α-N-Heteroarylation and α-Azidation of Ketones via Enolonium Species

Jan 15, 2018 - Enolonium Species, resulting from the umpolung of ketone enolates by Koser's hypervalent iodine reagents activated by boron trifluoride...
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Cite This: J. Org. Chem. 2018, 83, 2442−2447

α‑N‑Heteroarylation and α‑Azidation of Ketones via Enolonium Species Atul A. More,† Gulab K. Pathe,† Keshaba N. Parida, Shimon Maksymenko, Yuriy B. Lipisa, and Alex M. Szpilman* Department of Chemical Sciences, Ariel University, 4070000 Ariel, Israel S Supporting Information *

ABSTRACT: Enolonium species, resulting from the umpolung of ketone enolates by Koser’s hypervalent iodine reagents activated by boron trifluoride, react with a variety of nitrogen heterocycles to form α-aminated ketones. The reactions are mild and complete in 4−5 h. Additionally, α-azidation of the enolonium species takes place using trimethylsilyl azide as a convenient source of azide nucleophile. ntroduction of nitrogen at the α-position of ketones is an important reaction due to the ubiquity of this structural theme in biologically active compounds. Classically, it relies on the nucleophilic displacement of a halide by a nitrogen nucleophile (Scheme 1a). In the case of azoles (with the exception of simple pyrazoles), alkylation typically requires long reaction times and/or elevated temperatures.1 Indeed, αtriazolo ketones are often preferentially prepared by [2 + 3] (click) cycloaddition reactions.2 Alternatively, amination of ketones may be carried out by attack of the corresponding enolates on electrophilic nitrogen donors. Hypervalent iodine reagents3 containing iodine bound electrophilic nitrogen have been used in the amination of ketone enolates. However, this method is generally limited to sulfonated amines or ammonia and does not extend to azoles. Recently, the α-functionalization of carbonyl compounds via umpolung4 of carbonyl enolates has received much attention. Maulide has reported extensively on the umpolung functionalization of amide enolates,5 including amination.6 Wirth, Waser, our group, and others have reported on the amination,3b,7 azidation,8 alkylation,9 and alkynylation10 of ketone enolates. Earlier this year, we reported the characterization of enolonium species derived from ketones and hypervalent iodine reagents.11 A seminal part of this study was the development of conditions to produce the otherwise unstable enolonium species 4 as discrete entities (Scheme 1b). This in turn led us to develop a two-step strategy in which the lower oxidizing power of the enolonium species 4 compared to the parent hypervalent iodine reagent 2 would make it possible to use a much larger variety of nucleophiles (Scheme 1b). We reported the use of this strategy in arylation12 and allylation of ketones as well as in chlorination, tosylation, and enolate

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© 2018 American Chemical Society

dimerization.11 In our mechanistic study, we also reported the coupling of triazole with acetophenone in 58% yield.11 In this paper, we report the successful coupling of ketone enolates with a variety of azoles under mild conditions and short reaction times. In addition, we show that α-azidation may be carried out under similar conditions. In optimizing the conditions for coupling of enolonium species with triazole, we specifically targeted minimizing the amounts of reagents necessary to achieve an optimum yield. Unlike in the case of arylation,12 it was found that as little as 1.25 equiv of Koser’s reagent (2) and 1.2−1.6 equiv of BF3 (4) gave yields similar to those achieved using higher amounts. An excess of azole was used as nucleophiles because these are inexpensive commodity chemicals. The scope with respect to different parent azoles were first tested in the reaction with the enolonium species derived from acetophenone (Scheme 2). Pyrazole afforded the desired coupling product 9 in 72% yield. The influence of a nucleophilicity reducing nitro group was also tested in the reaction with nitro-pyrazole. The expected product 10 was formed in 65% yield. The indazole analogue reacted to give 11 in 66% yield. Imidazole afforded the coupling product 12 in 63% yield. As previously reported, triazole was coupled to give 13 in 58% yield. The benzotriazole congener afforded the coupling product (14) in 45% yield, mainly due to issues with low solubility of the benztriazole leading to competing formation of tosylated product. In the case of tetrazole, this solubility issue led us to modify the procedure. Thus, tetrazole substrates were dissolved in acetonitrile at room temperature, and the solution was slowly added to the −55 °C solution of enolonium species. This modification prevented Received: December 4, 2017 Published: January 15, 2018 2442

DOI: 10.1021/acs.joc.7b03058 J. Org. Chem. 2018, 83, 2442−2447

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The Journal of Organic Chemistry Scheme 1. Selected Examples of α-Amination and α-Azidation of Ketones

Scheme 2. Direct α-Amination of Ketones with Azolesa

a

The blue bond indicates the bond formed. All yields are isolated yields.

