ketones with aminopyrazoles toward the synthesis of pyrazolo[1,5-a]quinazolines

Accepted Manuscript Copper-Catalyzed Tandem Reactions of 2-Bromobenzaldehydes/ketones with Aminopyrazoles towards the synthesis of Pyrazolo[1,5-a]quinazolines Lin Gao, Yunping Song, Xinying Zhang, Shenghai Guo, Xuesen Fan PII: DOI: Reference:

S0040-4039(14)01181-2 http://dx.doi.org/10.1016/j.tetlet.2014.07.028 TETL 44871

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

25 March 2014 4 July 2014 7 July 2014

Please cite this article as: Gao, L., Song, Y., Zhang, X., Guo, S., Fan, X., Copper-Catalyzed Tandem Reactions of 2-Bromobenzaldehydes/ketones with Aminopyrazoles towards the synthesis of Pyrazolo[1,5-a]quinazolines, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.07.028

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Copper-Catalyzed Tandem Reactions of 2Bromobenzaldehydes/ketones with Aminopyrazoles towards the synthesis of Pyrazolo[1,5-a]quinazolines

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Lin Gao, Yunping Song, Xinying Zhang, Shenghai Guo, Xuesen Fan

1

Tetrahedron Letters journal homepage: www.elsevier.com

Copper-Catalyzed Tandem Reactions of 2-Bromobenzaldehydes/ketones with Aminopyrazoles towards the synthesis of Pyrazolo[1,5-a]quinazolines Lin Gao, Yunping Song, Xinying Zhang, Shenghai Guo, and Xuesen Fan School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory for Environmental Pollution Control, Henan Normal University, Xinxiang, Henan 453007, P. R. China

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

An efficient and straightforward synthesis of pyrazolo[1,5-a]quinazolines through coppercatalyzed tandem reactions of 2-bromobenzaldehydes or 2-bromophenyl alkyl/aryl ketones with 5-aminopyrazoles is presented. 2009 Elsevier Ltd. All rights reserved.

Keywords: Pyrazolo[1,5-a]quinazoline Copper catalysis Tandem reaction

Pyrazolo[1,5-a]quinazolines are important moieties in medicinal chemistry and are being developed as potential antiinflammatory, antiallergic, anti-parasitic agents,1 polymerase-12 and topoisomerase I inhibitors (Figure 1).3 Due to their importance, several synthetic methods for the preparation of pyrazolo[1,5-a]quinazolines have been developed.3-5 While these literature methods are generally reliable and efficient, there is still a strong motivation to search for new synthetic approaches to this skeleton under mild conditions and from readily available substrates.

three-component preparation of quinolizines from aqueous ammonia and other economical substrates.8 Following those encouraging results, we proposed a straightforward approach to pyrazolo[1,5-a]quinazolines via copper-catalyzed tandem reactions of commercially available 2-bromobenzaldehydes/2bromophenyl ketones with 5-aminopyrazoles as shown in Scheme 1.

Scheme 1. Proposed pathway leading to pyrazolo[1,5-a]quinazolines

Figure 1. Selected biologically active pyrazolo[1,5-a]quinazolines

In recent years, copper-catalyzed tandem reactions between aryl halides and nitrogen nucleophiles have been widely utilized in the construction of N-heterocycles.6, 7 In this regard, we have disclosed a copper-catalyzed one-pot four-component synthesis of pyrazolo[1,5-c]quinazolines and a copper-catalyzed one-pot

2-Bromobenzaldehyde (1a) and 1H-pyrazol-5-amine (2a) were chosen as model substrates. Conducting the reaction with 0.1 equiv. of CuI and 2 equiv. of K2CO3 in DMSO at 80 oC for 6 h afforded the desired pyrazolo[1,5-a]quinazoline (3a) in 18% yield (Table 1, entry 1). Encouraged by this result, the reaction conditions were then further optimized. Brief screening a variety of solvents, such as DMF, THF and dioxane (Table 1, entries 24), showed that DMF was the optimal solvent, generating the product in 30% yield. Next, we explored the copper salts and

———  Corresponding author. Tel.: +0-86-373-3329261; fax: +0-86-373-3329275; e-mail: [email protected]

2 Table 1. Optimization study for the synthesis of 3a a

Entry

Catalyst (eqiv.)

