Aminimide Synthesis Using Concerted Amination Reactions of

Note Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

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Aminimide Synthesis Using Concerted Amination Reactions of Alkenes: Scope and Mechanistic Information Ryan A. Ivanovich,† Jasper A. M. Quartus,† Nicolas Das Neves, Francis Loiseau, Michaël Raymond, and Andre ́ M. Beauchemin* Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, Ontario K1N 6N5, Canada

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S Supporting Information *

ABSTRACT: Aminimides are key intermediates in the thermal cycloadditions of suitable alkenyl-hydrazine derivatives. Substrate modifications (β-N,N-dialkyl) allowed the isolation of these reactive intermediates, and the analysis of their stereochemistry provided support for concerted (Copetype) hydroamination and concerted [3 + 2] aminocarbonylation reaction pathways. This work also establishes the applicability of these approaches to form complex aminimides in moderate to excellent yields.

N

and intramolecular cyclizations of tertiary hydrazines.11 Recently, an elegant report involving a Ag(I)-catalyzed chemoselective N-amidation of tertiary amines via nitrene transfer was published.12 To our knowledge, examples of hydroamination or aminocarbonylation of alkenes leading to aminimides have not been reported. Initial studies on the mechanism of these reactions were focused on the hydroamination of alkenes with hydrazides. Electron-withdrawing bis(trifluoromethyl)aryl hydrazides proved capable in both intra- and intermolecular systems due to their ability to inductively stabilize charges formed during the process as well as their increased H-bonding ability (if R1 = H).5c We rationalized that this could translate into the ability to stabilize the dipolar aminimide intermediate and allow its isolation. With the reaction proceeding through a planar, suprafacial, and concerted five-membered transition state, a single diastereomer would be expected to form (Figure 1B). The N−N bond of the aminimide and the methyl group would therefore be aligned in a syn orientation.13 To probe this reactivity, an Nβ-benzyl hydrazide (1a) was synthesized and subjected to the reaction conditions. Considering the precarious stability of the cyclic aminimide (the possibility of rapid cycloreversion or 1,2-rearrangement), we were delighted to observe a modest yield of the dipole (2a). Unfortunately, 2a proved to be challenging to separate from the product that had undergone 1,2-rearrangement. Nevertheless, nuclear magnetic resonance (NMR) analysis revealed that it was present solely as the cis diastereomer (see the Supporting Information). To clarify the stereochemical outcome of the reaction as well as identify the optimal precursor for the aminimide formation, the scope was explored with a small selection of Nβ-alkylated

ew methods for the metal-free syntheses of complex nitrogen-containing molecules are needed to contribute to the synthetic chemists’ amination toolbox.1 Hydroamination and aminocarbonylation of alkenes are particularly attractive due to the ability to convert feedstock chemicals to useful aminated2/carboxyaminated products.3 The bulk of the work in this field using hydrazine derivatives4 has focused on the synthesis of relatively simple amination products (e.g., hydrazides and hydrazones); the synthesis of more complex derivatives is scarcely observed. Toward this end, we developed the thermal hydroamination of alkenes with hydrazide derivatives and discovered the propensity of related carbazate precursors to undergo a divergent aminocarbonylation reaction.5 In each case, concerted cyclizations (Cope-type for hydroamination5,6/[3 + 2] for aminocarbonylation7) were proposed and supported by density functional theory (DFT) calculations. Despite these supporting data, corroborating experimental evidence was essential, both for the sake of fully understanding the mechanism and to guide potential future work on this system. Given the concerted nature of the cyclization proposed for each reaction, an aminimide was suggested as the reaction intermediate (Figure 1 A). It was hypothesized that further development could provide a new synthesis of aminimides and that the analysis of the relative stereochemistry of the dipoles could provide the desired experimental support of the concerted cyclizations. Herein we report our efforts toward these goals. Aminimides are rare dipolar compounds with the general molecular formula R3N(+)−N(−)R.8 Their zwitterionic nature9 induces distinctive physiochemical properties, leading to a host of applications ranging from polymer adhesive additives and surfactants to potential therapeutics.10 Traditional syntheses of aminimides rely on nitrenoid/nitrene transfer reactions, the quaternization of hydrazide derivatives, © XXXX American Chemical Society

Received: May 10, 2019 Published: July 10, 2019 A

DOI: 10.1021/acs.joc.9b01259 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

optimal hydroamination temperatures. Gratifyingly, Nβ-methyl proved to be the ideal alkyl group, effecting efficient hydroamination but proving reluctant to undergo a 1,2rearrangement under the reaction conditions, which allowed the formation of 2c in near-quantitative yield. The observation of a single cis diastereomer remained consistent for aminimides 2b and 2c, as determined by nuclear Overhauser effect spectroscopy (NOESY) (see the Supporting Information). To unambiguously assign these aminimides as intermediates in the overall hydroamination reaction, the isolated aminimides could be quantitatively converted to the alkyl rearranged hydroamination products upon microwave heating (eq 1). In

summary, the isolation of cyclic aminimides proves their involvement as intermediates in alkene hydroamination reactions of hydrazides, and their relative stereochemistry provides strong evidence that these are concerted processes analogous to Cope-type hydroamination with hydroxylamines.13 However, preparatively, the applicability appears limited to small alkyl groups due to destabilizing interactions that drive cycloreversion or the propensity of rearrangement. Having established the concerted nature of hydrazide hydroamination reactions, we sought to investigate the cyclization of related carbazate derivatives. In the original report on the divergent reactivity of hydrazine derivatives,5 carbazate precursors preferentially formed aminocarbonylation products (Figure 1C). This unusual cyclization was believed to occur through a concerted [3 + 2] cycloaddition involving an amino-isocyanate as the reactive intermediate. To provide experimental support for a concerted cycloaddition pathway, the isolation of the suggested aminimide and the determination of its relative stereochemistry were attempted. This came with its challenges due to the fact that (1) aminocarbonylation typically requires highly elevated temperatures, (2) the reactive N-isocyanate can only be formed in situ via thermal deblocking,5 and (3) although N,N-dialkyl isocyanates react at lower temperatures, a 1,2-rearrangement can occur readily under the reaction conditions.14,7b We reasoned that a hydrogen-bonding reaction medium could lead to the stabilization of the transient aminimide at elevated temperatures. After screening, a 1:1 mix of MeCN and i-PrOH resulted in excellent yields of aminimides and allowed the investigation of the substrate scope. We were delighted to observe that a variety of alkyl groups were tolerated (Table 2), leading to aminimides with benzyl, methyl, and alkenyl groups (4a−c), respectively. Interestingly, gem-dimethyl-containing substrate 4d was formed in relatively low yield, with mostly unreacted starting material observed by NMR. Bearing in mind the possibility of rapid cycloreversion, the presence of a syn-pentane-type interaction in aminimide 4d would greatly destabilize the desired product. It is possible that thermodynamic equilibrium was reached. To minimize steric destabilization, an N-methyl substituted analogue was synthesized, which provided 4e in excellent yield. A vinyl arenederived substrate also offered facile access to tricyclic

Figure 1. Aminimides were proposed as intermediates in both Copetype hydroamination and aminocarbonylation via N-isocyanates. Herein, aminimides are synthesized, and the analysis confirms their intermediacy in the proposed concerted pathways.

products (Table 1). Similarly, Nβ-allyl precursor 1b reacted to provide aminimide 2b; however, a low yield was obtained due to a facile Meisenheimer rearrangement that occurred at Table 1. Synthesis of Cyclic Aminimides Using Cope-Type Hydroaminationa

Conditions: Sealed microwave vials, microwave irradiation at 80 °C, 12 h under argon. Isolated yields are shown. bNMR yield using 1,3,5trimethoxybenzene as internal standard. c110 °C. a