products in 63 and 62% yield. Our previous studies have shown that these enolonium species are compatible with a range of other functionalities and substituent patterns, including alkenes.11,12 Primary alkyl amines and secondary alkyl amines are not suitable nucleophiles for enolonium species under these conditions. It was found that the former generally did not afford product. This is presumably due to the ability of primary amines to displace the enol-oxygen from the I(III) atom in preference to attack on the α-carbon of the enolonium species. Secondary amines did form the desired amines in up to 65% yield, but the yields were capricious and the source of the variable yields could not be identified. As an alternative to

precipitation, and the tetrazole acetophenone coupling product 15 was produced in 78% yield. Methyl-tetrazole gave the coupling product 16 in 88% yield. We also tested ortho- and para-DMAP in the reaction. These led to formation of the fluoride salts 17 and 18 in 55 and 65% isolated yield, respectively. We then examined the scope of the coupling reaction with respect to enolonium species using tetrazole as the azole component. Both electron-poor (p-chloro) and electron donating (p-methoxy) substituents on the phenyl group were tolerated, giving products 19 and 20 in 74 and 72% yield, respectively. The reaction is not limited to methylketones as both tetralone and dihydro-indenone afforded the coupling 2443

DOI: 10.1021/acs.joc.7b03058 J. Org. Chem. 2018, 83, 2442−2447

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The Journal of Organic Chemistry Scheme 3. Direct Azidation of Ketonesa

a

The blue bond indicates the bond formed. All yields are isolated yields.

including alkenes and dialkyl ketones.11,12 These conditions are preferable to the classical two-step halogenation-SN2 displacement technique in terms of ease, reaction time, and mildness. These conditions were also extended to azidation, and the scope of this reaction with respect to ketone was outlined. We believe that these azole and azido introducing reactions may find wide use in medicinal chemistry research.

amination, we therefore pursued the synthesis of azido ketones. Azido ketones are easily reduced and acylated or alkylated. There are numerous methods for the azidation via nucleophilic displacement of α-halo or α-sulfonyloxy ketones with azide anion.13,14 Many of these methods involve in situ formation of the α-halo or α-sulfonyloxy ketone. However, there are relatively few methods for direct umpolung azidation of ketone enolates, and most of these are restricted to β-keto esters.15,16 In a seminal contribution, Moriarty17 reported the use of TMSazide for the umpolung azidation of β-keto-esters; however, this procedure was not amenable for simple ketones. Waser reported an elegant direct azidation of TMS-enolates of simple ketones using azido-benziodoxoles as electrophilic azide equivalents,8 but such azidation reagents must be prepared before use and are potentially explosive.18 We investigated the α-azidation of ketone derived enolonium species with commercially available TMS-azide as the source of nucleophilic azide (Scheme 3). It was found that TMS-azide reacts readily with enolonium species 4 to afford the corresponding azido-ketones in 69−88% yield (Scheme 3). A variety of ketones was tested. Acetophenone enolate afforded the corresponding azide 23 in 88% yield. Propiophenone adduct 24 was formed in 73% yield. Cyclic ketones 2,3-dihydro-1H-inden-1-one and cyclohexanone were azidated via their enolonium species to afford 31 and 32 in 74 and 77% yield, respectively. The latter is an example of a dialkyl ketone. Further, the electron-rich methoxy substituted azido ketone 25 was prepared in 78% yield with no observable overoxidation. Electron poor nitro compound 26 was likewise prepared in 69% yield. The series of α-azido halogenated (F, Cl, Br, and I) acetophenones 27 to 30 were also formed successfully. Especially remarkable is para-iodo product 30 formed in 77% yield with no observable oxidation of the iodine atom. In conclusion, we report a convenient procedure for the coupling of azoles with ketones. The conditions are mild, and a variety of azoles participate efficiently in the reaction. Both electron-rich and electron-poor ketones may be used in the reaction. We previously showed that these conditions are compatible with an even wider array of functional groups,