Solvent

Base

Ligand b

Temp. (°C)

time (h)

Yield (%) c

1

CuI (0.1)

DMSO

K2CO3

-

80

6

18

2

CuI (0.1)

DMF

K2CO3

-

80

6

30

3

CuI (0.1)

THF

K2CO3

-

reflux

6

trace

4

CuI (0.1)

Dioxane

K2CO3

-

80

6

trace

5

CuBr (0.1)

DMF

K2CO3

-

80

6

15

6

CuCl (0.1)

DMF

K2CO3

-

80

6

22

7

Cu(OAc)2 (0.1)

DMF

K2CO3

-

80

6

trace

8

CuI (0.1)

DMF

K2CO3

-

90

6

34

9

CuI (0.1)

DMF

K2CO3

-

100

6

37

10

CuI (0.1)

DMF

K2CO3

-

110

6

42

11

CuI (0.2)

DMF

K2CO3

-

110

3

61

12

CuI (0.3)

DMF

K2CO3

-

110

3

62

13

CuI (0.2)

DMF

Cs2CO3

-

110

3

39

14

CuI (0.2)

DMF

KOH

-

110

3

32

15

CuI (0.2)

DMF

t-BuOK

-

110

3

trace

16

CuI (0.2)

DMF

Et3N

-

110

3

30

17

CuI (0.2)

DMF

K2CO3

L-proline

110

3

56

18

CuI (0.2)

DMF

K2CO3

DMEDA

110

3

58

19

CuI (0.2)

DMF

K2CO3

1,10-phen

110

3

55

20

CuI (0.2)

DMF

K2CO3

DBU

110

3

72

21

CuI (0.2)

DMF

K2CO3

en

110

3

78

22

CuI (0.2)

DMF

K2CO3

TMEDA

110

3

59

110

16

-

110

16

20

23

-

DMF

K2CO3

-

24

CuI (0.2)

DMF

-

-

a

Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), base (1 mmol), solvent (3 mL). Ligand: L-proline, N, N'-dimethylethylenediamine (DMEDA), 1,10-phenanthroline (1,10-phen), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), ethylenediamine (en) and N, N, N', N'-tetramethylethylenediamine (TMEDA). The amount of ligand was 0.2 equiv. c Isolated yield. b

temperature effect on the reaction outcome. The results indicated that other salts, such as CuBr, CuCl and Cu(OAc)2, were less effective than CuI (Table 1, entries 2, 5-7). Fortunately, we were pleased to find that elevating the reaction temperature from 80 ºC to 110 ºC and increasing the catalyst loading from 0.1 to 0.2 equiv. enhanced the yield to 61% (entries 2, 8-12). To further improve the reaction, different bases were investigated, but failed to further increase the yield (entries 11, 13-16). We then sought to different ligands,9 such as L-proline, N,N′-dimethylethylene diamine (DMEDA), 1,10-phenanthroline hydrate (1,10-phen), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), ethylenediamine (en) and N, N, N', N'-tetramethylethylenediamine (TMEDA) (entries 17-22). The yield was further improved to 78% by using en as the ligand. Controlled experiments indicated that no product was observed in the absence of copper catalyst, and the efficacy decreased without a base promoter (entries 23-24). In summary, treating 1a and 2a with 0.2 equiv. of CuI, 0.2 equiv. of en and 2 equiv. of K2CO3 in DMF at 110 ºC for 3 h was the optimal condition. With the optimized conditions in hand, the scope and generality of this new reaction was then studied as demonstrated in Table 2. The reaction has a broad substrate scope, bearing

different functionalities in the phenyl ring of 2-bromobenzaldehydes. Both electron-donating groups (Table 2, entries 3, 78) and electron-withdrawing substituents (entries 2, 4-6) led to the products in good yields. Various functional groups, such as methyl, methoxy, trifluoromethyl and halides, were well tolerated under the reaction conditions. Notably, 2-bromonicotinaldehyde was a suitable substrate for this tandem reaction affording pyrazolo[1,5-a]pyrido[3,2-e] pyrimidine (3i) in a good yield (entry 9). We then tested the substrate scope in the aminopyrazoles as listed in Table 3. Both alkyl- and aryl-substituted aminopyraloles could react with various 2-bromobenzaldehydes to afford substituted pyrazolo[1,5-a]quinazolines (3j-3aa) in good yields (Table 3, entries 1-18). Further experiments showed that 4cyanoaminopyrazole, an aminopyrazole with a strong electronwithdrawing substituent on the pyrazole ring, could also participate in this reaction albeit the yields were lower (entries 19-20).