B


Note


molecular sieves. Microwave reactions were performed using a Biotage Initiator Eight microwave reactor and microwave vials. Reactions were monitored by analytical thin layer chromatography (TLC) using aluminum-backed plates cut to size. TLC visualization was achieved by UV light, followed by staining with a potassium permanganate solution and heating. Flash column chromatography was carried out using 40−63 μm silica gel. 1H NMR and 13C{1H} NMR spectra were recorded on 300 and 400 MHz spectrometers at ambient temperature, except where noted. Spectral data are reported in ppm using solvent as the reference. 1H NMR: CDCl3 (7.26 ppm), DMSO-d6 (2.50 ppm). 13C{1H} NMR: CDCl3 (77.16 ppm), DMSOd6 (39.52 ppm). 1H NMR data are reported as multiplicity (br. s = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, sept = septet, m = multiplet), coupling constants (J) in Hz, and integration. 13C NMR is reported indicating information from distortionless enhancement by polarization Transfer (DEPT) experiments. Infrared (IR) spectra were obtained as thin films or as neat solids on Fourier transform infrared (FTIR) instruments. Highresolution mass spectroscopy (HRMS) was performed by magnetic sector electron impact (EI) or Q-TOF electrospray ionization (ESI). As a note, the aminimides formed herein are highly unstable to heating and are prone to decomposition during MS analysis and hightemperature NMR experiments. N,N-Dialkyl hydrazide precursors typically need to be heated to achieve acceptable NMR spectra. In this scenario, heating sometimes leads to reactivity or decomposition. General Procedure A: Synthesis of N-Alkyl Carbazates/ Hydrazides and Symmetrical N,N-Dialkyl Carbazates (3c, 3h, 6a−c). An alkenyl halide (1.0 equiv) was added to a screw-cap pressure vessel with a magnetic stir bar and diluted to 0.3 M using DMF. Following this, the carbazate/hydrazide (5.0−8.0 equiv) was added. The vial was sealed with a screw cap, and the mixture was heated to 100 °C in an oil bath for 5 h. The reaction solution was cooled to ambient temperature, and the DMF was removed from the mixture by the addition of ethyl acetate and seven organic phase washes with a 50% brine/H2O solution. The resulting organic phase was washed with aqueous saturated NaCl solution, dried with Na2SO4, and concentrated under reduced pressure. The mixture was analyzed by 1H NMR, and the product was isolated using silica gel column chromatography. The reaction was found to give not only the intended monoalkylated carbazate derivatives (at the β-nitrogen) but also low yields of symmetrically dialkenylated carbazates (at the βnitrogen). Both derivatives were applied in further synthesis. N′-(Pent-4-en-1-yl)-3,5-bis(trifluoromethyl)benzohydrazide (6a). The title compound was synthesized according to general procedure A using 5-bromopentene (1.18 mL, 10.0 mmol) and 3,5-bis(trifluoromethyl)benzohydrazide (13.6 g, 50.0 mmol) in DMF (60.0 mL). The product was isolated by column chromatography (gradient column with 10% EtOAc/hexanes to 20% EtOAc/hexanes after the elution of the dialkyl carbazate with Rf = 0.75 in 20% EtOAc/ hexanes, allowing the elution of monoalkyl carbazate). The product was obtained as a white solid (m = 1.42 g, 42% yield). TLC Rf = 0.41 in 20% EtOAc/hexanes; 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 2H), 8.06−7.99 (m, 1H), 5.81 (tdd, J = 16.9, 10.2, 6.7 Hz, 1H), 5.11−4.94 (m, 2H), 3.00 (t, J = 7.3 Hz, 2H), 2.22−2.09 (m, 2H), 1.75−1.57 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.5 (C), 137.8 (CH), 134.8 (C), 132.4 (q, J = 34.0 Hz, C), 127.3 (CH), 125.4 (CH), 122.8 (q, J = 273.0 Hz, C), 115.2 (CH2), 51.7 (CH2), 31.1 (CH2), 27.1 (CH2). 1H and 13C NMR are in accordance with those reported in the literature.6b tert-Butyl 2-(Pent-4-en-1-yl)hydrazinecarboxylate (6b). The title compound was synthesized according to general procedure A using 5iodopentene (1.70 g, 8.64 mmol) and tert-butyl carbazate (8.27 g, 62.6 mmol) in DMF (29.0 mL). The product was isolated by column chromatography (gradient column with 10% EtOAc/hexanes to 20% EtOAc/hexanes after the elution of the dialkyl carbazate with Rf = 0.61 in 20% EtOAc/hexanes, allowing the elution of monoalkyl carbazate). The product was obtained as a clear oil (m = 1.30 g, 75% yield). TLC R f = 0.28 in 20% EtOAc/hexanes; 1H NMR (300 MHz, CDCl3) δ 6.22 (s, 1H), 5.79 (tdd, J = 16.9, 10.2, 6.7 Hz, 1H), 5.01 (ddd, J = 17.1, 3.5, 1.6 Hz, 1H), 4.94 (tdd, J = 10.2, 2.1, 1.2 Hz, 1H),

Table 2. Synthesis of Cyclic Aminimides Using Concerted Alkene Aminocarbonylationa

a

Conditions: Sealed microwave vials, microwave irradiation at 150 °C, 3 h, (1:1 MeCN/i-PrOH) under argon. Isolated yields are shown. b Wax bath, 50 h. cWax bath, 15 h. d180 °C.

aminimide 4f in good yield. Attempts to form Nβ-benzyl sixmembered aminocarbonylation products were met with failure, and thus an Nβ-methyl substituent was selected, given its proficiency in the related Cope-type hydroaminations described above. This resulted in 4g, and meaningful stereochemical insight could be ascertained by the NOESY analysis of the 6,5-ring system. NOE signals for aminimide 4g reveal a single diastereomer present in the cis configuration (see the Supporting Information), as would be expected from a concerted [3 + 2] cycloaddition. Once again, a direct link between the aminimide and aminocarbonylation products was established by exposing aminimide 4a to higher temperatures without the presence of a polar cosolvent, inducing a quantitative 1,2-shift (eq 2).

Overall, the isolation and characterization of aminimides corroborate with early DFT calculations,5 implicating the involvement of concerted cyclizations at the heart of both hydroamination and aminocarbonylation reactions of hydrazide derivatives. In addition, this provides a protocol for stereocontrolled synthesis of cyclic/bicyclic aminimides. For the case of aminocarbonylation, the aminimide motif is fully integrated within the cyclic architecture and represents a new entry to bicyclic aminimides that would otherwise be challenging to form by traditional methods.

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EXPERIMENTAL SECTION

General Information. All commercially available materials were used without further purification unless otherwise noted. Solvents for reactions were obtained from the solvent system or dried over 4 Å C


