Selective CH functionalization of electron-deficient aromatics by carbamoylsilanes: synthesis of aromatic carbinolamines or amides

Tetrahedron Letters 57 (2016) 937–941

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Selective CAH functionalization of electron-deficient aromatics by carbamoylsilanes: synthesis of aromatic carbinolamines or amides Yanhong Liu, Pei Cao, Jianxin Chen ⇑ College of Chemistry and Materials Science, Shanxi Normal University, Linfen 041004, PR China

a r t i c l e

i n f o

Article history: Received 20 November 2015 Revised 15 January 2016 Accepted 18 January 2016 Available online 18 January 2016

a b s t r a c t Selective CAH functionalization of electron-deficient aromatics with various carbamoylsilanes is developed under catalysts-free conditions. These transformations provide a facile and efficient method for synthesizing some tertiary or secondary aromatic carbinolamines and amides in good yields. Ó 2016 Elsevier Ltd. All rights reserved.

Keywords: Carbamoylsilanes Carbinolamines Amides CAH functionalization Synthetic methods

Introduction In the past decades, a great deal of effort has been devoted to the development of aminocarbonylation reactions due to the significant role amide played in biological systems as well as in the fields of natural products, pharmaceuticals, and polymers.1 Among them, palladium-catalyzed aminocarbonylation from aryl halides, primary or secondary amines, and carbon monoxide is a powerful and most frequently used method in organic synthesis.2 Since the pioneering work of Heck and co-worker in regard to palladium-catalyzed aminocarbonylation in 1974,3 various improved methods were developed using CO as a source of the carbonyl group.4 However, this approach is fraught with troublesome handling of hazardous carbon monoxide gas, high pressure, high temperature, and other harsh reaction conditions.5 To avoid these problems, the development of new CO-free methods is of significant interest among organic chemists. In recent years, some CO-equivalents have been developed such as silacarboxylic acids,6 formic anhydrides and N-substituted formamides,7 alkyl formates,8 and carbamoylstannanes.9 Previously, we successfully realized the efficient preparation of various carbamoylsilanes in good yields,10 which are environmentally benign reagents and can be employed as an amide source to carry out a series of aminocarbonylation reactions, including the palladium-catalyzed aminocarbonylation ⇑ Corresponding author. E-mail address: [email protected] (J. Chen). http://dx.doi.org/10.1016/j.tetlet.2016.01.058 0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

of halides with carbamoylsilane,11 addition of carbamoylsilanes to the C@N bond of iminium salts or imines,12 the substitution reaction of carbamoylsilanes with acid chlorides or imidoyl chlorides,13 addition of carbamoylsilanes to the C@O bond of aldehydes or ketones.14 Recently, we found that the carbamoylsilanes could carry out the selective CAH functionalization reactions on the electron-deficient aromatics under mild conditions without the use of catalysts, leading to formation of aromatic carbinolamines (N,O-hemiacetals, potential carbonyl groups) or amides. To the best of our knowledge, most of the current CAH carbonylation reactions for forming carbonyl group need transition-metal-catalyzed direct and selective functionalization of CAH bonds,15 while the insertion of carbenes into CAH bonds is arguably the best approach for directly transforming a CAH bond into a CAC bond.16 We report here on the successful attempt in this regard by employing various carbamoylsilanes as a source of the carbonyl group in CAH functionalization reaction. Results and discussion Initially, the selective CAH functionalization of 3-cyanopyridine with N,N-dimethylcarbamoyl(trimethyl)silane under anhydrous conditions was chosen as a model reaction to investigate the activity of carbamoylsilanes in different solvents. Test experiments showed that different yields of desired product 2-(3-cyano)pyridine carbinolamine was achieved. As shown in Table 1, a significant solvent effect was observed: when the reaction was

