Reduction and Reductive Deuteration of Tertiary Amides Mediated by

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Reduction and Reductive Deuteration of Tertiary Amides Mediated by Sodium Dispersions with Distinct Proton Donor-Dependent Chemoselectivity Bin Zhang, Hengzhao Li, Yuxuan Ding, Yuhao Yan, and Jie An J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00617 • Publication Date (Web): 11 May 2018 Downloaded from http://pubs.acs.org on May 12, 2018

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The Journal of Organic Chemistry

Reduction and Reductive Deuteration of Tertiary Amides Mediated by Sodium Dispersions with Distinct Proton Donor-Dependent Chemoselectivity Bin Zhang, Hengzhao Li, Yuxuan Ding, Yuhao Yan and Jie An* College of Science, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, China.

ABSTRACT: A practical and scalable single electron transfer reduction mediated by sodium dispersions has been developed for the reduction and reductive deuteration of tertiary amides. The chemoselectivity of this method highly depends on the nature of the proton donor. The challenging reduction via C−N bond cleavage has been achieved using Na/EtOH, affording alcohol products, while the use of Na/NaOH/H2O leads to the formation of amines via selective C−O scission. Sodium dispersions with high specific surface areas are crucial to obtain high yields and good chemoselectivity. This new method tolerates a range of tertiary amides. Moreover, the corresponding reductive deuterations mediated by Na/EtOD-d1 and Na/NaOH/D2O afford useful α,α-dideuterio alcohols and α,α-dideuterio amines with excellent deuterium content.

INTRODUCTION The reduction of carboxamides represents one of the most important and valuable methods for the synthesis of amines or alcohols from bench-stable and widely available amide precursors.1 Among carboxylic acid derivatives, carboxamides are the most difficult to reduce due to their high stability originating from amidic resonance. At present, the moisture sensitive aluminum and boron hydrides are still the most common reagents for amide reductions, despite their pyrophoric properties, low atom economy and costly purification process.2 Over the past decades, transition metal catalyzed hydrosilylations have emerged as a promising amide reduction strategy to achieve high chemoselective and improved functional group tolerance.3 However, strict control of the reaction conditions and the use of stoichiometric high molecular weight silane reductants are clear drawbacks of those methods. While catalytic hydrogenation is a more atom-economical approach, this method typically requires harsh reaction conditions.2a,4 In most advanced chemoselective amide reduction protocols, the amide bond is reduced to the corresponding amine via C−O scission, while reducing amides into alcohols via selective C−N bond cleavage still represents a formidable challenge (Scheme 1). In pharmaceutical industry, expensive metal trialkylborohydrides and aminoborohydrides, such as LiEt3BH and LiNR2BH3, are the reagents of choice for amide reduction to afford alcohol products (A, Scheme 2).2b, 5 How-

ever, narrow substrate scope or low C−N bond cleavage selectivity are often observed. Recently, [Ru]4b-g, [Fe]4h or [Mn]4i catalyzed hydrogenation conditions have been developed for the reduction of amide and lactam substrates with excellent C−N bond cleavage selectivity at elevated temperatures and/or high H2 pressure (B, Scheme 2).

Scheme 1. General Pathways for the Reduction of Amides Szostak, Procter and co-workers reported the first general single electron transfer (SET) method for a highly C−N scission selective reduction of amides mediated by SmI2/amine/H2O.6 On the other hand, a chemoselective SET reduction mediated by cheap, bench-stable and commercially available electron donor reagents, such as alkali metal, would be more desirable and sustainable, especially for industrial processes. Traditionally, alkali metals in liquid NH3 or HMPA have been used to reduce amides to alcohols with moderate C−N bond cleavage selectivity.1a, 7 Moreover, C−O bond cleavage represents a more favorable reaction pathway in the dissolving metal reduction of lactams.1a Although alkali met-

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als are cheap and sustainable, their use in SET reductions has seen limited applications due to poor chemoselectivity and safety issues.

Scheme 2. Strategies for the C−N Cleavage Selective Amide Reductions and This Work. In this manuscript, we report a SET reduction of tertiary amides mediated by sodium dispersion (particle size 5-10 µm), which shows unusual proton donor-dependent chemoselectivity (C, Scheme 2). Several applications of sodium dispersion as a practical electron transfer reagent has been demonstrated by our group.8 Now, we discovered that, using hexanes as the key solvent, sodium dispersions with high specific surface areas is effective for the reduction of tertiary amides. In amide reduction, C−N bond cleavage is favorable using Na/EtOH (C, Scheme 2), as EtOH is not acidic enough to protonate the hemiaminal-like intermediate b. However, the chemoselectivity can be switched by using more acidic proton donor H2O, wherein Na/NaOH/H2O leads to the formation of amines via selective C−O cleavage. In this case, b is protonated to give hemiaminal c, the sequential reduction of c afford amines (C, Scheme 2). It is noteworthy that toxic solvents, such as liquid ammonia and HMPA, are not required. Furthermore, the use of hexanes, a solvent with low dielectric constant, is critical to increase both the yield and chemoselectivity in the reactions mediated by both reagents systems. While the reduction of secondary and primary amides resulted in lower yields under those conditions. Moreover, we report chemoselective reductive deuterations of tertiary amides mediated by Na/EtOD-d1 or Na/NaOH/D2O which achieves the net regioselective introduction of deuterium at unactivated sp3 carbons.9 Reductive deuteration of amides is of great importance, as deuterium labeled compounds are valuable drug candidates, and widely used as metabolic or pharmacokinetic probes, and internal standards in mass spectrometry.10 RESULTS AND DISCUSSION

