Ammonium Salt-Accelerated Hydrazinolysis of Unactivated Amides

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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Ammonium Salt-Accelerated Hydrazinolysis of Unactivated Amides: Mechanistic Investigation and Application to a Microwave Flow Process Megumi Noshita,† Yuhei Shimizu,† Hiroyuki Morimoto,*,† Shuji Akai,‡ Yoshitaka Hamashima,§ Noriyuki Ohneda,∥ Hiromichi Odajima,⊥ and Takashi Ohshima*,† †

Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan Graduate School of Pharmaceutical Sciences, Osaka University, Suita 567-0871, Japan § School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan ∥ SAIDA FDS Inc., 143-10 Isshiki, Yaizu, Shizuoka 425-0054, Japan ⊥ Pacific Microwave Technologies Corp., Seattle, Washington 98116, United States

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S Supporting Information *

ABSTRACT: A study of ammonium salt-accelerated hydrazinolysis of unactivated amides is described. We first studied the reaction mechanism by kinetic experiments and DFT calculations and found that cooperation of the hydrazinium salt and hydrazine is important for promoting the cleavage of unactivated amides. Next, we applied the reaction to a microwave flow process, and the amine products were isolated on a multigram scale. KEYWORDS: hydrazinolysis, amide, microwave flow chemistry, ammonium salt, mechanism

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INTRODUCTION Amide comprises a fundamental functional group of organic molecules. The stability of amide bonds makes amides useful in various chemical fields, such as organic synthesis, asymmetric catalysis, and medicinal chemistry.1 Recent advances toward the use of amides in selective C−H functionalization reactions has increased the demand for the application of amides in catalytic reactions.2 Although the synthetic utility of amides has rapidly expanded, methods for cleaving unactivated amides, often used for deprotection of acyl and directing groups, is underdeveloped because of difficulties in cleaving the stable amide bond.3 Therefore, chemical processes for cleaving amide bonds, especially in process chemistry, often rely on classical conditions with strong acids or bases, limiting functional group compatibility. Thus, the development of methods to cleave unactivated amides under reaction conditions without the use of strong acids and bases is in high demand. We previously developed the hydrazinolysis of unactivated amides4 and found that ammonium salts dramatically accelerate the reaction and that the reaction conditions allowed for broader functional group tolerance compared with ammonium salt-accelerated transamidation of amides, likely because of the higher nucleophilicity of hydrazine (Scheme 1).5 Although the cleavage of unactivated amides without the use of strong acids and bases has been realized, problems persisted. First, the reaction mechanism has not been clarified, and the key role of the ammonium salt in the acceleration of hydrazinolysis of amides is not well understood. Second, application to large-scale synthesis has not yet been explored, limiting the utility of the reaction to process chemistry. © XXXX American Chemical Society

Scheme 1. Ammonium Salt-Accelerated Hydrazinolysis of Amides

To investigate these issues, we initiated studies to improve our understanding of the reaction mechanism as well as to expand the utility of our hydrazinolysis reactions. We first studied the reaction mechanism using kinetic experiments and DFT calculations and found that cooperation of the hydrazinium salt and hydrazine is important for promoting the cleavage of unactivated amides. Next, we applied the reaction to a microwave flow process, and the amine products were isolated on a multigram scale.

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RESULTS AND DISCUSSION 1. Understanding the Reaction Mechanism. First, we attempted to clarify the reaction mechanism through kinetic experiments and DFT calculations. On the basis of our previous report, the reaction did not proceed without the addition of ammonium salts,4 and hydrazinium salts generated from the ammonium salts and hydrazine hydrate are proposed to be the active species, as experimentally verified in the Special Issue: Japanese Society for Process Chemistry Received: December 5, 2018

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DOI: 10.1021/acs.oprd.8b00424 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

reactions below. Thus, we first performed kinetic experiments with N-(4-methoxyphenyl)acetamide (1a) and hydrazinium bromide under the reaction conditions shown in Scheme 2.