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Y. Liu et al. / Tetrahedron Letters 57 (2016) 937–941

conducted in benzene, the product was obtained in high yields and the reaction time was short (Table 1, entry 5), but in dichloromethane carbamoylsilane showed no activity (Table 1, entry 1). Several other solvents, including acetonitrile, THF and toluene, gave inferior results compared to benzene (Table 1, entries 2–4). To study the selective CAH functionalization of aromatics by carbamoylsilanes, some aromatics 1a–1g bearing electron-withdrawing group were examined to react with N,N-dimethylcarbamoyl(trimethyl)silane (2) in benzene solvent under anhydrous conditions at 75 °C. Results are listed in Table 2. We found that 1a possessing acetyl and isocyanate groups and 1b possessing nitro and nitrile groups offered excellent yields of desired CAH functionalization products 3a and 3b (Table 2, entries 1 and 2). The former showed the fastest reaction rates and highest yield. However, 1c possessing dinitro groups proved to be totally inert even at 75 °C for 3 days (Table 2, entry 3). This result was caused by electrical field effect of nitro which may increase the electron density of

Table 1 Solvent effect on the CAH functionalization of 3-cyanopyridine with dimethylcarbamoyl(trimethyl)silane

Me3Si

N

a b c

CN

O

CN

N

N

N

OH

Entry

Solvent

Temp (°C)

Timea (h)

Yieldb,c (%)

1 2 3 4 5

Dichloromethane Acetonitrile THF Toluene Benzene

35 75 60 75 75

80 50 72 70 57

0 4 36 63 82

To complete consumption of carbamoylsilane. Isolated yield after chromatography on silica gel based on 3-cyanopyridine. 1:1.2 mol ratio of 3-cyanopyridine and carbamoylsilane.

Table 2 The reaction of N,N-dimethylcarbamoyl(trimethyl) silane with aromatics

O

O O +

Me 3Si

Benzene

N

NCO OH

NCO 1a Entry

2

3a

Aromatics

Timea (h)

Product

O

Yieldb,c (%)

O

1

1a

3a

N

4.5

92

NCO OH

NCO CN

CN N

1b

2

3b

44

83

3c

72

0

45 40 72

58 48d 60e

3e

72 68 102

82 70d 83e

3f

72

0

10 14

54 61e

72

0

NO2 OH

NO 2

NO2

NO 2 N

1c

3

NO2

NO2 O H

F

F NO2

NO 2 1d

4

3d

N CF3 OH

CF3

CN 5

N

CN 1e

N

N

N

OH O

O 6

1f

N

N

N

OH

NO2

NO2 7

Cl

N

1g

Cl

N

N

3g

O N

N 8

N

1h

N

N OH

3h

939

Y. Liu et al. / Tetrahedron Letters 57 (2016) 937–941 Table 2 (continued) Entry

Aromatics

N 9

N

Timea (h)

Product

N

CN 1i

Yieldb,c (%)

CN N

N

3i

31

86

OH a b c d e

To complete consumption of carbamoylsilane at 75 °C in benzene. Isolated yield after chromatography on silica gel based on aromatics. Characterization data are given.19 1:1.2 mol ratio of aromatics and carbamoylsilane unless otherwise indicated. 1:1.1 ratio. 1:1.5 ratio.

