH group, a triplet of triplets of the CHBr proton, and a singlet at 2.5 ppm, typical for the methyl group in the amidine fragment. The 13 C NMR spectrum displays the signal of the azomethine group C=N and a quartet of the CF 3 group. Note, that no products of the addition of the triflamide residue to the double bond were observed.
The reaction of allyl iodide 6 with triflamide under the same conditions gave amidine 5 identical to that obtained in the reaction of allyl bromide 3 (Scheme 4). The product does not contain iodine, which is apparently indicative of its substitution in the intermediate bromoiodo derivative 7 by bromine from NBS (Scheme 5). A possible explanation of the formation of the dibromo-substituted amidine 5 from allyl iodide 6 is given in Scheme 6, suggesting the bromine/iodine exchange in the intermediate 7. Scheme 6. Possible mechanism for the formation of dibromo-substituted amidine 5.
Replacing NBS with N-iodosuccinimide (NIS) in the reaction of triflamide with allyl halides 2 and 3, N-(2-iodo-3-halopropyl)-N'-(trifluoromethylsulfonyl)acetamidamides 8 and 9 were obtained (Scheme 7). The low yields in the reaction using NIS can be due to the lower Lewis acidity of the generated iodine cation than that of the bromine cation. The structure of products 8 and 9 was proved by NMR and IR spectroscopy, as well as elemental analysis data. The IR spectra of both products show two ν NH absorption bands at 3326 and 3231 cm -1 and the bands at 1577, 1553 cm -1 (ν C=N ). In the 1 H NMR spectrum of 8, a broad singlet of the NH group and a doublet of doublets of the CHI proton appears. The CHI signals in 8 strongly differ from that in 9 in the position and the character of splitting (ddd in 8 and a multiplet in 9).
Surprisingly, no reaction occurred between allyl iodide 6 and triflamide in the presence of NIS: the reagents were recovered unchanged.
No products could be isolated from the NBS-induced reaction of allyl amine 10 with triflamide because of the strong polymerization of the reaction mixture. In contrast, allyl alcohol 11 afforded a low yield of amidine 12, which was obtained earlier from the NBSinduced reaction of diallylformal with triflamide (Scheme 8) [16]. With acrylonitrile, neither in the system t-BuOCl/NaI nor in the presence of NBS, at room temperature or on cooling, any products were isolated, apparently, due to strong polymerization under oxidative conditions (see, e.g., [17]). As distinct from that, the NBS-induced reaction of triflamide with allyl cyanide 13 in acetonitrile gave the product of bromotriflamidation with solvent interception 14 similar to the reactions of other substrates under analogous conditions [16,18]. The yield of N-(2-bromo-3-cyanopropyl)-N'-(trifluoromethylsulfonyl)ethaneimidamide 14 isolated by column chromatography was 60%. Its structure was proved by the methods of IR, NMR spectroscopy, and HRMS. In particular, the IR spectrum of amidine 14 shows absorption bands ν NH (3324), ν C≡N (2259), and ν NHC=N (1560 cm -1 ), its 1 H NMR spectrum displays a broad NH singlet, the signals of diastereotopic CH 2 N protons and a singlet of the methyl group at the azomethine bond. The 13 C NMR spectrum contains the C=N and C≡N signals, the CF 3 quartet, and the corresponding signal appears in the 19 F NMR spectrum. The use of larger amounts of the reagents allowed to isolate the minor product, N-(2-bromo-3-cyanopropyl)triflamide 15 having no acetonitrile moiety (Scheme 9). Its structure was also proved by NMR and IR spectroscopy. The ratio of compounds 14:15, from 1 H NMR spectroscopy, was~4:1 (Scheme 9). By replacing acetonitrile with THF as a solvent, we hoped to synthesize amino esters, as was previously successfully completed in our works [18,19]. However, with allyl chloride, instead, the product of bromination, 1,2-dibromo-3-chloropropane 16, was isolated in a low yield (Scheme 10) indicating that triflamide is not involved in the reaction. The reason for this behavior is that triflamide practically does not react with unsaturated substrates in solvents of low basicity [20].
Carrying out the reaction of allyl cyanide 13 in Scheme 9 in THF instead of MeCN also led to the solvent interception product, N-[4-(2-bromo-3-cyanopropoxy)butyl]-triflamide 17 formed via the THF ring opening and its addition as an O-nucleophile (Scheme 11). Scheme 11. NBS-induced reaction of triflamide with allyl cyanide 13 in THF.
