Reductive Deuteration of Nitriles: The Synthesis of α,α-Dideuterio

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Cite This: J. Org. Chem. 2018, 83, 12269−12274

Reductive Deuteration of Nitriles: The Synthesis of α,α-Dideuterio Amines by Sodium-Mediated Electron Transfer Reactions Yuxuan Ding,† Shihui Luo,† Adila Adijiang, Hongye Zhao, and Jie An* College of Science, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China

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S Supporting Information *

ABSTRACT: The first general reductive deuteration of nitriles under single-electron transfer conditions has been developed for the synthesis of α,α-dideuterio amines. This practical and cost-efficient protocol requires only bench stable and commercially available sodium dispersions and EtOD-d1 and allows for the reductive deuteration of a variety of nitriles in excellent yields and deuterium incorporations. method for the α,β-deuteration of tertiary amines with excellent regioselectivity.4c In general, however, transition metal-catalyzed H/D exchange reactions may require expensive transition metal catalysts and harsh reaction conditions and often result in unsatisfactory regioselectivity and/or low levels of deuterium incorporation. Alternatively, reductive deuteration is an attractive strategy that can afford high levels of deuterium incorporation and good regioselectivity.3 However, expensive and pyrophoric alkali metal deuterides are required for the classic reductive deuterations of nitriles.3c In addition, reactions of this type often suffer from poor yields and tedious workup procedures (Scheme 1A). Therefore, a practical and cost-efficient reductive deuteration method of nitriles will be desirable for meeting the massive requirements of α,α-dideuterio amines. Common methods for nitrile reduction include catalytic hydrogenation,5 hydroboration,6 and hydride reductions.7 In 2014, Szostak reported the first general SET reduction of nitriles mediated by SmI2, Et3N, and H2O.8 We are particularly interested in SET reductive deuterations,9 as this emerging strategy can avoid the use of expensive deuterium sources, such as D2 gas, metal deuterides, and boron deuterides. Alkali metal will be a more practical electron donor reagent for large-scale synthesis compared to SmI2. It is known that nitriles can be reduced by the Na/NH3 system.10 However, it is not a viable method for the synthesis of primary amines, because of the inevitable decyanation and transimination side reactions (Scheme 1B). In this work, we discovered that efficient nitrile reduction can be achieved by sodium under heterogeneous conditions in hexane. The use of sodium dispersions with large specific surface areas and hexane are crucial for the success of this reaction. On the basis of those findings, herein, we report the first general SET reductive deuteration of nitriles mediated by sodium dispersions (particle size of 5−10 μm) and EtOD-d1. Both reagents are cheap, bench stable, and commercially

D

euterium-labeled compounds have found increasing applications in life sciences as biological probes and internal MS standards.1 In particular, significant effort has been spent in recent years to develop deuterated drugs. As the C−D bond is more stable toward metabolic oxidation than the C−H bond is, introduction of deuterium as a hydrogen bioisostere has been used to improve the pharmacokinetic and safety profile of drugs.1,2 In 2017, the first deuterated drug, Austedo, was approved by the U.S. Food and Drug Administration as a new chemical entity, while more deuterium-labeled drugs are currently in advanced clinical trials. Primary amines present in a plethora of bioactive compounds, such as pharmaceuticals and neurotransmitters (Figure 1). They are normally metabolized via oxidative

Figure 1. Examples of bioactive primary amines.

deamination, which involves α-C−H bond cleavage. The synthesis of bioactive α,α-dideuterio amines is of great importance, as incorporation of dideuterium at the α-position slows the metabolic oxidation of primary amines.3 For example, α,α-bisdeuteriotryptamine exhibits a significant intensification of blood pressure effect compared with unlabeled tryptamine.3a In addition, α,α-dideuterio amines are also valuable building blocks for the construction of deuterium-labeled probes, drugs, agrochemicals, and functional materials. Recently, the transition metal-catalyzed H/D exchange strategy has been applied in the synthesis of deuterated amines.4 Szymczak and co-workers developed a stereoretentive α-deuteration method for α-chiral and primary amines using a Ru catalyst.4a MacMillan reported a general photoredoxcatalyzed deuteration of tertiary amines mediated by an Ir catalyst.4b Beller developed a Ru-catalyzed H/D exchange © 2018 American Chemical Society