carbon at its alpha position. 1d bearing three electron-withdrawing groups provided the moderate yield of desired product 3d. It was observed that increasing amount of carbamoylsilane 2 from 1.2 to 1.5 equiv led to a slight increase in yields of product 3d, while reducing the carbamoylsilane 2 loading results in lower yields (Table 2, entry 4). 1e possessing an electron-withdrawing group afforded the CAH functionalization product 3e in good yields (Table 2, entry 5). Increasing or reducing the amount of carbamoylsilane 2, the yield of 3e was affected similar to the entry 4. 3-Acetylpyridine (1f) could not react with carbamoylsilane 2 since no product was obtained (Table 2, entry 6). To our surprise, 2chloro-5-nitropyridine (1g) reacted with carbamoylsilane 2 to give aminocarbonylation product 3g in good yields. Increasing amount of carbamoylsilane 2 from 1.2 to 1.5 equiv the yield of 3g was slightly increased (Table 2, entry 7). Pyrazine (1h) did not react with carbamoylsilane 2, while pyrazinecarbonitrile (1i) could react with 2 smoothly, furnishing excellent yields. As expected, 1i exhibited faster reaction rates than 3-cyanopyridine (1e) (Table 2, compare entries 5 and 9). To further explore the synthetic potential of this process, Nmethyl-N-(1-phenyl)ethylcarbamoyl(trimethyl)silane (4) was selected as the carbonyl source in this process, and reacted with 1a, 1b, 1d, 1e and 1g under the same reaction conditions. As summarized in Table 3, all aromatics were found to afford the corresponding aromatic carbinolamines or amides in this selective CAH functionalization process. Among them, 1a and 1d gave aromatic carbinolamines 5a and 5d in good yields. While 1b and 1e failed to give aromatic carbinolamine, gave the aminocarbonylation products 5b and 5e in respective yields 73% and 71%. 1g also gave the aminocarbonylation product 5g in 52% yield. The total yields of products are slightly lower than those of Table 2. Results obtained from above experiments specifically address the formation of (tertiary) N,N-diorganylcarbinolamines or N,Ndiorganylamides, for efficient application within these areas, the synthesis of secondary carbinolamines or amides are required. Subsequently, we attempted to apply this method to the synthesis of secondary carbinolamines or secondary amides. N-Methoxymethyl-N-methylcarbamoyl(trimethyl)silane (6) was employed as a carbonyl source and reacted with above five substrates 1a, 1b, 1d, 1e and 1g under the standard reaction conditions. The results are summarized in Table 4. We are pleased to find that all the corresponding products were obtained in good yields. In the case of above five substrates, 1.2 equiv of carbamoylsilane 6 was used, 1a, 1b, and 1d gave the moderate yields of carbinolamines 7a, 7b, and 7d (Table 4, entries 1–3). Through simple acid hydrolysis, 7a, 7b, and 7d can be transformed into secondary carbinolamines because methoxy-methyl on the N atom can be easily replaced by hydrogen in acid conditions.17 Secondary carbinolamines are unstable in high temperatures easily to convert to an imine by losing water. In the case of 1e and 1g, because CAH functionalization products are unstable, adding acid for hydrolysis after complete

Table 3 The reaction aromatics

of

N-methyl-N-(1-phenyl)ethylcarbamoyl(trimethyl)silane

O

O

O +

Me 3Si

Benzene

N

N

NCO

NCO OH

1a Entry

with

5a

4

Timea (h)

Yieldb,c (%)

5a

10

78

5b

35

73

N

5d

72

55

N

5e

72

71

5g

5

52

Aromatics

Product

O 1

1a

N NCO OH

CN 2

N

1b

NO2 O

F 3

NO2

1d

CF 3 OH

CN 4

1e

N O

NO2 5

1g

Cl

N

N O

a

To complete consumption of carbamoylsilane at 75 °C in benzene. Isolated yield after chromatography on silica gel based on aromatics. Characterization data are given.19 c 1:1.2 mol ratio of aromatics and carbamoylsilane. b

consumption of carbamoylsilane, secondary carbinolamine 7e and secondary amide 7g were directly prepared in respective yields of 67% and 50% (Table 4, entries 4 and 5). In the case of 1g, aminocarbonylation product was obtained under standard conditions. A comparison of the results obtained from Tables 2 and 4 indicates that the activity of carbamoylsilane 6 was lower than that of carbamoylsilane 2 in this reaction since lower yields of the desired products were obtained in case of 1a, 1b, and 1d in Table 4 than in Table 2.

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Y. Liu et al. / Tetrahedron Letters 57 (2016) 937–941

Table 4 The reaction aromatics

of

N-methoxymethyl-N-methylcarbamoyl(trimethyl)silane

O

O

O +

N

Me3S i

Benzene

O

N

NCO

O

NCO OH

1a Entry

with

6

7a

Aromatics

Timea (h)

Yieldb,c (%)