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The Journal of Organic Chemistry 3.93 (s, 1H), 2.83 (t, J = 7.2 Hz, 1H), 2.09 (q, J = 6.9 Hz, 1H), 1.55− 1.52 (m, 1H), 1.44 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 156.8 (C), 138.3 (CH), 114.8 (CH2), 80.4 (C), 51.5 (CH2), 31.2 (CH2), 28.4 (CH3), 27.0 (CH2). 1H and 13C NMR are in accordance with those reported in the literature.15 tert-Butyl 2-(Hex-5-en-1-yl)hydrazinecarboxylate (6c). The title compound was synthesized according to general procedure A using 6iodohexene (2.10 g, 10.0 mmol) and tert-butyl carbazate (9.52 g, 72.0 mmol) in DMF (33 mL). The product was isolated by column chromatography (gradient column with 20% EtOAc/hexanes to 30% EtOAc/hexanes after the elution of the dialkyl carbazate with Rf = 0.68 in 20% EtOAc/hexanes, allowing the elution of monoalkyl carbazate). The product was obtained as a clear oil (m = 1.46 g, 68% yield). TLC R f = 0.35 in 20% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) δ 6.17 (s, 1H), 5.78 (tdd, J = 16.9, 10.2, 6.7 Hz, 1H), 4.96 (ddd, J = 13.7, 10.9, 1.2 Hz, 2H), 3.64 (s, 1H), 2.82 (t, J = 6.6 Hz, 2H), 2.05 (q, J = 6.9 Hz, 2H), 1.47−1.36 (m, 13H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.7 (C), 138.6 (CH), 114.5 (CH2), 80.4 (C), 51.9 (CH2), 33.6 (CH2), 28.3 (CH3), 27.7 (CH2), 26.3 (CH2). 1H and 13C NMR are in accordance with those reported in the literature.15 tert-Butyl 2,2-Di(pent-4-en-1-yl)hydrazinecarboxylate (3c). The title compound was synthesized according to general procedure A using 5-iodopentene (1.70 g, 8.64 mmol) and tert-butyl carbazate (8.27 g, 62.6 mmol) in DMF (29.0 mL). The product was isolated by column chromatography (gradient column with 20% EtOAc/hexanes to 30% EtOAc/hexanes after the elution of the dialkyl carbazate with Rf = 0.61 in 20% EtOAc/hexanes, allowing the elution of monoalkyl carbazate with Rf = 0.28 in 20% EtOAc/hexanes). The product was obtained as a translucent yellow oil (m = 0.093 g, 4% yield). Note: This compound was obtained as a minor side product while forming the corresponding monoalkyl carbazate. Because this dialkyl carbazate was a suitable precursor for aminimide formation, it was submitted to the reaction conditions. TLC Rf = 0.61 in 20% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) δ 5.79 (tdd, J = 6.6, 10.3, 17.0 Hz, 2H), 5.23−4.7 (br. s, 1H), 5.06−4.89 (m, 4H), 2.65 (br. s, 4H), 2.29−1.99 (m, 4H), 1.67−1.53 (m, 4H), 1.44 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.4 (C), 138.8 (CH), 114.9 (CH2), 79.8 (C), 57.9 (CH2), 31.5(CH2), 28.7 (CH3), 26.5 (CH2); IR υ (neat): 3276, 3077, 2977, 2932, 2856, 1695, 1640, 1453, 1390, 1365, 1244, 1166 cm−1; HRMS (ESI): exact mass calcd for C15H28N2O2Na+ [M + Na+] 291.2048. Found: 291.2045. tert-Butyl 2,2-Di(hex-5-en-1-yl)hydrazinecarboxylate (3h). The title compound was synthesized according to general procedure B using 6-iodohexene (2.10 g, 10.0 mmol) and tert-butyl carbazate (9.52 g, 72.0 mmol) in DMF (33 mL). The product was isolated by column chromatography (gradient column with 20% EtOAc/hexanes to 30% EtOAc/hexanes after the elution of the dialkyl carbazate with Rf = 0.68 in 20% EtOAc/hexanes, allowing the elution of monoalkyl carbazate with Rf = 0.35 in 20% EtOAc/hexanes). The product was obtained as a transparent yellow oil (m = 0.116 g, 4% yield). Note: This compound was obtained as a minor side product while forming the corresponding monoalkyl carbazate. Because this dialkyl carbazate was a suitable precursor for aminimide formation, it was submitted to the reaction conditions. TLC Rf = 0.68 in 20% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) δ 5.79 (tdd, J = 6.7, 10.2, 17.0 Hz, 2H), 5.20 (br. s, 1H), 5.06−4.86 (m, 4H), 2.64 (br. s, 4H), 2.04 (q, J = 6.9 Hz, 4H), 1.55−1.34 (m, 17H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.4 (C), 139.2 (CH), 114.7 (CH2), 79.8 (C), 58.4 (CH2), 34.0 (CH2), 30.0 (CH2), 28.7 (CH3), 26.8 (CH2); IR υ (neat): 3236, 3076, 2977, 2928, 2856, 1696, 1640, 1456, 1390, 1365, 1245, 1167 cm−1; HRMS (ESI): exact mass calcd for C17H32N2O2Na+ [M + Na+] 319.2361. Found: 319.2343. General Procedure B: Synthesis of Unsymmetrical N,NDialkyl Carbazates and Hydrazides via Double Deprotonation (1a−c, 3a,b,d−g). A round-bottomed flask containing a magnetic stir bar was sealed with a septum and was flame-dried using a propane torch. The reaction flask was then purged with argon for 5 min. The desired alkenyl carbazate/hydrazide was solubilized in 5 mL of dry THF and added to the flask, followed by the addition of a volume of

dry THF to bring the carbazate/hydrazide concentration to 0.2 M. The solubilized starting material was cooled to −78 °C using a dry ice/acetone slurry for 15 min before the dropwise addition of 2.4 equiv of n-BuLi (2.5 M in hexanes). After n-BuLi addition, the mixture was allowed to stir at −78 °C for 0.5 h, giving quantitative double deprotonation of the carbazate. To this mixture, 1 equiv of alkyl halide was added dropwise. Stirring at −78 °C was maintained for a further 1.5 h, followed by 0.5 h of stirring upon the removal of the dry ice slurry. Solvent was removed from the crude reaction mixture under reduced pressure and replaced with an equivalent volume of 1:1 mixture of water and ethyl acetate. The aqueous phase was separated and extracted three times using ethyl acetate. The resulting organic phases were combined, dried with sodium sulfate, and concentrated in vacuo. The desired carbazate was isolated via silica gel column chromatography using a solvent system consisting of various ratios of EtOAc/hexanes.16 N′-Benzyl-N′-(pent-4-en-1-yl)-3,5-bis(trifluoromethyl)benzohydrazide (1a). The title compound was synthesized according to general procedure B using hydrazide 6a (0.500 g, 1.46 mmol), benzyl bromide (0.250 g, 1.46 mmol), and n-BuLi (0.350 mmol) in THF (7.5 mL) at −78 °C. The product was isolated by column chromatography (20% Et2O/hexanes). The product was obtained as a white powder (m = 0.423 g, 67% yield). TLC Rf = 0.40 in 2% i-PrOH in CH2Cl 2; 1H NMR (300 MHz, DMSO-d6, 100 °C) δ 9.65−9.24 (m, 1H), 8.31−8.00 (m, 3H), 7.53−7.09 (m, 5H), 5.97−5.63 (m, 1H), 5.04−4.85 (m, 2H), 4.23−3.92 (m, 2H), 3.06−2.91 (m, 2H), 2.31−1.94 (m, 2H), 1.69−1.51 (m, 2H); 13C{1H} NMR (75 MHz, DMSO-d6, 100 °C) δ 163.2 (C), 138.9 (CH), 138.5 (C), 137.4 (C), 131.0 (q, J = 29 Hz, C), 129.1 (CH), 128.4 (CH), 128.3 (CH), 127.4 (CH), 124.4 (m, CH), 122.9 (q, J = 272 Hz, C), 114.8 (CH2), 61.0 (CH2), 55.7 (CH2), 31.0 (CH2), 26.9 (CH2); IR (film) 3231, 3068, 2938, 2843, 1662, 1553, 1455, 1381, 1287, 1132, 908, 699 cm−1; HRMS (EI): Exact mass calcd for C21H20F6N2O [M]+: 430.1480 Not found. Exact mass calcd for C14H 13F6N2O [M − C 7H7]: 339.0932. Found: 339.0907. N′-Allyl-N′ -(pent-4-en-1-yl)-3,5-bis(t rifluoromethyl)benzohydrazide (1b). The title compound was synthesized following general procedure B using hydrazide 6a (0.150 g, 0.44 mmol), allyl bromide (41 uL, 0.44 mmol), and n-BuLi (0.968 mmol) in THF (3 mL) at −78 °C. The product was isolated by column chromatography (20% Et2O/hexanes). The product was obtained as a white powder (m = 0.110 g, 66% yield). TLC Rf = 0.51 in 20% Et2O/hexanes; 1H NMR (300 MHz, DMSO- d6, 120 °C) δ 9.69 (s, 1H), 8.40 (s, 2H), 8.24 (s, 1H), 5.82 (dddt, J = 26.8, 16.8, 10.1, 6.6 Hz, 2H), 5.22−4.88 (m, 4H), 3.50 (d, J = 6.3 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H), 2.09 (q, J = 7.2 Hz, 2H), 1.51 (quin, J = 7.2 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6, 120 °C) δ 162.2 (C), 138.6 (CH), 136.1 (C), 134.9 (CH), 130.2 (q, J = 33 Hz, C), 127.9 (m, CH), 124.7 (m, CH), 123.1 (q, J = 273 Hz, C), 118.0 (CH2), 115.1 (CH2), 59.9 (CH2), 55.1 (CH2), 30.7 (CH2), 26.2 (CH2); IR υ (neat): 3240, 2941, 1643, 1547, 1496, 1385, 1277, 1123 cm−1; HRMS (ESI): exact mass calcd for C17H18F6N2ONa+ [M + Na+] 403.1216. Found: 403.1213. N′-Methyl-N′-(pent-4-en-1-yl)-3,5-bis(trifluoromethyl)benzohydrazide (1c). The title compound was synthesized following general procedure B using hydrazide 6a (0.300 g, 0.880 mmol), methyl iodide (55 uL, 0.88 mmol), and n-BuLi (1.94 mmol) in THF (6 mL) at −78 °C. The product was isolated by column chromatography (20% EtOAc/hexanes). The product was obtained as a white powder (m = 0.110 g, 53% yield). TLC Rf = 0.15 in 20% EtOAc/hexanes; 1H NMR (300 MHz, DMSO-d6, 120 °C) δ 9.77 (s, 1H), 8.42 (s, 2H), 8.24 (s, 1H), 5.78 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.01−4.88 (m, 2H), 2.79 (t, J = 7.1 Hz, 2H), 2.62 (s, 3H), 2.08 (q, J = 7.3 Hz, 2H), 1.50 (quin, J = 7.3 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6, 120 °C) δ 161.6 (C), 138.6 (CH), 136.2 (C), 130.4 (q, J = 32 Hz C), 128.0 (m, CH), 124.6 (m, CH), 123.1 (q, J = 273 Hz, C), 114.7 (CH2), 57.2 (CH2), 45.0 (CH3), 30.7 (CH2), 26.2 (CH2); IR υ (neat): 3240, 3042, 2941, 2895, 1643, 1547, 1385, 1306, 1277, 1163, 1109 cm−1; HRMS (ESI): exact mass calcd for C15H16F6N2ONa+ [M + Na+] 377.1059. Found: 377.1051. D


