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Microwave-assisted synthesis of α-aryl malonates: Key intermediates for the preparation of azaheterocycles
⁎Address: Department of Pharmaceutical Chemistry, Almaarefa Colleges for Science and Technology, Riyadh 11597, Saudi Arabia. Tel.: +966531071097. drmmonem@yahoo.com (Mohamed A. Ibrahim)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
We disclose a new microwave-assisted protocol for the effective α-arylation of diethyl malonate. The coupling of aryl halides with diethyl malonate proceeds smoothly in short reaction time in the presence of a catalytic amount of Cu(OTf)2, 2-picolinic acid and Cs2CO3 in toluene using microwave irradiation. The resulting α-aryl malonates are then used as key intermediates for synthesis of variety of heterocyclic compounds, including benzodiazepines, isoquinolines and pyrrolopyridine scaffolds.
Keywords
Arylation
Benzodiazepine
Isoquinoline
Pyrrolopyridine
Diethyl malonate
1 Introduction
α-Aryl malonates represent an important class of molecules that have various pharmaceutical applications. α-Aryl malonates have been used as effective modulators in mammalian cell membranes and as enzyme inhibitors (Gorssman and Varner, 1997). Malonate chemistry is the best way to synthesize highly functionalized compounds containing quaternary centers. (Canet et al., 1992; Martin, 1980) α-Aryl malonates are used to synthesize a wide range of valuable intermediates in organic chemistry. One of these important intermediates leads to synthesis of α-aryl carboxylic acids (Toone and Jones, 1991; Shunsaku et al., 1996; Narisano and Riva, 1999; Guanti et al., 1998; Chenevert and Desjardins, 1994; Knabe et al., 1987; Meester et al., 1986).
α-Aryl acids represent an important class of molecules that are found in numerous natural products, as well as find various pharmaceutical applications (Sheldrick et al., 1978; Kong and Andersen, 1993; Hedge et al., 1998). α-Aryl acids are used for synthesis of different nonsteroidal anti-inflammatory drugs. For example, α-Aryl acetic acids and α-aryl propionic acids are used for synthesis of indomethacin, sulindac, ibufenac & diclofenac and ibuprofen, naproxen & ketoprofen, respectively (Rieu et al., 1986).
Several methods for the synthesis of α-aryl acids have been reported in literature; these include palladium-catalyzed cross coupling of enolates with aryl halides (Culkin and Hatrwig, 2003; Aramendia et al., 2002; Djakovitch and Kohler, 2000), as well as Cu(I)-catalyzed arylation of diethyl malonate in the presence of proline (Xie et al., 2005; Buchwald, 2005). Nonetheless, several protocols may suffer serious limitations such as long reaction times, use of expensive metal catalysts, and low reactivity of pyridyl halides or halobenzonitriles toward palladium catalysts (Jiang et al., 2005; Fox et al., 2000; Culkin and Hartwig, 2001; Katz and Aube, 2003; Richon et al., 1982; Shiotani et al., 1996). Along with the lack of versatility in preparing such α-aryl malonates, the arylation of activated methylene compounds in the presence of copper metal or copper salts, known as Hurtley reaction, is only effective for o-bromobenzoic acid and its closely related halides (Hurtley, 1929). Reports on the Cu-mediated arylation of malonates and their derivatives by aryl halides indicate that often a stoichiometric amount of Cu complex is required; in addition, high reaction temperatures should be attained to allow the reaction to take place. Furthermore, good yields are only achieved in the case of highly activated aryl halides (Setsune et al., 1982; Suzuki et al., 1983, 1987). However, milder reaction conditions have been achieved as described by Buchwald, who reported the synthesis of a variety of arylated malonates from aryl iodides using CuI and 2-phenylphenol monodentate as a supporting ligand (Hennessy and Buchwald, 2002).
As a result of the importance of α-aryl malonates as intermediates for synthesis of a wide array of pharmaceutical agents, we developed an alternative general method that provides feasible access to a wide number of α-aryl malonates in short reaction time. Herein, we show the various optimization studied (bases, catalysts, ligands, solvents, reaction times, reaction temperatures and leaving halides) toward the α-arylation of diethyl malonate. In addition, we employed the prepared α-aryl malonates for the synthesis of benzodiazepine, isoquinoline and pyrrolopyridine scaffolds.
2 Results and discussion
In a typical experiment, the desired aryl halides (1 mmole), cesium carbonate (3 mmole), copper triflate (0.1 mmole) and picolinic acid (0.2 mmole) were mixed together and flushed with argon. Anhydrous toluene was added followed by diethyl malonate (2 mmole). The mixture was irradiated in microwave at 90 °C for 30 min (Scheme 1).
Synthesis of substituted 2,3-benzodiazepine (A), substituted pyrrolopyridine ester (B) and substituted isoquinoline (C) scaffolds.
Firstly, we investigated the α-arylation of diethyl malonate on substituted iodo benzene (methyl 2-iodobenzoate, 2-iodobenzophenone, 2-iodo 4-methoxybenzophenone and 2-iodobenzonitrile) (Table 1). In all cases, cesium carbonate was chosen as the base. In the absence of any catalyst/ligand, microwave irradiation resulted in no successful arylation (entries 1, 2). On the other hand, this reaction was sluggish at room temperature, even in the presence of various copper catalysts, picolinic acid as a ligand (entry 3). Indeed, heating at 90 °C in the presence of the aforementioned reagents resulted in better yields where diethyl malonate is later added to the reaction mixture (entries 4, 5). With respect to solvent effect, both 1,4-dioxane and toluene showed comparable efficiency (entries 5, 9, 10, 11, 14, 15). However, the presence of the ligand is critical given that low yield is obtained when no ligand was added in a solution of 1,4-dioxane while no reaction was observed when DCE or DMF was used (entries 6, 7, 8). When comparing the various metal catalysts, only copper salts (Cu powder, CuI and copper triflate) showed excellent convergent results (entries 5, 9, 10, 11, 14, 15), while auric chloride indicated little reaction progress and silver trifluoroacetate (AgCF3CO2) was entirely ineffective (entries 12, 13).
