Intrinsically Safe and Shelf-Stable Diazo-Transfer Reagent for Fast

Article Cite This: J. Org. Chem. 2018, 83, 10916−10921

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Intrinsically Safe and Shelf-Stable Diazo-Transfer Reagent for Fast Synthesis of Diazo Compounds Shibo Xie,† Ziqiang Yan,† Yuanheng Li, Qun Song, and Mingming Ma* CAS Key Laboratory of Soft Matter Chemistry, iChEM (Innovation Center of Chemistry for Energy Materials), Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China

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S Supporting Information *

ABSTRACT: We report a crystalline compound 2-azido-4,6dimethoxy-1,3,5-triazine (ADT) as an intrinsically safe, highly efficient, and shelf-stable diazo-transfer reagent. Because the decomposition of ADT is an endothermal process (ΔH = 30.3 kJ mol−1), ADT is intrinsically nonexplosive, as proved by thermal, friction, and impact tests. The diazo-transfer reaction based on ADT gives diazo compounds in excellent yields within several minutes at room temperature. ADT is very stable upon >1 year storage under air at room temperature.

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INTRODUCTION Diazo compounds are versatile building blocks in organic synthesis, as they can serve as precursors for carbenes and carbenoids, which give rise to a wide variety of chemical transformations with a remarkable degree of chemo-, regio-, and stereoselectivity.1−4 Diazo groups are also found in natural products and amino acids that show unique antimicrobial and antitumor activities.5−7 Particularly, stabilized diazo compounds in which the electrons on α-carbon are delocalized onto adjacent functional groups (e.g., carbonyl and aromatic groups)8 are compatible with living systems and have great potentials for widespread applications in chemical biology.9 One efficient method of synthesizing stabilized diazo compounds is diazo-transfer reaction of active methylene compound.8 Sulfonyl azides are commonly used as diazotransfer reagents, and the reaction proceeds typically in the presence of excess organic base such as triethylamine.10 However, some sulfonyl azides such as p-tosyl azide and trifluoromethanesulfonyl azide are impact-sensitive and highly explosive. Aiming at safer reagents, chemists have developed many new sulfonyl azides, including mesyl azide,11 pdodecylbenzenesulfonyl azide,12 polystyrene-supported benzenesulfonyl azide,13 and heteroarylsulfonyl azide (e.g., imidazole-1-sulfonyl azide hydrochloride14 and benzotriazole-1sulfonyl azide15). Although the stability of these new sulfonyl azides are generally better than that of p-tosyl azide, serious concerns about the safety of their preparation have been raised,16 such as the generation of highly explosive and toxic hydrazoic acid and sulfuryl diazide. To overcome these issues of sulfonyl azides, 2-azide-1,3-dimethylimidazolinium (ADM) salts have been developed as a new class of diazo-transfer reagent.17,18 These ADM reagents show good thermal stability, low explosibility, and convenience in the isolation of diazo products. However, the starting materials for the synthesis of ADM reagents are relatively expensive, sensitive to moisture, and difficult to handle,17,18 which limits the application of © 2018 American Chemical Society

these highly efficient diazo-transfer reagents. Therefore, the development of a novel diazo- transfer reagent that is safe, efficient, and stable is strongly demanded. The new reagent is preferably a stable solid at room temperature and can be easily prepared from low-cost and convenient starting materials. Herein, we report 2-azido-4,6-dimethoxy-1,3,5-triazine (ADT, compound 1) as an intrinsically safe, highly efficient, and shelf-stable solid diazo-transfer reagent (Figure 1). Through a two-step procedure modified from Kayama’s synthesis procedure,19 ADT can be facilely synthesized as a white crystalline solid in 77% total yield from low-cost and

Figure 1. Synthesis and thermal stability characterization of ADT. (a, b) Facile synthesis of ADT as a white crystalline solid in good yield; (c) DSC trace and (d) TGA trace of ADT. Received: June 25, 2018 Published: August 18, 2018 10916