Received: July 9, 2018 Published: August 9, 2018 12269

DOI: 10.1021/acs.joc.8b01730 J. Org. Chem. 2018, 83, 12269−12274

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The Journal of Organic Chemistry

remaining mass balance (Table 1, entry 5). Given that MeOD-d4 has limited solubility in hexane, this observation indicated that sufficient dissolved deuterium donor was important for suppressing C−CN homolysis. As reactions were not conducted under strictly anhydrous conditions, the level of deuterium incorporation may be decreased by the water that is present. However, an attempt to further improve the levels of deuterium incorporation by increasing the amount of EtOD-d1 from 6 to 12 equiv was not effective (Table 1, entry 7), while a high level of deuterium incorporation was finally obtained by increasing both amounts of Na and EtODd1 to 8 equiv (Table 1, entry 8). The optimized conditions (Table 1, entry 8) were then applied to the reductive deuteration of a variety of nitriles (Table 2). A wide range of primary, secondary, and tertiary nitriles were reduced to the corresponding α,α-dideuterio amines in excellent yields and good deuterium incorporations. Terminal, internal, and cyclic alkenes (1i−1k) were well tolerated, while the alkene conjugated with the nitrile was reduced without the use of additional reagents (1l). Aliphatic amine and aliphatic ether did not interfere with the reaction conditions (1g and 1h). In the case of aryl ether 1o, partial loss of the methyl group can also be controlled by decreasing the reaction time to 5 min. The terminal alkyne group in nitrile substrate 1m could be fully converted to the corresponding [D3]-alkenyl by using 16.0 equiv of Na/EtOD-d1. Partial deuterium labeling at the β-position was detected in the reductive deuteration of benzylic nitrile 1n, indicating the formation of sodium (2-mesitylvinylidene)amide 2n′. Scaling up the reaction from 0.5 to 5.0 mmol did not have a detrimental effect on the yield or deuterium incorporation [1a (Table 2)]. Among all the tested substrates, byproducts derived from C−CN homolysis or transimination were not observed. Under the SET conditions, decyanation of nitrile proceeds via radical anion fragmentation to form an alkyl radical. Therefore, decyanation is more favorable with tertiary and allylic nitriles. Under outer sphere electron conditions mediated by alkali metal/ammonia, decyanation products were formed exclusively (Scheme 1B),10b whereas under our conditions, tertiary nitrile 1f and allylic nitrile 1l were converted into the corresponding primary amines in excellent yields using Na/EtOD-d1 in hexane. These results indicate that, under inner sphere electron transfer conditions in hexane,11 the first deuterium transfer and the second electron transfer [3 → 4 → 5 (Scheme 2)] are faster than C−CN homolysis of intermediate 3, which stops the decyanation process. The absence of the secondary amine byproduct indicated that the reduction of the imine intermediate [6 → 7 (Scheme 2)] is fast, and the transimination reaction between 2 and 6 is, therefore, minimized. Next, the synthetic utility of this new deuteration method was demonstrated by the synthesis of deuterated tryptamine and deuterated dopamine (Scheme 3). Both compounds are of pharmacological interest. Deuterated tryptamine was formed in good yield and deuterium incorporation, which demonstrated that this new method was amenable to substrates with heterocycles. Compared with the LiAlD4-mediated reductive deuteration of 1q (Scheme 1A), this new method afforded a higher yield and comparable deuterium incorporations. Hydrolysis of 1q can be achieved by the reported method3c and gives deuterium-labeled dopamine 2q′.