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EXPERIMENTAL SECTION

General Methods. Air- and/or moisture-sensitive reactions were carried out in anhydrous solvents under Ar atmosphere in oven-dried glassware. All anhydrous solvents were distilled prior to use: CH2Cl2 and CH3CN from CaH2. All commercial reagents were used without purification. Column chromatography was carried out by using silica gel (100−200 mesh). NMR spectra were recorded on Bruker Avance III 400 spectrometers operating at 400 MHz (1H) and 101 MHz (13C). 1H and 13C NMR chemical shifts are reported in ppm relative to chloroform-D (δ = 7.26 for 1H and 77.16 for 13C) or TMS (0.0 ppm) and coupling constants (J) are reported in Hertz (Hz). The following abbreviations have been used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra were recorded as films on a Bruker FT-IR. TOF-ESI-HSMS (m/z): was recorded on a Waters Micromass LCT premier instrument at 70 eV in the positive or negative mode. APCI-HRMS was recorded on a Bruker Maxis Impact QTOF instrument using the APCI solid probe. General Procedure for Preparation of α-Amination of Ketones with Various Azoles. At −78 °C, BF3·OEt2 (1.6 equiv) was added to a suspension of hydroxy(tosyloxy)iodobenzene (1.25 equiv) in anhydrous CH2Cl2 (8 mL) under positive argon pressure. The mixture was stirred at room temperature for 10 min, and the resulting yellow solution was cooled to −78 °C. To the reaction mixture was added dropwise trimethylsilyl enolate (1.0 equiv) in CH2Cl2 (4 mL). After 10 min. N-heterocycle (2.5 to 5.0 equiv) in CH2Cl2 (5 mL) was added. The reaction mixture was stirred for 15 min at −78 °C and then at −55 °C for 4−5 h. The reaction mixture was quenched by addition of H2O (5 mL) and then extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography (20 → 60% EtOAc in hexane) to afford the corresponding products. 1-Phenyl-2-(1H-pyrazol-1-yl)ethenone (9). Umpolung addition of 1H-pyrazole (4.95 equiv, 420 mg, 6.176 mmol) over trimethyl((12444

DOI: 10.1021/acs.joc.7b03058 J. Org. Chem. 2018, 83, 2442−2447

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The Journal of Organic Chemistry

128.3, 125.7, 114.7, 68.9, 54.8 (2C) ppm. HRMS (ESI+) m/z calculated for C15H17N2O+ 241.1341 [M-F]+; found 241.1359. 4-(Dimethylamino)-1-(2-oxo-2-phenylethyl)pyridin-1-ium fluoride (18). Umpolung addition of 4-dimethylaminopyridine (5 equiv, 760 mg, 6.23 mmol) on trimethyl((1-phenylvinyl)oxy)silane (0.24g, 1.247 mmol) following the general procedure (reaction time 20 h at −55 °C) gave 18 (211 mg, 65%) as a colorless solid; Rf 0.2 (1:99 v/v MeOH/CH2Cl2); mp 133−135 °C; FT-IR: Vmax 1652, 1577, 996, 761 cm−1; 1H NMR (400 MHz, CD3OD) δ 7.98−8.04 (m, 4H), 7.68 (tt, J = 7.5, 1.2 Hz, 1H), 7.54 (m, 2H), 6.98 (dt, J = 8.1, 3.1 Hz, 2H), 5.85 (m, 2H) 3.23 (s, 6H); 13C NMR (101 MHz, CD3OD) δ 194.1, 158.8, 145.2, 136.4, 136.0, 130.9, 130.1, 109.3, 64.4, 41.2 (2C) ppm; HRMS (ESI+) m/z calculated for C15H17N2O+ 241.1341 [M-F]+; found 241.1309. General procedure for the preparation of α-tetrazoleketones. At−78 °C, BF3·OEt2 (1.6 equiv) was added to a suspension of hydroxy(tosyloxy)iodobenzene (1.5 equiv) in anhydrous CH2Cl2 (5 mL) under positive argon pressure. The mixture was stirred at