DOI: 10.1021/acs.joc.8b01587 J. Org. Chem. 2018, 83, 10916−10921

Article

The Journal of Organic Chemistry

reaction as a model system (Table 1). In low-polarity solvents with polarity index P < 5, no diazo product was obtained (Table 1, entries 1−4). Using medium-polarity solvents such as MeOH and ACN only affords a very little amount of diazo product (Table 1, entries 5 and 6). In contrast, when highpolarity solvent such as DMSO was used, diazo compound 3a was obtained in 70% NMR yield, which is much higher than the yield in DMF. The solvent-screening result indicates that high-polarity organic solvents are preferred for the diazotransfer reaction based on ADT. Therefore, DMSO was selected as the solvent for the next-step screening of base (Table 2). Excess amount of organic base such as triethylamine

convenient starting materials: cyanuric chloride, sodium azide, and methanol.19

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RESULTS AND DISCUSSION The structure of ADT in solution and in solid state has been characterized by using NMR, IR, and X-ray diffraction (XRD) (see Supporting Information for details). The strong and sharp peak at 2143 cm−1 in IR spectrum indicates that ADT exists in the azido form in the solid state. The thermal stability of ADT has been characterized by using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). There are two endothermal peaks on the DSC trace at 84.7 and 174.2 °C (Figure 1c), which correspond to the melting and thermal decomposition of ADT (Figure 1d), respectively. The safety issues of most of diazo-transfer reagents are mainly due to their fast exothermal decomposition processes.8 In contrast, the endothermal decomposition of ADT (ΔH = 30.3 kJ mol−1) implies that ADT could be an intrinsically safe and nonexplosive compound. Indeed, the safety of ADT is further examined by BAM friction test and BAM fall hammer impact test (see Supporting Information for details), which demonstrate that ADT is insensitive upon the highest friction loading (360 N) and the highest impact energy (100 J) under standard test conditions. On the other hand, with inorganic solid base as the catalyst, ADT reacts with active methylene compounds to give stabilized diazo compounds in excellent yields within several minutes at room temperature. In addition, ADT crystalline solid is very stable upon long-term storage, whose reactivity remains unchanged after being stored for >1 year under air at room temperature. The lifetime of ADT is much better than those of most of the other diazo-transfer reagents, which are typically within several weeks.8 We began our study by testing the reaction between ethyl acetoacetate 2a and ADT in DMF at 25 °C (Table 1, entry 7).

Table 2. ADT-Based Diazo-Transfer Reaction: Survey of Base and Reaction Timea

solvent

polarity index

yieldb

1 2 3 4 5 6 7 8

DCM isopropanol THF 1,4-dioxane MeOH MeCN DMF DMSO

3.1 3.9 4.0 4.8 5.1 5.8 6.4 7.2

trace trace 48% 70%

base

time

NMR yieldc

1 2 3 4 5 6 7b 8b 9 10

4-methylmorpholine Et3N KOAc K2CO3 Na2CO3 NaHCO3 4-methylmorpholine + KCl Et3N + KCl NaHCO3 NaHCO3

1h 1h 1h 1h 1h 1h 1h 1h 20 min 2 min

70% 86% 86% 90% 93% 30% 86% 96% 95%

a

Conditions: ADT 1 (0.6 mmol), ethyl acetoacetate 2a (0.5 mmol), and base (0.2 mmol) in DMSO (2 mL), 25 °C. bBoth base and KCl were 0.2 mmol. cThe yield was determined by using 1H NMR with mesitylene as the internal standard.