3 Table 2. Scope for the synthesis of 3 (I) a 6

67 3o

Entry

Substrate (1)

Yield (%) b

Product (3)

1

7

83 3p

78 3a

8

2

75 3q

66 3b

3

9

60 3c

77 3r

4

73

10

3d

69 3s

5

69 3e 11

6

70

74

3t

3f 7

12

68

62

3g

3u

8

71 3h

13

9

65 3v

79

3i Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), CuI (0.2 mmol), K2CO3 (2 mmol), en (0.2 mmol), DMF (5 mL), 110 °C, 3 h. b Isolated yield. a

Table 3. Scope for the synthesis of 3 (II)

14

81 3w

a

58 c

15 3x

62 c

16 Entry

1

2

Yield (%) b

Product (3)

1

3y 63 c

17

74

3z

3j

2 3k

3

3aa

3bb

3l

3m

3n

3cc a

67

41 d

20

78

5

45 d

19

79

4

69c

18

62

Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), CuI (0.2 mmol), K2CO3 (2 mmol), en (0.2 mmol), DMF (5 mL), 110 °C, 3 h. b Isolated yield. c The reaction was run for 5 h. d The reaction was run for 10 h.

4 Table 4. Scope for the synthesis of 3 (III) a

Entry

1

2

Yield (%) b

Product (3)

1

65

Scheme 2. Plausible mechanism for the formation of 3a

66

Some control experiments were conducted to support the plausible mechanism. When 1a was treated with 2a in DMF at 110 ºC for 4 h, only N-(2-bromobenzylidene)-1H-pyrazol-5amine (B) was detected without any formation of 3a. Subsequent adding of 0.2 equiv. of CuI and 2 equiv. of K2CO3 to the resulting mixture led to the formation of 3a in 63% yield.

3dd

2 3ee

3

69 3ff

4

51 3gg

5

43 3hh

6

67 3ii

7

In conclusion, an efficient and straightforward synthesis of diversely substituted pyrazolo[1,5-a]quinazolines via coppercatalyzed tandem reactions of 2-bromobenzaldehydes or 2-bromo phenyl alkyl/aryl ketones with 5-aminopyrazoles has been developed. With advantages such as commercially available starting materials, simple synthetic procedures, and mild reaction conditions, the method developed herein is expected to serve as promising protocol for the construction of relevant nitrogencontaining heterocycles.

Acknowledgments This work was financially supported by the National Natural Science Foundation of China (21172057, 21202040), RFDP (20114104110005), and PCSIRT (IRT 1061). References and notes

62

1. 2.

3jj 8

58

3.

3kk 4. 9

54

3ll a Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), CuI (0.2 mmol), K2CO3 (2 mmol), en (0.2 mmol), DMF (5 mL), 110 °C, 5 h. b Isolated yield.

Having explored the reaction of various 2-bromobenzaldehydes with 5-aminopyraloles, we were then interested in the suitability of 2-bromophenyl ketones as substrates for this tandem reaction. Our studies showed that both 2-bromophenyl methyl ketones (Table 4, entries 1-8) and 2-bromophenyl phenyl ketone (entry 9) could participate in this tandem process to afford pyrazolo[1,5-a]quinazolines with an alkyl or aryl group attached on the 5-position of the heterocyclic ring in moderate to good yields (Table 4). Based on the above facts, a plausible pathway for the formation of 3a was proposed in Scheme 2. Initially, 1a condenses with 2a to give an imine intermediate (B). A subsequent Cu(I)-catalyzed intramolecular C-N coupling occurs to afford 3a.

5. 6.

7.

8.

9.