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Initially, the effect of proton donors on the chemoselectivity of sodium dispersion mediated tertiary amide reduction was examined using 1a as a model substrate. The reactions were conducted in hexane at 0 °C with 10 equiv of sodium dispersion (Table 1). In general, alcoholic proton donors lead to the formation of alcohol 2a as the major product via C−N bond cleavage. Compared with EtOH and i-PrOH (entries 1-2), the reaction with MeOH (entry 3) resulted in lower yield and selectivity, possibly due to the low solubility of MeOH in hexane. The C−N scission selectivity increased with higher loading of alcoholic proton donor (entries 5-6). >9:1 C−N/C−O bond cleavage selectivity was achieved by using 30 equiv EtOH (entry 6). Excess EtOH also increased the solubility of amide substrate in the solvent. On the contrary, the C−N bond cleavage was significantly prohibited with Na/H2O. Under these conditions, amine 3a derived from the C−O bond scission was formed as the major product with high 19:81 C−N/C−O bond cleavage selectivity (entry 4, Table 1). The conditions for selective C−O cleavage were further improved by using NaOH as the additive (entry 9). Interestingly, a neutral salt NaCl can also increase the yield and selectivity of the amine product (entry 10). Of particular note, the amide reductions mediated by both Na/EtOH or Na/ NaOH/H2O were highly solvent dependent. Hexane, a solvent rarely used in dissolving metal reductions, increases the chemoselectivity and yield under both conditions. However, solvents with higher dielectric constant, such as THF, result in much lower yields and chemoselectivity (entries 7 and 11, Table 1), indicative of inner sphere mechanism in the present case.11 Table 1. Optimization Studies in the Tertiary Amides Reduction Mediated by Sodium Dispersionsa

entry

H donor (equiv)

additive (equiv)

solvent

yield (%)

2a:3a

-

hexane

2a, 78

78:22 81:19

1

i-PrOH (10)

2

EtOH (10)

-

hexane

2a, 78

3

MeOH (10)

-

hexane

2a, 63

68:32

4

H2O (10)

-

hexane

3a, 35

19:81

5

EtOH (20)

-

hexane

2a, 84

84:16

6

EtOH (30)

-

hexane

2a, 90

91:9

7

EtOH (30)

-

THF

2a, 40

66:34

8

H2O (20)

-

hexane

3a, 46

18:82

9

H2O (20)

NaOH (4)

hexane

3a, 86

11:89

10

H2O (20)

NaCl (2)

hexane

3a, 69

4:96

11

H2O (20)

NaOH (4)

THF

only 1a recovered

a Conditions: sodium dispersions in oil (34.5 wt %, particle size 510 µm, 10.0 equiv) was added to a mixture of 1a (0.50 mmol, 1.0 equiv) H donor and additive in hexane (2.5 mL) at 0 °C, and stirred for 20 min to 3 h under N2. Yields were determined by 1H NMR.

The optimized conditions were then applied to the reduction and reductive deuteration of a range of tertiary amides (Tables 2-4). Generally, >9:1 C−N/C−O and >5:1 C−O/C−N selectivity, respectively, was observed for all substrates examined. Aldol-type or amide esterification products were not detected


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in any reactions. The substrate scope of Na/EtOH mediated amide reduction was first investigated. Hydrocinnamic acid amides bearing both acyclic (1b-e) and cyclic N-substitution (1a, 1f and 1g) were all reduced in high yields to the corresponding alcohols with excellent C−N/C−O bond cleavage selectivity (Table 2). Interestingly, the reaction of strained amide 1g lead to the formation of trace amount of 3-phenyl-Npropylpropanamide via N-C cleavage of the pyrrolidine ring.6h Fluorides (1i) are tolerated under the reaction conditions, while chloride and bromide substituents (1j and 1k) were fully reduced. Substrates bearing both internal and terminal olefins (1s and 1r) were reduced without the reduction and isomerization of the alkene group. α, β-Unsaturated amide 1u underwent double reduction to give the saturated alcohol in high yield. Sterically-hindered substrates (1m and 1o) are relatively less reactive and resulted in lower conversions. The selective reduction of unhindered amide at the presence of sterically demanding substrate can be achieved in an intermolecular competition reaction with 10 equiv Na and 30 equiv EtOH (eq. 1). In addition, the selective reduction of ester substrate with the existence of unhindered amide 1b is also possible using 4.5 equiv of Na/EtOH (eq. 3). This protocol is also amendable to heterocyclic functional groups, such as indoles (1t). Of particular note is the high C−N scission selectivity in the reduction of lactam 1v, while the amine is formed as the major product under the traditional dissolving metal reduction conditions.1a Reduction of secondary amide 1h resulted in lower yield with the recovered starting materials accounting for the majority of the remaining mass balance. This method is also amenable to aromatic amide 1x, although trace amount of by-product derived from dearomatization was observed. The reaction is easily scalable as demonstrated in the reduction of 1b on a 10 mmol scale. (1b, Table 2). Table 2. Chemoselective Reduction of Tertiary Amides to Alcohols Using Na/EtOHa

a

Conditions: sodium dispersions in oil (5.0 mmol) was added to a solution of 1 (0.50 mmol) and EtOH (15.0 mmol ) in hexane (2.5 mL) at 0 °C, and stirred for 20 min under N2. bIsolated yields. c 10.0 mmol scale. Na-EtOH Ph

Ph

OH

(1) 1w >95% recovered

N

1w >95% recovered (2)

hexane, 0 oC

N

2a, 94%

1w O O Ph

N

1b

Na-NaOH-H 2O Ph hexane, 0 oC

3a, 78%

O O

Ph O

Na-EtOH

Ph o

Ph

N

hexane, 0 C

2a, 98%

OH 1b >95% recovered (3)

1b

Table 3. Reductive Deuteration of Tertiary Amides to Alcohols Using Na/EtOD-d1a


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a Conditions: sodium dispersions in oil (5.0 mmol) was added to a solution of 1 (0.50 mmol) and EtOD-d1 (15.0 mmol ) at 0 °C, and stirred for 20 min under N2. bIsolated yields; percentage of exchanged protons at the specified position are indicated in brackets, determined by 1H NMR.

