English

• 1.   Introduction

  2-Methyquinoline is an important scaffold, which is widely used in organic synthesis. With its active methyl, it could be not only prefunctionlized in short reaction steps with high atom economy, ^[1] but also represents a potential synthon for the access of functionalized compounds, such as aldehydes, ^[2] nitriles^[3] as well as halomethylation products.^[4] 2-Quinoline carboxaldehydes commonly used as pharmaceutical intermediates, have a profound influence on the biological activities, such as antineoplastic and antimalarial activities of the following drugs^[5] (Figure 1).

  Figure 1

  

  Figure 1.  Compounds derived from 2-quinoline carboxaldehydes

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  The preparation of 2-quinoline carboxaldehydes has been extensively studied and reviewed.^[6] Holzapfel and co-workers^[7] reported the direct formylation of aryl halides into 2-quinoline carboxaldehydes in the presence of carbon monoxide and hydrogen using palladium as a catalyst. Ding et al.^[8] described a method to synthesize 2-quinoline carboxaldehydes by treating 2-methylquinolines with SeO₂ at 170 ℃. Moreover, trioxane-promoted formylation of quinolines was established for the synthesis of 2-quinoline carboxaldehydes by Minisci et al.^[9] Wang et al.^[10] found that 2-methyquinolines could be oxidized in hours by O₂ in the presence of copper catalyst, generating the corresponding 2-quinoline carboxaldehydes. However, the generality of these methods was severely hampered by their drawbacks such as high pressure, high toxicity, limited environmental acceptability in view of the demand of industry and long reaction time.

  Over the past decade, ferric salts have attracted considerable attention as an inexpensive and commercially available substance to promote a diverse number of reactions.^[11] In most of these reports, Fe(NO₃)₃·9H₂O was demonstrated as a good catalyst or oxidant exhibiting high activity in oxidative process.^[12] In light of the recently developed applications of 2-quinoline carboxaldehydes, herein, we report the iron(Ⅲ)/O₂-promoted oxidative formylation of 2-methyl quinolines, yielding various 2-quinoline carboxaldehydes under microwave irradiation through a radical mechanism. This protocol has a lot of advantages, such as short reaction time, easy operation, non-toxicity and good selectivity.

  2.   Results and discussion

  As an initial test, 2-methylquinoline was chosen as the model substrate in order to ascertain the feasibility and optimize the reaction conditions (Table 1).

  Table 1

  

  Table 1.  Optimization of the reaction conditions^a

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  Entry	Promoter	Fe3+/1a (molar ratio)	Solvent	Temp./℃	Timeb/min	Yieldc/%
  1	FeCl2	1/1	DMSO	130	30	Trace
  2	FeCl3	1/1	DMSO	130	10	60
  3	FeCl3·6H2O	1/1	DMSO	130	10	62
  4	Fe(NO3)3·9H2O	1/1	DMSO	130	10	65
  5	Fe(NO3)3·9H2O	0.5/1	DMSO	130	10	46
  6	Fe(NO3)3·9H2O	1.5/1	DMSO	130	10	58
  7	Fe(NO3)3·9H2O	1/1	DMF	130	15	61
  8	Fe(NO3)3·9H2O	1/1	Toluene	130	30	53
  9	Fe(NO3)3·9H2O	1/1	Dioxane	130	30	48
  10	Fe(NO3)3·9H2O	1/1	DMAC	130	15	60
  11	Fe(NO3)3·9H2O	1/1	DMSO	140	8	70
  12	Fe(NO3)3·9H2O	1/1	DMSO	150	5	78
  13	Fe(NO3)3·9H2O	1/1	DMSO	160	5	71
  14	Fe(NO3)3·9H2O	1/1	DMSO	150	1	37
  15	Fe(NO3)3·9H2O	1/1	DMSO	150	10	76
  16d	Fe(NO3)3·9H2O	1/1	DMSO	150	30	45
  17e	Fe(NO3)3·9H2O	1/1	DMSO	150	30	18
  a Reaction conditions: 1a (1 mmol), solvent (10 mL), under microwave irradiation in O2; b Monitored by TLC; c Isolated yield; d The reaction was heated in an oil bath in Air; e The reaction was heated in N2