Chen, D.; Chen, Q.; Liu, M.; Dai, S.; Huang, L.; Yang, J.; Bao, W. Tetrahedron 2013, 69, 6461 and references cited therein. Orvieto, F.; Branca, D.; Giomini, C.; Jones, P.; Koch, U.; Ontoria, J. M.; Palumbi, M. C.; Rowley, M.; Toniatti, C.; Muraglia. E. Bioorg. Med. Chem. Lett. 2009, 19, 4196. Taliani, S.; Pugliesi, I.; Barresi, E.; Salerno, S.; Marchand, C.; Agama, K.; Simorini, F.; La Motta, C.; Marini, A. M.; Di Leva, F. S.; Marinelli, L.; Cosconati, S.; Novellino, E.; Pommier, Y.; Di Santo, R.; Da Settimo, F. J. Med. Chem. 2013, 56, 7458. Chimichi, S.; Boccalini, M.; Selleri, S.; Costagli, C.; Guerrini, G.; Viola, G. Org. Biomol. Chem. 2008, 6, 739. Sadek, K. U.; Mekheimer, R. A.; Mohamed, T. M.; Moustafa, M. S.; Elnagdi, M. H. Beilstein J. Org. Chem. 2012, 8, 18. For selected reviews, see: (a) Liu, Y.; Wan, J. P. Chem. Asian. J. 2012, 7, 1488; (b) Rao, H.; Fu, H. Synlett 2011, 745; (c) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464; (d) Beletskaya, I. P.; Cheprakov, A.V. Organometallics 2012, 31, 7753; (e) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054; (f) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829; (g) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450; For selected examples, see: (a) Sang, P.; Yu, M.; Tu, H.; Zou, J.; Zhang, Y. Chem. Commun. 2013, 49, 701; (b) Wang, Z.; Yang, F.; Lv, X.; Bao, W. J. Org. Chem. 2011, 76, 967; (c) Liu, T.; Fu, H. Synthesis 2012, 44, 2805; (d) Zhang, H.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Eur. J. Org. Chem. 2012, 6798; (e) Sang, P.; Xie, Y.; Zou, J.; Zhang, Y. Org. Lett. 2012, 14, 3894; (f) Truong, V. L.; Morrow, M.; Tetrahedron Lett. 2010, 51, 758; (g) Lv, Y.; Li, Y.; Xiong, T.; Pu, W.; Zhang, H.; Sun, K.; Liu, Q.; Zhang, Q. Chem. Commun. 2013, 6439; (h) Yang, X.; Luo, Y.; Jin, Y.; Liu, Y.; Jiang, Y.; Fu, H. RSC Adv. 2012, 2, 8258; (i) Ohta, Y.; Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. lett. 2010, 12, 3963; (j) Zhang, J.; Yu, C.; Wang, S.; Wan, C.; Wang, Z. Chem. Commun. 2010, 5244. (a) Guo, S. H.; Wang, J. L.; Fan, X. S.; Zhang, X. Y.; Guo, D. Q. J. Org. Chem. 2013, 78, 3262; (b) Fan, X. S.; Li, B.; Guo, S. H.; Wang, Y. Y.; Zhang, X. Y. Chem. Asian J. 2014, 9, 739. Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059.