Table 4. Chemoselective Reduction of Tertiary Amides to Amines Using Na/NaOH/H2Oa

a

Conditions: sodium dispersions in oil (5.0 mmol) was added to a mixture of 1 (0.50 mmol), NaOH (1.9 mmol) and H2O or D2O (10.0 mmol) in hexane (2.5 mL) at 0 °C, and stirred for 3 h under N2. Isolated yields. Percentage of exchanged protons at the specified position are indicated in brackets, determined by 1H NMR.

The reductive deuteration mediated by Na/EtOD-d1 was tested with different classes of tertiary amides (Table 3). High [D2] incorporation was obtained across all substrates examined (Table 2). The chemoselectivity and yields were comparable with the Na/EtOH mediated reactions. Chloride (1y) were

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reduced with 91% deuterium incorporations without the use of additional reagents. Furthermore, partial deuterium labeling via enolization was observed, indicative of minor enolization pathway under these conditions. Next, representative tertiary amides with different functional groups were reduced to amines using Na/NaOH/H2O (Table 4). All the substrates were reduced with high C−O bond cleavage selectivity. Na/NaOH/D2O is also amendable for the reductive deuteration of amides and affords unique α,αdideuterio amines, which are not accessible via transition metal catalyzed H–D exchange strategy (Table 4). CONCLUSION In summary, an operationally-simple and cost-effective method for reduction of tertiary amides has been developed. A range of tertiary amides is reduced to the corresponding alcohols using Na/EtOH with high selectivity for the C−N bond cleavage. The chemoselectivity of Na dispersion mediated amide reduction highly depends on the acidity of the reagent system. By switching to Na/NaOH/H2O, tertiary amides are conveniently converted into amines via selective C−O bond cleavage. This method represents a rare example of additive controlled switch of the reaction pathways in the SET processes of carboxylic acid derivatives. The utility of this method has been further demonstrated in the synthesis of valuable α,αdideuterio alcohols or α,α-dideuterio amines. Further application of sodium dispersion mediated SET methods are ongoing and will be reported in due course. EXPERIMENTAL SECTION Warning Statement. Sodium dispersions mediated tertiary amide reductions are exothermic and may involve gas formation, which may not be negligible for multi gram reactions. Sodium dispersions is not pyrophoric and easy to handle in an open atmosphere. However, mixing a large amount of sodium dispersions with water should be avoided. General Information. Glassware was dried in an oven overnight before use. Thin layer chromatography was carried out on SIL G/UV254 silica-aluminum plates and plates were visualized using ultra-violet light (254 nm) and KMnO4 solution. For flash column chromatography, silica gel 60, 35-70 µ was used. NMR data was collected at 300, 400, or 500 MHz. Data was manipulated directly from the spectrometer or via a networked PC with appropriate software. All samples were analyzed in CDCl3 unless otherwise stated. Reference values for residual solvent were taken as δ = 7.27 (CDCl3) for 1H NMR; δ = 77.1 (CDCl3) for 13C NMR. Multiplicities for coupled signals were designated using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, br = broad signal, and are given in Hz. Sodium dispersions in oil (34.5 wt %) was purchased from Alfa Aesar and titrated before use. All compounds used in this study have been described in the literature or are commercially available. All solvents and reagents were used as supplied. Amides were purchased from commercial suppliers or prepared by standard methods.6b Titration Method for Sodium Dispersions in Oil. To a suspension of sodium dispersion in oil (about 1.0 mmol, mass was measured accurately) in anhydrous hexane (2.0 mL) was added a solution of 4-phenylbutan-2-one (1.500 mmol) and iPrOH (3.00 mmol) in hexane (1.5 mL) under N2 at 0 °C and the resulting solution was stirred vigorously. After 10 min the reaction was quenched by an aqueous solution of NaHCO3 (2.0 mL, saturated) and the reaction mixture was diluted with


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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 yield of 4-phenylbutan-2-ol using internal standard (Cl2CHCHCl2) and comparison with corresponding samples. The mass fraction of sodium was calculated according to the equation below: ωNa = 2(

)(

)×100%

Optimization Studies (Table 1). To a solution of amide (0.500 mmol) in anhydrous hexane (2.5 mL), was added proton donor (5.00 mmol-15.0 mmol), and additive (2.2-3.8 mmol) followed by sodium dispersions (34.5 wt %, 5.00 mmol) under N2 at 0 °C and the resulted solution was stirred vigorously. After 20 min-3 h, sodium was all consumed and the reaction was quenched by an aqueous solution of NaHCO3 (5.0 mL, saturated solution). 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 sample was then analyzed by 1H NMR (CDCl3, 300/400/500 MHz) to obtain the yield using internal standard (Cl2CHCHCl2) and comparison with corresponding samples. General Procedure for the Reduction of Tertiary Amides by Na/EtOH. To a solution of amides (0.500 mmol) in hexane (2.5 mL), was added EtOH (15.0 mmol, 876 µL), followed by sodium dispersions (34.5 wt %, 5.00 mmol) under N2 at 0 °C and the mixture was stirred vigorously. The reaction mixture was stirred at 0 °C for 20 min and was then quenched by aqueous solution of NaHCO3 (5.0 mL, saturated solution). 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 purified by flash chromatography (silica, 0-20% EtOAc/petroleum ether). 3-Phenylpropan-1-ol 2a6b (entry 1, Table 2). According to the general procedure, the reaction of N,N-dimethyl-3phenylpropanamide 1b (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2a 65.4 mg in 96% yield as a colorless oil with C−N/C−O selectivity of 96:4. 1H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 2H), 7.24-7.19 (m, 3H), 3.69 (t, J = 6.3, 2H), 2.73 (t, J = 7.8, 2H), 1.96-1.88 (m, 2H), 1.41 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 141.9, 128.5, 128.4, 125.9, 62.3, 34.2, 32.1. 3-Phenylpropan-1-ol 2a6b (entry 2, Table 2). According to the general procedure, the reaction of N-ethyl-N-methyl-3phenylpropanamide 1c (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2a 49.7 mg in 73% yield with C−N/C−O selectivity of 91:9. Spectroscopic properties matched those previously described. 3-Phenylpropan-1-ol 2a6b (entry 3, Table 2). According to the general procedure, the reaction of N-allyl-N-methyl-3phenylpropanamide 1d (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2a 63.3 mg in 93% yield with C−N/C−O selectivity of 93:7. Spectroscopic properties matched those previously described.