Scheme 1. Reductive Deuteration and SET Reduction of Nitriles

available. The sodium dispersion in oil is a practical reagent for both laboratory-scale and large-scale industrial synthesis. Transimination and decyanation can be controlled well under our conditions. We started our investigation by optimizing the reaction conditions using a primary nitrile 1a as the model compound. The reduction of nitrile is a four-electron process. 1a was converted to primary amine 2a in quantitative yield using a 1.5-fold excess of Na/EtOD-d1 in hexane (Table 1, entry 1). Table 1. Optimization of the Reductive Deuteration of Nitrilesa

entry

Na (equiv)

ROD (equiv)

solvent

yield (%)b

[D2] (%)b

1 2 3 4 5 6 7 8

6.0 6.0 6.0 6.0 6.0 6.0 6.0 8.0

EtOD-d1 (6.0) EtOD-d1 (6.0) EtOD-d1 (6.0) EtOD-d1 (6.0) MeOD-d4 (6.0) i-PrOD-d1 (6.0) EtOD-d1 (12.0) EtOD-d1 (8.0)

hexane THF toluene Et2O hexane hexane hexane hexane

>98 45 69 93 64 >98 >98 >98

87 70 94 80 93 87 88 94

a Conditions: a solution of 1a (0.50 mmol, 1.0 equiv) and ROD was added to sodium dispersions in oil (34.5 wt %, particle size of 5−10 μm) at 0 °C, and the mixtures were stirred for 10 min under N2. b Determined by 1H NMR.

This reaction is highly solvent-dependent. When THF, a common solvent for dissolvent metal reductions, was used, an only 45% yield was obtained (Table 1, entry 2) and the formation of complicated byproducts was observed. The aromatic solvent toluene also led to a much lower yield (Table 1, entry 3). Then, the effects of various deuterium donors on reductive deuteration were studied. i-PrOD-d1 can be used instead of EtOD-d1 (Table 1, entry 6). However, replacing EtOD-d1 with MeOD-d4 resulted in a lower yield with propylbenzene accounting for the majority of the 12270

DOI: 10.1021/acs.joc.8b01730 J. Org. Chem. 2018, 83, 12269−12274

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The Journal of Organic Chemistry Table 2. Reductive Deuteration of Nitriles by Na/EtOD-d1a

Scheme 3. Synthesis of Bioactive Deuterated Primary Amines

dideuterio amines under single-electron transfer conditions using Na/EtOD-d1 in hexane. This reaction also represents the first general nitrile reduction mediated by alkali metal. This developed method is practical, scalable, and amenable to a broad range of nitrile substrates. Byproducts derived from transimination and C−CN homolysis were not detected in any tested examples, indicating the good chemoselectivity of this reaction. The potential application of this new method has been demonstrated by the successful synthesis of pharmacologically interesting deuterated amines. This method is costeffective and regioselective and gives high deuterium incorporations, which compares favorably with the transition metal-catalyzed H/D exchange reaction and metal deuteridemediated reductive deuterations.

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EXPERIMENTAL SECTION

General Information. Glassware was dried in an oven overnight before use. Thin layer chromatography was performed on SIL G/ UV254 silica-aluminum plates, and plates were visualized using ultraviolet light (254 nm) and a KMnO4 solution. For flash column chromatography, silica gel 60 (35−70 μm) was used. NMR data were collected at 300 MHz. Data were manipulated directly from the spectrometer or via a networked personal computer with the appropriate software. All samples were analyzed in DMSO unless otherwise stated. Reference values for residual solvent were taken to be δ 2.50 (DMSO-d6) for 1H NMR and δ 39.5 (DMSO-d6) for 13C NMR. Multiplicities for coupled signals were designated using the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; br, broad signal. J values are given in hertz. All compounds used in this study are commercially available. All solvents and reagents were used as supplied. Sodium dispersions in oil (34.5 wt %, particle size of 5−10 μm) were purchased from Alfa Aesar and titrated before use. The deuterium incorporation of EtOD-d1 used in this study was 99%. Optimization Studies (Table 1). To a suspension of a sodium dispersion in oil (34.5 wt %, 3.00−4.00 mmol) in anhydrous solvent (2.0 mL) was added a solution of substrate (0.500 mmol) and RODd1 (3.00−6.00 mmol) in the same solvent (2.0 mL) under N2 at 0 °C, and the resulting solution was stirred vigorously. After 10 min, the reaction was quenched with an aqueous solution of NaHCO3 (2.0 mL, saturated), and the reaction mixture was diluted with Et2O (10 mL) and brine (10 mL). The aqueous layer was extracted with Et2O (2 × 10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated. Then the sample was analyzed by 1H NMR (300 MHz) to obtain the deuterium incorporation and yield using an

a Conditions: 1 (0.50 mmol, 1.0 equiv), Na/EtOD-d1 (8.0 equiv), hexane (4.0 mL), 0 °C, 5−10 min. Isolated as HCl salts. bIsolated yields. Percentages of exchanged protons are determined by 1H NMR and indicated in square brackets. c1a (5.0 mmol).