Note

The Journal of Organic Chemistry tert-Butyl 2-Benzyl-2-(pent-4-en-1-yl)hydrazinecarboxylate (3a). The title compound was synthesized according to general procedure B using carbazate 6b (1.50 g, 7.15 mmol), benyzl bromide (1.22 g, 7.15 mmol), and n-BuLi (17.2 mmol) in THF (35.0 mL) at −78 °C. The product was isolated by column chromatography (10% EtOAc/ hexanes). The product was obtained as a clear oil (m = 1.27 g, 61%). TLC Rf = 0.38 in 10% EtOAc/hexanes; 1H NMR (300 MHz, CDCl3) δ 7.34−7.22 (m, 5H), 5.77 (d, J = 6.7 Hz, 1H), 5.52−5.34 (m, 1H), 5.02−4.88 (m, 2H), 3.94 (s, 2H), 2.74 (s, 2H), 2.11 (d, J = 7.0 Hz, 2H), 1.59 (t, J = 7.3 Hz, 2H), 1.37 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.8 (C), 138.5 (CH), 137.0 (CH), 129.4 (CH), 128.2 (CH), 127.3 (CH), 114.6 (CH2), 79.4 (C), 61.5 (CH2), 55.6 (CH2), 31.1 (CH2), 28.3 (CH3), 26.4 (CH2). 1H and 13C NMR are in accordance with those reported in the literature.7b tert-Butyl 2-(pent-4-en-1-yl)-2-methylhydrazinecarboxylate (3b). The title compound was synthesized following general procedure B using carbazate 6b (1.25 g, 6.25 mmol), methyl iodide (0.887 g, 6.25 mmol), and n-BuLi (15.0 mmol) in THF (31.0 mL) at −78 °C. The product was isolated by column chromatography (gradient column with 10% EtOAc/hexanes to elute spot with TLC Rf = 0.61 in 20% EtOAc/hexanes, then 20% EtOAc/hexanes). The product was obtained as a translucent yellow oil (m = 0.209 g, 16% yield). TLC Rf = 0.29 in 20% EtOAc/hexanes; 1H NMR (400 MHz, CDCl 3) δ 5.73 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.41 (s, 1H), 4.97− 4.86 (m, 2H), 2.57 (t, J = 7.3 Hz, 2H), 2.51 (s, 3H), 2.07−2.02 (m, 2H), 1.52 (quint., J = 7.4 Hz, 2H), 1.39 (s, 11H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.7 (C), 138.3 (CH), 114.6 (CH2), 79.7 (C), 59.0 (CH2), 46.3 (CH3), 31.2 (CH2), 28.3 (CH3), 26.3 (CH2); IR υ (neat): 3264, 2978, 1706, 1641, 1454, 1391, 1365, 1245, 1157 cm−1; HRMS (ESI): exact mass calcd for C11H22N2O2Na+ [M + Na+] 237.1579. Found: 237.1568. tert-Butyl 2-Benzyl-2-(2,2-dimethylpent-4-en-1-yl)hydrazine-carboxylate (3d). The title compound was synthesized according to general procedure B using carbazate 6d (1.15 g, 5.00 mmol), benzyl bromide (0.855 g, 5.00 mmol), and n-BuLi (12.0 mmol) in THF (25.0 mL) at −78 °C. The product was isolated by column chromatography (10% EtOAc/hexanes). The product was obtained as a clear oil (m = 0.573 g, 36%). TLC Rf = 0.33 in 10% EtOAc/hexanes; 1 H NMR (300 MHz, CDCl3) δ 7.37−7.24 (m, 5H), 5.86−5.66 (m, 2H), 5.05−4.97 (m, 2H), 4.03 (s, 2H), 2.72 (s, 2H), 2.06 (d, J = 7.5 Hz, 2H), 1.37 (s, 9H), 0.90 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 156.9 (C), 135.1 (CH), 117.1 (CH2), 80.3 (C), 62.3 (CH2), 44.7 (CH2), 33.8 (C), 28.3 (CH3), 25.3 (CH3). 1H and 13C NMR are in accordance with those reported in the literature.7b tert-Butyl 2-(2,2-Dimethylpent-4-en-1-yl)-2-methylhydrazinecarboxylate (3e). The title compound was synthesized following general procedure B using carbazate 6d (0.348 g, 1.53 mmol), methyl iodide (0.217 g, 1.53 mmol), and n-BuLi (3.82 mmol) in THF (7.6 mL) at −78 °C. The product was isolated by column chromatography (20% EtOAc/hexanes). The product was obtained as a transparent yellow oil (m = 0.051 g, 14% yield). TLC Rf = 0.33 in 20% EtOAc/hexanes; 1 H NMR (400 MHz, CDCl3) δ 5.80−5.70 (m, 1H), 5.63 (s, 1H), 4.98−4.93 (m, 2H), 2.58 (s, 3H), 2.44 (s, 2H), 1.99 (d, J = 7.5 Hz, 2H), 1.40 (s, 9H), 0.84 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.5 (C), 135.6 (CH), 116.8 (CH2), 79.7 (C), 69.7 (CH2), 48.6 (CH3), 44.7 (CH2), 35.1 (C), 28.4 (CH3), 25.6 (CH3); IR υ (neat): 2920, 2851, 1733, 1601, 1456, 1376, 1262; HRMS (ESI): exact mass calcd for C13H26N2O2Na+ [M + Na+] 265.1886. Found: 265.1892. tert-Butyl 2-Benzyl-2-(2-vinylbenzyl)hydrazinecarboxylate (3f). The title compound was synthesized following general procedure B using carbazate 6e (0.689 g, 2.78 mmol), benzyl bromide (0.475 g, 2.78 mmol), and n-BuLi (6.66 mmol) in THF (14.0 mL) at −78 °C. The product was isolated by column chromatography (gradient column from 5% EtOAc/hexanes to 30% EtOAc/hexanes). The product was obtained as a white powder (m = 0.409 g, 43% yield). TLC Rf = 0.27 in 10% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 1H), 7.35−7.19 (m, 9H), 5.65 (d, J = 17.3 Hz, 2H), 5.29−5.26 (m, 1H), 5.14 (d, J = 0.4 Hz, 1H), 4.15−4.12 (m, 2H), 3.87−3.84 (m, 2H), 1.34 (s, 9H), 1.34 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.2 (C), 138.2 (C), 135.2 (CH), 131.2