3-Phenylpropan-1-ol 2a6b (entry 4, Table 2). According to the general procedure, the reaction of N-benzyl-N-methyl-3phenylpropanamide 1e (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2a 62.0 mg in 91% yield with C−N/C−O selectivity of 91:9. Spectroscopic properties matched those previously described. 3-Phenylpropan-1-ol 2a6b (entry 5, Table 2). According to the general procedure, the reaction of 3-phenyl-1-(piperidin-1yl)propan-1-one 1f (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2a 64.0 mg in 94% yield with C−N/C−O selectivity of 94:6. Spectroscopic properties matched those previously described. 3-Phenylpropan-1-ol 2a6b (entry 6, Table 2). According to the general procedure, the reaction of 3-phenyl-1-(pyrrolidin1-yl)propan-1-one 1g (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2a 53.1 mg in 78% yield with C−N/C−O selectivity of 91:9. Spectroscopic properties matched those previously described. 3-Phenylpropan-1-ol 2a6b (entry 7, Table 2). According to the general procedure, the reaction of 3-phenyl-Npropylpropanamide 1h (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2a 17.7 mg in 26% yield. Spectroscopic properties matched those previously described. 3-(4-Fluorophenyl)propan-1-ol 2i6b (entry 8, Table2). According to the general procedure, the reaction of 3-(4fluorophenyl)-N,N-dimethylpropanamide 1i (0.500 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2i 69.4 mg in 90% yield as a colourless oil with C−N/C−O selectivity of 90:10. 1H NMR (500 MHz, CDCl3) δ 7.19-7.14 (m, 2H), 6.99-6.95 (m, 2H), 3.67 (t, J = 6.5, 2H), 2.69 (t, J = 7.7, 2H), 1.91-1.84 (m, 2H), 1.39 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 161.3 (d, J = 242.9), 137.4 (d, J = 2.7), 129.2 (d, J = 7.3), 115.2 (d, J = 21.0), 62.1, 34.4, 31.3. 3-Phenylpropan-1-ol 2a6b (entry 9, Table 2). According to the general procedure, the reaction of 3-(4-chlorophenyl)-N,Ndimethylpropanamide 1j (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2a 65.4 mg in 96% yield with C−N/C−O selectivity of 96:4. Spectroscopic properties matched those previously described. 3-Phenylpropan-1-ol 2a6b (entry 10, Table 2). According to the general procedure, the reaction of 3-(4-bromophenyl)-N,Ndimethylpropanamide 1k (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2a 60.6 mg in 89% yield with C−N/C−O selectivity of 92:8. Spectroscopic properties matched those previously described. 3-(4-Methoxyphenyl)propan-1-ol 2l6b (entry 11, Table 2). According to the general procedure, the reaction of 3-(4methoxyphenyl)-N,N-dimethylpropanamide 1l (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2l 76.5 mg in 92% yield as a colourless oil with C−N/C−O selectivity of 92:8. 1H NMR (500 MHz, CDCl3) δ 7.15-7.10 (m, 2H), 6.86-6.82 (m, 2H), 3.80 (s,


5


3H), 3.68 (t, J = 6.3, 2H), 2.66 (t, J = 7.6, 2H), 1.91-1.84 (m, 2H), 1.33 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 157.8, 133.9, 129.4, 113.9, 62.3, 55.3, 34.5, 31.2. 2-(4-Isobutylphenyl)propan-1-ol 2m8a (entry 12, Table 2). According to the general procedure, the reaction of methyl 2(4-isobutylphenyl)-N,N-dimethylpropanamide 1m (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes20% EtOAc/hexane), afforded 2m 59.6 mg in 62% yield as a colorless oil with C−N/C−O selectivity of 90:10. 1H NMR (500 MHz, CDCl3) δ 7.17-7.14 (m, 2H), 7.14-7.10 (m, 2H), 3.69 (d, J = 6.9, 2H), 2.98-2.90 (m, 1H), 2.46 (d, J = 7.3, 2H), 1.92-1.81 (m, 1H), 1.28 (d, J = 6.9, 3H), 0.92 (d, J = 6.6, 6H); 13 C NMR (125 MHz, CDCl3) δ 140.8, 140.1, 129.4, 127.2, 68.8, 45.1, 42.1, 30.3, 22.5, 17.7. 2-Methyl-3-phenylpropan-1-ol 2n12 (entry 13, Table 2). According to the general procedure, the reaction of N,N,2trimethyl-3-phenylpropanamide 1n (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-30% EtOAc/hexane), afforded 2n 54.1 mg in 72% yield as a colourless oil with C−N/C−O selectivity of 94:6. 1H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.24-7.17 (m, 3H), 3.55 (dd, J = 10.7, 5.8, 1H), 3.49 (dd, J = 10.7, 6.0, 1H), 2.77 (dd, J = 13.6, 6.3, 1H), 2.44 (dd, J = 13.6, 8.2, 1H), 2.02-1.91 (m, 1H), 1.38 (br, 1H), 0.93 (d, J = 6.9, 3H); 13C NMR (100 MHz, CDCl3) δ 140.7, 129.2, 128.3, 126.0, 67.8, 39.8, 37.9, 16.5. 1-Adamantanemethanol 2o6b (entry 14, Table 2). According to the general procedure, the reaction of N,Ndimethyladamantane-1-carboxamide 1o (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2o 59.0 mg in 71% yield as a white solid with C−N/C−O selectivity of 82:18. Mp 117-118 °C; 1H NMR (500 MHz, CDCl3) δ 3.21 (s, 2H), 2.03-1.98 (m, 3H), 1.77-1.71 (m, 3H), 1.69-1.63 (m, 3H), 1.54-1.50 (m, 6H), 1.27 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 74.0, 39.1, 37.3, 34.6, 28.3. 3-Cyclopentylpropan-1-ol 2p8a (entry 15, Table 2). According to the general procedure, the reaction of 3-cyclopentylN,N-dimethylpropanamide 1p (0.500 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2p 48.7 mg in 76% yield as a colorless oil with C−N/C−O selectivity of 85:15. 1H NMR (400 MHz, CDCl3) δ 3.65 (t, J = 6.6, 2H), 1.82-1.71 (m, 3H), 1.65-1.46 (m, 6H), 1.43-1.33 (m, 3H), 1.14-1.04 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 63.4, 40.0, 32.8, 32.2, 32.1, 25.3. Decan-1-ol 2q12 (entry16, Table 2). According to the general procedure, the reaction of N,N-dimethyldecanamide 1q (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes20% EtOAc/hexane), afforded 2q 57.8 mg in 73% yield as a colorless oil with C−N/C−O selectivity of 92:8. 1H NMR (400 MHz, CDCl3) δ 3.65 (t, J = 6.3, 2H), 1.61-1.53 (m, 2H), 1.401.21 (m, 15H), 0.89 (t, J = 6.9, 3H); 13C NMR (100 MHz, CDCl3) δ 63.2, 32.9, 32.0, 29.7, 29.6, 29.5, 29.4, 25.8, 22.8, 14.2. Undec-10-en-1-ol 2r8a (entry 17, Table 2). According to the general procedure, the reaction of N,N-dimethylundec-10enamide 1r (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2r 70.7 mg in