Scheme 2. Proposed Mechanism

In conclusion, we have demonstrated the first general reductive deuteration of nitriles to the corresponding α,α12271

DOI: 10.1021/acs.joc.8b01730 J. Org. Chem. 2018, 83, 12269−12274

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The Journal of Organic Chemistry

1H), δ 8.29 (br, 3H), 3.42 (m, 2H), 3.09 (m, 2H), 2.96 (m, 2H), 2.03−1.66 (m, 6H), 1.60 (m, 2H); 13C NMR (75 MHz, DMSO) δ 52.9, 52.6, 37.5 (m), 23.8, 22.7, 22.0. 3-Butoxypropan-1-amine-d2 Hydrochloride12 (2h, Table 2). According to the general procedure, the reaction of 3-butoxypropanenitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 61.9 mg of 2h in 73% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.20 (br, 3H), 3.39 (t, J = 5.9 Hz, 2H), 3.32 (t, J = 6.4 Hz, 2H), 1.78 (t, J = 5.9 Hz, 2H), 1.43 (m, 2H), 1.28 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, DMSO) δ 69.7, 66.9, 36.0 (m), 31.2, 27.0, 18.8, 13.7. (Z)-Non-6-en-1-amine-d2 Hydrochloride12 (2i, Table 2). According to the general procedure, the reaction of (Z)-non-6-enenitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 67.4 mg of 2i in 75% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.07 (br, 3H), 5.42−5.23 (m, 2H), 2.06−1.91 (m, 4H), 1.54 (m, 2H), 1.33−1.24 (m, 4H), 0.90 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, DMSO) δ 131.5, 128.7, 38.0 (m), 28.6, 26.5, 26.3, 25.4, 20.0, 14.2; HRMS (ESI-TOF) m/z M+ calcd for C9H18D2N 144.1716, found 144.1715. Undec-10-en-1-amine-d2 Hydrochloride12 (2j, Table 2). According to the general procedure, the reaction of undec-10-enenitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 99.7 mg of 2j in 96% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.16 (br, 3H), 5.76 (m, 1H), 5.02−4.87 (m, 2H), 1.98 (m, 2H), 1.52 (m, 2H), 1.34−1.19 (m, 12H); 13C NMR (75 MHz, DMSO) δ 138.9, 114.7, 38.2 (m), 33.3, 28.9, 28.9, 28.7, 28.6, 28.4, 26.8, 26.0. Cyclohex-3-en-1-ylmethanamine-d2 Hydrochloride12 (2k, Table 2). According to the general procedure, the reaction of cyclohex-3ene-1-carbonitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 53.1 mg of 2k in 71% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.23 (br, 3H), 5.69−5.56 (m, 2H), 2.18−1.64 (m, 6H), 1.18 (m, 1H); 13C NMR (75 MHz, DMSO) δ 126.7, 125.3, 43.0 (m), 31.2, 28.5, 25.3, 23.8. 3,7-Dimethyloct-6-en-1-amine-d4 Hydrochloride12 (2l, Table 2). According to the general procedure, the reaction of (E)-3,7dimethylocta-2,6-dienenitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 85.2 mg of 2l in 87% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.16 (br, 3H), 5.05 (t, J = 7.1 Hz, 1H), 1.90 (m, 2H), 1.61 (s, 3H), 1.54 (s, 3H), 1.24 (m, 1H), 1.08 (m, 1H), 0.81 (s, 3H); 13C NMR (75 MHz, DMSO) δ 130.6, 124.4, 36.2(m), 36.1, 33.1 (m), 29.0 (m), 25.4, 24.7, 18.9, 17.5. Hex-5-en-1-amine-d5 Hydrochloride12 (2m, Table 2). According to the general procedure, the reaction of hex-5-ynenitrile (0.500 mmol), EtOD-d1 (8.00 mmol), and a Na dispersion in oil (8.00 mmol) afforded 68.9 mg of 2m in 98% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.07 (br, 3H), 2.01 (t, J = 7.2 Hz, 2H), 1.54 (t, J = 7.5 Hz, 2H), 1.38 (m, 2H); 13C NMR (75 MHz, DMSO) δ 137.8 (m), 114.5 (m), 37.9 (m), 32.4, 26.2, 25.0. 2-Mesitylethan-1-amine-d4 Hydrochloride12 (2n, Table 2). According to the general procedure, the reaction of 2-mesitylacetonitrile (1.000 mmol), EtOD-d1 (8.00 mmol), and a Na dispersion in oil (8.00 mmol) afforded 199.7 mg of 2n in 98% yield as a white solid:13 1 H NMR (300 MHz, DMSO) δ 8.42 (br, 3H), 6.79 (s, 2H), 2.25 (s, 6H), 2.16 (s, 3H); 13C NMR (75 MHz, DMSO) δ 136.1, 135.2, 130.9 (m), 128.7, 37.0 (m), 26.7 (m), 20.4, 19.3. 2-(4-Methoxyphenyl)ethan-1-amine-d4 Hydrochloride8 (2o, Table 2). According to the general procedure, the reaction of 2-(4methoxyphenyl)acetonitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) for 5 min afforded 70.0 mg of 2o in 73% yield as a white solid:13 1H NMR (300 MHz, DMSO) δ 7.21−7.13 (m, 2H), 6.91−6.83 (m, 2H), 3.71 (s, 3H); 13C NMR (75 MHz, DMSO) δ 158.0, 129.6, 129.2 (m), 114.0, 55.0, 31.7 (×2) (m). 2-(1H-Indol-3-yl)ethan-1-amine-d2 Hydrochloride8 (2p, Scheme 3). According to the general procedure, the reaction of 2-(1H-indol-3yl)acetonitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 96.4 mg of 2p in 97% yield as a white solid:13 1H NMR (300 MHz, DMSO) δ 11.04 (br, 1H), 8.20