(CH), 129.6 (CH), 128.5 (CH), 128.1 (CH), 127.8 (CH), 127.6 (CH), 125.9 (CH), 115.6 (CH2), 80.1 (C), 59.7 (CH2), 57.4 (CH2), 28.6 (CH3). *Two aromatic quaternary are overlapped. IR υ (neat): 3263, 2966, 2927, 2865, 1705, 1628, 1489, 1388, 1362, 1281, 1240, 1141 cm−1; HRMS (ESI): exact mass calcd for C21H26N2O2Na+ [M + Na+] 361.1892. Found: 361.1900. tert-Butyl-2-(hex-5-en-1-yl)-2-methylhydrazinecarboxylate (3g). The title compound was synthesized following general procedure B using 6c (1.82 g, 8.49 mmol), methyl iodide (1.20 g, 8.49 mmol), and n-BuLi (20.4 mmol) in THF (43.0 mL) at −78 °C. The product was isolated by column chromatography (gradient column with 10% EtOAc/hexanes to elute spot with TLC Rf = 0.25 in 10% EtOAc/ hexanes, then 20% EtOAc/hexanes). The product was obtained as a transparent yellow oil (m = 0.433 g, 22% yield). TLC Rf = 0.30 in 20% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) δ 5.72 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.38 (s, 1H), 4.94−4.84 (m, 2H), 2.56 (t, J = 6.8 Hz, 2H), 2.50 (s, 3H), 2.01−1.95 (m, 2H), 1.43−1.38 (m, 16H); 13 C{1H} NMR (100 MHz, DMSO-d6, 90 °C) δ 154.3 (C), 138.2 (CH), 113.8 (CH2), 77.4 (C), 57.5 (CH2), 44.7 (CH3), 32.4 (CH2), 27.8 (CH3), 25.9 (CH2), 25.4 (CH2); IR υ (neat): 3267, 2977, 2932, 2860, 1708, 1640, 1456, 1391, 1365, 1245, 1160 cm−1; HRMS (ESI): exact mass calcd for C12H24N2O2Na+ [M + Na+] 251.1735. Found: 251.1751. General Procedure C: Synthesis of Aminimides via Cope-Type Hydroamination (2b,c, 5a). The hydrazide was added to an oven or flame-dried sealed tube with a stir bar. The compound was solubilized using α,α,α-trifluorotoluene to achieve a final concentration of 0.05 M. The vial was sealed with a septum and purged with argon. The mixture was then heated for 12 h to 80−110 °C. The reaction solution was cooled to ambient temperature, concentrated under reduced pressure, and analyzed by 1H NMR. The aminimide product was either pure after the reaction or isolated using silica gel column chromatography. cis-1-Allyl-N-(3,5-bis(trifluoromethyl)benzoyl)-2-methylpyrrolid1-ium 1-Amidine (2b). The title compound was synthesized according to general procedure C (80 °C, 12 h) using hydrazide 1b (0.167 g, 0.44 mmol). The product was isolated by column chromatography (2% MeOH/CH2Cl2). The product was obtained as an oil (m = 0.059 g, 35% yield). TLC Rf = 0.42 in 2% MeOH/ CH2Cl2; 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 2H), 7.82 (s, 1H), 6.11−5.82 (m, 1H), 5.64−5.39 (m, 2H), 5.24 (dd, J = 13.50, 7.10 Hz, 1H), 4.75−4.50 (m, 1H), 3.94 (dd, J = 13.50, 7.65 Hz, 1H), 3.73 (d, J = 7.10 Hz, 1H), 3.52−3.35 (m, 1H), 2.21−1.98 (m, 2H), 1.99−1.77 (m, 2H), 1.48 (d, J = 6.40 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.3 (C), 141.4 (C), 131.3 (q, J = 33 Hz, C), 127.7 (m, CH), 127.3 (CH), 125.3 (CH2), 123.9 (q, J = 273 Hz, C), 122.5 (quint. J = 3.8 Hz, CH), 69.7 (CH), 60.2 (CH2), 58.5 (CH2), 29.0 (CH2), 18.9 (CH2), 13.8 (CH3). NOESY spectra are provided and analyzed in the Supporting Information. IR (film) 3747, 2361, 2323, 1703, 1652, 1638, 1548, 1089 cm−1; HRMS (EI): Exact mass calcd for C17H16F6N2O [M]+ = 380.1323. Not found. Exact mass calcd for [M − CH2 CHCH 2]+ = 339.0932. Found: 339.0964. cis-N-(3,5-Bis(trifluoromethyl)benzoyl)-1,2-dimethylpyrrolid-1ium 1-Amidine (2c). The title compound was synthesized according to general procedure C (110 °C, 12 h) using hydrazide 1c (0.156 g, 0.44 mmol). Upon completion, the reaction mixture was concentrated under reduced pressure. The aminimide was obtained as an oil (m = 0.156 g, >98% pure by 1H NMR) and characterized without further purification. TLC Rf = 0.33 in 2% MeOH/CH2Cl2; 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 2H), 7.79 (s, 1H), 4.86−5.08 (m, 1H), 3.49 (s, 3H), 3.33−3.48 (m, 1H), 3.14−3.31 (m, 1 H), 1.85−2.25 (m, 4H), 1.50 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.5 (C), 141.3 (C), 130.6 (q, J = 33 Hz, C), 127.7 (m, CH), 123.5 (q, J = 273 Hz, C), 122.6 (quin, J = 3.8 Hz, CH), 74.9 (CH3), 62.7 (CH2), 47.8 (CH), 29.30 (CH2), 19.1 (CH2), 13.4 (CH3). NOESY spectra are provided and analyzed in the Supporting Information. IR (film): 3746, 3629, 2364, 2341, 2323, 1698, 1653, 1563, 1504, 1454, 1081 cm−1; HRMS (EI): Exact mass calcd for C15H16F6N 2O [M]+ = 354.1167. Found: 354.1151. E