7a

4

75

7b

40

69

Product

O 1

1a

N

O

NCO OH CN 2

N

1b

O

NO2 OH

Conclusions

F NO2 3

1d

N

O

7d

50

53

7e

72d

67

7g

9d

50

CF 3 OH

4

1e

N

CN H N OH

5

1g

Cl

N

charged to the cooled Schlenk tube under argon, followed by addition of 105 mg (0.60 mmol) of carbamoylsilane 6. The sealed reaction mixture was stirred at 75 °C until no carbamoylsilane could be detected by TLC. Volatiles were removed in vacuum to afford the crude product, which were dissolved in the mixture of concentrated hydrochloric acid and ethanol. After 24 h stirring at room temperature, the reaction solution was concentrated in a rotary evaporator and added dichloromethane, then washed with sodium bicarbonate solution (25 mL). The aqueous phase extracted with dichloromethane (15 mL). The combined organic layers were dried over MgSO4, and evaporated to afford the crude products which were purified by column chromatography on silica gel (petroleum ether/ethyl acetate combination) to afford 54.8 mg of 7e in 67% yield. 7e: IR: 3429, 1660, 1579, 1292, 1114, 925, 693 cm 1. 1H NMR (600 MHz, CDCl3): d 9.56 (s, 1H), 8.85 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.22 (s, 1H), 3.02, 3.01 (ss, 3H), 1.68 (s, 1H). 13C NMR (151 MHz, CDCl3): d 186.5, 161.4, 154.3, 152.3, 138.6, 129.2, 123.3, 26.1. Anal. Calcd for C8H9N3O: C, 58.88; H, 5.56; N, 25.75. Found: C, 58.98; H, 5.70; N, 25.90.

NO2 H N O

a

To complete consumption of carbamoylsilane at 75 °C in benzene. Isolated yield after chromatography on silica gel based on aromatics. Characterization data are given.19 c 1:1.2 mol ratio of aromatics and carbamoylsilane. d Afterward, adding HCl (concd), EtOH, rt and stirring 24 h. b

In summary, we have successfully developed a novel method to direct carbonylation or aminocarbonylation on the electron-deficient aromatics under catalysts-free conditions by the CAH bonds’ insertion of aminosiloxycarbenes generated from carbamoylsilanes. In comparison with previous approaches about the insertion of carbenes into CAH bonds, which were limited by the precursors and reaction conditions of generating carbene intermediates, usually employing high temperatures or other vigorous conditions such as microwave,18 this method in general provides good yields of the products under mild reaction conditions. The mild and no catalysts conditions, simple procedure, and good yields provide a valuable method for the preparation of aromatic carbonyl compounds (aminoacetals, potential carbonyl groups). We anticipate that our study may draw significant attention of chemists working on the development of synthetic methodologies and will find applications in organic and medicinal chemistry. Acknowledgments

General procedure for the reaction of carbamoylsilane 2 (4, 6) with aromatics 1 A Schlenk tube fitted with a Teflon vacuum stopcock and micro stirbar was flame heated under vacuum and refilled with Ar. Aromatics (0.50 mmol) and benzene (1.5 mL) were charged to the cooled Schlenk tube under argon, followed by addition of carbamoylsilane (0.60 mmol). The sealed reaction mixture was stirred at 75 °C until no carbamoylsilane could be detected by TLC. Volatiles were removed in vacuum to afford the crude product which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate combination) to give 3. 3a: mp 88.6–89.7 °C. IR: 3310, 1638, 1595, 1431, 1272, 1131, 681 cm 1. 1H NMR (600 MHz, CDCl3): d 9.83 (s, 1H), 8.21 (s, 1H), 7.89–7.39 (m, 3H), 3.42 (s, 3H), 3.04 (s, 3H), 2.56 (s, 3H). 13C NMR (151 MHz, CDCl3): d 197.7, 161.8, 159.2, 137.8, 137.6, 129.3, 124.6, 124.5, 119.8, 38.7, 37.4, 26.7. Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found: C, 61.82; H, 6.31; N, 12.13. Typical procedure for the reaction of carbamoylsilane 6 with aromatics 1e (1g) A Schlenk tube fitted with a Teflon vacuum stopcock and micro stirbar was flame-heated under vacuum and refilled with Ar. 3Cyanopyridine (52 mg, 0.50 mmol) and benzene (1.5 mL) were