Table 1. ADT-Based Diazo-Transfer Reaction: Survey of Solventa

entry

entry

(2−3 equiv to active methylene compound) is typically used for diazo-transfer reaction.8,18 To reduce the potential side effect due to the excess base, we controlled the usage of base at 40 mol % to activate methylene compound. When 4methylmorpholine was used as the base, no diazo product was obtained, but low yield of triazole product was obtained. In contrast, inorganic base such as K2CO3, Na2CO3, and NaHCO3 provided much better yield of diazo product than triethylamine (Table 2, entries 4−6). Among them, NaHCO3 gave the best performance of 93% NMR yield of diazo product (Table 2, entry 6). Remarkably, with NaHCO3 as the base, the reaction time can be greatly reduced from 1 h to 2 min without sacrificing the yield (Table 2, entries 9 and 10). The superior activity of inorganic base over organic base on this ADT-based diazo-transfer reaction could be attributed to the alkali metal ions that may coordinate and stabilize the formed enolate, which is an active intermediate attacking diazo-transfer reagent to initiate the diazo-transfer reaction.18 To verify this hypothesis, the combination of KCl (providing K+) and organic bases was used in the reaction (Table 2, entries 7 and 8), which gave significantly enhanced yield of 2a over corresponding organic base (Table 2, entries 1 and 2). Particularly, the combination of KCl and Et3N resulted in a high yield that is comparable to the result with KOAc or K2CO3 as the base. Therefore, when an inorganic base was used in DMSO, the anion performs as the base to deprotonate

a Conditions: ethyl acetoacetate 2a (0.5 mmol), ADT 1 (0.6 mmol), and Et3N (0.2 mmol) in solvent (2 mL), 25 °C, 1 h. bThe yield was determined by using 1H NMR with mesitylene as the internal standard.

The corresponding diazo compound 3a was obtained after 1 h reaction with a 48% NMR yield using 40 mol % trimethylamine as the base. There was also ∼40% yield of triazole product from 2a and ADT, as reported previously.20,21 Because the polarity of solvent is known to affect diazo-transfer reactions,8 we explored the effect of solvent using 2a/ADT 10917

DOI: 10.1021/acs.joc.8b01587 J. Org. Chem. 2018, 83, 10916−10921

Article

The Journal of Organic Chemistry Scheme 1. Proposed Mechanism for ADT-Based Diazo-Transfer Reaction

been facilely prepared in a good yield (70%) (Table 3, entry 14). The reaction between indene and ADT is completed in 3 min at 25 °C, which minimizes the decomposition of the unstable 1-diazoindene and achieves this good yield. On the other hand, nonactive ethylene compounds could not react with ADT to give diazo products (entries 15−17) even after 90 min reaction. For entry 16, only a small amount of benzyl alcohol was detected, due to the hydrolysis of ester. The scalability of this diazo-transfer reaction was examined by conducting a gram-scale reaction of 2a and ADT (12 mmol of ADT and 10 mmol of 2a) at the same concentration, reactant ratio, solvent, and temperature as in entry 1 in Table 3. The gram-scale reaction was completed in 2 min with a 90% isolation yield of 3a, indicating the good scalability of this diazo-transfer reaction. In Table 4, representative diazo-transfer reagents are summarized and compared with ADT based on their reactions with ethyl acetoacetate 2a. Although most of these diazotransfer reagents can provide high yield (>80%) of diazo product 3a, the reaction with ADT is the fastest (2 min at rt), followed by ionic liquid-supported sulfonyl azide (3 min at rt)29 and ADMP (10 min at 0 °C).18 Other reagents, including the only two commercially available diazo-transfer reagents (4acetamidobenzenesulfonyl azide and p-tosyl azide) require longer reaction time (up to several hours) to give diazo product 3a in good yields. It is noticeable that the lifetimes of most of these reagents are limited within several weeks, including the highly efficient reagents ionic liquid-supported sulfonyl azide29 and ADMP18 (a hygroscopic salt). In contrast, ADT is a hydrophobic solid and does not absorb water in air. Figure S3 shows the comparison of the IR spectrum of a freshly prepared ADT solid sample and a 1-year-old ADT solid sample stored at room temperature. These two IR spectra are almost identical, which indicates that ADT remains stable during the >1 year storage in air at room temperature. The exceptional stability of ADT crystalline solid is probably due to the conjugation and stabilization effect of the triazine ring on the azide group.19