room temperature for 10 min and the resulting yellow solution was cooled to −78 °C. To the reaction mixture was added dropwise trimethylsilyl enolate (1.0 equiv) in CH2Cl2 (5 mL). After 10 min. 1H-tetrazol (3.95 to 5.0 equiv) in CH3CN (10 mL) was added dropwise. The reaction mixture was stirred for 15 min at −78 °C and then at −55 °C for overnight. The reaction mixture was stirred at rt for 2−3 h before it was quenched by addition of H2O (5 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (5 × 30 mL). The combined organic layers were dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography (20 → 70% EtOAc in hexane) to afford the corresponding tetrazol product. 1-Phenyl-2-(1H-tetrazol-1-yl)ethan-1-one (15). Umpolung addition of 1H-tetrazole (4.9equiv, 17 mL, 0.45 M, 7.65 mmol) over trimethyl((1-phenylvinyl)oxy)silane (300 mg, 1.56 mmol) following the general procedure gave 15 (229 mg, 78%) as a white solid; Rf 0.3 (1:1 v/v EtOAc/hexane); mp 122−124 °C; FT-IR: Vmax 3141, 2936, 2869, 2115, 1695, 1596, 1449, 1351, 1228, 1173 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.86 (s, 1H), 7.99 (dd, J = 8.5, 1.2 Hz, 2H), 7.70 (tt, J = 7.5, 2.9 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 5.98 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 189.0, 144.2, 135.2, 133.5, 129.5, 128.3, 53.5 ppm; HRMS (ESI+): m/z calcd for C9H9N4O 189.0776 [M + H]+; found 189.0745. 2-(5-Methyl-1H-tetrazol-1-yl)-1-phenylethan-1-one (16). Umpolung addition of 5-Methyl-1H-tetrazole (5 equiv, 655 mg, 7.80 mmol) over trimethyl((1-phenylvinyl)oxy)silane (300 mg, 1.56 mmol) following the general procedure gave 16 (277 mg, 88%) as a white solid; Rf 0.3 (1:1 v/v EtOAc/hexane); mp 111−113 °C; FT-IR: Vmax 3008, 2938, 2874, 1694, 1594, 1562, 1452, 1357, 1227, 1181 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.00 (dd, J = 8.3, 1.1 Hz, 2H), 7.71 (tt, J = 7.4, 1.1 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 5.81 (s, 2H), 2.50 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 188.8, 153.3, 135.1, 133.6, 129.5, 128.4, 52.7, 9.0 ppm; HRMS (ESI+): m/z calcd for C10H11N4O 203.0933 [M + H]+; found 203.0922. 1-(4-Methoxyphenyl)-2-(1H-tetrazol-1-yl)ethenone (19). Umpolung addition of 1H-tetrazole (5 equiv 13.6 mL, 0.45 M, 6.12 mmol) over ((1-(4-methoxyphenyl)vinyl)oxy)trimethylsilane (280 mg, 1.26 mmol) following the general procedure gave 19 (203 mg, 74%) as an yellow solid; Rf 0.15 (1:4 v/v EtOAc/hexane); mp 115−116 °C; FTIR: Vmax 3114, 2977, 2943, 2845, 1722, 1698, 1598, 1349, 1264, 972, 720, 590, 567 cm−1; 1H NMR: (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.04−7.91 (m, 2H), 7.03 (d, J = 9.0 Hz, 2H), 5.90 (s, 2H), 3.92 (s, 3H); 13C NMR: (101 MHz, CDCl3) δ 187.0, 165.1, 144.1, 130.7, 126.4, 114.7, 55.8, 53.0 ppm; HRMS (ESI+): m/z calcd for C10H11N4O2 219.0882 [M + H]+; found 219.0871. 1-(4-Chlorophenyl)-2-(1H-tetrazol-1-yl)ethenone (20). Umpolung addition of 1H-tetrazole (5 equiv, 350 mg, 5.0 mmol) over ((1-(4chlorophenyl)vinyl)oxy)trimethylsilane (226 mg, 1.0 mmol) following the general procedure gave 20 (159 mg, 72%) as a colorless solid; Rf 0.4 (1:1 v/v EtOAc/hexane); mp 164−169 °C; FT-IR: Vmax 1691, 1518, 1245, 894 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 6.36 (s, 2H);