Entry
Catalyst
Ligand
Solvent
Temp. before adding DEM
Temp (°C)
Time (h)
Yield (%)a
1a
1b
1c
1d
3a
3b
3c
3d
1
No catalyst
No ligand
Dioxane
r.t.
r.t.
3
7
7
6
No reaction
2
No catalyst
No ligand
Dioxane
90
90
3
7
7
6
No reaction
3
CuI
Picolinic acid
Dioxane
r.t.
r.t.
3
14
14
6
6
5
8
8
4
CuI
Picolinic acid
Dioxane
90
90
3
7
7
6
71
63
80
84
5
CuI
Picolinic acid
Dioxane
r.t.
90
3
7
7
6
76
69
89
86
6
CuI
No ligand
Dioxane
90
90
3
7
7
6
14
12
11
14
7
CuI
No ligand
DCE
r.t.
90
3
7
7
6
No reaction
8
CuI
No ligand
DMF
r.t.
90
3
7
7
6
No reaction
9
CuI
Picolinic acid
Toluene
r.t.
90
3
7
7
6
78
69
90
89
10
Cu powder
Picolinic acid
Dioxane
r.t.
90
3
7
7
6
77
70
90
90
11
Cu powder
Picolinic acid
Toluene
r.t.
90
3
7
7
6
80
72
90
91
12
AuCl3
Picolinic acid
Dioxane
r.t.
90
3
7
7
6
5
4
6
5
13
Ag(CF3CO2)
Picolinic acid
Dioxane
r.t.
90
3
7
7
6
No reaction
14
Cu(OTf)2
Picolinic acid
Dioxane
r.t.
90
3
5
5
6
83
75
91
94
15
Cu(OTf)2
Picolinic acid
Toluene
r.t.
90
3
5
5
6
85
76
91
94
16
Cu(OTf)2
Picolinic acid
Toluene
r.t.
M.W 90
0.5
0.5
0.5
0.5
86
75
91
95
Finally, shorter reaction times were achieved when microwave oven was used in place of conventional heating methods. Indeed, optimum results can be obtained when Cs2CO3, copper triflate, and picolinic acid were used as additives in toluene at 90 °C for 30 min (entry 16).
Next, we aimed at investigating the scope of the arylation of diethyl malonate with N-heterocyclic compounds, namely, 2-bromopyridine and 2-bromo-5-methylpyridine (Table 2).
Entry
Catalyst
Ligand
Solvent
Temp. before adding DEM
Temp. (°C)
Time (h)
Yield (%)a
5a + 6a
5b + 6b
1
No catalyst
No ligand
Dioxane
r.t.
r.t.
14
No reaction
2
No catalyst
No ligand
Dioxane
90
90
14
No reaction
3
CuI
Picolinic acid
Dioxane
r.t.
r.t.
14
No reaction
4
CuI
Picolinic acid
Dioxane
90
90
7:
65% of 5a
35% of 5a
14:
70% of 5a + 15% of 6a
39% of 5a + 5% of 6a
5
CuI
Picolinic acid
Dioxane
r.t.
90
7:
85% of 5a
43% of 5a
14:
80% of 5a + 10% of 6a
40% of 5a + 6% of 6a
6
CuI
No ligand
Dioxane
90
90
14
No reaction
7
CuI
No ligand
DCE
r.t.
90
14
No reaction
8
CuI
No ligand
DMF
r.t.
90
14
No reaction
9
CuI
Picolinic acid
Toluene
r.t.
90
7:
87% of 5a
45% of 5a
14:
80% of 5a + 10% of 6a
41% of 5a + 6% of 6a
10
CuI
Picolinic acid
Toluene/MgSO4
r.t.
90
7:
88% of 5a
46% of 5a
14:
81% of 5a + 11% of 6a
42% of 5a + 6% of 6a
11
Cu powder
Picolinic acid
Dioxane
r.t.
90
7:
88% of 5a
47% of 5a
14:
81% of 5a + 11% of 6a
42% of 5a + 7% of 6a
12
Cu powder
Picolinic acid
Toluene/MgSO4
r.t.
90
7:
88% of 5a
47% of 5a
14:
81% of 5a + 10% of 6a
43% of 5a + 7% of 6a
13
AuCl3
Picolinic acid
Dioxane
r.t.
90
14
No reaction
14
Ag(CF3CO2)
Picolinic acid
Dioxane
r.t.
90
14
No reaction
15
Cu(OTf)2
Picolinic acid
Dioxane
r.t.
90
7:
89% of 5a
52% of 5a
14:
83% of 5a + 11% of 6a
47% of 5a + 9% of 6a
16
Cu(OTf)2
Picolinic acid
Toluene/MgSO4
r.t.
90
7:
91% of 5a
54% of 5a
14:
84% of 5a + 12% of 6a
49% of 5a + 11% of 6a
17
Cu(OTf)2
Picolinic acid
Acetonitrile/MgSO4
r.t.
90
7:
90% of 5a
54% of 5a
14:
84% of 5a + 12% of 6a
49% of 5a + 11% of 6a
18
Cu(OTf)2
Picolinic acid
Toluene/MgSO4
r.t.