Table 2. Summary of Initial-Rate Kinetic Parameters d[3a]/dt (M s−1)

[1a] (M)

0.5 7.21 × 10−6 1.0 1.25 × 10−5 2.0 2.69 × 10−5 order with respect to 1a: [H2NNH2·H2O] d[3a]/dt (M) (M s−1)

Scheme 2. Summary of Kinetic Experiments

0.5 5.99 × 10−6 1.0 1.25 × 10−5 2.0 2.73 × 10−5 order with respect to H2NNH2·H2O: [H2NNH2·HBr] d[3a]/dt (M) (M s−1)

The initial-rate experiment results indicated that the reaction was first-order with respect to amide 1a, hydrazinium bromide, and hydrazine monohydrate (Tables 1 and 2), suggesting that

[1a] = 0.50 M yield (%)a

0.5 1.2 1.8 2.5

0.8 1.4 3.7 5.8 [H2NNH2· H2O] = 0.50 M

time (h)

yield (%)a

2 4 5 −

6.6 11.2 13 − [H2NNH2· HBr] = 0.50 M

[1a] = 1.0 M time (h)

yield (%)a

1 3 5 −

6 15 24 − [H2NNH2· H2O] = 1.0 M

time (h)

yield (%)a

1 3 5 −

6 15 24 − [H2NNH2· HBr] = 1.0 M

temp. = 80 °C

yield (%)a

1 2 3 4

2.8 14.2 23 32.2 [H2NNH2· H2O] = 2.0 M

time (h)

−11.840 −11.290 −10.522

ln([H2NNH2·H2O])

ln(d[3a]/dt)

−0.693 0.000 0.693 1.094

−12.025 −11.290 −10.509

ln([H2NNH2· HBr])

ln(d[3a]/ dt)

−0.693 0.000 0.693 0.975

−12.005 −11.290 −10.653

Table 3. Experimental Results of Initial-Rate Kinetics at Various Temperatures

[1a] = 2.0 M time (h)

ln(d[3a]/dt)

−0.693 0.000 0.693 0.951

0.5 6.11 × 10−6 1.0 1.25 × 10−5 2.0 2.36 × 10−5 order with respect to [H2NNH2·HBr]:

Table 1. Experimental Results of Initial-Rate Kinetics for Amide 1a, Hydrazine Monohydrate, and Hydrazinium Bromide time (h)

ln([1a])

temp. = 90 °C

temp. = 100 °C

time (h)

yield (%)a

time (h)

yield (%)a

time (h)

yield (%)a

1 3 5

3 7 11

1 3 5

6 15 24

0.5 1.3 2.5

7 13 23

a

Yields were determined by 1H NMR analyses of the crude mixtures.

yield (%)a

amine from the tetrahedral intermediate (III-TS) have high activation energies and that the presence of hydrazinium salt provides the activation energies (ΔG⧧ = 27.7 and 29.9 kcal mol−1, respectively), consistent with the experimental observations. According to the structure of I-TS, the hydrazinium salt activates the amide carbonyl group to facilitate simultaneous nucleophilic addition of hydrazine in the transition state of the addition process, and according to the structure of III-TS, the hydrazinium salt also facilitates the elimination of the amine from the tetrahedral intermediate. Elimination of the amine from the tetrahedral intermediate was the rate-limiting step in the overall reaction pathway in the presence of hydrazinium salt, presumably because the higher nucleophilicity of the hydrazine compared with the amine could reduce the activation energy of the addition step (I-TS) relative to the elimination step (III-TS). In both cases, the proton-transfer step from intermediate II to intermediate III was faster than the addition/elimination steps. We also examined the effect of the solvent using the same SMD solvation model, and the results in Table 5 show that the activation energies were lower in ethanol (ΔG⧧ = 26.9 and 28.3 kcal mol−1, respectively) than in water. The computational results suggested that the reaction could be faster in ethanol than in water. To understand the role of the hydrazinium salt in facilitating the hydrazinolysis of unactivated amides, the reaction pathway in the absence of hydrazinium salt was evaluated with Nmethylacetamide and two hydrazine molecules. The additional hydrazine molecule was used to facilitate the proton-transfer processes during the reaction. The results shown in Scheme 4 and Table 6 show that the reaction pathway is similar to that in

0.5 1.2 1.8 2.5

4.2 7.4 17.4 22.7 [H2NNH2· HBr] = 2.0 M

time (h)

yield (%)a

time (h)

yield (%)a

time (h)

yield (%)a

1 2 3 4

1 4.1 5.7 7.8

1 3 5 −

6 15 24 −

0.5 1.5 2.3 3.0

5.5 14.4 21.3 24

a

Yields were determined by 1H NMR analyses of the crude mixtures.