Note

The Journal of Organic Chemistry N-Allyl-N-(2-methylpyrrolidin-1-yl)-3,5-bis(trifluoromethyl)-benzamide (5a). The title compound was synthesized according to general procedure C with a slight modification (110 °C, 12 h) using ylide 2b (0.038 g, 0.1 mmol). The reaction mixture was concentrated under reduced pressure, and NMR analysis revealed the complete conversion to the shifted product (m = 0.038 g, 99% yield). TLC Rf = 0.58 in 2% MeOH/CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 2H), 7.88 (s, 1H), 6.21−5.92 (m, 1H), 5.42−5.10 (m, 2H), 4.36− 3.81 (m, 2H), 3.17−2.86 (m, 3H), 1.98−1.78 (m, 1 H), 1.76−1.59 (m, 2H), 1.31−1.10 (m, 1H), 0.77 (d, J = 6.1 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 169.5 (C), 138.5 (C), 133.6 (CH), 131.3 (q, J = 33 Hz, C), 128.5 (CH), 122.9 (CH), 123.2 (q, J = 272 Hz, C), 117.5 (CH2), 56.0 (CH), 50.8 (CH2), 42.7 (CH2), 29.9 (CH2), 19.8 (CH2), 17.5 (CH3); IR (film): 2357, 2322, 1757, 1703, 1695, 1652, 1471, 1461, 1403, 1363, 899 cm−1; HRMS (EI): Exact mass calcd for C17H18F6N2O [M]+ = 380.1323. Found: 380.1334. General Procedure D: Synthesis of Aminimides via Intramolecular Aminocarbonylation (4a−h). The carbazate was added to an oven or flame-dried microwave vial with a stir bar. The compound was solubilized using a 1:1 (v/v) mixture of i-PrOH and MeCN to achieve a final concentration of 0.05 M, unless otherwise noted. The vial was sealed with a septum and purged with argon. The mixture was heated to 150−180 °C in a microwave reactor for 3 h or wax bath for 15−50 h. The reaction solution was cooled to ambient temperature, concentrated under reduced pressure, and analyzed by 1 H NMR. The aminimide product was isolated using silica gel column chromatography treated with 1% triethylamine. 7-Benzyl-2-oxohexahydro-2H-pyrrolo[1,2-b]pyrazol-7-ium-1-ide (4a). The title compound was synthesized according to general procedure D using carbazate 3a (0.290 g, 1.00 mmol) in a 1:1 (v/v) mixture of i-PrOH and MeCN (20.0 mL). The reaction was heated to 150 °C for 3 h. The product was isolated by column chromatography using silica treated with 1% triethylamine (CH2Cl2 to remove excess starting material and byproducts, then 10% MeOH/CH2Cl2 to elute the product). The product was obtained as a white-beige powder (m = 0.194 g, 89% yield). TLC Rf = 0.09 in 10% MeOH/CH2Cl 2; 1H NMR (400 MHz, CDCl3) δ 7.61−7.50 (m, 2H), 7.48−7.32 (m, 3H), 4.56 (d, J = 12.3 Hz, 1H), 4.34 (d, J = 12.3 Hz, 1H), 4.32−4.23 (m, 1H), 3.81−3.67 (m, 1H), 3.56−3.43 (m, 1H), 2.41−2.23 (m, 2H), 2.23−2.08 (m, 2H), 2.02−1.88 (m, 1H), 1.88−1.75 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ 179.1 (C), 132.8 (CH), 130.3 (CH), 129.4 (C), 129.1 (CH), 71.2 (CH), 70.1 (CH2), 67.1 (CH2), 41.2 (CH2), 33.1 (CH2), 23.5 (CH2); IR υ (neat): 3378, 2960, 2945, 1610, 1592, 1576, 1396, 1386, 1310, 1277 cm−1; HRMS (ESI): exact mass calcd for C13H16N2ONa+ [M + Na+] 239.1160. Found: 239.1161. 7-Methyl-2-oxohexahydro-2H-pyrrolo[1,2-b]pyrazol-7-ium-1-ide (4b). The title compound was synthesized according to general procedure D using carbazate 3b (0.107 g, 0.500 mmol) in a 1:1 (v/v) mixture of i-PrOH and MeCN (10.0 mL). The reaction was heated to 150 °C for 3 h. The product was isolated by column chromatography using silica treated with 1% triethylamine (gradient column with 10% MeOH/CH2Cl2 to elute spots with Rf > 0.15, then 20% MeOH/ CH2Cl2). The product was obtained as a brown-yellow powder (m = 0.040 g, 57% yield). TLC Rf = 0.06 in 10% MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) δ 4.15−4.04 (m, 1H), 3.79−3.70 (m, 1H), 3.31 (dt, J = 6.1, 10.7 Hz, 1H), 3.19 (s, 3 H), 3.09 (dd, J = 9.0, 16.3 Hz, 1H), 2.48 (dd, J = 3.1, 16.3 Hz, 1H), 2.43−2.19 (m, 2H), 2.01−1.84 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.2 (C), 74.7 (CH), 68.5 (CH2), 55.2 (CH3), 40.6 (CH2), 33.1 (CH2), 23.9 (CH2); IR υ (neat): 3006, 2957, 1582, 1443, 1387, 1301, 1275, 1262 cm−1; HRMS (ESI): exact mass calcd for C7H13N2O+ [M + H+] 141.1028. Found: 141.1037. 2-Oxo-7-(pent-4-en-1-yl)hexahydro-2H-pyrrolo[1,2-b]pyrazol-7ium-1-ide (4c). The title compound was synthesized according to general procedure D using carbazate 3c (0.091 g, 0.340 mmol) in a 1:1 (v/v) mixture of i-PrOH and MeCN (6.80 mL). The reaction was heated to 150 °C for 3 h. The product was isolated by column chromatography using silica treated with 1% triethylamine (10% MeOH/CH2Cl2). The product was obtained as a transparent yellow

oil (m = 0.057 g, 86% yield). TLC Rf = 0.09 in 10% MeOH/CH2Cl2; H NMR (400 MHz, CDCl3) δ 5.69 (tdd, J = 6.6, 10.3, 17.0 Hz, 1H), 5.04−4.90 (m, 2H), 4.19 (tt, J = 3.6, 9.2 Hz, 1H), 3.71−3.60 (m, 1H), 3.40−3.15 (m, 3H), 3.00 (dd, J = 9.3, 16.4 Hz, 1H), 2.41 (dd, J = 3.1, 16.5 Hz, 1H), 2.38−2.29 (m, 1H), 2.27−2.13 (m, 1H), 2.10− 2.02 (m, 2H), 2.00−1.79 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.4 (C), 136.5 (CH), 116.5 (CH2), 73.2 (CH), 66.9 (CH2), 66.9 (CH2), 41.1 (CH2), 33.0 (CH2), 30.7 (CH2), 23.4 (CH2), 23.1 (CH2); IR υ (neat): 1594, 1202 cm−1; HRMS (ESI): exact mass calcd for C11H18N2ONa+ [M + Na+] 217.1317. Found: 217.1306. 7-Benzyl-5,5-dimethyl-2-oxohexahydro-2H-pyrrolo[1,2-b]pyrazol-7-ium-1-ide (4d). The title compound was synthesized according to general procedure D using carbazate 3d (0.146 g, 0.458 mmol) in a 1:1 (v/v) mixture of i-PrOH and MeCN (9.2 mL). The reaction mixture was heated to 150 °C for 50 h in a wax bath. The product was isolated by column chromatography using silica treated with 1% triethylamine (CH2Cl2 to remove excess starting material and byproducts, then 10% MeOH/CH2Cl2 to elute the product). The product was obtained as a white-yellow powder (m = 0.019 g, 17% yield). TLC Rf = 0.13 in 10% MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) δ 7.63−7.54 (m, 2H), 7.51−7.34 (m, 3H), 4.65 (d, J = 12.3 Hz, 1H), 4.52−4.43 (m, 1H), 4.40 (d, J = 12.3 Hz, 1H), 3.84−3.66 (m, 2H), 2.26−2.11 (m, 2H), 1.95−1.80 (m, 2H), 1.21 (s, 3H), 1.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.7 (C), 133.0 (CH), 130.6 (CH), 129.3 (CH), 129.1 (C), 80.0 (CH2), 71.9 (CH2), 71.8 (CH), 46.7 (CH2), 39.2 (CH2), 38.5 (C), 27.9 (CH3), 27.7 (CH3); IR υ (neat): 3205, 2958, 2919, 2889, 1713, 1588, 1578, 1405, 1214 cm−1; HRMS (ESI): exact mass calcd for C15H20N2ONa+ [M + Na+] 267.1473. Found: 267.1481. 5,5,7-Trimethyl-2-oxohexahydro-2H-pyrrolo[1,2-b]pyrazol-7ium-1-ide (4e). The title compound was synthesized according to general procedure D using carbazate 4e (0.048 g, 0.200 mmol) in a 1:1 (v/v) mixture of i-PrOH and MeCN (4.0 mL). The reaction mixture was heated to 150 °C for 15 h in a wax bath. The product was isolated by column chromatography using silica treated with 1% triethylamine (gradient column with 10% MeOH/CH2Cl2, then 20% MeOH/CH2Cl2). The product was obtained as an off-white powder (m = 0.030 g, 90% yield). TLC Rf = 0.11 in 10% MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) δ 4.30−4.24 (m, 1H), 3.78 (d, J = 12.4 Hz, 1H), 3.40 (d, J = 12.2 Hz, 1H), 3.19 (s, 3H), 3.04 (dd, J = 16.1, 8.5 Hz, 1H), 2.50 (dd, J = 16.1, 1.7 Hz, 1H), 2.18 (dd, J = 13.2, 7.0 Hz, 1H), 1.98 (dd, J = 13.3, 10.7 Hz, 1H), 1.22 (d, J = 5.5 Hz, 7H); 13 C{1H} NMR (100 MHz, CDCl3) δ 177.1 (C), 81.3 (CH2), 75.2 (CH), 57.4 (CH3), 46.9 (CH2), 38.9 (C), 38.4 (CH2), 28.1 (CH3), 27.6 (CH3); IR υ (neat): 3406, 3216, 2958, 2870, 1683, 1588, 1570, 1445, 1396, 1371, 1312, 1269 cm−1; HRMS (ESI): exact mass calcd for C9H16N2ONa+ [M + Na+] 191.1160. Found: 191.1169. 9-Benzyl-2-oxo-3,3a,8,9-tetrahydro-2H-pyrazolo[5,1-a]isoindol9-ium-1-ide (4f). The title compound was synthesized according to general procedure D using carbazate 3f (0.161 g, 0.476 mmol) in a 1:1 (v/v) mixture of i-PrOH and MeCN (9.5 mL). The reaction was heated to 150 °C for 3 h. The product was isolated by column chromatography using silica treated with 1% triethylamine (CH2Cl2 to remove excess starting material and byproducts and then 10% MeOH/CH2Cl2 to elute the product). The product was obtained as a white fluffy powder (m = 0.089 g, 71% yield). TLC Rf = 0.13 in 10% MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 1.7, 7.7 Hz, 2H), 7.54−7.40 (m, 3H), 7.40−7.31 (m, 2H), 7.25−7.17 (m, 1H), 7.17−7.07 (m, 1H), 5.42 (dd, J = 1.8, 8.6 Hz, 1H), 5.10 (d, J = 14.3 Hz, 1H), 4.98 (d, J = 14.3 Hz, 1H), 4.76 (d, J = 12.3 Hz, 1H), 4.53 (d, J = 12.3 Hz, 1H), 2.50 (dd, J = 2.3, 15.6 Hz, 1H), 2.24 (dd, J = 8.7, 15.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.4 (C), 137.6 (C), 132.9 (CH), 132.7 (C), 130.7 (CH), 129.8 (CH), 129.6 (CH), 129.4 (CH), 129.0 (C), 123.3 (CH), 123.3 (CH), 76.9 (CH), 72.0 (CH2), 70.5 (CH2), 39.7 (CH2); IR υ (neat): 3041, 2938, 2805, 1599, 1583, 1458, 1372, 1344, 1279 cm−1; HRMS (ESI): exact mass calcd for C17H16N2ONa+ [M + Na+] 287.1160. Found: 287.1155. 8-Methyl-2-oxooctahydropyrazolo[1,5-a]pyridin-8-ium-1-ide (4g). The title compound was synthesized according to general 1