M.W 100
0.5:
91% of 5a
55% of 5a
1:
84% of 5a + 12% of 6a
49% of 5a + 12% of 6a
In all the following reaction trials, we used cesium carbonate as a base. The reaction resulted in no successful arylation in the presence of other bases (ALO-, Ba(OH)2, NaH). The reaction did not work without any catalyst or ligand (entries 1, 2). Doing the reaction at room temperatures using copper salts as a catalyst, picolinic acid as a ligand and cesium carbonate as a base did not show a good progress (entry 3). The reaction did not work in the absence of picolinic acid in different solvents (dioxane, DCE, DMF) (entries 6–8).
α-Arylation of diethyl malonate on 2-bromopyridine 4a for 7 h yielded 5a in 65–91% yield while arylation of 2-bromo-5-methylpyridine 4b for the same period afforded 5b in 35–55% yield according to the employed conditions. On the other hand, longer reaction times using either 4a or 4b as a starting material (14 h) results in a mixture of 5a and 6a, and 5b and 6b, respectively (entry 5). Similarly, solvents with different polarity (dioxane, toluene, acetonitrile) were examined; toluene showed the best results especially upon addition of MgSO4 as a drying agent (entries 10, 12, 16, 18). Acetonitrile exhibited almost similar results as toluene (entry 17). Auric chloride and silver salt did not show any reaction progress (entries 13, 14).
Copper salts (Cu powder, CuI and copper triflate) in toluene/MgSO4 showed the best results (entries 10, 12, 16). Microwave irradiation has been used to optimize the reaction conditions. The reaction proceeded in the presence of cesium carbonate, Cu(OTf)2 and picolinic acid in toluene/MgSO4 under microwave irradiations for 30 min to give 5a in 91% yield (entry 18). Increasing the irradiation time to 1 h gives mixture of 5a and 6a in 84% and 12% yields respectively. (entry 18).
Next, we tested the arylation of diethyl malonate on 2-chloro-3-nitropyridine, 2-chloro-5-nitropyridine and 2,6-dichloro-3-nitropyridine (Table 3). In all the following reaction trials, we used cesium carbonate as a base. The reaction has been progressed at room temperature without ligand and catalyst due to presence of electron withdrawing group (nitro group) (entry 1). Heating the reaction at 90 °C gives almost the same results but with shorter reaction time (entry 2). Using picolinic acid ligand and the copper salt catalyst and stirring at room temperature for 2 h improves the yield (entries 3, 6, 8) while heating the previous mixture gives better yields than stirring at room temperature (entries 5, 7, 9). Different positions of the nitro group in either the ortho (7a) or the para (7b) positions did not show significant difference in the reaction yield (entry 10). The best reaction result has been obtained when we used microwave. The reaction proceeds well in the presence of cesium carbonate, copper triflate, and picolinic acid in toluene at 90 °C for 20 min (entry 10). Cesium carbonate worked at room temperature for only 60 min with high yield while other bases in the literature need high temperatures for long time (Shirude et al., 2013; Li, 2011; Dunn et al., 2009; Frank et al., 2013; Alam et al., 2013).
Entr y
Catalyst
Ligand
Solvent
Temp. before adding DEM
Temp. (°C)
Time (h)
Yield (%)a
7a
7b
7c
8a
8b
8c + 8d
1
No catalyst
No ligand
Toluene
r.t.
r.t.
2
2
2
70
69
60% 8c
2
No catalyst
No ligand
Toluene
r.t.
90
1
1
1
73
70
65% 8c
3
CuI
Picolinic acid
Toluene
r.t.
r.t.
2
2
2
75
72
68% 8c
5
CuI
Picolinic acid
Toluene
r.t.
90
1
1
1
80
79
70% 8c + 20% 8d
6
Cu powder
Picolinic acid
Toluene
r.t.
r.t
2
2
2
76
72
69% 8c
7
Cu powder
Picolinic acid
Toluene
r.t.
90
1
1
1
81
80
71% 8c + 22% 8d
8
Cu(OTf)2
Picolinic acid
Toluene
r.t.
r.t.
2
2
2
85
85
75% 8c
9
Cu(OTf)2
Picolinic acid
Toluene
r.t.
90
1
1
1
88
90
75% 8c + 21% 8d
10
Cu(OTf)2
Picolinic acid
Toluene
r.t.
M.W 90
0.2
0.2
0.2
87
90
75% 8c + 22% 8d
Different reaction conditions have been investigated for arylation of diethyl malonate on 2,6-dichloro-3-nitropyridine. When the reaction is performed at room temperature, it gives only one product (entries 1, 3, 6, 8). Heating the reaction mixture under different conditions gives mixture of the monoarylated product in high yield and the diarylated product in low yield (entries 5, 7, 9, 10).
After screening different reaction conditions on synthesis of α-aryl derivatives of diethyl malonate, we found that using catalytic amount of Cu(OTf)2, 2-picolinic acid and Cs2CO3 in toluene using microwave irradiation is the ideal condition. Under these conditions, the reaction gives high yields in short reaction time.
The devised protocol overcomes some drawbacks in the literature including long reaction time, low yields, and poor reactivity of aryl bromide, and is applicable toward substrates containing certain functional groups in the ortho position (e.g., –NO2, –CN) (Hennessy and Buchwald, 2002).
As our research interest involves the preparation and study of azaheterocycles (Elagawany et al., 2013; Ibrahim et al., 2013, 2012), we employed the prepared α-aryl malonate in the synthesis of benzodiazepine, isoquinoline and pyrrolopyridine scaffolds (Scheme 1).