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83% yield as a colorless oil with C−N/C−O selectivity of 94:6. 1 H NMR (500 MHz, CDCl3) δ 5.86 - 5.77 (m, 1H), 5.03 - 4.97 (m, 1H), 4.96 - 4.91 (m, 1H), 3.64 (t, J = 6.6, 2H), 2.07 - 2.02 (m, 2H), 1.61 - 1.53 (m, 2H), 1.46 - 1.24 (m, 13H); 13C NMR (125 MHz, CDCl3) δ 139.3, 114.2, 63.2, 33.9, 32.9, 29.6, 29.5× 2, 29.2, 29.0, 25.8. (Z)-Octadec-9-en-1-ol 2s8a (entry 18, Table 2). According to the general procedure, the reaction of N,N-dimethyloleamide 1s (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2s 111.4 mg in 83% yield as a colorless oil with C−N/C−O selectivity of 94:6. 1H NMR (500 MHz, CDCl3) δ 5.38-5.31 (m, 2H), 3.65 (t, J = 6.8, 2H), 2.05-2.00 (m, 4H), 1.61-1.55 (m, 2H), 1.39-1.22 (m, 23H), 0.89 (t, J = 7.1, 3H); 13C NMR (125 MHz, CDCl3) δ 130.1, 129.9, 63.2, 32.9, 32.0, 29.9, 29.8, 29.6× 2, 29.5, 29.4× 2, 29.3, 27.3× 2, 25.8, 22.8, 14.2. 2-(1H-Indol-3-yl)ethanol 2t6b (entry 19, Table 2). According to the general procedure, the reaction of 2-(1H-indol-3-yl)N,N-dimethylacetamide 2t (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after preparative TLC (20% EtOAc/Hexane), afforded 2t 68.5 mg in 85% yield as a brown oil with C−N/C−O selectivity of 90:10. 1H NMR (500 MHz, CDCl3) δ 8.08 (br, 1H), 7.65-7.63 (m, 1H), 7.41-7.39 (m, 1H), 7.24-7.21 (m, 1H), 7.17-7.14 (m, 1H), 7.11-7.09 (m, 1H), 3.93 (t, J = 6.3, 2H), 3.06 (m, 2H), 1.59 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 136.5, 127.5, 122.6, 122.3, 119.6, 118.9, 112.4, 111.3, 62.7, 28.8. 3-(4-Methoxyphenyl)propan-1-ol 2l6b (entry 20, Table 2). According to the general procedure, the reaction of (E)-3-(4methoxyphenyl)-N,N-dimethylacrylamide 1u (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexanes-20% EtOAc/hexane), afforded 2l 75.6 mg in 91% yield as a colourless oil with C−N/C−O selectivity of 91:9. Spectroscopic properties matched those previously described. 4-(Ethylamino)butan-1-ol 2v13 (entry 21, Table 3). According to the general procedure, the reaction of 1-ethylpyrrolidin2-one 1v (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (30% EtOAc/hexane-100% EtOAc), afforded 2v 45.7 mg in 78% yield as a colorless oil with C−N/C−O selectivity of 90:10. DCM was used as the extracting solvent instead of Et2O. 1H NMR (400 MHz, CDCl3) δ 3.79 (br, 2H), 3.56 (t, J = 4.6, 2H), 2.70-2.63 (m, 4H), 1.72-1.59 (m, 4H), 1.12 (t, J = 7.2, 3H); 13C NMR (125 MHz, CDCl3) δ 62.6, 49.4, 43.7, 32.7, 29.0, 14.8. (4-Methoxyphenyl)methanol 2x6b (entry 22, Table 3). According to the general procedure, the reaction of 4-methoxyN,N-dimethylbenzamide 1x (0.50 mmol), EtOH (15.0 mmol) and sodium dispersions (5.00 mmol) for 20 min at 0 °C, after chromatography (hexane-10% EtOAc/hexane), afforded 2x 49.7 mg in 72% yield as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 2H), 6.88 (m, 2H), 4.60 (s, 2H), 3.80 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.2, 133.2, 128.7, 114.0, 65.0, 55.3. General Procedure for the Reductive Deuteration of Tertiary Amides by Na/EtOD-d1. To a solution of amides (0.500 mmol) in hexane (2.5 mL), was added EtOD-d1 (15.0 mmol, 876 µL), followed by sodium dispersions (34.5 wt %, 5.00 mmol) under N2 at 0 °C and the mixture was stirred vigorously. The reaction mixture was stirred at 0 °C for 20 min