This research was supported by Shanxi Province Foundation for Returness (No. 0713), the Natural Science Foundation of Shanxi Province (No. 2012011046-9) and Foundation of Shanxi Normal University (No. SD2015CXXM-83), China. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.01. 058. References and notes 1. (a) Li, J.; Xu, F.; Zhang, Y.; Shen, Q. J. Org. Chem. 2009, 74, 2575–2577; (b) Luszczki, J. J.; Swiader, M. J.; Swiader, K.; Paruszewski, R.; Turski, W. A.; Czuczwar, S. J. Fund. Clin. Pharmacol. 2008, 22, 69–74; (c) Reddy, K. R.; Maheswari, C. U.; Venkateshwar, M.; Kantam, M. L. Eur. J. Org. Chem. 2008, 3619–3622; (d) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798– 13799; (e) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 790–792; (f) Malawska, B. Curr. Top. Med. Chem. 2005, 5, 69–85; (g) Kobayashi, I.; Muraoka, H.; Hasegawa, M.; Saika, T.; Nishida, M.; Kawamura, M.; Ando, R. J. Antimicrob. Chemother. 2002, 50, 129–132; (h) Graul, A.; Castaner, J. Drugs Future 1997, 22, 956–968. 2. (a) Soderberg, B. C. In Comprehensive Organometallic Chemistry II; Hegedus, L. S., Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, UK, 1995; Vol. 12, pp 249–251; (b) Colguhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation; Plenum: New York, 1991. pp 145–149.