ethyl acetoacetate to form enolate, and the metal ions serve as counterions to coordinate and stabilize the formed enolate. Therefore, a plausible mechanism of diazo group transfer from ADT to active methylene compound 2 is depicted in Scheme 1 based on the previously reported mechanism.15,18 First, the base removes a proton from the active methylene group to afford enolate 4, which is stabilized by metal ions in DMSO. Then, the nucleophilic attack of enolate 4 onto ADT occurs, followed by a proton transfer to afford intermediates 5 and 6. The cleavage of N−N bond in 6 leads to the desired diazo product 3. 4,6-Dimethoxy-1,3,5-triazin-2-amine 7 is obtained as a hydrophilic byproduct, which can be easily separated from diazo product 3. With the optimal reaction condition in hand, the scope of the ADT-based diazo-transfer reaction was examined (Table 3). Various stabilized diazo compounds 3 were afforded in good to excellent isolation yields with the tolerance of different functional groups, such as carbonyl, ester group, phosphoryl, and aryl. The nature of the substitution groups attaching to the carbonyl or ester groups shows little effect on the reaction (Table 3, entries 1−7). It is worth noting that diazo products 3a and 3d are volatile, so the isolation yields were lower than the NMR yields shown in parentheses (Table 3, entries 1 and 4). Regarding the inorganic base, NaHCO3 is efficient for most of 1,3-dicarbonyl compounds due to the high acidity of their methylene groups (Table 3, entries 1−5). With lower acidity of methylene groups due to the aryl, ester, or phosphoryl group substitution, a stronger base, K2CO3, can facilitate the reaction smoothly (Table 3, entries 6−9). Remarkably, the ADT-based diazo-transfer reaction can be used beyond highly active methylene compounds such as 1,3-dicarbonyl and carbonyl/ phosphoryl compounds. For example, ethyl phenylacetate can be converted to corresponding diazo compound in 6 min using solid KOH as base with 92% isolation yield (Table 3, entry 10). If using sulfonyl azides as reagents, this conversion needs 24 h to reach a good yield.22 This comparison also implies that ADT is compatible with strong inorganic base such as KOH, while most of the sulfonyl azides are not compatible with such a strong base. Cyclic 1,3-dicarbonyl compounds were also examined as substrates (Table 3, entries 11−13). Because cyclic 1,3-dicarbonyl compounds are more acidic than linear 1,3-dicarbonyl compounds, a weaker base, KOAc, was used that can afford the corresponding diazo compounds with a high isolation yield (∼90%). Besides carbonyl-containing compounds, indene was also tested as a very challenging substrate for diazo-transfer reaction.23 The previous synthesis method of 1-diazoindene was reported by Rewicki and Tuchscherer in 1972,23 where indene was reacted with ptosyl azide in diethylamine as solvent for 72 h to afford a 15% yield. In our case, with KOAc as the base, 1-diazoindene has

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CONCLUSION We have developed an intrinsically safe, highly efficient, and shelf-stable crystalline solid reagent ADT for diazo-transfer reaction of activate methylene compounds. ADT can be facilely synthesized from low-cost and convenient starting materials. With inorganic solid base as catalyst, the diazotransfer reaction based on ADT gives various diazo compounds in excellent yields within several minutes at room temperature, making ADT a promising diazo-transfer reagent for quick preparation of diazo compounds. 10918

DOI: 10.1021/acs.joc.8b01587 J. Org. Chem. 2018, 83, 10916−10921

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The Journal of Organic Chemistry Table 3. ADT-Based Diazo-Transfer Reaction with Different Active Methylene Compoundsa

Table 4. Comparison of Different Diazo-Transfer Reagents with 2a as the Substratea entry

temp

yield

Me− SO2N3 C4F9− SO2N3 TsN3

0 °C−rt

92%

liquid, used as freshly prepared

rt

88%

liquid, used as freshly prepared

rt

92%

rt rt

82% 93%

f27

p-CBSA PS− SO2N3 p-ABSA

liquid, stored as diluted solution under N2 solid solid, stable for 1−2 weeks

0 °C−rt

95%

g14

IMSA·HCl

40 °C

59%

h29 i18

ILSSA ADMP

rt 0 °C

89% 99%

j

ADT

rt

90%

a24 b25 26

c

d13 e13

reagent

stability

solid, stable at 2−8 °C for several weeks solid, stable in desiccator for several weeks28 solid, 4 weeks solid, stable at −10 °C for ∼2 months crystalline solid, stable at RT for >1 year

a rt = room temperature; p-CBSA = 4-carboxybenzenesulfonyl azide; PS-SO2N3 = polystyrene-supported benzenesulfonyl azide; p-ABSA = 4-acetamidobenzenesulfonyl azide; IMSA·HCl = imidazole-1-sulfonyl azide hydrochloride; ILSSA = ionic liquid-supported sulfonyl azide; ADMP = 2-azide-1,3-dimethylimidazolinium hexafluorophosphate.