Excluding the possibility of the formation of amidine 14 by replacing acetonitrile with methylene chloride, we obtained two regioisomers of the product of bromotriflamidation 18 and 19, isolated them as individual compounds and proved their structure and composition by IR, NMR spectroscopy and elemental analysis. 3-Bromo-4-hydroxybutanenitrile 20 was also obtained in a comparable yield (Scheme 12). The prevalence of bromination over bromotriflamidation is probably due to the low solubility of triflamide in methylene chloride. For comparison, the reaction of allyl cyanide 13 with tosylamide was examined under the same conditions. However, no products of sulfonamidation were obtained, but only dibromide 19 and unreacted tosylamide were recovered.
Amidines 4 and 5 were examined in the reaction with K 2 CO 3 in acetonitrile. As a result of intramolecular cyclization, substituted 4,5-dihydro-1H-imidazoles 21, 22 were obtained in quantitative yield. However, upon prolonged exposure to humid air, the bromo-substituted imidazoline 22 hydrolyzed to linear adduct 23 (Scheme 13): The structure of imidazolines 21, 22 was proved by IR and NMR spectroscopy, as well as elemental analysis data. The presence of two NH signals in the 1 H NMR spectrum, as well as the presence of signals for CH 2 NH, CHNH and C=O groups in the 13 C spectrum, indicates the formation of adduct 23.
Amidines 8 and 9 having two halogen atoms could give the products of cyclization with different ring sizes, but neither of them was formed; no reaction with K 2 CO 3 occurred.
The structure of isomers 25 and 26 was deduced from their 1 H NMR spectra, in particular, from the multiplicity pattern of the high-field signal of the methylene group. In isomer 25, the signal of -CH 2 N-group appears as a triplet of doublets at 4.22 ppm due to splitting on the NH and =CH protons with almost equal constants of~6 Hz, and subsplitting with small constant of 1.5 Hz on the CHC≡N proton. In accordance with this, the CHC≡N signal at 5.65 ppm is detected as a doublet of triplets with coupling constants of 11.2 and 1.5 Hz, and the CH=CHCH 2 signal at 6.49 as a doublet of triplets with the J values of 11.2 and 6.2 Hz. The structure of 25 is unequivocally proved by the 2D 1 H-1 H COSY NMR spectrum, which contains cross-peaks between the CH 2 and NH signals, as well as between the CH 2 and the signals of the adjacent (more intense) and remote (less intense) vinylic protons (Supplementary Materials Figure S30). The C=C bond is polarized towards the cyano group, ∆δ = 0.84 ppm. In contrast, in isomer 26, the signal of the -CH 2 N-group at 3.28 ppm appears as a doublet of doublets coupled only with the adjacent and remote vinylic protons with J = 7.3 and 1.2 Hz, respectively. Both compounds have trans-configuration about the double bond. Polarization of the C=C bond in 26 (∆δ = 1.90 ppm) is much larger than in 25, in compliance with the oppositely directed effects of the CN and -CH 2 N groups in 25, and the unidirectional effect of the NCCH 2 and NH groups in 26.
Earlier, the products of oxidative sulfonamidation with THF interception have been shown to undergo base-induced intramolecular heterocyclization to the corresponding 1,4-oxazocanes [19]. However, as in Scheme 15, the reaction of compound 17 with potassium carbonate, instead of cyclization, occurred as dehydrobromination to the isomeric linear products, N-(4-((3-cyanoallyl)oxy)butyl)triflamide 27 and N-(4-((3-cyanoprop-1-en-1yl)oxy)butyl)triflamide 28 in the ratio of 1:2 (Scheme 15) and the total yield of 80%. The formation of two regioisomers 27 and 28 by dehydrobromination of ether 17 as distinct from the reaction of amidine 14 (Scheme 14) can be due to better conjugation of the C=C bond with the oxygen atom than with the amine nitrogen atom in amidine 26 because of very strong conjugation of the latter in the amidine fragment [22]. The structure of regioisomers 27 and 28 was proved by their 1 H NMR spectra as described above for regioisomers 25 and 26.