these three molecules are involved in the rate-determining step. In addition, the activation parameters were experimentally determined using the Eyring equation (Tables 3 and 4), and the values were ΔH⧧ = 17.5 kcal mol−1, ΔS⧧ = −33.3 cal mol−1 K−1, and ΔG⧧ = 27.4 kcal mol−1. The large negative value of ΔS⧧ also suggests that the three molecules are involved in the rate-determining step. The reaction pathways of the hydrazinolysis reactions were then calculated in the absence or presence of hydrazinium salt using N-methylacetamide as a model substrate at the M06-2X/ 6-311+G(d,p)//B3LYP/6-31G(d) level6 in water with the SMD solvation model.7 Water was considered to be a solvent that simulated neat conditions because 10 equiv of hydrazine hydrate was used as the reagent and an excess amount of water was present in the reaction mixture. The results shown in Scheme 3 and Table 5 indicate that both the addition of hydrazine to the amide (I-TS) and the elimination of the B



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Table 4. Summary of Eyring Plot Parameters temp. (°C) 80 90 100

T (K) 353.15 363.15 373.15

parameter slope = −ΔH⧧/R (K) ΔH⧧ (kcal mol−1)

k (M−2 s−1)

1/T (K−1)

−6

k/T (M−2 s−1 K−1)

−3

5.56 × 10 1.25 × 10−5 2.23 × 10−5 value

1.57 × 10−8 3.44 × 10−8 5.98 × 10−8

2.83 × 10 2.75 × 10−3 2.68 × 10−3 parameter

−8.813 × 10−3 17.51

y intercept = ln(kb/h) + ΔS⧧/R ΔS⧧ (cal mol−1 K−1)

ln(k/T) −17.97 −17.18 −16.63 value 7.019 −33.27

Scheme 3. Computed Reaction Pathway in the Presence of Hydrazinium Salt

Table 5. Computed Energies of the Reaction Pathways in the Presence of Hydrazinium Salta

Scheme 4. Computed Reaction Pathway in the Absence of Hydrazinium Salt

ΔG (kcal mol−1) structure

in H2O

in EtOH

I I-TS II II-TS III III-TS IV

7.5 27.7 22.3 25.3 20.1 29.9 6.7

5.9 26.9 21.3 24.3 18.9 28.3 4.9

a

DFT calculations were performed at the M06-2X/6-311+G(d,p)// B3LYP/6-31G(d) level using the SMD solvation model, and the computed energies (ΔG) are reported relative to the sum of the energies of the starting materials at 298.15 K.

the presence of the hydrazinium salt in Scheme 3, but the activation energies of these steps are extremely high in the absence of the hydrazinium salt (ΔG⧧ = 44.4 and 43.2 kcal mol−1, respectively). On the other hand, the proton-transfer step between II′ and III′ involves an additional transition state, II″-TS. Nevertheless, the energy difference during the process is small (∼1 kcal/mol), and we assume that the process can be considered as a single, essentially barrierless process. 2. Application to a Microwave Flow Reactor. With the above mechanistic information in hand, we next examined the application of ammonium salt-accelerated cleavage of amide bonds to flow microwave technology.8 The development of a safer method for large-scale synthesis is a critical issue for chemical industries. Chemical manufacturing processes have mostly relied on traditional batch reaction systems, which along with several safety issues are associated with problems

regarding the long development time and reproducibility. The application of continuous flow synthesis is a potential solution to this problem of batch reactions,9 and its use is expanding in synthetic organic chemistry in both academia and industry. Continuous operation of the flow system can constantly provide products, and because the reaction scale depends on the operation time, scale-up of the flow system from the lab scale to an industrial scale is easier than scale-up of the batch system. Furthermore, the flow method is safer than the batch system because the reaction volume of the reactor is smaller than that of the batch system. The flow system has limitations regarding the residence time in the reactor, however, depending on the volume of the C



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Table 6. Computed Energies of the Reaction Pathway in the Absence of Hydrazinium Salta structure

ΔG in H2O (kcal mol−1)

I′ I′-TS II′ II′-TS II″ II″-TS III′ III′-TS IV′

21.1 44.4 25.4 27.8 28.7 27.6 25.1 43.2 16.4

Table 7. Optimization of Flow Reaction Conditions

entry

amide

conc. (M)