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EXPERIMENTAL SECTION

General Information. Reagents involved in experiments were commercially purchased and were used as received without further purification for the reactions. Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectroscopy were performed on Bruker Advance 400 M NMR spectrometers. Chemical shifts 1H NMR spectra are reported in units of parts per million (ppm) downfield from SiMe4 (0.0) and relative to the signal of chloroform-d (J = 7.264, singlet). Multiplicities were given as s (singlet); t (triplet); q (quartet); and m (multiplets). The number of protons (n) for a given resonance is indicated by nH. Coupling constants are reported as a J value in Hz. Carbon nuclear magnetic resonance spectra (13C NMR) are reported in units of parts per million (ppm) downfield from SiMe4 (0.0) and relative to the signal of chloroform-d (J = 77.03, triplet). Synthetic Procedures and Spectra Data of 2-Azido-4,6dimethoxy-1,3,5-triazine. Cyanuric chloride (1.00 g, 5.4 mmol), NaHCO3 (1.10 g, 13.0 mmol), and 8 mL of MeOH were introduced to a round-bottom flask equipped with a magnetic stirring bar. The solution was stirred at 0 °C for 0.5 h. Then, the reaction mixture was allowed to warm back to room temperature while stirring for 1.5 h. After that, it was heated to 50 °C and stirred for an additional 2.0 h. The reaction mixture was concentrated in vacuum. Then, the mixture was extracted with DCM and H2O. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuum to provide the crude product. The crude product was purified by flash column chromatography (n-hexane/EtOAc = 10:1) on silica gel to afford 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.76 g, 4.3 mmol, 80% yield). If the reaction scale was tripled (with 3.0 g of cyanuric chloride as starting material), the yield of ADT was 2.46 g (86% yield). 1H NMR (400 MHz, CDCl3): δ 4.08 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 172.7, 172.6, 56.1. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.76 g, 4.3 mmol) and 5 mL of acetonitrile were introduced to a round-bottom flask equipped with a magnetic stirring bar. Sodium azide solution (4.7 mmol NaN3 in 2 mL of H2O) was added to the above-mentioned solution while stirring. Then, the reaction mixture was stirred at 35 °C for 2.5 h. The reaction mixture was concentrated in vacuum. Then, the mixture was extracted with DCM and H2O. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuum to provide the product ADT (0.75 g, 4.1 mmol, 96% yield) as a white

a

Condition: compounds 2 (0.5 mmol), ADT 1 (0.6 mmol), and base (0.2 mmol) in DMSO (2 mL), 25 °C. bIsolation yield; number in parentheses is NMR yield. cProduct is volatile. dnd = no reaction. 10919

DOI: 10.1021/acs.joc.8b01587 J. Org. Chem. 2018, 83, 10916−10921

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The Journal of Organic Chemistry