Y. Liu et al. / Tetrahedron Letters 57 (2016) 937–941 3. (a) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3318–3326; (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327–3331. 4. (a) Cheng, J.; Qi, X.-X.; Li, M.; Chen, P.-H.; Liu, G.-S. J. Am. Chem. Soc. 2015, 137, 2480–2483; (b) Fang, W.-W.; Deng, Q.-Y.; Xu, M.-Z.; Tu, T. Org. Lett. 2013, 15, 3678–3681; (c) Dang, T.-T.; Zhu, Y.-H.; Ngiam, J. S. Y.; Ghosh, S. C.; Chen, A.; Seayad, A. M. ACS Catal. 2013, 3, 1406–1410; (d) Li, Y.; Xue, D.; Wang, C.; Liu, Z.T.; Xiao, J. Chem. Commun. 2012, 1320–1322; (e) Grigg, R.; Mutton, S. P. Tetrahedron 2010, 66, 5515–5548; (f) Csajagi, C.; Borcsek, B.; Niesz, K.; Kovacs, I.; Szekelyhidi, Z.; Bajko, Z.; Urge, L.; Darvas, F. Org. Lett. 2008, 10, 1589–1592; (g) Martinelli, J. R.; Freckmann, D. M. M.; Buchwald, S. L. Org. Lett. 2006, 8, 4843–4846; (h) Schnyder, A.; Beller, M.; Mehltretter, G.; Nsenda, T.; Studer, M.; Indolese, A. F. J. Org. Chem. 2001, 66, 4311–4315. 5. (a) Sawant, D. N.; Wagh, Y. S.; Bhatte, K. D.; Bhanage, B. M. J. Org. Chem. 2011, 76, 5489–5494; (b) Morimsoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5580–5588. 6. Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 18114–18117. 7. (a) Jo, Y.; Ju, J.; Choe, J.; Song, K.-H.; Lee, S. J. Org. Chem. 2009, 74, 6358–6361; (b) Muzart, J. Tetrahedron 2009, 65, 8313–8323; (c) Ju, J.; Jeong, M.; Moon, J.; Jung, H.-M.; Lee, S. Org. Lett. 2007, 9, 4615–4618; (d) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Comb. Chem. 2003, 5, 82–84; (e) Hosoi, K.; Nozaki, K.; Hiyama, T. Org. Lett. 2002, 4, 2849–2851; (f) Wan, Y.; Alterman, M.; Larhed, M.; Hallbeg, A. J. Org. Chem. 2002, 67, 6232–6235. 8. Schareina, T.; Zapf, A.; Gotta, C. M.; Beller, M. Adv. Synth. Catal. 2010, 352, 1205– 1209. 9. Lindsay, C. M.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1988, 569–573. 10. Cunico, R. F.; Chen, J.-X. Synth. Commun. 2003, 33, 1963–1968. 11. (a) Cunico, R. F.; Pandey, R. K. J. Org. Chem. 2005, 70, 9048–9050; (b) Cunico, R. F.; Maity, B. C. Org. Lett. 2003, 5, 4947–4949; (c) Cunico, R. F.; Maity, B. C. Org. Lett. 2002, 4, 4357–4359. 12. (a) Tong, W.-T.; Liu, H.; Chen, J.-X. Tetrahedron Lett. 2015, 56, 1335–1337; (b) Chen, J.-X.; Pandey, R. K.; Cunico, R. F. Tetrahedron: Asymmetry 2005, 16, 941– 947; (c) Chen, J.-X.; Cunico, R. F. Tetrahedron Lett. 2002, 43, 8595–8597. 13. (a) Cunico, R. F.; Pandey, R. K. J. Org. Chem. 2005, 70, 5344–5346; (b) Chen, J.-X.; Cunico, R. F. J. Org. Chem. 2004, 69, 5509–5511. 14. (a) Li, W.-D.; Liu, Y.-H.; Chen, J.-X. Tetrahedron Lett. 2015, 56, 4328–4330; (b) Yao, Y.; Tong, W.-T.; Chen, J.-X. Mendeleev Commun. 2014, 24, 176–177; (c) Yao, Y.; Li, W.-D.; Chen, J.-X. Chin. J. Org. Chem. 2014, 34, 2124–2129; (d) Chen, X.-J.; Chen, J.-X. Mendeleev Commun. 2013, 23, 106–107; (e) Ma, F.; Chen, J.-X. Acta Chem. Sinica 2013, 71, 1118–1120. 15. (a) Wu, X.-F.; Neumann, H.; Beller, M. ChemSusChem 2013, 6, 229–241; (b) Gabriele, B.; Mancuso, R.; Salerno, G. Eur. J. Org. Chem. 2012, 6825–6839; (c) Liu, Q.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2011, 50, 10788–10799; (d) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013–1025. 16. Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2878. 17. Schollkopf, U.; Beckhaus, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 293. 18. (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77–80; (b) Shen, Z. M.; Dong, V. M. Angew. Chem., Int. Ed. 2009, 48, 784–786. 19. Characterization data for aromatic carbinolamines and aromatic amides. All NMR spectra were obtained in CDCl3 unless otherwise indicated. 3b: mp 91.3– 92.4 °C. IR: 3437, 1633, 1529, 1352, 1196, 944, 709 cm 1. 1H NMR: d 10.05 (s, 1H), 8.72 (s, 1H), 8.39–7.66 (m, 3H), 3.15 (s, 3H), 2.96 (s, 3H). 13C NMR: d 171.5, 167.1, 148.7, 135.9, 133.2, 130.0, 126.3, 122.4, 37.8, 34.4. Anal. Calcd for C10H11N3O3: C, 54.29; H, 5.01; N, 19.00. Found: C, 54.12; H, 5.23; N, 19.11. 3d: mp 74.6–76.1 °C. IR: 3435, 1634, 1538, 1327, 1130, 1088, 850 cm 1. 1H NMR: d 8.46 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 3.18 (s, 3H), 2.86 (s, 3H). 13C NMR: d 166.4, 145.2, 136.6, 132.4, 132.2, 131.2, 131.1, 129.1, 123.4, 122.1, 38.2, 34.9. Anal. Calcd for C10H10N2O3F4: C, 42.56; H, 3.57; N, 9.93. Found: C, 42.66; H, 3.85; N, 9.99. 3e: IR: 3399, 1646, 1412, 1249, 1150, 991, 700 cm 1. 1H NMR: d 9.15 (s, 1H), 8.86 (m, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.50– 7.48 (m, 1H), 3.15 (s, 3H), 3.02 (s, 3H), 1.27 (s, 1H). 13C NMR: d 190.1, 165.8,