MW power (W)

temp. (°C)

conv. (%)a

1 2 3 4b 5 6 7 8 9

1b 1b 1b 1b 1c 1c 1c 1c 1c

0.50 0.67 0.67 0.67 0.67 0.67 0.67 0.67 0.67

40 45 50 − 40 45 50 55 60

134 137 145 145 100 135 138−143 142−147 161−170

96 91 97 75 36 56 75 85 93

a

DFT calculations were performed at the M06-2X/6-311+G(d,p)// B3LYP/6-31G(d) level using the SMD solvation model, and the computed energies (ΔG) are reported relative to the sum of the energies of the starting materials at 298.15 K.

reactor and the flow rate. Therefore, fast reactions are required to achieve efficient synthesis, and appropriate reaction conditions are often necessary to accelerate the transformations. To overcome these limitations, we focused our efforts on the use of microwave-assisted organic synthesis, which has recently attracted increasing attention.10 Microwave heating is highly energy-efficient, and the temperature rises rapidly as a result of the direct energy transfer to the solutes and solvents. Thus, application of microwave technology to flow systems would make a much broader range of transformations synthetically useful, and such examples have been reported in the recent literature.11 Nevertheless, their use remains limited to several synthetic transformations, and no application to the hydrazinolysis of amides has been reported. We next attempted to scale up this reaction by using a microwave flow reactor (Figure 1). We explored the reaction

a Determined by 1H NMR analyses of the crude mixtures. bUnder batch conditions with conventional heating.

concentration, and the operation was executable with 45 W microwave irradiation at 0.67 M 1b (entry 2). Further increasing the irradiation power to 50 W gave the optimal result of 97% conversion (entry 3), and we assume that the higher conversion is attributable to the higher reaction temperature with the increased microwave power. For comparison, we performed the same reaction under batch conditions, and the reaction proceeded with 75% conversion (entry 4), most likely because of the inefficient heat transfer under conventional heating conditions in comparison with the microwave heating conditions. Next, the flow reaction conditions were optimized with 0.67 M N-benzylacetamide (1c). Similar to the observations with amide 1b, the conversion was improved with an increase in the microwave irradiation, and the optimal result (93% conversion) was obtained with 60 W microwave irradiation (entry 9). With these results in hand, we examined the deprotection of acetyl groups in the continuous flow system (Table 8). Amide 1b was deprotected to give 4.52 g of amine 3b with a 2 h operation of the flow system (19 mmol h−1). Amide 1c gave the corresponding amine 3c at 60 W, and 11.0 g of amine 3c was isolated as the hydrochloride salt with a 3.3 h operation of the system (23 mmol h−1). It is noted that the product 3 could

Figure 1. Schematic representation of the microwave flow reactor.

Table 8. Application to a Continuous Flow Reaction

conditions using commercially available N-(4-hydroxyphenyl)acetamide (1b, paracetamol) as a model substrate, hydrazine monohydrate, and hydrazinium bromide in ethanol at a flow rate of 1.0 mL/min (Table 7) to demonstrate the applicability of our protocol for deprotection of the acetyl group, one of the most frequently used protecting groups for amines. We selected ethanol as the solvent because it would not only accelerate the reaction but also dissolve the reactants and facilitate the absorption of the microwaves in the flow process. In addition, we replaced the ammonium salt with commercially available hydrazinium bromide, a proposed active species generated from the ammonium salt and hydrazine, to prevent the generation of gaseous ammonia in the reactor. The reaction proceeded with 96% conversion under microwave irradiation conditions (40 W) at 0.50 M 1b (entry 1). To improve the productivity per unit time, we tried a higher amide

a

D

Isolated yields. bIsolated as the HCl salt. DOI: 10.1021/acs.oprd.8b00424 Org. Process Res. Dev. XXXX, XXX, XXX−XXX