  Iron(Ⅲ) was found to be crucial for this reaction, while iron(Ⅱ) failed to give any desired product (Entry 2 vs Entry 1). Notably, other kind of iron(Ⅲ) also succeed in producing the expected product, and Fe(NO₃)₃·9H₂O turned out to be the optimal to afford 2a in 65% yield (Entries 3 and 4). Changing the ratio of iron(Ⅲ) to 1a led to a decrease in reaction yield (Entries 4~6). The effect of solvent on the reaction was also examined. The reaction was completed in 10 mins with a good yield of 65% in dimethyl sulfoxide (DMSO). Other solvents such as N, N-dimethylformamide (DMF), toluene, dioxane, and N, N-dimethylacetamide (DMAC) gave a lower yield of the product with longer reaction time (Entries 4, 7~10). The temperature of this conversion was also screened, 150 ℃ was found to be the optimal temperature, producing 2a in 78% yield in 5 min (Entries 4, 11~13). The materials decomposed at a higher temperature. The results obtained by changing reaction time were similar to those obtained by changing reaction temperature, 5 min being the best choice for this transformation (En- tries 12, 14~15). Other trials, such as performing the reaction under N₂ atmosphere, decrease the yield compared with that under air (Entries 16 and 17), indicating that O₂ was essential for the present conversion.

  Based on the above results, the optimized conditions for the conversion of 2-methylquinolines (1.0 mmol) into 2-quinoline carboxaldehydes were as follows: iron nitrate nonahydrate (1.0 equiv.) and DMSO (10 mL) in a sealed tube full of O₂ under microwave irradiation.

  With the optimized reaction conditions in hand, the scope of a variety of 2-methylquinolines was then tested to investigate the impact of electronic as well as steric factors on the reaction profile. The results were summarized in Table 2. Delightedly, compared with other oxidative methods, the major drawback of overoxidation of aldehydes was not observed under current reaction conditions. What's more, we found that the reaction was selective and only occurred on the methyl group at 2-position in the presence of other methyl groups on the quinoline ring (Entries 4, 5, and 6). It was observed that 2-methylquinolines with both electron-donating groups (Entries 2~6) and electron-withdrawing groups (Entries 7~10) gave the corresponding products in moderate to good yield. Interestingly, more iron(Ⅲ) and time were needed with electron-donating substituents viz. 6-OMe (1b), 7-OMe (1c), 3-Me (1d), 6-Me (1e), 8-Me (1f). It was noteworthy that disubstituted ones viz. 3-Me (1d), 8-Me (1f), 8-Cl (1g) underwent difficultly in providing the corresponding 2-quinoline carboxaldehydes in modest yields (48%~54%), which might be due to the steric effect at C(3) or C(8) position of 2-methylquinolines. Furthermore, 2-methylquinoxaline (1k) was also compatible to access aldehyde derivative 2k in a good yield of 80% (Entries 11).

  Table 2

  

  Table 2.  Synthesis of 2-quinoline carboxaldehydes^a

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  Entry	X	R	Timeb/min	Fe3+/1 (molar ratio)	Product	Yieldc/%
  1	CH	H	5	1.0	2a	78
  2	CH	6-OMe	10	1.5	2b	60
  3	CH	7-OMe	10	1.5	2c	64
  4	CH	3-Me	10	1.5	2d	54
  5	CH	6-Me	10	1.5	2e	63
  6	CH	8-Me	10	1.5	2f	48
  7	CH	8-Cl	5	1.0	2g	52
  8	CH	6-NO2	5	1.0	2h	81
  9	CH	6-F	5	1.0	2i	73
  10	CH	6-Cl	5	1.0	2j	67
  11	N	H	5	1.0	2k	80
  a Reaction conditions: 1 (1 mmol), DMSO (10 mL), MW 150 ℃, power 150 W in O2. b Monitored by TLC. c Isolated yield.

  According to the optimization of process conditions, the amplification experiments to investigate the impurities were studied with the reaction condition of 1a (10 mmol), Fe(NO₃)₃·9H₂O (10 mmol), DMSO (10 mL), MW 150 ℃, power 150 W in O₂. The impurities 3 and 4 were determined in the yields of 10.8% and 3.5% (Figure 2).

  Figure 2

  

  Figure 2.  Impurities of 3 and 4

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  To explore the reaction mechanism, the radical trapping experiment was carried out by using 2, 2, 6, 6-tetramethylpiperidine-1-oxyl (TEMPO) as a radical scavenger (Scheme 1). As expected, the reaction failed to give 2-quinoline carboxaldehydes. This result indicated that the reaction might involve a radical pathway.