Firstly, the role of α-aryl malonate in the synthesis of 2,3-benzodiazepine-4-one and isoquinoline scaffolds has been described. Commercially available 2-iodobenzoic acid was activated into the corresponding aroyl chloride which is then involved in a Friedel–Crafts reaction in the presence of benzene to give 1b or methoxybenzene to give 1c. Then, we synthesized α-Aryl malonate derivatives 3b,c by our optimized condition using diethyl malonate, copper-triflate and picolinic acid in toluene in microwave for 30 min. α-Aryl malonate derivatives were then decarboxylated in alkaline medium in microwave at 120 °C for 5 min in mixture of methanol and water to give the decarboxylated form 10a,b. Condensation of the decarboxylated intermediate 10a,b with hydrazine hydrate gives the corresponding 2,3-benzodiazepines-4-one 11a,b while coupling the decarboxylated intermediate 10a with tert-butyl-carbazate using EDCI, triethylamine and HOBt in dimethylformamide at room temperature for 7 h gives isoquinoline scaffold 13. N-methylation of the amide function in compound 11a was eventually performed with chloro-2-methoxy ethane and benzyl chloride in the presence of Cs2CO3 and tetrahydrofuran to give compounds 12a,b. Our methodology for synthesis of 2,3 benzodiazepine derivatives is more time saving and gives higher yield (29% overall yield, 8.5 h) than literature method (14% overall yield, more than 3 days) (Mcdonald and Dunstone, 2006; Flammang and Wermuth, 1976) (Scheme 2).
Synthesis of benzodiazepine derivatives 12a,b and isoquinoline scaffold 13.
Further, the importance of α-aryl malonate in the synthesis of 1-imino-2,3 benzodiazepine-4-one and substituted 1-imino-isoquinoline has been described. (Scheme 3) A copper-catalyzed reaction was performed on 2-iodobenzophenone leading to the substitution of the iodine atom by a diethyl malonate moiety using our optimized methodology in the presence of copper-triflate and picolinic acid in toluene in microwave for 30 min. Alkaline hydrolysis of α-aryl malonate 3d in microwave at 120 °C for 5 min in mixture of methanol and water gives the decarboxylated form 14. Coupling the decarboxylated intermediate with benzyl tert-butyl-carbazate 15 using BOP, triethylamine in dichloromethane at room temperature for 7 h gives compound 16 which is then deprotected by trifluoroacetic acid at room temperature for 10 min to compound 17. Several trials were performed for intramolecular cyclization of the deprotected form 17 between the amino group and the nitrile group to obtain 1-imino-2,3 benzodiazepine-4-one 18. The reaction has been investigated in trifluoroacetic acid at different temperature degrees starting from room temperature to 130 °C. Microwave irradiation of compound 17 in trifluoroacetic acid for 30 min at 135 °C gives compound 18 in 10% yield. Also, we tried to use isopropanol and butanol as solvents for intramolecular cyclization at 135 °C for 24 h but the yield was 5%. Coupling reaction of compound 14 with tert-butyl carbazate 19 in the presence of BOP and triethylamine at room temperature for 7 h gives the unseparated compound 20 which then attacks another molecule of compound 14 to give compound 21 in 83% (Scheme 3).
Synthesis of 1-imino 2,3 benzodiazepine 18 and 1-imino isoquinoline 21 scaffolds.
Furthermore, α-aryl malonate has been used in synthesis of pyrrolopyridine scaffold. Our optimized copper-catalyzed reaction was performed on the commercially available 2-chloro-3-nitropyridine to give 8a. Cyclization of compound 8a in acetic acid 100% and iron in microwave at 130 °C for 15 min gives pyrrolopyridine ester 22. Our methodology for synthesis of pyrrolopyridine ester is more time saving and gives higher yield (82% overall yield, 35 min) than literature method (10% overall yield, 13 h) (Dogan et al., 2015) (Scheme 4).
Synthesis of pyrrolopyridine ester 22.
3 Conclusion
In conclusion, an efficient and simple method to synthesize the α-aryl diethyl malonates in good yields and shorter reaction time is described. The optimized condition is achieved by using catalytic amounts of copper triflate, picolinic acid and Cs2CO3 in toluene using microwave irradiation. Then, α-aryl malonate was employed as intermediate for the synthesis of benzodiazepines, isoquinolines and pyrrolopyridine scaffolds. Currently, efforts toward the synthesis of new scaffolds using α-aryl malonates are underway.
4 Experimental
All materials from commercial suppliers were used as purchased. The melting points reported are uncorrected. 13C NMR spectra were recorded on a Bruker Avance 400 spectrometer operating at 100 MHz. 1H NMR spectra were recorded on a Bruker 300 MHz Avance DPX; probe dual. Chemical shifts are given in parts per million (ppm) relative to tetramethylsilane (TMS), and coupling constants J are given in Hertz. Mass spectra were determined by ESI–mass spectra obtained on an LC/MS instrument (AGILENT, MS: MSD-SL, LC: 1200SL). For MW reactions, irradiation was performed using a Biotage Initiator EXP.
5 General procedure for α-arylation of diethyl malonate
The corresponding arylhalides 1a–d or 4a,b or 7a–c (0.620 mmole), cesium carbonate (615 mg, 1.860 mmole), copper triflate (22 mg, 0.062 mmole), picolinic acid (15 mg, 0.124 mmole) were mixed together and flushed with argon. Anhydrous toluene (2 mL) was added followed by diethyl malonate (195 μL, 1.240 mmole). The mixture was irradiated by microwave at 90 °C for 30 min. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate and washed with ammonium chloride, saturated solution of sodium bicarbonate and brine solution. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography using gradient of ethyl acetate/heptane to give the corresponding arylated malonate 3a–d or 5a,b or 6a,b or 8a–d respectively.