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hydrazinium bromide (0.50 mmol, 1.0 equiv), and hydrazine monohydrate (0.50 mmol, 1.0 equiv) in DMSO (1.0 M) under air, and the vial was sealed with a Teflon-lined screw cap. The vial was stirred at the desired temperature (80, 90, or 100 °C) on a heating block, and the yield of 3a was determined by 1H NMR analysis of the crude mixture. The experimental data are summarized in Table 3. With these data, the rate constant k (M−2 s−1) was calculated according to the kinetic equation k = (d[3a]/dt)/([1a][H2NNH2·H2O][H2NNH2·HBr]), where [1a] = [H2NNH2· H2O] = [H2NNH2·HBr] = 1.0 M, and the activation parameters were analyzed according to the Eyring equation: ln(k/T) = −ΔH⧧/RT + ln(kb/h) + ΔS⧧/R, where R is the gas constant (8.314 J mol−1 K−1), kb is the Boltzmann constant (1.381 × 10−23 J K−1), and h is the Planck constant (6.626 × 10−34 J s). The results are summarized in Table 4. General Computational Details (Schemes 3 and 4 and Tables 5 and 6). The DFT calculations were performed using Gaussian 16, revision A.03.15 Geometry optimizations were performed using the B3LYP functional6a−c with the 631G(d) basis set for all of the atoms. After optimization of the structures, frequency calculations were performed at the same level of theory to confirm that the obtained structures were either a stationary point (no imaginary frequencies) or a transition state (one imaginary frequency). IRC calculations were performed for each transition state structure to confirm that the transition state connected the reaction pathway between the starting materials and the products or intermediates. Thermal corrections to the Gibbs energy at 298.15 K were obtained from the frequency calculations. Single-point energy calculations for the optimized geometry were performed using the M06-2X functional6d with the 6311+G(d,p) basis set for all of the atoms and the SMD solvation model7 (H2O or EtOH). Optimization of Flow Microwave Conditions for Amide 1 (Table 7). A solution of amide 1 in EtOH (0.50 or 0.67 M) and a solution of hydrazinium bromide (1.0 equiv) in hydrazine monohydrate (10 equiv) were combined. The mixture was pumped at a flow rate of 1.0 mL/min into the microwave flow reactor (5.5 mL reactor volume, 5.5 min residence time) with microwave irradiation at the indicated power, and after the temperature at the outlet reached a steady state at the indicated temperature, the crude reaction mixture was collected into a flask. The conversion of amide 1 to the product 3 was determined by 1H NMR analysis of the crude mixture. Optimized Procedure for Amide 1b under Flow Microwave Conditions (Table 8). The mixture was pumped at a flow rate of 1.0 mL/min into the microwave flow reactor (5.5 mL reactor volume, 5.5 min residence time) with microwave irradiation at 50 W. After the outlet temperature reached a steady state at 145 °C, the crude reaction mixture was collected into a flask for 120 min (60 mmol for 1b). The conversion of the reaction was determined by 1H NMR analysis of the crude mixture. The crude mixture was then purified by flash silica gel column chromatography with EtOAc as the eluent to give an orange solid. The solid was recrystallized from EtOAc, and the resulting solid was filtered and washed with hexane to give 3b as an orange solid (4.52 g, 69% yield). 4-Aminophenol (3b)13 (Table 8). 1H NMR (500 MHz, DMSO-d6) δ 8.32 (s, 1H), 6.50−6.45 (m, 2H), 6.45−6.35 (m, 2H), 4.34 (s, 2H).

be separated from the excess hydrazine hydrate by either silica gel column chromatography or aqueous workup. Although future studies are indeed necessary to further optimize the isolation process of the amines to make it safer and more efficient, these results implied that the hydrazinolysis of unactivated amides can be scaled up and thus could be applicable for larger-scale synthesis of amines.

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CONCLUSIONS

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EXPERIMENTAL SECTION

We have reported a detailed study of ammonium saltaccelerated hydrazinolysis of amides. The reaction mechanism was investigated, and the cooperative activation mechanism found using DFT calculations was consistent with the experimental observations. In addition, we realized the scaled-up synthesis of amines using continuous microwave flow technology. Although the examination of additional substrates as well as different solvent systems under microwave flow conditions is yet to be performed, we hope that the above results will facilitate the applications of hydrazinolysis reactions and the future development of cleavage reactions of unactivated amide bonds.