  Scheme 1

  

  Scheme 1.  Radical trapping experiment with TEMPO

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  On the basis of above experiment and literature examples, ^[13] a plausible mechanism was deduced (Scheme 2). In this hypothesis, it is assumed that 1a can be isomerized to a nonaromatic enamine intermediate A, which then coordinates with iron(Ⅲ) nitrate nonahydrate to generate iron-enamide species B. Fe³⁺ replaces the nitro to react firstly with molecular oxygen to form a Fe³⁺ peroxo species C, subsequent isomerization gives peroxide D. Elimination of [Fe²⁺]OH affords 2-quinoline carboxaldehydes 2a.

  Scheme 2

  

  Scheme 2.  Plausible mechanism

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  3.   Conclusions

  In summary, the oxidative formylation of various quinolone derivatives was presented in the presence of iron(Ⅲ) nitrate nonahydrate and DMSO under O₂ atmosphere promoted by microwave irradiation. Availability, stability and non-toxicity of the reagents, mild reaction conditions, relatively short reaction time, promising yields, and easy work-up are advantages which make this methodology be an important alternative for the preparation of 2-quinoline carboxaldehydes.

  4.   Experimental section

  4.1   General information

  All reagents were obtained from commercial suppliers and used without further purification, unless otherwise indicated. TLC analysis was performed using pre-coated glass plates. Silica gel for column chromatography was purchased from Qingdao Haiyang Chemical Co., Ltd. Microwave reactor was CEM Discover 908010 microwave reactor with IR-monitored temperature control. Melting points were determined using a Büchi B-540 capillary melting point apparatus. ¹H NMR and ¹³C NMR spectra were measured on a Varian 400 (400 MHz) spectrometer (chemical shifts in δ) using tetramethylsilane as internal standard.

  4.2   Synthesis of 2-quinoline carboxaldehydes

  2-methylquinolines (1, 1 mmol), Fe(NO₃)₃·9H₂O (1 mmol) and DMSO (10 mL) were mixed in an 80 mL microwave tube full of O₂. The mixture was stirred at 150 ℃ for 5 min under microwave irradiation using a CEM Discover microwave reactor. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered firstly, then washed by sodium bicarbonate solution and filtered. The aqueous layer extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo and the crude residue was purified by flash chromatography on silica gel using hexane/EtOAc as eluent to give the product 2a~2k.

  Quinoline-2-carboxaldehyde (2a): Yield 78%. White solid, m.p. 68~69 ℃ (lit.^[14] 70~72 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 10.21 (s, 1H), 8.29 (d, J＝8.4 Hz, 1H), 8.23 (d, J＝8.4 Hz, 1H), 8.01 (d, J＝8.4 Hz, 1H), 7.88 (d, J＝8.0 Hz, 1H), 7.83~7.79 (m, 1H), 7.69~7.66 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 192.8, 152.0, 147.4, 137.0, 130.1, 130.0, 129.7, 128.8, 127.5, 117.1.

  6-Methoxyquinoline-2-carbaldehyde (2b): Yield 60%. Yellow solid, m.p. 101~102 ℃ (lit.^[15] 105 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 10.16 (s, 1H), 8.15 (d, J＝8.4 Hz, 1H), 8.11 (d, J＝9.2 Hz, 1H), 7.98 (d, J＝8.4 Hz, 1H), 7.45 (dd, J＝9.2 Hz, 2.8 Hz, 1H), 7.11 (d, J＝2.8 Hz, 1H), 3.97 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 192.4, 159.2, 149.9, 143.3, 135.2, 131.4, 131.2, 123.2, 117.5, 104.8, 55.9.

  7-Methoxyquinoline-2-carbaldehyde (2c): Yield 64%. Yellow solid, m.p. 103~105 ℃ (lit.^[16]); ¹H NMR (400 MHz, CDCl₃) δ: 10.15 (s, 1H), 8.15~8.08 (m, 2H), 7.98~7.94 (m, 1H), 7.45~7.42 (m, 1H), 7.10 (s, 1H), 3.96 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 193.2, 159.7, 150.4, 143.8, 135.4, 131.7, 131.4, 123.4, 117.7, 104.9, 55.7.

  3-Methylquinoline-2-carbaldehyde (2d): Yield 54%. Yellow solid, m.p. 111~112 ℃ (lit.^[17] 115~116 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 10.30 (s, 1H), 8.17 (d, J＝8.4 Hz, 1H), 7.99 (s, 1H), 7.78 (d, J＝8.4 Hz, 1H), 7.75~7.71 (m, 1H), 7.65~7.61 (m, 1H), 2.78 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 195.0, 150.6, 146.2, 138.0, 130.8, 129.7, 129.2, 129.0, 126.6, 19.2.