Diethyl 2-(2-(methoxycarbonyl)phenyl)malonate (3a): (Setsune et al., 1981) Starting reactant (1a). Oily (86%); Purification eluent; ethyl acetate/heptane 15%. 1H NMR (CDCl3) δ 1.27 (t, J = 7 Hz, 6H), 1.74 (s, 3H), 4.15–4.29 (m, 4H), 5.10 (s, 1H), 7.41–7.46 (m, 1H), 7.59–7.71 (m, 3H).
Diethyl 2-(2-benzoylphenyl)malonate (3b): (Kobayashi et al., 1994) Starting reactant (1b). Oily (75%); Purification eluent; ethyl acetate/heptane 15%. 1H NMR (CDCl3) δ 1.62 (t, J = 7 Hz, 6H), 4.09–4.18 (m, 4H), 5.05 (s, 1H), 7.33–7.42 (m, 4H), 7.47–7.60 (m, 3H), 7.73–7.76 (m, 2H). 13C NMR (CDCl3) δ 14.0, 54.4, 61.8, 127.3, 128.4, 129.8, 130.2, 130.4, 131.0, 132.6, 133.3, 137.7, 138.4, 168.2, 197.5.
Diethyl 2-(2-(4-methoxybenzoyl)phenyl)malonate (3c): Starting reactant (1c). Oily (91%); Purification eluent; ethyl acetate/heptane 15%. 1H NMR (CDCl3) δ 1.18 (t, J = 7 Hz, 6H), 3.84 (s, 3H), 4,09–4,20 (m, 4H), 5.00 (s, 1H), 6.88–6.91 (m, 2H), 7.35–7.36 (m, 2H), 7.47–7.62 (m, 2H), 7.74–7.77 (m, 2H). 13C NMR (CDCl3) δ 14.1, 55.7, 61.9, 113.8, 127.4, 129.3, 130.2, 130.5, 130.6, 132.3, 133.0, 139.1, 163.9, 168.4, 195.8.
Diethyl 2-(2-cyanophenyl)malonate (3d): (Beugelmans et al., 1982) Starting reactant (1d). Oily (95%); Purification eluent; ethyl acetate/heptane 20%. 1H NMR (CDCl3) δ 1.22 (t, J = 7 Hz, 6H), 4.10–4.25 (m, 4H), 5.05 (s, 1H), 7.36–7.41 (m, 1H), 7.54–7.66 (m, 3H). 13C NMR (CDCl3) δ 14.2, 55.7, 62.5. 113.7, 117.3, 128.8, 130.1, 133.0, 133.1, 136.3, 166.9.
5.1 Diethyl 2-(pyridin-2-yl)malonate (5a) + Ethyl 2-(pyridin-2-yl)acetate (6a)
Using our generalized procedure gives mixture of 5a + 6a: Starting reactant (4a).
Diethyl 2-(pyridin-2-yl)malonate (5a): (Bob et al., 2009) Oily; Purification eluent; ethyl acetate/heptane 30%. 1H NMR (CDCl3) δ 1.26 (t, J = 7 Hz, 6H), 4.20–4.36 (m, 4H), 4.93 (s, 1H), 7.20–7.28 (m, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 8.55 (d, J = 4.3 Hz, 1H).
Ethyl 2-(pyridin-2-yl)acetate (6a): (Firth et al., 2014) Oily; Purification eluent; ethyl acetate/heptane 30%. 1H NMR (CDCl3) δ 1.24 (t, J = 7.2 Hz, 3H), 3.82 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 7.14–7.29 (m, 2H), 7.63 (t, J = 8.5 Hz, 1H), 8.54 (d, J = 4.3 Hz, 1H).
Diethyl 2-(5-methylpyridin-2-yl)malonate (5b) + Ethyl 2-(5-methylpyridin-2-yl)acetate (6b): (Beigelman et al., 2009; Akio, 2007) Using our generalized procedure gives mixture of 5b + 6b: Starting reactant (4b).
Diethyl 2-(5-methylpyridin-2-yl)malonate (5b): (Beigelman et al., 2009) Oily; Purification eluent; ethyl acetate/heptane 30%. 1H NMR (CDCl3) δ 1.25 (t, J = 7.2 Hz, 6H), 2.31 (s, 3H), 4.21–4.23 (m, 4H), 7.36 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 8.37 (d, J = 1.6 Hz, 1H).
Ethyl 2-(5-methylpyridin-2-yl)acetate (6b): (Akio, 2007) Oily; Purification eluent; ethyl acetate/heptane 30%. 1H NMR (CDCl3) δ 1.24 (t, J = 7.2 Hz, 3H), 2.29 (s, 3H), 3.78 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 7.8 Hz, 2 Hz, 1H), 8.36 (s, 1H).
Diethyl 2-(3-nitropyridin-2-yl)malonate (8a): (Shirude et al., 2013) Oily; Purification eluent; ethyl acetate/heptane 30%. 1H NMR (CDCl3) δ 1.25 (t, J = 7.2 Hz, 6H), 4.21–4.30 (m, 4H), 5.49 (s, 1H), 7.49–7.53 (m, 1H), 8.46 (d, 1H, J = 8.3 Hz, 1H), 8.77 (d, J = 4.7 Hz, 1H).
Diethyl 2-(5-nitropyridin-2-yl)malonate (8b): (Frank et al., 2013) Oily; Purification eluent; ethyl acetate/heptane 30%. 1H NMR (CDCl3) δ 1.27 (t, J = 7.2 Hz, 6H), 4.21–4.29 (m, 4H), 5.04 (s, 1H), 7.74 (d, 1H, J = 8.6 Hz), 8.48 (dd, J = 8.7 Hz, 2.7 Hz, 1H), 9.36 (d, J = 2.5 Hz, 1H).