internal standard (1,1,2,2-tetrachloroethane) and comparison with corresponding samples. General Procedure for the Reductive Deuteration of Nitriles by Na/EtOD-d1. To a suspension of a sodium dispersion in oil (34.5 wt %, 4.00 mmol) in anhydrous hexane (2.0 mL) was added a solution of substrate (0.500 mmol) and EtOD-d1 (4.00 mmol) in hexane (2.0 mL) under N2 at 0 °C, and the resulting solution was stirred vigorously. After 10 min, the reaction was quenched with an aqueous solution of NaHCO3 (2.0 mL, saturated), and the reaction mixture was diluted with Et2O (10 mL) and brine (10 mL). The aqueous layer was extracted with Et2O (2 × 10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was treated with a 2 M solution of HCl in Et2O and filtered. The solid was then washed with hexane and dried under vacuum to give the pure product. See Table 2 for the deuterium incorporations of the corresponding products. Warning Statement. Hydrogen generation may occur during the reductive deuteration reactions of nitriles and/or during the quench process. Proper venting and setup are required to avoid pressurization and hydrogen accumulation. The quench process is exothermic, which should be considered in a large-scale reaction. 4-Phenylbutan-1-amine-d2 Hydrochloride8 (2a, Table 2). According to the general procedure, the reaction of 4-phenylbutanenitrile (5.00 mmol), EtOD-d1 (40.0 mmol), and a Na dispersion in oil (40.0 mmol) afforded 921 mg of 2a in 98% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.24 (br, 3H), 7.34− 7.25 (m, 2H), 7.25−7.14 (m, 3H), 2.58 (t, J = 6.8 Hz, 2H), 1.71− 1.54 (m, 4H); 13C NMR (75 MHz, DMSO) δ 141.7, 128.3, 128.2, 125.7, 38.1 (m), 34.6, 27.7, 26.4. 3-Phenylpropan-1-amine-d2 Hydrochloride8 (2b, Table 2). According to the general procedure, the reaction of 3-phenylpropanenitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 80.8 mg of 2b in 93% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.29 (br, 3H), 7.35−7.26 (m, 2H), 7.26−7.15 (m, 3H), 2.66 (t, J = 7.7 Hz, 2H), 1.89 (t, J = 7.7 Hz, 2H); 13C NMR (75 MHz, DMSO) δ 140.9, 128.3, 128.2, 125.9, 37.6 (m), 31.8, 28.4. Dodecan-1-amine-d2 Hydrochloride8 (2c, Table 2). According to the general procedure, the reaction of dodecanenitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 80.6 mg of 2c in 72% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.14 (br, 3H), 1.52 (t, J = 6.8 Hz, 2H), 1.30−1.17 (m, 18H), 0.83 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, DMSO) δ 38.0 (m), 31.3, 29.1, 29.0 (×2), 28.9, 28.7, 28.6, 26.7, 25.9, 22.1, 13.9. Cyclopentylmethanamine-d2 Hydrochloride4e (2d, Table 2). According to the general procedure, the reaction of cyclopentanecarbonitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 66.1 mg of 2d in 96% yield as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.12 (br, 3H), 2.06 (m, 1H), 1.67 (m, 2H), 1.57−1.36 (m, 4H), 1.15 (m, 2H); 13C NMR (75 MHz, DMSO) δ 43.0 (m), 37.4, 30.0, 24.8. Cycloheptylmethanamine-d2 Hydrochloride8 (2e, Table 2). According to the general procedure, the reaction of cycloheptanecarbonitrile (1.000 mmol), EtOD-d1 (8.00 mmol), and a Na dispersion in oil (8.00 mmol) afforded 162.4 mg of 2e in 98% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.22 (br, 3H), 1.83− 1.63 (m, 3H), 1.63−1.29 (m, 8H), 1.16 (m, 2H); 13C NMR (75 MHz, DMSO) δ 44.1 (m), 36.6, 31.0, 27.8, 25.4. [(3r,5r,7r)-Adamantan-1-yl]methanamine-d2 Hydrochloride8 (2f, Table 2). According to the general procedure, the reaction of (3r,5r,7r)-adamantane-1-carbonitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 96.8 mg of 2f in 95% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 8.09 (br, 3H), 1.92 (m, 3H), 1.77−1.40 (m, 12H); 13C NMR (75 MHz, DMSO) δ 49.5 (m), 38.9, 36.1, 31.5, 27.4. 4-(Pyrrolidin-1-yl)butan-1-amine-d 2 Dihydrochloride12 (2g, Table 2). According to the general procedure, the reaction of 4(pyrrolidin-1-yl)butanenitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) afforded 103.2 mg of 2g in 95% yield as a white solid: 1H NMR (300 MHz, DMSO) δ 11.01 (br, 12272