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and was then quenched by aqueous solution of NaHCO3 (5.0 mL, saturated solution). 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 purified by flash chromatography (silica, 0-20% EtOAc/petroleum ether). See Table 3 for the deuterium incorporations of the corresponding products. 3-Phenylpropan-1,1-d2-1-ol 4a6b (entry1, Table 3). According to the general procedure, the reaction of N,N-dimethyl-3phenylpropanamide (0.50 mmol), EtOD-d1 (15.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 10 min at 0 °C, after chromatography (20% EtOAc/hexane), afforded 4a 65.6 mg in 95% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.32-7.23 (m, 2H), 7.23-7.14 (m, 3H), 2.70 (t, J = 7.7 Hz, 2H), 1.87 (t, J = 7.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 141.9, 128.5, 128.4, 125.9, 61.5 (m), 34.0, 32.1. 3-Phenylpropan-1,1-d2-1-ol 4a6b (entry2, Table 3). According to the general procedure, the reaction of N-ethyl-N-methyl3-phenylpropanamide (0.50 mmol), EtOD-d1 (15.0 mmol) and sodium dispersions (34.1 wt %, 5.00 mmol) for 10 min at 0 °C, after chromatography (20% EtOAc/hexane), afforded 4a 55.3 mg in 80% yield as a colorless oil. Spectroscopic properties matched those previously described. 3-Phenylpropan-1,1-d2-1-ol 4a6b (entry3, Table 3). According to the general procedure, the reaction of 3-phenyl-1(pyrrolidin-1-yl)propan-1-one (0.50 mmol), EtOD-d1 (15.0 mmol) and sodium dispersions (34.1 wt %, 5.00 mmol) for 10 min at 0 °C, after chromatography (20% EtOAc/hexane), afforded 4a 62.9 mg in 91% yield as a colorless oil. Spectroscopic properties matched those previously described. 3-Phenylpropan-1,1-d2-1-ol 4a6b (entry 4, Table 3). According to the general procedure, the reaction of 3-phenyl-1(piperidin-1-yl)propan-1-one 1f (0.50 mmol), EtOD-d1 (15.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 10 min at 0 °C, after chromatography (50% EtOAc/hexane), afforded 4a 64.3 mg in 93% yield as a colorless oil. Spectroscopic properties matched those previously described. 3-Phenylpropan-1,1-d2-1-ol 4a6b (entry 5, Table 3). According to the general procedure, the reaction of 1-morpholino-3phenylpropan-1-one 1x (0.50 mmol), EtOD-d1 (15.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 10 min at 0 °C, after chromatography (20% EtOAc/hexane), afforded 4a 60.8 mg in 88% yield as a colorless oil. Spectroscopic properties matched those previously described. 3-(Phenyl-3-d)propan-1,1-d2-1-ol 4y6b (entry 6, Table 3). According to the general procedure, the reaction of 3-(3chlorophenyl)-1-(pyrrolidin-1-yl)propan-1-one 1y (0.50 mmol), EtOD-d1 (15.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 10 min at 0 °C, after chromatography (hexane-20% EtOAc/hexane), afforded 4y 64.0 mg in 92% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 1H), 7.24-7.14 (m, 3H), 2.71 (t, J = 7.7 Hz, 2H), 1.88 (t, J = 7.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 141.9, 128.5 (C×2), 128.4, 128.2 (m), 125.8, 61.6 (m), 34.1, 32.1. 3-(4-Fluorophenyl)propan-1,1-d2-1-ol 4z6b (entry 7, Table 3). According to the general procedure, the reaction of 3-(4fluorophenyl)-1-(pyrrolidin-1-yl)propan-1-one 1z (0.50 mmol), EtOD-d1 (15.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 10 min at 0 °C, after chromatography (50% EtOAc/hexane), afforded 4z 68.7 mg in 88% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.19-7.01 (m, 2H),

7.01-6.91 (m, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.85 (t, J = 7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 161.4 (d, JC-F = 243.4 Hz), 137.5 (d, JC-F = 3.2 Hz), 129.8 (d, JC-F = 7.8 Hz), 115.2 (d, JC-F = 21.2 Hz), 61.4 (m), 34.2, 31.3. 3-(4-Methoxyphenyl)propan-1,1-d2-1-ol 4aa6b (entry 8, Table 3). According to the general procedure, the reaction of 3(4-methoxyphenyl)-1-(pyrrolidin-1-yl)propan-1-one 1aa (0.50 mmol), EtOD-d1 (15.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 10 min at 0 °C, after chromatography (hexane-20% EtOAc/hexane), afforded 4aa 79.1 mg in 94% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.11 (m, 2H), 6.83 (m, 2H), 3.78 (s, 3H), 2.65 (t, J = 7.6 Hz, 2H), 1.84 (t, J = 7.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 157.8, 134.0, 129.3, 113.9, 61.6 (m), 55.3, 34.3, 31.1. 3-(P-tolyl)propan-1,1-d2-1-ol 4ab12 (entry 9, Table 3). According to the general procedure, the reaction of 1-(pyrrolidin1-yl)-3-(p-tolyl)propan-1-one 1ab (0.50 mmol), EtOD-d1 (15.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 10 min at 0 °C, after chromatography (20% EtOAc/hexane), afforded 4ab 72.3 mg in 95% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.08 (m, 4H), 2.64 (t, J = 7.7 Hz, 2H), 2.31 (s, 3H), 1.84 (t, J = 7.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 138.8, 135.3, 129.1, 128.3, 61.4 (m), 34.1, 31.6, 21.0. General Procedure for the Reduction of Tertiary Amides by Na/NaOH/H2O. To a solution of amides (0.500 mmol) in anhydrous hexane (2.5 mL) was added a solution of NaOH (1.89 mmol) in H2O (10.0 mmol), followed by sodium dispersions (34.5 wt %, 5.00 mmol) under N2 at 0 °C and the mixture was stirred vigorously. After 3 h, the reaction was quenched by an aqueous solution of HCl (3M, 15 mL). The aqueous layer was washed by Et2O (3×15 mL) to remove the hydrophobic impurities and then basified with aqueous solution of NaOH (3 M) to pH >10. The aqueous phase was extracted with Et2O (2×15 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to give the pure product. N,N-dimethyl-3-phenylpropan-1-amine 3b3j (Table 4). According to the general procedure, the reaction of N,Ndimethyl-3-phenylpropanamide 1b (0.50 mmol), NaOH (1.89 mmol), H2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol), afforded 3b 68.6 mg in 84% yield as a colorless oil with C−O/C−N selectivity of 88:12. 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 2H), 7.22-7.14 (m, 3H), 2.63 (t, J = 7.8, 2H), 2.30 (t, J = 7.5, 2H), 2.22 (s, 6H), 1.79 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 142.3, 128.4, 128.4, 125.8, 59.4, 45.5, 33.8, 29.5. 1-(3-Phenylpropyl)piperidine 3f14 (Table 4). According to the general procedure, the reaction of 3-phenyl-1-(piperidin-1yl)propan-1-one 1f (0.50 mmol), NaOH (1.89 mmol), H2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol), afforded 3f 65.1 mg in 64% yield as a colorless oil with C−O/C−N selectivity of 89:11. 1H NMR (300 MHz, CDCl3) δ 7.31-7.22 (m, 2H), 7.21-7.12 (m, 3H), 2.61 (t, J = 7.8, 2H), 2.43-2.25 (m, 6H), 1.82 (m, 2H), 1.63-1.53 (m, 4H), 1.43 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 142.4, 128.4, 128.3, 125.7, 59.0, 54.7, 34.0, 28.7, 26.1, 24.6. 4-(3-Phenylpropyl)morpholine 3x15 (Table 4). According to the general procedure, the reaction of 1-morpholino-3phenylpropan-1-one 1x (0.50 mmol), NaOH (1.89 mmol), H2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol), afforded 3x 81.1 mg in 79% yield as a colorless oil with C−O/C−N selectivity of 86:14. 1H NMR (300 MHz,