  6-Methylquinoline-2-carbaldehyde (2e): Yield 63%. Yellow solid, m.p. 105~106 ℃ (lit.^[18] 105~106 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 10.18 (s, 1H), 8.18 (d, J＝8.4 Hz, 1H), 8.11 (d, J＝8.8 Hz, 1H), 7.97 (d, J＝8.4 Hz, 1H), 7.64~7.63 (m, 2H), 2.58 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 192.6, 151.2, 145.9, 139.1, 136.0, 132.3, 129.7, 129.5, 126.2, 117.1, 22.3.

  8-Methylquinoline-2-carbaldehyde (2f): Yield 48%. Yellow solid, m.p. 78~79 ℃ (lit.^[15] 81 ℃); ¹HNMR (400 MHz, CDCl₃) δ: 10.21 (s, 1H), 8.23 (d, J＝8.4 Hz, 1H), 7.98 (d, J＝8.4 Hz, 1H), 7.70 (d, J＝8.8 Hz, 1H), 7.64~7.62 (m, 1H), 7.56~7.52 (m, 1H), 2.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 193.9, 151.4, 146.8, 138.7, 137.2, 130.2, 130.0, 128.8, 125.6, 116.8, 17.9.

  8-Chloroquinoline-2-carbaldehyde (2g): Yield 52%. Yellow solid, m.p. 143~145 ℃ (lit.^[19] 129~131 ℃); ¹H NMR (400 MHz, CDCl₃) δ:: 10.28 (s, 1H), 8.33 (d, J＝8.4 Hz, 1H), 8.08 (d, J＝8.4 Hz, 1H), 7.92 (d, J＝8.0 Hz, 1H), 7.82 (d, J＝8.0 Hz, 1H), 7.59 (t, J＝8.0, Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) ℃: 192.3, 152.2, 143.7, 137.4, 134.4, 130.9, 130.1, 128.6, 126.4, 117.7.

  6-Nitro-quinoline-2-carboxaldehyde (2h): Yield 81%. Yellow solid, m.p. 190~192 ℃ (lit.^[20] 188~189 ℃); ¹H NMR (400 MHz, DMSO) δ: 10.12 (s, 1H), 9.17 (d, J＝2.4 Hz, 1H), 8.92 (d, J＝8.4 Hz, 1H), 8.55 (dd, J＝9.2 Hz, 2.4 Hz, 1H), 8.40 (d, J＝9.6 Hz, 1H), 8.13 (d, J＝8.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 193.2, 154.4, 148.7, 146.2, 140.2, 131.4, 128.5, 124.9, 123.6, 118.4.

  6-Fluoro-quinoline-2-carboxaldehyde (2i): Yield 73%. White solid, m.p. 116~117 ℃ (lit.^[21] 122~124 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 10.18 (s, 1H), 8.26~8.23 (m, 2H), 8.03 (d, J＝8.8 Hz, 1H), 7.61~7.56 (m, 1H), 7.51 (dd, J＝8.4 Hz, 2.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 192.3, 161.2 (d, ¹J_CF＝249.4 Hz), 151.5, 144.4, 136.1 (d, ⁴J_CF＝5.4 Hz), 132.6 (d, ³J_CF＝9.3 Hz), 130.5 (d, ³J_CF＝10.5 Hz), 120.6 (d, ²J_CF＝25.7 Hz), 117.7, 110.6 (d, ²J_CF＝21.8 Hz).

  6-Chloroquinoline-2-carbaldehyde (2j): Yield 67%; Yellow solid, m.p. 136~137 ℃ (lit.^[15] 170~171 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 10.18 (s, 1H), 8.22~8.16 (m, 2H), 8.03 (d, J＝8.4 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J＝8.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 192.2, 152.1, 145.7, 135.9, 134.7, 131.5, 131.0, 130.1, 126.1, 117.9.

  Quinoxaline-2-carboxaldehyde (2k): Yield 80%. Yellow solid, m.p. 97~98 (lit.^[22] 107~108 ℃); ¹H NMR (400 MHz, CDCl₃) δ:: 10.20 (s, 1H), 9.35 (s, 1H), 8.20~8.11 (m, 2H), 7.92~7.82 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ:: 191.6, 145.0, 141.9, 132.8, 132.4, 131.4, 130.7, 130.0, 129.2.