941

154.7, 151.3, 136.8, 128.8, 123.9, 37.1, 34.3. Anal. Calcd for C9H11N3O: C, 61.00; H, 6.26; N, 23.71. Found: C, 61.27; H, 6.49; N, 23.95. 3g: mp 143.4–144.6 °C. IR: 1787, 1736, 1450, 1192, 892, 653 cm 1. 1H NMR: d 8.04 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 3.21, 3.17 (ss, 6H). 13C NMR: d 161.9, 152.7, 150.2, 144.6, 129.7, 127.8, 38.0. Anal. Calcd for C8H8N3O3Cl: C, 41.85; H, 3.51; N, 18.30. Found: C, 41.97; H, 3.60; N, 18.51. 3i: mp 97.0–98.0 °C. IR: 3438, 1697, 1656, 1574, 1403, 1254, 997 cm 1. 1H NMR: d 9.32, 9.31 (ss, 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.73 (m, 1H), 3.16 (s, 3H), 3.01 (s, 3H), 1.26 (s, 1H). 13C NMR: d 190.8, 166.6, 148.6, 146.0, 144.9, 144.4, 36.8, 34.0; Anal. Calcd for C8H10N4O: C, 53.92; H, 5.66; N, 31.44. Found: C, 54.12; H, 5.52; N, 31.58. 5a: IR: 1787, 1736, 1450, 1192, 892, 653 cm 1. 1H NMR: d 10.22, 10.07 (ss, 1H), 8.32, 8.30 (ss, 1H), 7.95– 7.25 (m, 8H), 6.14, 6.13 (qq, J = 7.2 Hz, 1H), 3.05, 2.70 (ss, 3H), 2.56 (s, 3H), 1.69, 1.56 (dd, J = 7.2 Hz, 3H). 13C NMR: d 197.7, 163.3, 162.5, 160.4, 159.9, 139.1, 139.0, 137.8, 137.7, 129.3, 128.7, 128.5, 127.8, 127.7, 127.3, 127.2, 124.7, 124.6, 120.0, 119.9, 55.4, 52.6, 30.9, 28.6, 26.7, 17.0, 15.4. Anal. Calcd for C8H8N3O3Cl: C, 41.85; H, 3.51; N, 18.30. Found: C, 41.97; H, 3.60; N, 18.51. 5b: IR: 3231, 1633, 1535, 1349, 1314, 1094, 921, 701 cm 1. 1H NMR: d 8.39–7.14 (m, 8H), 6.18, 4.86 (qq, J = 7.2 Hz, 1H), 2.91, 2.59 (ss, 3H), 1.66, 1.57 (dd, J = 7.2 Hz, 3H). 13 C NMR: d 171.6, 171.5, 167.3, 167.1, 148.6, 138.9, 138.6, 136.0, 135.8, 133.3, 132.9, 130.1, 130.0, 129.0, 128.9, 128.2, 128.1, 127.4, 126.4, 126.3, 122.6, 121.3, 56.3, 50.5, 30.1, 27.2, 17.8, 15.3. Anal. Calcd for C17H17N3O3: C, 65.58; H, 5.50; N, 13.50. Found: C, 65.79; H, 5.75; N, 13.61. 5d: mp 130.2–132.1 °C. IR: 3434, 1641, 1545, 1325, 1132, 901, 692 cm 1. 1H NMR: d 8.50 (s, 1H), 8.00, 7.99 (ss, 1H), 7.90–7.23 (m, 7H), 6.21, 4.70 (qq, J = 7.2 Hz, 1H), 3.05, 2.50 (ss, 3H), 1.70, 1.65 (dd, J = 7.2 Hz, 3H); 13C NMR: d 166.5, 145.0, 136.8, 132.4, 132.2, 131.2, 130.1, 129.1, 129.0, 128.9, 128.7, 127.8, 127.6, 126.0, 123.4, 122.3, 122.2, 121.6, 57.1, 50.9, 30.7, 28.2, 17.9. Anal. Calcd for C17H16N2O3F4: C, 54.84; H, 4.33; N, 7.52. Found: C, 54.99; H, 4.10; N, 7.69. 5e: IR: 1651, 1578, 1407, 1250, 1114, 962, 692 cm 1. 1H NMR: d 8.11–9.20 (m, 3H), 7.49–7.26 (m, 5H), 6.10, 5.80, 4.91, 4.78 (qqqq, J = 7.2 Hz, 1H), 2.82, 2.64 (ss, 3H), 1.64, 1.62 (dd, J = 7.2 Hz, 3H). 