phenylvinyl)oxy)silane (0.24 g, 1.247 mmol) following the general procedure gave 9 (168 mg, 72%) as a colorless solid; Rf 0.2 (1:3 v/v EtOAc/hexane); mp 66−71 °C; FT-IR: Vmax 2962, 1699, 1220, 960, 750 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.96−7.98 (m, 2H), 7.58− 7.64 (m, 2H), 7.46−7.52 (m, 3H), 6.37 (t, J = 2.1 Hz, 1H), 5.61 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 192.5, 140.0, 134.4, 134.2, 131.0, 129.0, 128.2, 106.6, 57.7 ppm; HRMS (ESI+) m/z calculated for C11H11N2O 187.0871 [M + H]+; found 187.0871. 2-(4-Nitro-1H-pyrazol-1-yl)-1-phenylethanone (10). Umpolung addition of 4-nitro pyrazole (5 equiv, 776 mg, 6.24 mmol) over trimethyl((1-phenylvinyl)oxy)silane (0.24 g, 1.247 mmol) following the general procedure gave 10 (188 mg, 65%) as a white solid; Rf 0.2 (2:3 v/v EtOAc/hexane); mp 109−111 °C; FT-IR: Vmax 3412, 2916, 1729, 1691, 1517, 1345, 735 cm−1; 1H NMR: (400 MHz, DMSO-d6) δ 8.85 (d, J = 0.6 Hz, 1H), 8.33 (d, J = 0.6 Hz, 1H), 8.05 (dd, J = 8.3, 1.2 Hz, 2H), 7.73 (d, J = 7.4 Hz, 1H), 7.62 (dd, J = 10.9, 4.5 Hz, 2H), 5.99 (s, 2H); 13C NMR: (101 MHz, DMSO-d6) δ 192.1, 135.6, 134.3, 133.7, 132.1, 129.0, 128.1, 79.1, 58.9 ppm; HRMS (APCI+): m/z calcd for C11H10N3O3 232.0717 [M + H]+; found 232.0746. 2-(1H-Indazol-1-yl)-1-phenylethanone (11). Umpolung addition of 1H-indazole (5 equiv, 739 mg, 6.25 mmol) over trimethyl((1phenylvinyl)oxy)silane (0.24 g, 1.247 mmol) following the general procedure gave compound 11 (195 mg, 66%) as a thick liquid; Rf 0.2 (2:3 v/v EtOAc/hexane); FT-IR: Vmax 3123, 2981, 2937, 2871, 1690, 1586, 1509, 1405, 1302, 1221, 991, 817, 755, 642, 468 cm−1; 1H NMR: (400 MHz, CDCl3) δ 8.00−7.97 (m, 3H), 7.75−7.57 (m, 3H), 7.48 (t, J = 7.7 Hz, 2H), 7.31−7.24 (m, 1H), 7.13−7.02 (m, 1H), 5.85 (s, 2H); 13C NMR: (101 MHz, CDCl3) δ 191.6, 149.2, 134.5, 134.4, 129.1, 128.3, 126.5, 124.9, 122.5, 122.1, 120.5, 117.6, 59.1 ppm; HRMS (APCI+): m/z calcd for C15H13N2O 237.1028 [M + H]+; found 237.1056. 2-(1H-Imidazol-1-yl)-1-phenylethanone19 (12). Umpolung addition of 1H-imidazole (4.95 equiv, 5 equiv, 420 mg, 6.176 mmol) on trimethyl((1-phenylvinyl)oxy)silane (0.24 g, 1.247 mmol) following the general procedure gave compound 12 (146 mg, 63%) as a colorless solid; Rf 0.3 (1:99 v/v EtOH/hexane); mp 72−76 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (dt, J = 8.0, 1.2 Hz, 2H), 7.64 (tt, J = 7.3, 1.2 Hz, 1H), 7.51 (t, 7.7 Hz, 3H,), 7.10 (s, 1H), 6.92 (s, 1H), 5.38 (s, 2H); 13 C NMR (101 MHz, CDCl3) δ 191.7, 138.2, 134.4, 134.2, 129.4, 129.2, 128.0, 120.5, 52.6 ppm. 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone11 (13). Umpolung addition of 1H-1,2,3-triazole (2.5 equiv, 180 mg, 2.60 mmol) over trimethyl((1-phenylvinyl)oxy)silane (200 mg, 1.04 mmol) following the general procedure gave 13 (113 mg, 58%) as a white solid; Rf 0.6 (1:5 v/v EtOAc/hexane); mp 82−84 °C; 1H NMR (400 MHz, CDCl3): δ 8.00 (dd, J = 8.3, 1.2 Hz, 2H), 7.80 (d, J = 0.5 Hz, 1H), 7.74 (d, J = 0.5 Hz, 1H), 7.67 (tt, J = 14.9, 7.4 Hz, 1H), 7.54 (t, J = 7.9 Hz, 2H), 5.89 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 190.4, 134.8, 134.3, 134.1, 129.3, 128.3, 125.5, 55.4 ppm. 2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-phenylethanone (14). Umpolung addition of 1H-benzotriazole (3 equiv, 560 mg, 4.70 mmol) over trimethyl((1-phenylvinyl)oxy)silane (300 g, 1.56 mmol) following the general procedure gave 14 (165 mg, 45%) as a pale yellow solid; Rf 0.6 (1:1 v/v EtOAc/hexane); mp 114−115 °C; FT-IR: Vmax 1681.46, 1265.17, 745.38 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05−8.10 (m, 3H), 7.65−7.69 (m, 1H), 7.53−7.57 (m, 2H), 7.46−7.50 (m, 1H), 7.36−7.42 (m, 2H), 6.10 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 190.4, 146.1, 134.6, 134.1, 133.8, 129.2, 128.3, 127.8, 124.0, 120.2, 109.5, 53.9 ppm; HRMS (APCI+) m/z calculated for C14H12N3O 238.0980 [M + H]+ found 238.1007. 2-(Dimethylamino)-1-(2-oxo-2-phenylethyl)pyridin-1-ium fluoride (17). Umpolung addition of 2-dimethylaminopyridine (5 equiv, 760 mg, 6.23 mmol) over trimethyl((1-phenylvinyl)oxy)silane (0.24 g, 1.247 mmol) following the general procedure (reaction time 20 h at −55 °C) gave 17 (179 mg, 55%) as a colorless solid; Rf 0.3 (1:99 v/v MeOH/CH2Cl2); mp 120−125 °C; FT-IR: Vmax 687, 1597, 1025, 747 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.37 (ddd, J = 4.7, 1.8, 0.7 Hz, 1H), 8.05 (qd, J = 7.0, 1.8 Hz, 1H), 7.93 (m, 3H), 7.59 (tt, J = 7.4, 1.2 Hz, 1H), 7.42−7.47 (m, 3H), 5.83 (s, 2H), 3.80 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 190.0, 156.5, 148.6, 141.3, 135.1, 133.5, 129.2, 2445