  Quinoline (3): Yield 10.8%. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.90 (d, J＝8.4 Hz, 1H), 8.23 (d, J＝3.2 Hz, 1H), 8.12 (t, J＝9.6 Hz, 1H), 7.80 (d, J＝8.0 Hz, 1H), 7.71 (t, J＝7.2 Hz, 1H), 7.53 (t, J＝7.2 Hz, 1H), 7.38 (dd, J＝8.4, 4.4 Hz, 1H).; ¹³C NMR (100 MHz, CDCl₃) δ: 150.6, 148.4, 136.3, 129.7, 129.6, 128.5, 128.0, 126.7, 121.2; HRMS (ESI) calcd for [M+H]⁺ C₉H₈N, m/z 130.0651, found 130.0652.

  Di-2-quinolinylmethanone (4): Yield 3.5%, yellow solid. ¹H NMR (400 MHz, CDCl₃) δ: 8.31 (d, J＝8.4 Hz, 2H), 8.18 (d, J＝8.4 Hz, 2H), 7.90 (d, J＝8.0 Hz, 2H), 7.85 (t, J＝7.6 Hz, 2H), 7.73~7.69 (m, 4H); HRMS (ESI) calcd for [M+H]⁺ C₁₉H₁₃N₂O, m/z 285.1022, found 285.1030.

  Supporting Information  ¹H NMR and ¹³C NMR spectra copies of the products. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
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• 

  Figure 1  Compounds derived from 2-quinoline carboxaldehydes

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  Figure 2  Impurities of 3 and 4

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  Scheme 1  Radical trapping experiment with TEMPO

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  Scheme 2  Plausible mechanism

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  Table 1.  Optimization of the reaction conditions^a

  Entry	Promoter	Fe3+/1a (molar ratio)	Solvent	Temp./℃	Timeb/min	Yieldc/%
  1	FeCl2	1/1	DMSO	130	30	Trace
  2	FeCl3	1/1	DMSO	130	10	60
  3	FeCl3·6H2O	1/1	DMSO	130	10	62
  4	Fe(NO3)3·9H2O	1/1	DMSO	130	10	65
  5	Fe(NO3)3·9H2O	0.5/1	DMSO	130	10	46
  6	Fe(NO3)3·9H2O	1.5/1	DMSO	130	10	58
  7	Fe(NO3)3·9H2O	1/1	DMF	130	15	61
  8	Fe(NO3)3·9H2O	1/1	Toluene	130	30	53
  9	Fe(NO3)3·9H2O	1/1	Dioxane	130	30	48
  10	Fe(NO3)3·9H2O	1/1	DMAC	130	15	60
  11	Fe(NO3)3·9H2O	1/1	DMSO	140	8	70
  12	Fe(NO3)3·9H2O	1/1	DMSO	150	5	78
  13	Fe(NO3)3·9H2O	1/1	DMSO	160	5	71
  14	Fe(NO3)3·9H2O	1/1	DMSO	150	1	37
  15	Fe(NO3)3·9H2O	1/1	DMSO	150	10	76
  16d	Fe(NO3)3·9H2O	1/1	DMSO	150	30	45
  17e	Fe(NO3)3·9H2O	1/1	DMSO	150	30	18
  a Reaction conditions: 1a (1 mmol), solvent (10 mL), under microwave irradiation in O2; b Monitored by TLC; c Isolated yield; d The reaction was heated in an oil bath in Air; e The reaction was heated in N2

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  Table 2.  Synthesis of 2-quinoline carboxaldehydes^a

  Entry	X	R	Timeb/min	Fe3+/1 (molar ratio)	Product	Yieldc/%
  1	CH	H	5	1.0	2a	78
  2	CH	6-OMe	10	1.5	2b	60
  3	CH	7-OMe	10	1.5	2c	64
  4	CH	3-Me	10	1.5	2d	54
  5	CH	6-Me	10	1.5	2e	63
  6	CH	8-Me	10	1.5	2f	48
  7	CH	8-Cl	5	1.0	2g	52
  8	CH	6-NO2	5	1.0	2h	81
  9	CH	6-F	5	1.0	2i	73
  10	CH	6-Cl	5	1.0	2j	67
  11	N	H	5	1.0	2k	80
  a Reaction conditions: 1 (1 mmol), DMSO (10 mL), MW 150 ℃, power 150 W in O2. b Monitored by TLC. c Isolated yield.

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