5.2 Diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonate (8c) + Tetraethyl 2,2′-(3-nitropyridine-2,6-diyl)dimalonate (8d)
Our generalized procedure gives mixture of 8c + 8d: Starting reactant (7c).
Diethyl 2-(6-chloro-3-nitropyridin-2-yl)malonate (8c): (Alam et al., 2013) Oily; Purification eluent; ethyl acetate/heptane 30%. 1H NMR (CDCl3) δ 1.24 (t, J = 7.2 Hz, 6H), 4.10–4.14 (m, 4H), 5.39 (s, 1H), 7.74 (d, 1H, J = 8.6 Hz), 8.39 (d, 1H, J = 8.6 Hz).
Tetraethyl 2,2′-(3-nitropyridine-2,6-diyl)dimalonate (8d): Oily; Purification eluent; ethyl acetate/heptane 30%. 1H NMR (CDCl3) δ 1.21–1.27 (m, 12H), 4.16–4.30 (m, 8H), 4.94 (s, 1H), 5.46 (s, 1H), 7.74 (d, 1H, J = 8.6 Hz), 8.47 (d, 1H, J = 8.6 Hz). 13C NMR (CDCl3) δ 14.1, 14.2, 59.6, 60.3, 62.3, 62.6, 124.6, 134.1, 148.5, 157.1, 166.3, 168.1, 168.4. Anal. calcd. for C19H24N2O10: C, 51.82; H, 5.49; N, 6.36; found: C, 51.83; H, 5.48; N, 6.35.
5.3 General procedure for synthesis of compounds 10a,b
A mixture of compounds 3b or 3c (0.58 mmole) and Lithium hydroxide (74.1 mg, 1.761 mmole) in methanol (2 mL) and water (1 mL) was irradiated in microwave at 120 °C for 5 min. The mixture was then diluted with saturated solution of Na2CO3 (20 mL) and extracted with ethyl acetate (20 mL). The aqueous layer was then acidified with conc. HCl to PH 2 and extracted by ethyl acetate (3 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give compound 10a or 10b.
2-(3-Benzoylphenyl)acetic acid (10a): (Mcdonald and Dunstone, 2006) White microcrystal, m.p. = 105–107 °C (85%) 1H NMR (CD3OD) δ 3.86 (s, 2H), 7.34–7.53 (m, 6H), 7.58–7.63 (m, 1H), 7.75–7.77 (m, 2H). 13C NMR (CD3OD) δ 39.6, 127.7, 129.5, 131.1, 131.5, 132.2, 133.2, 134.3, 135.9, 139.2, 139.7, 174.9, 200.1.
2-(2-(4-Methoxybenzoyl)phenyl)acetic acid (10b): (Flammang and Wermuth, 1976; Tang et al., 2010; Dogan et al., 2015) White microcrystal, m.p. = 124–126 °C (80%) 1H NMR (CD3OD) δ 3.79 (s, 2H), 3.88 (s, 3H), 7.00 (d, J = 8.9 Hz, 2H), 7.37–7.42 (m, 3H), 7.48–7.52 (m, 1H), 7.77 (d, J = 8.9 Hz, 2H).
5.4 General procedure for synthesis of compounds 11a,b
A mixture of 10a or 10b (1.23 mmole) and hydrazine hydrate (119.7 μL, 3.71 mmole) in isopropanol (2 mL) was irradiated in microwave for 1 h at 140 °C. The mixture was diluted in ethyl acetate and washed with saturated solution of sodium bicarbonate. The organic layer was purified by column chromatography using ethyl acetate/heptane 1:1 to give compound 11a or 11b.
1-Phenyl-2,3-benzodiazepin-4(3H)-one (11a): (Mcdonald and Dunstone, 2006; Flammang and Wermuth, 1976) White microcrystal, m.p. = 217–219 °C (65%) 1H NMR (CDCl3) δ 3.61 (s, 2H), 7.23–7.63 (m, 9H), 9.20 (s, 1H). 13C NMR (CDCl3) δ 42.3, 127.0, 128.2, 128.5, 129.4, 129.7, 130.1, 131.4, 132.0, 136.3, 136.0, 162.2, 171.3. m/z: 237 (m+1).
1-(4-Methoxyphenyl)-2,3-benzodiazepin-4(3H)-one (11b): White microcrystal, m.p. = 232–234 °C (70%) 1H NMR (CDCl3) δ 3.50 (s, 2H), 3.79 (s, 3H), 6.86 (d, J = 8.9 Hz, 2H), 7.17–7.19 (m, 1H), 7.24–7.32 (m, 2H), 7.43–7.50 (m, 3H), 8.64 (s, 1H). 13C NMR (CDCl3) δ 42.3, 55.6, 114.0, 127.0, 128.2, 129.9, 130.5, 131.0, 131.5, 132.0, 136.4, 161.4, 162.2, 171.5. m/z: 267 (m+1). Anal. calcd. for C16H14N2O2: C, 72.17; H, 5.30; N, 10.52; found: C, 72.25; H, 5.64; N, 10.90.
5.5 General procedure for synthesis of compounds 12a,b
A mixture of compound 11a (100 mg, 0.424 mmole), cesium carbonate (152 mg, 0.466 mmole) in tetrahydrofuran (1 mL) and chloro-2-methoxy ethane (31 μL, 0.466 mmole) or benzyl chloride (56 μL, 0.466 mmole) was irradiated in microwave at 120 °C for 45 min. The solvent was evaporated and the residue was purified by flash chromatography using ethyl acetate/heptane 50% to give compound 12a or 12b. The reaction could be performed also using sodium hydride (11 mg, 0.466 mmole) in dimethylformamide (1 mL).