DOI: 10.1021/acs.joc.7b03058 J. Org. Chem. 2018, 83, 2442−2447

Note

The Journal of Organic Chemistry C NMR (101 MHz, DMSO-d6) δ 190.4, 145.2, 139.4, 132.5, 130.2, 129.2, 53.9 ppm; HRMS (ESI+) m/z calculated for C9H8ClN4O 223.0387; [M + H]+ found 223.0372. 2-(1H-Tetrazol-1-yl)-3,4-dihydronaphthalen-1(2H)-one (21). Umpolung addition of 1H-tetrazole (3.95 equiv, 380 mg, 5.42 mmol,) on (3,4-dihydronaphthalen-1-yloxy)trimethylsilane (300 mg, 1.37 mmol) following the general procedure gave 21 (185 mg, 63%) as an yellow solid; Rf 0.2 (1:9 v/v MeOH/CH2Cl2); mp 108−113 °C; FT-IR: Vmax 3119, 1697, 1596, 1273, 814 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.08 (dd, J = 7.9, 1.2 Hz, 1H), 7.62 (td, J = 7.5, 1.4 Hz, 1H), 7.36−7.43 (m, 2H), 5.54 (dd, J = 12.6, 5.8 Hz, 1H), 3.24−3.43 (m, 2H), 2.80−2.89 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 189.7, 143.1, 143.1, 135.1, 130.6, 129.1, 128.4, 127.6, 63.9, 30.1, 28.3 ppm; HRMS (ESI+) m/z calculated for C11H10N4O 214.0855; [M]+ found 214.0843. 2-(1H-Tetrazol-1-yl)-2,3-dihydro-1H-inden-1-one (22). Umpolung addition of 1H-tetrazole (5 equiv, 350 mg, 5.0 mmol) over ((1Hinden-3-yl)oxy)trimethylsilane (204 mg, 1.0 mmol) following the general procedure gave 22 (124 mg, 62%) as a colorless solid; Rf 0.4 (1:1 v/v EtOAc/hexane); mp 147−152 °C; FT-IR: Vmax 1721, 1597, 1097, 757 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 5.45 (dd, J = 8.4, 5.5 Hz, 1H), 4.01 (dd, 1 H, J = 17.2, 8.5 Hz, 1H), 3.87 (dd, J = 17.2, 5.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 196.6, 150.8, 142.8, 137.2, 133.5, 129.1, 126.9, 125.5, 61.7, 33.2 ppm; HRMS (ESI+) m/z calculated for C10H9N4O 201.0776; [M + H]+ found 201.0775. General Procedure for Preparation of α-Keto Azides. Caution. Azides are energetic compounds and often unstable. Care to avoid static electricity, shock, and heat is advised when preparing such compounds. At−78 °C, BF3·OEt2 (1.6 equiv) was added to a suspension of hydroxy(tosyloxy)iodobenzene (1.5 equiv) in anhydrous CH2Cl2 (5 mL) under positive argon pressure. The mixture was stirred at room temperature for 10 min, and the resulting yellow solution was cooled to −78 °C. To the reaction mixture was added dropwise trimethylsilyl enolate (1.0 equiv) in CH2Cl2 (5 mL). After 10 min, azidotrimethylsilane (2.5−3.66 equiv) was added dropwise. The reaction mixture was stirred for 15 min at −78 °C and then at −55 °C for 2−3 h. The reaction mixture was quenched by addition of H2O (5 mL) and then extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column chromatography to afford the corresponding phenacyl azide product. 2-Azido-1-phenylethan-1-one20 (23). Umpolung addition of azidotrimethylsilane (0.35 mL, 2.60 mmol) over trimethyl((1phenylvinyl)oxy)silane (200 mg, 1.04 mmol) following the general procedure gave 23 (148 mg, 88%) as a white solid: Rf 0.6 (1:5 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3): δ 7.91 (dt, J = 8.4, 1.6 Hz, 2H), 7.70−7.59 (m, 1H), 7.54−7.44 (m, 2H), 4.56 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 193.3, 134.5, 134.3, 129.1, 128.1, 55.0 ppm. 2-Azido-1-phenylpropan-1-one8 (24). Umpolung addition of azidotrimethylsilane (0.41 mL, 3.12 mmol) on trimethyl((1-phenylprop-1-en-1-yl)oxy)silane (255 mg, 1.238 mmol) following the general procedure gave 24 (158 mg, 73%) as a colorless liquid; Rf 0.4 (1:19 v/ v EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 7.94 (dt, J = 7.2, 1.6 Hz, 2H), 7.61 (tt, J = 7.4, 1.2 Hz, 1H), 7.49 (tt, J = 7.4, 1.6 Hz, 2H), 4.71 (q, J = 7.0 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 196.8, 134.4, 134.0, 129.0, 128.7, 58.5, 16.5 ppm. 2-Azido-1-(4-methoxyphenyl)ethenone20 (25). Umpolung addition of azidotrimethylsilane (0.35 mL, 2.60 mmol) over ((1-(4methoxyphenyl)vinyl)oxy)trimethylsilane (231 mg, 1.04 mmol) following the general procedure gave 25 (155 mg, 78%) as a white solid; Rf 0.6 (1:5 v/v EtOAc/hexane); 1H NMR: (400 MHz, CDCl3) δ 7.92−7.83 (m, 2H), 7.01−6.91 (m, 2H), 4.50 (s, 2H), 3.88 (s, 3H); 13 C NMR: (101 MHz, CDCl3) δ 191.8, 164.4, 130.4, 127.5, 114.3, 55.7, 54.7 ppm.