2-Diazo-1-phenylbutane-1,3-dione (3e) (General Procedure A). White solid, 0.0840 g, 89% yield. (Eluent: n-hexane/EtOAc = 5:1.) 1H NMR (400 MHz, CDCl3): δ 7.67−7.62 (m, 2H), 7.61−7.56 (m, 1H), 7.52−7.48 (m, 2H), 2.58 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 190.9, 185.1, 137.3, 132.7, 128.9, 127.4, 29.3. Ethyl-2-diazo-3-oxo-3-phenylpropanoate (3f) (General Procedure B). Pale yellow liquid, 0.0958 g, 88% yield. (Eluent: n-hexane/ EtOAc = 5:1.) 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.0 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 186.9, 161.0, 137.1, 132.3, 128.4, 127.9, 61.6, 14.2. Ethyl-2-diazo-3-(4-nitrophenyl)-3-oxopropanoate (3g) (General Procedure B). Pale yellow liquid, 0.1014 g, 77% yield. (Eluent: nhexane/EtOAc = 4:1.) 1H NMR (400 MHz, CDCl3): δ 8.34−8.21 (m, 2H), 7.80−7.68 (m, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 185.6, 160.4, 149.6, 142.5, 129.3, 123.1, 62.0, 14.2. Diethyl-2-diazomalonate (3h) (General Procedure B). Yellow liquid, 0.0837 g, 90% yield. (Eluent: n-hexane/EtOAc = 5:1.) 1H NMR (400 MHz, CDCl3): δ 4.31 (q, J = 7.1 Hz, 4H), 1.32 (t, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 161.1, 61.6, 14.4. Ethyl-2-diazo-2-(diethoxyphosphoryl)acetate (3i) (General Procedure B). Pale yellow liquid, 0.1226 g, 98% yield. (Eluent: n-hexane/ EtOAc = 3:1.) 1H NMR (400 MHz, CDCl3): δ 4.34−4.11 (m, 6H), 1.37 (t, J = 7.1 Hz, 6H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 163.5, 163.4, 63.7, 63.6, 61.7, 16.2, 16.1, 14.3. Ethyl-2-diazo-2-phenylacetate (3j) (General Procedure C). Red liquid, 0.0876 g, 92% yield. (Eluent: n-hexane/EtOAc = 4:1.) 1H NMR (400 MHz, CDCl3): δ 7.50−7.47 (m, 2H), 7.42−7.34 (m, 2H), 7.22−7.14 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 165.3, 128.9, 125.8, 125.7, 123.9, 61.0, 14.5. 2-Diazocyclohexane-1,3-dione (3k) (General Procedure D). Pale yellow liquid, 0.0622 g, 90% yield. 1H NMR (400 MHz, CDCl3): δ 2.55 (t, J = 8.0 Hz, 4H), 2.03 (m, (eluent: n-hexane/EtOAc = 5:1), 2H). 13C NMR (100 MHz, CDCl3): δ 190.5, 36.9, 18.6. 2-Diazocyclopentane-1,3-dione (3l) (General Procedure D). Yellow liquid, 0.0552 g, 89% yield. (Eluent: n-hexane/EtOAc = 4:1.) 1H NMR (400 MHz, CDCl3): δ 2.75 (s, 4H). 13C NMR (100 MHz, CDCl3): δ 193.0, 33.9. 2-Diazo-5,5-dimethylcyclohexane-1,3-dione (3m) (General Procedure D). White solid, 0.0764 g, 92% yield. (Eluent: n-hexane/ EtOAc = 3:1.) 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 4H), 1.10 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 190.0, 50.6, 31.2, 28.5. 1-Diazoindene (3n) (General Procedure E). Red solid, 0.0498 g, 70% yield. 1H NMR (400 MHz, CDCl3): δ 7.56−7.53 (m, 1H), 7.47−7.45 (m, 1H), 7.21−7.19 (m, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 135.3, 133.5, 124.1, 123.0, 122.7, 120.1, 118.7, 116.9.