7


CDCl3) δ 7.31-7.22 (m, 2H), 7.21-7.13 (m, 3H), 3.73-3.67 (m, 4H), 2.63 (t, J = 7.7 Hz, 2H), 2.46-2.38 (m, 4H), 2.35 (t, J = 7.6, 2H), 1.81 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 142.1, 128.4, 128.3, 125.8, 67.0, 58.4, 53.7, 33.6, 28.3. N-ethyl-N-methyl-3-phenylpropan-1-amine 3c16 (Table 4). According to the general procedure, the reaction of N-ethyl-Nmethyl-3-phenylpropanamide 1c (0.50 mmol), NaOH (1.89 mmol), H2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol), afforded 3c 55.0 mg in 62% yield as a colorless oil with C−O/C−N selectivity of 91:9. 1H NMR (300 MHz, CDCl3) δ 7.32-7.23 (m, 2H), 7.22-7.13 (m, 3H), 2.62 (t, J = 7.8, 2H), 2.45-2.32 (m, 4H), 2.21 (s, 3H), 1.80 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 142.4, 128.4, 128.3, 125.7, 56.9, 51.5, 41.7, 33.9, 29.1, 12.3. 1-(3-Phenylpropyl)pyrrolidine 3a14 (Table 4). According to the general procedure, the reaction of 3-phenyl-1-(pyrrolidin1-yl)propan-1-one 2a (0.50 mmol), NaOH (1.89 mmol), H2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) afforded 3a 81.4 mg in 86% yield as a colorless oil with C−O/C−N selectivity of 86:14. 1H NMR (300 MHz, CDCl3) δ 7.31-7.22 (m, 2H), 7.21-7.13 (m, 3H), 2.65 (t, J = 7.8, 2H), 2.53-2.41 (m, 6H), 1.84 (m, 2H), 1.80-1.71 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 142.3, 128.4, 128.3, 125.7, 56.1, 54.2, 34.0, 30.7, 23.5. 1-(3-(4-Methoxyphenyl) propyl)pyrrolidine 3aa (Table 4). According to the general procedure, the reaction of 3-(4methoxyphenyl)-1-(pyrrolidin-1-yl) propan-1-one 1aa (0.50 mmol), NaOH (1.89 mmol), H2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol), afforded 3aa 77.9 mg in 71% yield as a colorless oil with C−O/C−N selectivity of 85:15. 1H NMR (300 MHz, CDCl3) δ 7.10 (m, 2H), 6.81 (m, 2H), 3.77 (s, 3H), 2.59 (t, J = 7.7, 2H), 2.52-2.41 (m, 6H), 1.87-1.70 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 157.8, 134.4, 129.2, 113.7, 56.1, 55.2, 54.2, 33.0, 31.0, 23.5; HRMS (ESITOF) m/z: [M + H]+ Calcd for C14H22NO 220.1696, found 220.1694. 1-(3-(P-tolyl ) propyl)pyrrolidine 3ab (Table 4). According to the general procedure, the reaction of 1-(pyrrolidin-1-yl)-3(p-tolyl) propan-1-one 1ab (0.50 mmol), NaOH (1.89 mmol), H2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol), afforded 3ab 62.0 mg in 61% yield as a colorless oil with C−O/C−N selectivity of 91:9. 1H NMR (300 MHz, CDCl3) δ 7.10-7.04 (m, 4H), 2.60 (m, J = 7.8, 2H), 2.52-2.41 (m, 6H), 2.30 (s, 3H), 1.88-1.71 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 139.2, 135.1, 129.0, 128.3, 56.1, 54.2, 33.5, 30.8, 23.5, 21.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H22N 204.1747, found 204.1745. 1-(3-Phenylpropyl)pyrrolidine 3a14 (Table 4). According to the general procedure, the reaction of 3-(3-fluorophenyl)-1(pyrrolidin-1-yl)propan-1-one 1z (0.50 mmol), NaOH (1.89 mmol), H2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol), afforded 3a 67.2 mg in 71% yield as a colorless oil with C−O/C−N selectivity of 89:11. 1H NMR (300 MHz, CDCl3) δ 7.31-7.22 (m, 2H), 7.21-7.13 (m, 3H), 2.65 (t, J = 7.8, 2H), 2.53-2.41 (m, 6H), 1.84 (m, 2H), 1.80-1.71 (m, 4H); 13 C NMR (75 MHz, CDCl3) δ 142.3, 128.4, 128.3, 125.7, 56.1, 54.2, 34.0, 30.7, 23.5. 1-(3-Phenylpropyl)pyrrolidine 3a14 (Table 4). According to the general procedure, the reaction of 3-phenyl-1-(pyrrolidin1-yl) prop-2-en-1-one 1ac (0.50 mmol), NaOH (1.89 mmol), H2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol), afforded 3a 66.3 mg in 70% yield as a colorless oil with C−O/C−N selectivity of 86:14. 1H NMR (300 MHz,