The proposed pathways for the formation of products 14, 15, and 18 are presented in Scheme 16. The process could start with the reaction of TfNH 2 and NBS leading to the reactive species TfNHBr, which acts as a source of electrophilic Br + . The latter adds to the double bond of the substrate to give bromonium cation. The further course of the reaction is determined by the reaction medium. In acetonitrile, having higher basicity than triflamide (780 [23] vs. 740 kJ/mol [24]), the molecule of MeCN is captured by the cation with further addition of the triflamide anion to give amidine 14. The most challenging question is why the reaction of dehydrobromination of compound 14 in Scheme 15 results in the formation of isomeric linear products 25 and 26, being drastically different from all earlier studied reactions of similar β-bromoamidines with bases leading to cyclization to imidazolines. The formation of imidazolines in all our previous works is not surprising because of the higher energy of the bonds of different types (C-C, C-N, and C-H in imidazolines vs. C=C and N-H in linear products of dehydrogenation). In the search for a rationale for the specific behavior of compound 14, we assumed that there could be two reasons for the formation of linear products 25 and 26: (i) conjugation of the formed C=C bond with the nitrile group in 25 or with the NH group in 26, and (ii) the presence of acidic NH proton in the amidine motif of 25 and 26, capable of associating with the basic sites of the second molecule. For this, we performed high-level MP2/6-311++G(d,p) calculations including frequency analysis of molecules 25, 26, their dimers, and the isomeric imidazoline 24 shown in Scheme 15. The relative energies and free energies are given in Table 1. Remarkably, isomers 25 and 26 form different types of associates: while for 26 it is a 12-membered cyclic dimer with two N-H···O=S hydrogen bonds, for the similar dimer of compound 25 the geometry optimization results in its transformation to the eight-membered dimer with two N-H···N hydrogen bonds (Figure 1). The analysis of the data of Table 1 allowed us to explain two apparent inconsistencies with the experiment. First, the ∆E and ∆G differences of 3-4 kcal/mol between the monomers 25 and 26 seem to contradict the formation of both isomers. However, for the dimers, the corresponding differences in ∆E become equal. In spite of different types of H-bonding, the entropy losses upon the formation of dimers in Figure 1 and the ∆G values are also equal. Apparently, the lowering of the energy of 25-dimer is due to higher basicity of the azomethine nitrogen caused by strong conjugation in the NH-C=N tryad, whereas in 26-dimer this effect is reduced by the rivalry with that in the NH-C=C fragment. Second, while the monomers of amidines 25 and 26 are far less favorable than imidazoline 24, the dimers are much closer in energy and free energy to this heterocycle. Calculations of higher associates at the used very high level of theory are practically impossible, but the presence of acidic NH protons in monomeric molecules 25 and 26 allows them to be formed. This will certainly further increase the stability of the associates and make it highly probable the reversal of the relative stability with respect to imidazoline 24.

General Details
All starting materials have been described in the literature. All products were identified using IR, 1 H, 13 C, and 19 F NMR spectroscopy. IR spectra were taken on a Bruker Vertex 70 spectrophotometer in KBr. 1 H, 13 C, and 19 F NMR spectra were recorded in CDCl 3 or CD 3 CN on Bruker DPX 400 spectrometer at working frequencies 400 ( 1 H), 100 ( 13 C), and 376 ( 19 F) MHz. All shifts are reported in parts per million (ppm) relative to residual CHCl 3 peak (7.27 and 77.1 ppm, 1 H and 13 C), and CFCl 3 ( 19 F). All coupling constants (J) are reported in hertz (Hz). Abbreviations are: s, singlet; d, doublet; t, triplet; q, quartet; brs, broad singlet. High-resolution mass spectra were measured on an Agilent 1200 HPLC chromatograph (Palo Alto, CA, USA) with Agilent 6210 mass spectrometer (Santa Clara, CA, USA) (HR-TOF-MS, ESI + ionization in acetonitrile with 0.1% HFBA). Elemental compositions were determined by accurate mass measurement with standard deviation. Melting points were measured on a Boetius apparatus. Flash chromatography was performed using silica gel, 60 Å, 300 mesh. TLC analysis was carried out on aluminum plates coated with silica gel 60 F 254 , 0.2 mm thickness. The plates were visualized using a 254 nm UV lamp.

Theoretical Calculations
All structures were optimized without restrictions at the MP2/6-311++G(d,p) level of theory. Frequency calculations were performed on the optimized geometry at the same level of theory. All calculations were performed by the use of Gaussian09 program suite [25].