General. All reactions were performed in flame-dried or oven-dried glassware under an argon atmosphere unless otherwise noted. Reagents and catalysts were obtained from commercial sources and used as received unless otherwise stated. Solvents were purchased from commercial sources and dried over molecular sieves before use. Flash silica gel column chromatography was performed with Kanto Chemical silica gel 60N (spherical, neutral, particle size 40−50 μm). Microwaveassisted flow reactions were performed with a continuous flow microwave apparatus from SAIDA FDS Inc.12 NMR spectra were acquired on 500 MHz Bruker Avance III spectrometers. 1 H and 13C{1H} NMR chemical shifts are reported in parts per million and referenced to tetramethylsilane or residual solvent peaks as internal standards (for tetramethylsilane, 0 ppm for 1 H; for CDCl3, 77.0 ppm for 13C{1H}). Coupling constants are reported in hertz. The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Amides 1a, 1b, and 1c were purchased from Tokyo Chemical Industry Co. Ltd. It is noted that all of the amine products 3 are known in the literature.13,14 General Procedure for Initial-Rate Kinetic Experiments (Scheme 2 and Tables 1 and 2). To a 4 mL vial equipped with a magnetic stir bar were added amide 1a (0.50 mmol), hydrazinium bromide (0.50 mmol, 1.0 equiv), and hydrazine monohydrate (0.50 mmol, 1.0 equiv) in DMSO (1.0 M) under air, and the vial was sealed with a Teflon-lined screw cap. The vial was stirred at 90 °C on a heating block, and the yield of 3a was determined by 1H NMR analysis of the crude mixture. The above standard reaction conditions were varied as follows: [1a] = 0.50, 1.0, 2.0 M; [H2NNH2·H2O] = 0.50, 1.0, 2.0 M; [H2NNH2·HBr] = 0.50, 1.0, 2.0 M. The experimental data and kinetic parameters are summarized in Tables 1 and 2. These results indicated that the reaction was first order with respect to 1a, H2NNH2·H2O, and H2NNH2·HBr. General Procedure for Eyring Experiments (Scheme 2 and Tables 3 and 4). To a 4 mL vial equipped with a magnetic stir bar were added amide 1a (0.50 mmol), E



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Optimized Procedure for Amide 1c under Flow Microwave Conditions (Table 8). The mixture was pumped at a flow rate of 1.0 mL/min into the microwave flow reactor (5.5 mL reactor volume, 5.5 min residence time) with microwave irradiation at 60 W. After the outlet temperature reached a steady state at 161−170 °C, the crude reaction mixture was collected into a flask for 200 min (100 mmol for 1c). The conversion of the reaction was determined by 1H NMR analysis of the crude mixture. The crude mixture was roughly evaporated and then diluted with 1 M aqueous NaOH solution and extracted with Et2O. The organic layer was evaporated, and 1 M HCl solution in Et2O (120 mL, 120 mmol) was added at 0 °C. The mixture was stirred overnight at room temperature, and the solvent was evaporated to completely remove residual EtOH. The resulting residue was diluted with CH2Cl2 and extracted with 1 M aqueous HCl solution. The aqueous layer was basified with aqueous NaOH solution and back-extracted with Et2O. The organic layer was evaporated to give a pale-yellow oil. To the oil was added 1 M HCl solution in Et2O (120 mL, 120 mmol), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated, and the residue was filtered and washed with Et2O to give benzylamine hydrochloride as a white solid (10.9 g, 76% yield). Benzylamine Hydrochloride (3c·HCl)14 (Table 8). 1H NMR (500 MHz, DMSO-d6) δ 8.57 (br, 3H), 7.51 (d, J = 6.5 Hz, 2H), 7.45−7.30 (m, 3H), 4.00 (s, 2H).

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REFERENCES

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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.oprd.8b00424. Additional computational results and spectra (PDF)

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Article

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hiroyuki Morimoto: 0000-0003-4172-2598 Shuji Akai: 0000-0001-9149-8745 Yoshitaka Hamashima: 0000-0002-6509-8956 Takashi Ohshima: 0000-0001-9817-6984 Notes

The authors declare the following competing financial interest(s): One of the authors (N.O.) belongs to SAIDA FDS Inc., which sells the flow microwave apparatus used in this study.

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ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (JSPS KAKENHI Grant JP15H05846 in Middle Molecular Strategy for T.O.) from JSPS, Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) (Grant JP17am0101091) from AMED, and the Takasago Award in Synthetic Organic Chemistry, Japan (for H.M.). M.N. and Y.S. thank JSPS for Research Fellowships for Young Scientists. The computations were carried out using the computer resources offered under the category of General Projects by the Research Institute for Information Technology at Kyushu University. F



Article

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Ammonium Salt-Accelerated Hydrazinolysis of Unactivated Amides

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