13C NMR: d 190.2, 189.9, 166.1, 165.9, 162.6, 162.4, 154.8, 154.7, 151.4, 151.3, 138.7, 138.1, 136.7, 136.6, 128.8, 127.4, 127.0, 124.0, 123.9, 56.5, 55.7, 50.6, 48.7, 29.6, 29.4, 26.8, 26.1, 17.9, 17.0, 15.3, 15.2. Anal. Calcd for C16H15N3O: C, 72.34; H, 5.70; N, 15.84. Found: C, 72.12; H, 5.86; N, 15.89. 5g: IR: 1658, 1450, 1394, 1286, 1097, 1031, 912, 771, 694 cm 1. 1H NMR: d 7.67–7.28 (m, 7H), 6.03–5.25 (m, 1H), 3.76–2.65 (m, 3H), 1.72–1.54 (m, 3H). 13 C NMR: d 168.2, 161.5, 140.6, 140.3, 139.4, 139.3, 128.5, 128.4, 128.3, 128.2, 127.7, 127.5, 127.4, 127.3, 127.2, 125.7, 125.5, 56.4, 54.5, 51.6, 31.5, 30.6, 29.7, 28.2, 19.2, 16.2, 15.5, 13.8. Anal. Calcd for C15H14N3O3Cl: C, 56.35; H, 4.41; N, 13.14. Found: C, 56.17; H, 4.21; N, 13.30. 7a: mp 135.4–137.1 °C. IR: 3269, 1670, 1535, 1298, 1114, 912, 682 cm 1. 1H NMR: d 9.56 (s, 1H), 8.21(s, 1H), 7.89–7.45 (m, 3H), 5.35, 4.91 (ss, 2H), 3.46, 3.37 (ss, 3H), 3.35, 3.10 (ss, 3H), 2.62 (s, 3H). 13C NMR: d 197.6, 162.6, 162.4, 158.5, 158.3, 137.9, 137.3, 129.4, 125.0, 124.9, 124.5, 124.3, 119.7, 119.6, 80.9, 79.6, 56.4, 55.5, 35.0, 34.0, 26.7. Anal. Calcd for C13H16N2O4: C, 59.08; H, 6.10; N, 10.60. Found: C, 59.27; H, 6.35; N, 10.80. 7b: IR: 3282, 1730, 1640, 1535, 1103, 925, 699 cm 1. 1H NMR: d 8.82, 8.80 (ss, 1H), 8.50–7.74 (m, 3H), 5.02, 4.70 (ss, 2H), 3.48, 3.24 (ss, 3H), 3.22, 3.03 (ss, 3H), 1.27 (s, 1H). 13C NMR: d 188.2, 187.9, 166.7, 166.5, 148.7, 148.6, 135.2, 135.0, 134.8, 134.2, 130.4, 130.2, 128.9, 128.7, 124.6, 124.5, 80.9, 56.5, 55.7, 33.4, 31.8. Anal. Calcd for C11H13N3O4: C, 52.59; H, 5.22; N, 16.73. Found: C, 52.81; H, 5.49; N, 16.56. 7d: IR: 3430, 1644, 1535, 1315, 1132, 912, 692 cm 1. 1H NMR: d 8.50, 8.45 (ss, 1H), 7.59–7.02 (m, 2H), 5.03, 4.42 (ss, 2H), 3.53, 3.26 (ss, 3H), 3.23, 2.87 (ss, 3H). 13C NMR: d 167.8, 167.0, 145.8, 145.2, 136.3, 135.6, 132.7, 132.5, 131.2, 130.6, 129.6, 129.0, 123.3, 122.3, 122.1, 121.5, 82.2, 56.7, 55.9, 34.4, 33.5. Anal. Calcd for C11H12N2O4F4: C, 42.32; H, 3.87; N, 8.97. Found: C, 42.56; H, 3.99; N, 9.09. 7g: mp 147.1–148.5 °C. IR: 3399, 1780, 1736, 1456, 1267, 864, 692 cm 1. 1H NMR: d 8.35 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 6.08 (s, 1H), 3.04, 3.03 (ss, 3H). 13C NMR: d 161.9, 152.7, 150.2, 144.6, 129.7, 127.8, 38.0. Anal. Calcd for C7H6N3O3Cl: C, 39.00; H, 2.81; N, 19.49. Found: C, 39.17; H, 2.90; N, 19.57.