solid. ADT can by recrystallized by dissolving in hot benzene and crystallized by adding petroleum ether. 1H NMR (400 MHz, CDCl3): δ 4.05 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 173.2, 172.2, 55.6. General Procedures A for the Synthesis of Diazo Compounds (3a−3e). Ethyl acetoacetate 2a (0.0650 g, 0.5 mmol), NaHCO3 (0.0168 g, 0.2 mmol), and 2 mL of DMSO were added to a 4 mL vial equipped with a magnetic stirring bar. ADT (0.1092 g, 0.6 mmol) was added to the solution. The solution was stirred at 25 °C for 2 min (monitored by TLC). Then, the mixture was extracted with DCM and H2O. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash column chromatography on silica gel to afford 3. General Procedures B for the Synthesis of Diazo Compounds (3f−3i). Ethyl benzoylacetate 2f (0.0961 g, 0.5 mmol), K2CO3 (0.0276 g, 0.2 mmol), and 2 mL of DMSO were added to a 4 mL vial equipped with a magnetic stirring bar. ADT (0.1092 g, 0.6 mmol) was added to the solution. The solution was stirred at 25 °C for 2 min (monitored by TLC). Then, the mixture was extracted with EA and H2O. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash column chromatography on silica gel to afford 3. General Procedures C for the Synthesis of Diazo Compounds (3j). Ethyl phenylacetate 2j (0.0821 g, 0.5 mmol), KOH (0.0112 g, 0.2 mmol), and 2 mL of DMSO were added to a 4 mL vial equipped with a magnetic stirring bar. ADT (0.1092 g, 0.6 mmol) was added to the solution. The solution was stirred at 25 °C for 6 min (monitored by TLC). Then, the mixture was extracted with EA and H2O. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash column chromatography on silica gel to afford 3j. General Procedures D for the Synthesis of Diazo Compounds (3k−3m). 1,3-Cyclohexanedione 2k (0.0568 g, 0.5 mmol), KOAc (0.0202 g, 0.2 mmol), and 2 mL of DMSO were added to a 4 mL vial equipped with a magnetic stirring bar. Compound 1 (0.1092 g, 0.6 mmol) was added to the solution. The solution was stirred at 25 °C for 2 min (monitored by TLC). Then, the mixture was extracted with DCM and H2O. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by flash column chromatography on silica gel to afford 3. General Procedures E for the Synthesis of Diazo Compounds (3n). Indene 2n (0.0592 g, 0.5 mmol), KOAc (0.0205 g, 0.2 mmol), and 2 mL of DMSO were added to a 4 mL vial equipped with a magnetic stirring bar. ADT (0.1092 g, 0.6 mmol) was added to the solution. The solution was stirred at 25 °C for 3 min (monitored by TLC). Then, the mixture was extracted with DCM and H2O. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuum. The organic phases were combined, dried with Na2SO4, and concentrated under a reduced pressure of ca. 20 Torr at 30 °C to afford 3n. Ethyl-2-diazo-3-oxobutanoate (3a) (General Procedure A). Pale yellow liquid, 0.0703 g, 90% yield. (Eluent: n-hexane/EtOAc = 10:1.) 1 H NMR (400 MHz, CDCl3): δ 4.31 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 190.3, 161.4, 61.4, 28.3, 14.3. tert-Butyl-2-diazo-3-oxobutanoate (3b) (General Procedure A). Yellow liquid, 0.0825 g, 90% yield. (Eluent: n-hexane/EtOAc = 10:1.) 1 H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 1.53 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 190.6, 160.6, 83.2, 28.3, 28.2. Methyl-2-diazo-3-oxohexanoate (3c) (General Procedure A). Pale yellow liquid, 0.0754 g, 89% yield. (Eluent: n-hexane/EtOAc = 10:1.) 1H NMR (400 MHz, CDCl3): δ 3.84 (s, 3H), 2.83 (t, J = 7.4 Hz, 2H), 1.72−1.62 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 192.8, 161.8, 52.1, 42.2, 17.8, 13.7. 3-Diazopentane-2,4-dione (3d) (General Procedure A). Pale yellow liquid, 0.0485 g, 77% yield. (Eluent: n-hexane/EtOAc = 10:1.) 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 188.3, 28.5.

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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.8b01587. IR, XRD, DSC, and TGA data of ADT; BAM friction and impact tests of ADT; and 1H and 13C spectra of all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Mingming Ma: 0000-0002-7967-8927 Author Contributions †

S.X. and Z.Y. contributed equally.

Notes

The authors declare no competing financial interest. 10920

DOI: 10.1021/acs.joc.8b01587 J. Org. Chem. 2018, 83, 10916−10921

Article

The Journal of Organic Chemistry

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21474094 and 21722406) and the Fundamental Research Funds for the Central Universities (WK2060200025).

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DOI: 10.1021/acs.joc.8b01587 J. Org. Chem. 2018, 83, 10916−10921