Reactions of Allyl Halides with Triflamide in the Presence NBS + MeCN
To solution of 1 g (6.7 mmol) of triflamide and 6.7 mmol of allyl halide 1, 2 in 30 mL of acetonitrile added 1.19 g (6.7 mmol) of NBS and reaction mixture was stirred in the dark for 24 h. Solvent was removed in vacuum, then the succinimide was precipitated with diethyl ether, filtered off, and ether removed in a vacuum. Analytically pure samples of substances were separated by column chromatography (0.063-0.

Reaction of Allyl Alcohol with Triflamide in the NBS + MeCN System
To a solution of 1.00 g (6.7 mmol) of triflamide and 0.39 g (6.7 mmol) of allyl alcohol 4 in 25 mL of acetonitrile was added 1.19 g (6.7 mmol) of NBS, and the reaction mixture was kept in the dark for 24 h. The solvent was removed under reduced pressure, the residue was dissolved in 20 mL of diethyl ether, cooled and the formed succinimide was filtered off. The filtrate was evaporated in vacuum, the residue (1.79 g) was placed on a silica gel column (0.063-0.2 mm, Acros Organics, Waltham, MA, USA) and eluted with ether:hexane = 1:1 mixture, isolating unreacted triflamide (~0.4 g), then with ether, obtaining N-(2-bromo-3-hydroxypropyl)-N'-(trifluoromethylsulfonyl)acetamidamide 12 as a colorless oil.

Reaction of Allyl Chloride with Triflamide in the NBS + THF System
To a solution of 1.00 g (6.7 mmol) of triflamide and 0.51 g (6.7 mmol) of allyl chloride 1 in 30 mL of tetrahydrofuran was added 1.19 g (6.7 mmol) of NBS, and the reaction mixture was kept in the dark for 24 h. The solvent was removed under reduced pressure, the residue was dissolved in 20 mL of diethyl ether, mixture was cooled and succinimide was filtered off. The filtrate was evaporated in vacuo, the residue (~2.20 g) was placed on a silica gel column (0.063-0.2 mm, Acros Organics, Waltham, MA, USA) and eluted with ether:hexane = 1:1 mixture, isolating unreacted triflamide, then with ether, obtaining 0.30 g of 1,2-dibromo-3-chloropropane 16 as a yellow oil. Product 16 was obtained and described earlier [26].

Reaction of Allyl Cyanide with Triflamide in the System NBS + THF
To a solution of 1.00 g (6.7 mmol) of triflamide and 0.45 g (6.7 mmol) of allyl cyanide in 40 mL of THF 1.19 g (6.7 mmol) of NBS was added. The reaction was carried out for 24 h in the dark. The solvent was removed under reduced pressure, the residue dissolved in 40 mL of diethyl ether, placed in a refrigerator for 1 h, and the formed succinimide was filtered off. The ether fraction was evaporated in vacuum, and the residue (~2.21 g) was placed on a silica gel column (0.063-0.2 mm, Acros Organics, Waltham, MA, USA) and eluted with ether:hexane (1:1), isolating unreacted triflamide (0.4 g), then with ether:hexane (4:1) to give N-(4-(2-bromo-3-cyanopropoxy)butyl)triflamide 17 (    converted to the corresponding imidazolidines in good yields. Allyl cyanide reacts with triflamide in the presence of NBS to give, depending on the solvent, different products of oxidative triflamidation. In methylene chloride, two regioisomers of the product of halosulfonamidation are formed, whereas in acetonitrile and THF the main products are those with a solvent interception. The amidine, obtained from the reaction in acetonitrile, behaves differently from all other earlier studied β-bromoamidines, which, when treated with a base, underwent cyclization to imidazolines in quantitative yield. In contrast, N-(2-bromo-3cyanopropyl)-N'-(triflyl)ethaneimidamide undergoes dehydrobromination with the formation of isomeric linear products, N-[(E)-3-cyanopropen-1-yl)]-N'-(triflyl)ethaneimidamides with the new C=C bond in the αor β-position to the cyano group. In the same manner, N-[4-(2-bromo-3-cyanopropoxy)butyl]triflamide obtained as the solvent interception product from the reaction in THF, was dehydrobrominated to the equimolar isomeric mixture of linear products with the new C=C conjugated with either the cyano group or the oxygen atom. No cyclization occurred to 1,4-oxazocanes as in all other earlier studied similar products. High-level calculations allowed us to explain the observed unusual course of dehydrobromination and the formation of different regioisomers.