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Note


and allowed to stir overnight. The product was isolated by column chromatography (30% EtOAc/hexanes). The product was obtained as a clear oil (m = 2.22 g, 92%). TLC Rf = 0.53 in 20% EtOAc/hexanes; 1 H NMR (300 MHz, CDCl3) δ 5.90−5.76 (m, 1H), 5.06−4.99 (m, 2H), 2.67 (s, 2H), 2.02 (d, J = 7.4 Hz, 2H), 1.47 (s, 9H), 0.91 (s, 6H); 13C{ 1H} NMR (75 MHz, CDCl3) δ 154.5 (C), 137.9 (C), 135.6 (CH), 129.5 (CH), 128.1 (CH), 127.3 (CH), 116.8 (CH2), 79.6 (C), 66.9 (CH2), 62.6 (CH2), 44.7 (CH2), 35.4 (C), 28.3 (CH3), 25.6 (CH3). 1H and 13C NMR are in accordance with those reported in the literature.7b tert-Butyl 2-(2-Vinylbenzyl)hydrazinecarboxylate (6e). The title compound was synthesized according to general procedure E using 2vinylbenzaldehyde (0.790 g, 5.98 mmol) and tert-butylcarbazate (0.790 g, 5.98 mmol). After condensation was judged to be complete, NaCNBH3 (1.13 g, 17.9 mmol) was added and allowed to stir overnight. The product was isolated using column chromatography (100% CH2Cl2 to 2.5% EtOAc/CH2Cl2). The product was obtained as a white solid (m = 1.43 g, 96%). TLC Rf = 0.10 in 100% CH2Cl2; 1 H NMR (400 MHz, CDCl3) δ 7.54−7.51 (m, 1H), 7.30−7.21 (m, 3H), 7.14 (dd, J = 17.4, 10.9 Hz, 1H), 6.06 (s, 1H), 5.68 (dd, J = 17.4, 1.4 Hz, 1H), 5.32 (dd, J = 11.0, 1.4 Hz, 1H), 4.11 (s, 1H), 4.05 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.5 (C), 137.6 (C), 134.5 (C), 134.2 (CH), 130.6 (CH), 128.0 (CH), 127.8 (CH), 125.8 (CH), 116.1 (CH2), 80.5 (C), 53.3 (CH2), 28.4 (C). 1H and 13C NMR are in accordance with those reported in the literature.7b

procedure D using carbazate 3g (0.114 g, 0.500 mmol) in a 1:1 (v/v) mixture of i-PrOH and MeCN (10.0 mL). The reaction was heated to 180 °C for 3 h. The product was isolated by column chromatography using silica treated with 1% triethylamine (gradient column with 10% MeOH/CH2Cl2 to elute spots with Rf > 0.15 then 20% MeOH/ CH2Cl2). The product was obtained as a brown-yellow powder (m = 0.054 g, 70% yield). TLC Rf = 0.08 in 10% MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) δ 3.87−3.80 (m, 1H), 3.43−3.37 (m, 1H), 3.32− 3.26 (m, 1H), 3.14 (s, 3H), 2.76 (dd, J = 15.8, 7.4 Hz, 1H), 2.58 (dd, J = 15.8, 8.1 Hz, 1H), 2.01−1.86 (m, 3H), 1.76−1.59 (m, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 178.7 (C), 70.4 (CH), 63.3 (CH2), 53.9 (CH3), 38.2 (CH2), 25.7 (CH2), 21.1 (CH2), 18.5 (CH2). NOESY spectra are provided and analyzed in the Supporting Information. IR υ (neat): 3258, 2948, 1570, 1451, 1396, 1306, 1231 cm−1; HRMS (ESI): exact mass calcd for C8H14N2ONa+ [M + Na+] 177.1009. Found: 177.1004. 8-(Hex-5-en-1-yl)-2-oxooctahydropyrazolo[1,5-a]pyridin-8-ium1-ide (4h). The title compound was synthesized according to general procedure D using carbazate 3h (0.080 g, 0.271 mmol) in a 1:1 (v/v) mixture of i-PrOH and MeCN (5.4 mL). The reaction was heated to 180 °C for 3 h. The product was isolated by column chromatography using silica treated with 1% triethylamine (10% MeOH/CH2Cl2). The product was obtained as a brown oil (m = 0.018 g, 30% yield). TLC Rf = 0.15 in 10% MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) δ 5.79−5.69 (m, 1H), 5.02−4.95 (m, 2H), 4.01−3.98 (m, 1H), 3.45− 3.25 (m, 4H), 2.78−2.70 (m, 2H), 2.08 (q, J = 7.1 Hz, 2H), 1.99− 1.64 (m, 8H), 1.46−1.40 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.2 (C), 137.8 (CH), 115.8 (CH 2), 68.7 (CH), 64.2 (CH2), 60.3 (CH2), 37.2 (CH2), 33.5 (CH2), 26.1 (CH2), 25.1 (CH2), 22.7 (CH2), 20.5 (CH2), 17.7 (CH2); IR υ (neat): 3377, 2927, 1728, 1639, 1574, 1464, 1370, 1271, 1243 cm−1; HRMS (ESI): exact mass calcd for C13H22N2ONa+ [M + Na+] 245.1630. Found: 245.1638. 1-Benzyltetrahydro-1H-pyrrolo[1,2-b]pyrazol-2(3H)-one (5b). The title compound was synthesized according to modified general procedure D from ylide 4a (0.022 g, 0.1 mmol) in α,α,αtrifluorotoluene (0.05 M) at 200 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure, and NMR analysis revealed complete conversion to the shifted product (m = 0.022 g, 99%), and the yield was corrected for residual α,α,α-trifluorotoluene. TLC Rf = 0.39 in 5% MeOH/CH2Cl2; 1H NMR (300 MHz, CDCl3) δ 7.37− 7.18 (m, 5H), 4.71−4.59 (m, 1H), 4.58−4.44 (m, 1H), 4.02−3.87 (m, 1H), 3.06−2.89 (m, 1H), 2.73−2.60 (m, 2H), 2.59−2.43 (m, 1H), 2.13−1.98 (m, 1H), 1.97−1.82 (m, 1H), 1.81−1.59 (m, 2H); 13 C{1H} NMR (75 MHz, DMSO-d6) δ 170.8 (C), 136.7 (C), 128.5 (CH), 128.1 (CH), 127.5 (CH), 59.4 (CH), 55.2 (CH2), 47.7 (CH2), 37.6 (CH2), 30.2 (CH2), 23.7 (CH2). 1H and 13C NMR are in accordance with those reported in the literature.7b General Procedure E: Synthesis of N-Alkyl Carbazates by Reductive Amination (6d,e). In a flame-dried round-bottomed flask, the corresponding aldehyde (1.00 equiv) was dissolved in dry MeOH (0.3 M) to which tert-butylcarbazate (1.00 equiv) was added. The reaction was stirred under argon until consumption of the aldehyde or ketone was judged to be complete by TLC (30% EtOAc/ hexanes). Acetic acid was added to the crude carbazone solution such that a 2:1 MeOH/acetic acid (0.2 M) solution was formed. To this solution was added NaCNBH3 (3.00 equiv), and it was then allowed to stir at room temperature overnight. Volatiles were removed by rotary evaporation, and the remaining solution was quenched with a saturated solution of NaHCO3 and then gradually basified with 2 M NaOH to a pH of 8. The solution was extracted three times with EtOAc, dried with Na2SO4, filtered, and concentrated by rotary evaporation. The crude product was then purified by silica gel chromatography to give the corresponding pure monoalkenyl carbazates. tert-Butyl 2-(2,2-Dimethylpent-4-en-1-yl)hydrazinecarboxylate (6d). The title compound was synthesized according to general procedure E using 2,2-dimethylpent-4-enal (1.19 g, 10.6 mmol) and tert-butylcarbazate (1.40 g, 10.6 mmol). After condensation was judged to be complete, NaCNBH3 (1.99 g, 31.8 mmol) was added