2-Azido-1-(4-nitrophenyl)ethenone21 (26). Umpolung addition of azidotrimethylsilane (0.35 mL, 2.60 mmol) over trimethyl((1-(4nitrophenyl)vinyl)oxy)silane (247 mg, 1.04 mmol) following the general procedure gave 26 (147 mg, 69%) as a yellow solid; Rf 0.6 (1:5 v/v EtOAc/hexane); 1H NMR: (400 MHz, CDCl3) δ 8.43−8.28 (m, 2H), 8.11−8.02 (m, 2H), 4.61 (s, 2H); 13C NMR: (101 MHz, CDCl3) δ 192.2, 151.0, 138.9, 129.3, 124.3, 55.4 ppm. 2-Azido-1-(4-fluorophenyl)ethan-1-one22 (27). Umpolung addition of azidotrimethylsilane (0.35 mL, 2.60 mmol) over ((1-(4fluorophenyl)vinyl)oxy)trimethylsilane (150 mg, 0.71 mmol) following the general procedure gave 27 (98 mg, 77%) as a white solid: Rf 0.5 (1:20 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3): δ 8.01− 7.88 (m, 2H), 7.23−7.12 (m, 2H), 4.53 (s, 2H).; 13C NMR (101 MHz, CDCl3) δ 192.9, 167.5 (d, J = 256.7 Hz), 132.1 (d, J = 3.1 Hz), 131.95 (d, J = 9.5 Hz), 129.7 (d, J = 106.6 Hz), 117.5 (d, J = 22.1 Hz), 56.0 ppm. 2-Azido-1-(4-chlorophenyl)ethenone20 (28). Umpolung addition of azidotrimethylsilane (0.41 mL, 3.12 mmol) over ((1-(4chlorophenyl)vinyl)oxy)trimethylsilane (282 mg, 1.25 mmol) following the general procedure gave 28 (196 mg, 80%) as a white solid; Rf 0.4 (1:9 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 7.83 (dt, J = 8.7, 2.2 Hz, 2H), 7.45 (dt, J = 8.7, 2.2 Hz, 2H), 4.52 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 192.2, 140.8, 132.8, 129.44, 129.43, 54.9 ppm. 2-Azido-1-(4-bromophenyl)ethan-1-one23 (29). Umpolung addition of azidotrimethylsilane (0.35 mL, 2.60 mmol) over ((1-(4bromoophenyl)vinyl)oxy)trimethylsilane (270 mg, 1 mmol) following the general procedure gave 29 (172 mg, 72%) as a white solid: Rf 0.5 (1:20 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3): δ 7.83−7.71 (m, 2H), 7.69−7.58 (m, 2H), 4.53 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 192.5, 133.2, 132.4, 129.52, 129.47, 54.9 ppm. 2-Azido-1-(4-iodophenyl)ethenone (30). Umpolung addition of azidotrimethylsilane (0.17 mL, 1.30 mmol) over ((1-(4-iodophenyl)vinyl)oxy)trimethylsilane (166 mg, 0.52 mmol) following the general procedure gave 30 (115 mg 77%) as a white solid; Rf 0.5 (1:20 v/v EtOAc/hexane); FT-IR: Vmax 3083, 3031, 2891, 2091, 1686, 1578, 1277, 1217 cm−1; 1H NMR: (400 MHz, CDCl3) δ 7.91−7.83 (m, 2H), 7.67−7.56 (m, 2H), 4.51 (s, 2H); 13C NMR: (101 MHz, CDCl3) δ 192.7, 138.4, 133.7, 129.3, 102.4, 54.8 ppm; HRMS: The compound decomposed under all conditions tested. This compound is commercially available. 2-Azido-2,3-dihydro-1H-inden-1-one8 (31). Umpolung addition of azidotrimethylsilane (0.41 mL, 3.12 mmol) over ((1H-inden-3yl)oxy)trimethylsilane (255 mg, 1.25 mmol) following the general procedure gave 31 (161 mg, 74%) as a yellow liquid; Rf 0.4 (1:9 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.7 Hz, 1H), 7.64 (td, J = 7.9, 1.0 Hz, 1H), 7.39−7.45 (m, 2H), 4.31 (dd, J = 8.1, 4.6 Hz, 1H), 3.50 (dd, J = 17.1, 8.2 Hz, 1H), 2.92 (dd, J = 17.1, 4.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 201.8, 151.3, 136.2, 134.3, 128.3, 126.7, 124.7, 62.1, 33.1 ppm. 2-Azidocyclohexanone14 (32). Umpolung addition of azidotrimethylsilane (0.45 mL, 3.38 mmol) over (cyclohex-1-en-1-yloxy)trimethylsilane (230 mg, 1.35 mmol) following the general procedure gave 32 (145 mg, 77%) as a pale orange liquid; Rf 0.3 (1:10 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 3.93 (dd, J = 11.0, 6.0 Hz, 1H), 2.51−2.57 (m, 1H), 2.26−2.37 (m, 2H), 2.02−2.09 (m, 1H), 1.93−2.09 (m, 1H), 1.66−1.73 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 205.7, 66.6, 40.9, 33.7, 27.2, 23.9 ppm.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.joc.7b03058. Reproductions of 1H and compounds (PDF) 2446