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CDCl3) δ 7.31-7.22 (m, 2H), 7.21-7.13 (m, 3H), 2.65 (t, J = 7.8, 2H), 2.53-2.41 (m, 6H), 1.84 (m, 2H), 1.80-1.71 (m, 4H); 13 C NMR (75 MHz, CDCl3) δ 142.3, 128.4, 128.3, 125.7, 56.1, 54.2, 34.0, 30.7, 23.5. General Procedure for the Reductive Deuteration of Tertiary Amides by Na/NaOH/D2O. To a solution of amides (0.500 mmol) in anhydrous hexane (2.5 mL) was added a solution of NaOH (1.89 mmol) in D2O (10.0 mmol), followed by sodium dispersions (34.5 wt %, 5.00 mmol) under N2 at 0 oC and the mixture was stirred vigorously. After 3 h, the reaction was quenched by an aqueous solution of HCl (3M, 15 mL). The aqueous layer was washed by Et2O (3×15 mL) to remove the hydrophobic impurities and then basified with aqueous solution of NaOH (3 M) to pH >10. The aqueous phase was extracted with Et2O (2×15 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to give the pure product. See Table 4 for the deuterium incorporations of the corresponding products. N,N-dimethyl-3-phenylpropan-1-amine-1,1-d2 5b3j (Table 4). According to the general procedure, the reaction of N,Ndimethyl-3-phenylpropanamide 1b (0.50 mmol), NaOH (1.89 mmol), D2O (10.0 mmol) and sodium dispersions (34.1 wt %, 5.00 mmol) for 3 h at 0 °C, afforded 5b 66.1 mg in 80% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.34-7.27 (m, 2H), 7.25-7.16 (m, 3H), 2.87-2.69 (m, 8H), 2.20 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 139.3, 128.8, 128.3, 126.4, 56.7 (m), 42.9, 32.6, 25.4. 1-(3-Phenylpropyl-1,1-d2)pyrrolidine 5a3j (Table 4). According to the general procedure, the reaction of 3-phenyl-1(pyrrolidin-1-yl)propan-1-one 1a (0.50 mmol), NaOH (1.89 mmol), D2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 3 h at 0 °C afforded 5a 85.1 mg in 89% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.22-7.13 (m, 3H), 2.65 (t, J = 7.6 Hz,2H), 2.48 (m, 4H), 1.84 (t, J = 7.6 Hz 2H), 1.77 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 142.3, 128.4, 128.3, 125.7, 55.2 (m), 54.1, 33.9, 30.4, 23.5. N-ethyl-N-methyl-3-phenylpropan-1-amine-1,1-d2 5c16 (Table 4). According to the general procedure, the reaction of Nethyl-N-methyl-3-phenylpropanamide 1c (0.50 mmol), NaOH (1.89 mmol), D2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 3 h at 0 °C, afforded 5c 62.8 mg in 70% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.327.23 (m, 2H), 7.21-7.14 (m, 3H), 2.62 (t, J = 7.7 Hz, 2H), 2.41 (q, J = 7.2 Hz, 2H), 2.21 (s, 3H), 1.78 (t, J = 7.7 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 142.4, 128.5, 128.4, 125.8, 55.9 (m), 51.4, 41.6, 33.8, 28.8, 12.3. 1-(3-(4-Methoxyphenyl)propyl-1,1-d2)pyrrolidine 5aa (Table 4). According to the general procedure, the reaction of 3(4-methoxyphenyl)-1-(pyrrolidin-1-yl)propan-1-one 1aa (0.50 mmol), NaOH (1.89 mmol), D2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 3 h at 0 °C, afforded 5aa 94.1 mg in 85% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.10 (m, 2H), 6.82 (m, 2H), 3.78 (s, 3H), 2.58 (t, J = 7.7 Hz, 2H), 2.49 (m, 4H), 1.85 -1.73 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 157.8, 134.4, 129.3, 113.8, 55.3 (m), 55.3, 54.2, 33.0, 30.7, 23.5. 4-(3-Phenylpropyl-1,1-d2)morpholine 5x15 (Table 4). According to the general procedure, the reaction of 1morpholino-3-phenylpropan-1-one 1x (0.50 mmol), NaOH (1.89 mmol), D2O (10.0 mmol) and sodium dispersions (34.5 wt %, 5.00 mmol) for 3 h at 0 °C, afforded 5x 84.0 mg in 81%


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yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.327.24 (m, 2H), 7.22-7.15 (m, 3H), 3.71 (m, 4H), 2.64 (t, J = 7.7 Hz, 2H), 2.43 (m, 4H), 1.81 (t, J = 7.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 142.1, 128.4, 128.4, 125.8, 67.1, 57.7 (m), 53.7, 33.6, 28.1. Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H and 13C NMR spectra for all compounds and photos of sodium dispersions and reaction (PDF).

AUTHOR INFORMATION Corresponding Author * [email protected]

ACKNOWLEDGMENT We thank national key research and development plan of China (2017YFD0200504) and national natural science foundation of China (No. 21602248, 21711530213) for support.

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Reduction and Reductive Deuteration of Tertiary Amides Mediated by

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