3-(2-Methoxyethyl)-1-phenyl-2,3-benzodiazepin-4-one (12a): oily (85%) 1H NMR (CDCl3) δ 3.29 (s, 3H), 3.46–3.66 (m, 4H), 4.11 (br s, 2H), 7.24–7.28 (m, 1H), 7.32–7.37 (m, 1H), 7.42–7.49 (m, 4H), 7.53–7.58 (m, 1H), 7.64–7.66 (m, 2H). 13C NMR (CDCl3) δ 42.5, 49.5, 58.8, 69.9, 126.9, 127.9, 128.5, 129.4, 129.6, 130.3, 131.1, 132.1, 137.1, 138.1, 162.6, 167.9 m/z: 295 (m+1). Anal. calcd. for C18H18N2O2: %C, 73.45; H, 6.16; N,9.52; found: 73.80; H, 6.22; N,9.19.
3-benzyl-1-phenyl-2,3-benzodiazepin -4-one (12b): oily (84%) 1H NMR (CDCl3) δ 3.39–3.63 (m, 2H), 4.79–5.23 (m, 2H), 7.07–7.17 (m, 5H), 7.19–7.37 (m, 7H), 7.41–7.48 (m, 2H). 13C NMR (CDCl3) δ 42.5, 53.7, 126.9, 127.3, 127.9, 128.2, 128.5, 128.7, 129.5, 130.4, 131.1, 132.2, 137.1, 137.6, 138.0, 163.3, 167.8. m/z: 327 (m+1). Anal. calcd. for C22H18N2O: C, 80.96; H, 5.56; N,8.58; found: C, 80.95; H, 5.56; N, 8.60.
5.6 Tert-butyl (3-oxo-1-phenylisoquinolin-2(3H)-yl)carbamate (13)
Method A: A mixture of compound 10a (467 mg, 1.94 mmole), N-methyl morpholine (433 mg, 4.270 mmole), and BOP (946 mg, 2.130 mmole) was dissolved in dichloromethane. The mixture was stirred for 10 min at room temperature then tert-butyl-carbazate (257 mg, 2.138 mmole) was added and the reaction was stirred at room temp for 4 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate and washed with 1 N HCl, saturated solution of Na2CO3 and saturated solution of sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to dryness. The residue was purified by column chromatography using ethyl acetate/heptane 1:1 to give yellow microcrystal 13 in 83% yield.
Method B: EDCI, HCl (315 mg, 2.333 mmol) and triethylamine (812 μL, 5.831 mmol) were added to a solution of tert-butyl-carbazate (257 mg, 2.138 mmol), 10a (467 mg, 1.944 mmol) and HOBt (946 mg, 2.130 mmol) in dimethylformamide (25 mL) and stirred for 7 h at room temperature under nitrogen. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate and washed with 1 N HCl, saturated solution of Na2CO3 and saturated solution of sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography using ethyl acetate/heptane 1:1 to give compound 13 in 95% yield.
White microcrystal, m.p. = 181–183 °C; 1H NMR (CDCl3) δ 1.34 (s, 9H), 6.77–6.84 (m, 2H), 7.02–7.05 (m, 1H), 7.23–7.35 (m, 3H), 7.47–7.56 (m, 3H), 8.16 (s, 1H). 13C NMR (CDCl3) δ 28.0, 82.8, 109.4, 117.0, 122.6, 125.3, 128.1, 128.4, 129.5, 129.7, 130.1, 131.7, 131.9, 143.5, 153.5, 159.3. m/z: 337 (m+1). Anal. calcd. for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33; found: C, 71.42; H, 5.98; N, 8.33.
5.7 2-(2-cyanophenyl)acetic acid (14): (Tang et al., 2010)
A mixture of compound 3d (442 mg, 1.692 mmole) and lithium hydroxide (227 mg, 5.412 mmole) in methanol (4 mL) and water (2 mL) was irradiated in microwave at 120 °C for 5 min. The reaction was diluted in water and saturated solution of NaHCO3, and extracted with dichloromethane. The aqueous layer was acidified with Conc. HCl to PH 2, and extracted with dichloromethane; the organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give white microcrystal 14 in 81% yield, m.p.: 103–105 °C. 1H NMR (CD3OD) δ 3.87 (s, 2H), 7.42–7.50 (m, 2H), 7.60–7.73 (m, 2H). 13C NMR (CD3OD) δ 40.4, 114.6, 118.6, 129.0, 132.2, 133.9, 134.3, 140.0, 173.5.
Tert-butyl 2-benzyl-2-(2-(2-cyanophenyl)acetyl)hydrazinecarboxylate (16): A mixture of compound 14 (100 mg, 0.621 mmole), triethylamine (190 μL, 1.365 mmole) and BOP (302 mg, 0.683 mmole) in dichloromethane (2 mL) was stirred at room temperature for 3 min. Then, tert-butyl 2-benzylhydrazinecarboxylate (138 mg, 0.621 mmole) was added and the mixture was stirred at room temperature for 14 h. The mixture was diluted with DCM, washed with saturated solution of NaHCO3, and purified by flash chromatography (ethyl acetate/heptanes 40%) to give oily compound 16 in 70% yield. 1H NMR (CDCl3) δ 1.35 (s, 9H), 3.72–3.77 (m, 1H), 4.06–4.11 (m, 2H), 5.21–5.37 (m, 1H), 6.44 (s, 1H), 7.17–7.56 (m, 9H). 13C NMR (CDCl3) δ 28.2, 38.1, 50.8, 82.6, 113.4, 118.0, 127.6, 128.2, 129.0, 129.2, 131.1, 132.7, 132.9, 135.2, 139.3, 154.1, 171.9. Anal. calcd. for C21H23N3O3: C, 69.02; H, 6.34; N, 11.50; found: C, 69.01; H, 6.33; N, 11.51.