DOI: 10.1021/acs.joc.8b01730 J. Org. Chem. 2018, 83, 12269−12274

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The Journal of Organic Chemistry

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(br, 3H), 7.57 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23 (m, 1H), 7.08 (m, 1H), 6.99 (m, 1H), 3.02 (s, 2H); 13C NMR (75 MHz, DMSO) δ 136.3, 126.8, 123.3, 121.1, 118.4, 118.1, 111.5, 109.5, 28.7 (m), 22.9. 2-(3,4-Dimethoxyphenyl)ethan-1-amine-d2 Hydrochloride3c (2q, Scheme 3). According to the general procedure, the reaction of 2(3,4-dimethoxyphenyl)acetonitrile (0.500 mmol), EtOD-d1 (4.00 mmol), and a Na dispersion in oil (4.00 mmol) for 5 min afforded 102.0 mg of 2q in 92% yield as a white solid:13 1H NMR (300 MHz, DMSO) δ 8.22 (br, 3H), 6.89−6.84 (m, 2H), 6.74 (dd, J = 8.1, 1.8 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H); 13C NMR (75 MHz, DMSO) δ 148.7, 147.3, 131.4, 120.4, 112.6, 112.0, 55.5, 55.4, 41.7 (m), 35.9 (m).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01730. 1 H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jie An: 0000-0002-1521-009X Author Contributions †

Y.D. and S.L. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the National Natural Science Foundation of China (21602248 and 21711530213) for financial support. REFERENCES

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