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01259. Copies of 1H and 13C NMR spectra for all compounds (S2−S35) as well as NOESY of aminimides 2b−c and 4g (S36−S38) (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Ryan A. Ivanovich: 0000-0002-2647-3223 André M. Beauchemin: 0000-0003-0667-6215 Author Contributions †

R.A.I. and J.A.M.Q. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the University of Ottawa and NSERC for support of this work. R.A.I. thanks NSERC and the Ontario government for graduate scholarships. F.L. thanks the FQRNT for a graduate scholarship. Jean-François Vincent Rocan and Christian Clavette (University of Ottawa) are thanked for the synthesis of starting materials.

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REFERENCES

(1) (a) Dauban, P.; Darses, B.; Jarvis, A. Addition Reactions with Formation of Carbon Nitrogen Bonds. In Comprehensive Organic Synthesis II; Knochel, P., Molander, G., Eds.; Elsevier: Waltham, MA, 2014; Vol. 7; pp 538−604. (2) (a) Severin, R.; Doye, S. The catalytic hydroamination of alkynes. Chem. Soc. Rev. 2007, 36, 1407−1420. (b) Mueller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Hydroamination: Direct Addition of Amines to Alkenes and Alkynes. Chem. Rev. 2008, 108, 3795−3892. (c) Bernoud, E.; Lepori, C.; Mellah, M.; Schulz, E.; Hannedouche, J. Recent advances in metal free- and late transition

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Toderian, A. B.; Gorelsky, S. I.; Beauchemin, A. M. A Tunable Route for the Synthesis of Azomethine Imines and β-Aminocarbonyl Compounds from Alkenes. J. Am. Chem. Soc. 2012, 134, 16111− 16114. (e) Bongers, A.; Clavette, C.; Gan, W.; Gorelsky, S. I.; Betit, L.; Lavergne, K.; Markiewicz, T.; Moon, P. J.; Das Neves, N. D.; Obhi, N. K.; Toderian, A. B.; Beauchemin, A. M. Intermolecular Aminocarbonylation of Alkenes using Concerted Cycloadditions of Iminoisocyanates. J. Org. Chem. 2017, 82, 1175−1194. For a review on the reactivity of N-isocyanates/N-isothiocyanates, see: (f) VincentRocan, J.-F.; Beauchemin, A. M. N-Isocyanates, N-Isothiocyanates and Their Masked/Blocked Derivatives: Synthesis and Reactivity. Synthesis 2016, 48, 3625−3645. (8) (a) Jain, S. L.; Sharma, V. B.; Sain, B. Copper-catalyzed imination of pyridines using PhI = NTs as nitrene precursor. Tetrahedron Lett. 2003, 44, 4385−4387. (b) Ochiai, M.; Kawano, Y.; Kaneaki, T.; Tada, N.; Miyamoto, K. Direct Transfer of the Sulfonylimino Group of Imino-λ3-Bromane to N-Heterocycles and Trialkylamines: Synthesis of N-Iminoammonium Ylides under MetalFree Conditions. Org. Lett. 2009, 11, 281−284. (c) Ochiai, M.; Miyamoto, K.; Hayashi, S.; Nakanishi, W. Hypervalent Nsulfonylimino-λ3-bromane: active nitrenoid species at ambient temperature under metal-free conditions. Chem. Commun. 2010, 46, 511−521. (d) Pujari, S. A.; Guénée, L.; Lacour, J. Efficient Synthesis of Imino-methano Tröger Bases by Nitrene Insertions into C−N Bonds. Org. Lett. 2013, 15, 3930−3933. For reviews on aminimides, see: (e) McKillip, W. J.; Sedor, E. A.; Culbertson, B. M.; Wawzonek, S. Chemistry of aminimides. Chem. Rev. 1973, 73, 255−281. (f) Gaber, A-A. M; Wentrup, C. Pyrolysis of hydrazine derivatives and related compounds with NN single bonds. J. Anal. Appl. Pyrolysis 2017, 125, 258−278. (9) (a) Illien, B.; Berthelot, M.; Morris, D. G.; Laurence, C. R3N+N−: a substituent with extreme electronic effects. J. Phys. Org. Chem. 2000, 13, 293−299. (b) Chardin, A.; Laurence, C.; Berthelot, M.; Morris, D. G. Hydrogen-bond basicity of the sulfonyl group. The case of strongly basic sulfonamidates RSO2NNMe3. J. Chem. Soc., Perkin Trans. 2 1996, 2, 1047−1051. (10) For examples of their use in adhesives, see: (a) Throckmorton, P. E.; Luckman, E. R. Halogen-Containing Aminimide Compounds as Tire Cord Adhesives. Rubber Chem. Technol. 1980, 53, 270−284. For examples of their use in surfactants, see: (b) Oba, G.; Coleman, B. E.; Hart, D. J.; Zakin, J.; Zhang, Y.; Kawaguchi, Y.; Talmon, Y. Synthesis of aminimides derived from oleic acid: a new family of drag-reducing surfactants. Tetrahedron 2006, 62, 10193−10201. For examples of their study in the context of CNS-acting agents, see: (c) Capuano, B.; Crosby, I. T.; Lloyd, E. J.; Neve, J. E.; Taylor, D. A. Aminimides as Potential CNS-Acting Agents. III. Design, Synthesis, and Receptor Binding of Aminimide Analogues of Dopamine, Serotonin, Morphine, and Nicotine. Aust. J. Chem. 2008, 61, 422−431. For examples of their study in the context of antifungal agents, see: (d) Abel, M. D.; Hewgill, R. T.; Malczyk, K. J.; Micetich, R. G.; Daneshtalab, M. The synthesis of aminimide-containing azole antifungals. J. Heterocycl. Chem. 1998, 35, 193−199. For examples of their study in the context of cancer therapeutics, see: (e) Gangapuram, M.; Redda, K. K. Synthesis of substituted N-[4(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)3,6-dihydropyridin-1(2H)-yl]benzamide/benzene sulfonamides as anti-inflammatory and anti-cancer agents. J. Heterocycl. Chem. 2009, 46, 309−316. For examples of their study in the context of antiperoxidation agents, see: (f) Grisar, J. M.; Marciniak, G.; Bolkenius, F. N.; Verne-Mismer, J.; Wagner, E. R. Cardioselective Ammonium, Phosphonium, and Sulfonium Analogs of.alpha.Tocopherol and Ascorbic Acid That Inhibit in Vitro and ex Vivo Lipid Peroxidation and Scavenge Superoxide Radicals. J. Med. Chem. 1995, 38, 2880−2886. For examples of their study in the context of HIV-1 protease inhibitors, see: (g) Rutenber, E. E.; McPhee, F.; Kaplan, A. P.; Gallion, S. L.; Hogan, J. C., Jr.; Craik, C. S.; Stroud, R. M. A new class of HIV-1 protease inhibitor: The crystallographic structure, inhibition and chemical synthesis of an aminimide peptide isostere. Bioorg. Med. Chem. 1996, 4, 1545−1558. For examples of their study in the context of peptidomimetics, see: (h) Peisach, E.; H


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Aminimide Synthesis Using Concerted Amination Reactions of

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