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C NMR spectra for all DOI: 10.1021/acs.joc.7b03058 J. Org. Chem. 2018, 83, 2442−2447

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The Journal of Organic Chemistry

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(10) Fernández González, D.; Brand, J. P.; Mondière, R.; Waser, J. Adv. Synth. Catal. 2013, 355, 1631−1639. (11) Arava, S.; Kumar, J. N.; Maksymenko, S.; Iron, M. A.; Parida, K. N.; Fristrup, P.; Szpilman, A. M. Angew. Chem., Int. Ed. 2017, 56, 2599−2603. (12) Maksymenko, S.; Parida, K. N.; Pathe, G. K.; More, A. A.; Lipisa, Y. B.; Szpilman, A. M. Org. Lett. 2017, 19, 6312−6315. (13) (a) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297−368 For an example, see:. (b) Kumar, D.; Sundaree, S.; Rao, V. S. Synth. Commun. 2006, 36, 1893−1896. (14) Patonay, T.; Hoffman, R. V. J. Org. Chem. 1994, 59, 2902−2905. (15) (a) Deng, Q.-H.; Bleith, T.; Wadepohl, H.; Gade, L. H. J. Am. Chem. Soc. 2013, 135, 5356−5359. (b) Galligan, M. J.; Akula, R.; Ibrahim, H. Org. Lett. 2014, 16, 600−603. (16) Harschneck, T.; Hummel, S.; Kirsch, S. F.; Klahn, P. Chem. Eur. J. 2012, 18, 1187−1193 S1187/1-S1187/106.. (17) Moriarty, R. M.; Vaid, R. K.; Ravikumar, V. T.; Vaid, B. K.; Hopkins, T. E. Tetrahedron 1988, 44, 1603−7. (18) The Waser group reported the accidental explosion of Zhdankin’s reagent, while reporting that 1-azido-3,3-dimethyl-1,3dihydro-1λ3-benzo[d][1,2]iodaoxole should be more stable. (19) Florentino, L.; Aznar, F.; Valdés, C. Chem. - Eur. J. 2013, 19, 10506−10510. (20) Schrittwieser, J. H.; Coccia, F.; Kara, S.; Grischek, B.; Kroutil, W.; d’Alessandro, N.; Hollmann, F. Green Chem. 2013, 15, 3318− 3331. (21) Gaikwad, S.; Goswami, A.; De, S.; Schmittel, M. Angew. Chem., Int. Ed. 2016, 55, 10512−10517. (22) Patonay, T.; Juhász-Tóth, É.; Bényei, A. Eur. J. Org. Chem. 2002, 2002, 285−295. (23) Muthyala, M. K.; Choudhary, S.; Kumar, A. RSC Adv. 2014, 4, 14297−14303.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alex M. Szpilman: 0000-0001-7790-4129 Author Contributions †

A.A.M. and G.K.P. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by Ariel University. Support by the Israel Science Foundation (Grant 1914/15) is gratefully acknowledged.

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DOI: 10.1021/acs.joc.7b03058 J. Org. Chem. 2018, 83, 2442−2447