N-benzyl-2-(2-cyanophenyl)acetohydrazide (17): Compound 16 (50 mg, 0.136 mmole) was dissolved in trifluoroacetic acid (2 mL) for 5 min. Trifluoroacetic acid was evaporated; the residue was diluted in ethyl acetate, washed with saturated solution of NaHCO3, dried over Na2SO4, filtered, evaporated, and purified by flash chromatography ethylacetate/heptanes 1:1 to give compound 17 in 90% yield. m.p.: 120–122 °C. 1H NMR (CDCl3) δ 3.68 (br s, 2H), 4.25 (br s, 2H), 4.77 (br s, 2H), 7.25–7.48 (m, 7H), 7.44–7.66 (m, 2H). 13C NMR (CDCl3) δ 38.7, 53.4, 113.6, 118.3, 127.2, 128.2, 128.6, 128.7, 129.1, 130.7, 132.8, 135.4, 140.6, 172.0. Anal. calcd. for C16H15N3O: C, 72.43; H, 5.70; N, 15.84 found: C, 72.45; H, 5.71; N, 15.80.
3-benzyl-1-imino-1,2,3,5-tetrahydro-4H-benzo[d][1,2]diazepin-4-one (18): Compound 17 (50 mg, 0.188 mmole) dissolved in trifluoroacetic acid (1 mL) was irradiated in microwave at 120 °C for 5 min. Trifluoroacetic acid was evaporated under reduce pressure and the residue was purified by flash chromatography ethylacetate/heptanes 1:1 to give compound 18 in 10% yield. 1H NMR (CDCl3) δ 3.08 (br s, 1H), 3.70 (br s, 2H), 4.62 (br s, 1H), 5.31 (br s, 2H), 7.23–7.29 (m, 3H), 7.32–7.42 (m, 3H), 7.48–7.74 (m, 3H). 13C NMR (CDCl3) δ 39.0, 51.6, 127.4, 127.6, 128.5, 128.7, 129.1, 130.8, 132.6, 132.8, 136.3, 139.2, 162.2, 167.7. m/z: 266 (m+1). Anal. calcd. for C16H15N3O: C, 72.43; H, 5.70; N, 15.84 found: C, 72.44; H, 5.69; N, 15.83.
5.8 Tert-butyl (1-((2-(2-cyanophenyl)acetyl)imino)-3-hydroxyisoquinolin-2(1H)-yl)carbamate (21)
A mixture of compound 19 (100 mg, 0.621 mmole), BOP (302 mg, 0.683 mmole), and triethylamine (190 μL, 1.365 mmole) in dichloromethane (4 mL) was stirred at room temperature for 3 min at room temperature then tert-butyl carbazate (82 mg, 0.621 mmole) was then added and the mixture was stirred at room temperature for 14 h. The reaction was diluted with dichloromethane and washed with saturated solution of Na2CO3. The organic layer was then dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to dryness. The residue was purified by flash chromatography ethyl acetate/heptanes 80% to obtain yellow microcrystal 21 in 75% yield. m.p = 183–185 °C.
1H NMR (CD3OD) δ 1.56 (s, 9H), 4.64 (s, 2H), 7.11–7.15 (m, 1H), 7.34–7.69 (m, 6H), 8.01 (d, J = 7.2 Hz, 1H), 8.99 (d, J = 8.7 Hz, 1H). 13C NMR (DMSO-d6) δ 28.8, 50.2, 81.9, 108.4, 114.1, 119.2, 121.8, 124.4, 126.5, 127.5, 131.8, 133.0, 133.4, 135.2, 141.2, 143.4, 155.7, 159.0, 159.3, 193.8. m/z: 417(m−1). Anal. calcd. for C23H22N4O4: C, 66.02; H, 5.30; N, 13.39; found: C, 66.00; H, 5.34; N, 13.35.
5.9 Ethyl 2-hydroxy-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (22): (Dogan et al., 2015)
A mixture of compound 8a (50 mg, 0177 mmole) and iron (29.7 mg, 0.537 mmole) in acetic acid 100% (1 mL) was irradiated in microwave at 130 °C for 15 min. Upon completion of the reaction, dichloromethane (25 mL) was added and iron is filtered on small piece of cotton. Dichloromethane was evaporated on rotavap to residue and purified by flash chromatography using gradient of 100% DCM to 10% MeOH/DCM to give scarlet red compound 22 in 95% yield.
1H NMR (DMSO-d6) δ 1.25 (t, J = 8.9 Hz, 3H), 4.21 (q, J = 7.0 Hz, 2H), 6.77 (t, J = 7.0 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 6.2 Hz, 1H), 10.3 (s, 1H), 12.5 (s, 1H). 13C NMR (DMSO-d6) δ 14.8, 58.0, 82.6, 111.4, 111.5, 125.6, 131.1, 143.1, 164.1, 165.2. m/z: 207 (m+1). Anal. calcd. for C10H10N2O3: C, 58.25; H, 4.89; N, 13.59; found: C, 58.26; H, 4.91; N, 13.62.
Acknowledgment
I am grateful to Professor Alan R. Katritzky, University of Florida for his support.
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Appendix A
Supplementary material
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2016.01.007.
Appendix A
Supplementary material
Supplementary data 1
Supplementary data 1