5 10. Typical procedure for the preparation of 3a: To a solution of 2bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine (0.2 mmol). The mixture was stirred at 110 °C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by column chromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner. Details of analytical data of selected compounds are presented as follows: 3a: white solid; 1H NMR (400MHz, CDCl3) δ: 6.75 (d, J = 2.0 Hz, 1H), 7.40-7.45 (m, 1H), 7.76-7.82 (m, 2H), 8.04 (d, J = 2.0 Hz, 1H), 8.34-8.36 (m, 1H), 8.77 (d, J = 2.0 Hz, 1H); 13C NMR (100MHz, CDCl3) δ: 99.8, 114.6, 118.3, 125.2, 128.3, 134.1, 136.2, 142.7, 145.7, 151.7; HRMS calcd for C10H8N3: 170.0718 [M+H], found: 170.0711. 3b: white solid; 1H NMR (400MHz, CDCl3) δ: 6.79 (d, J = 2.0 Hz, 1H), 7.24 (td, J1 =8.4 Hz, J2 =2.0 Hz, 1H), 7.94 (dd, J1 = 8.8 Hz, J2 = 5.2 Hz, 1H), 8.09-8.11 (m, 2H), 8.81 (s, 1H); 13C NMR (100MHz, CDCl3) δ: 100.0, 101.4, 101.6, 114.2, 114.4, 115.3, 115.3, 131.2, 131.3, 137.8, 137.9, 143.3, 145.7, 150.8, 164.7, 167.2; HRMS calcd for C10H7FN3: 188.0624 [M+H], found: 188.0618. 3c: white solid; 1H NMR (400MHz, CDCl3) δ: 2.63 (s, 3H), 6.80 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 8.29 (s, 1H), 8.84 (s, 1H); 13C NMR (100MHz, CDCl3) δ: 22.4, 99.5, 114.4, 116.5, 126.8, 128.2, 136.3, 142.6, 145.8, 145.9, 151.5; HRMS calcd for C11H10N3: 184.0875 [M+H], found: 184.0881. 3f: white solid; 1H NMR (400MHz, CDCl3) δ: 6.86 (d, J = 2.0 Hz, 1H), 8.08 (dd, J1 =8.8 Hz, J2 =2.0 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.90 (s, 1H); 13C NMR (100MHz, CDCl3) δ: 100.8, 115.8, 117.7, 122.2, 124.9, 125.99, 126.03, 126.08, 126.11, 127.3, 127.7, 130.30, 130.33, 130.37, 130.40, 137.8, 143.8, 146.1, 151.2; HRMS calcd for C11H7F3N3: 238.0592 [M+H], found: 238.0599. 3n: yellow solid; 1H NMR (400MHz, CDCl3) δ: 2.53 (s, 3H), 3.90 (s, 3H), 6.54 (s, 1H), 7.21 (d, J =2.4 Hz, 1H), 7.43 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 8.29 (d, J =9.2 Hz, 1H), 8.72 (s, 1H); 13C NMR (100MHz, CDCl3) δ: 14.5, 55.8, 98.7, 108.3, 116.0, 119.0, 124.0, 131.1, 145.9, 150.7, 152.0, 156.6; HRMS calcd for C12H12N3O: 214.0980 [M+H], found: 214.0985. 3o: yellow solid; 1H NMR (400MHz, CDCl3) δ: 2.53 (s, 3H), 6.14 (s, 2H), 6.49 (s, 1H), 7.15 (s, 1H), 7.79 (s, 1H), 8.60 (s, 1H); 13C NMR (100MHz, CDCl3) δ: 14.6, 94.5, 97.9, 102.4, 104.9, 113.3, 134.0, 145.8, 146.3, 149.7, 152.5, 153.5; HRMS calcd for C12H10N3O2: 228.0773 [M+H], found: 228.0767. 3s: yellow solid; 1H NMR (400MHz, CDCl3) δ: 0.91-0.95 (m, 2H), 1.05-1.10 (m, 2H), 2.13-2.17 (m, 1H), 6.43 (s, 1H), 7.74 (dd, J1 =9.2 Hz, J2 =2.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.68 (s, 1H); 13C NMR (100MHz, CDCl3) δ: 9.2, 10.0, 96.3, 116.3, 118.8, 127.3, 130.0, 134.3, 134.4, 146.2, 150.1, 159.7; HRMS calcd for C13H11ClN3: 244.0642 [M+H], found: 244.0649. 3w: yellow solid; 1H NMR (400MHz, CDCl3) δ: 0.97-1.05 (m, 4H), 2.19-2.23 (m, 1H), 6.49 (s, 1H), 7.41 (dd, J1 = 8.0 Hz, J2 = 4.4 Hz, 1H), 8.17-8.19 (m, 1H), 8.72 (s, 1H), 8.88-8.89 (m, 1H); 13C NMR (100MHz, CDCl3) δ: 9.4, 10.2, 97.5, 113.1, 120.8, 137.2, 145.6, 148.4, 150.8, 154.5, 161.0; HRMS calcd for C12H11N4: 211.0984 [M+H], found: 211.0978. 3y: yellow solid; 1H NMR (400MHz, CDCl3) δ: 7.06 (s, 1H), 7.40 (t, J =7.6 Hz, 1H), 7.48 (t, J =8.0 Hz, 2H), 7.77 (dd, J1 =8.8, J2 = 1.6 Hz, 1H), 7.78 (d, J =2.0 Hz, 1H), 8.01 (d, J =7.6 Hz, 2H), 8.42 (d, J =8.8 Hz, 1H), 8.72 (s, 1H); 13C NMR (100MHz, CDCl3) δ: 97.0, 116.6, 119.2, 126.3, 127.4, 128.8, 128.9, 130.6, 132.7, 134.3, 134.5, 146.6, 150.4, 154.4; HRMS calcd for C16H11ClN3: 280.0642 [M+H], found: 280.0635. 3z: yellowish solid; 1H NMR (400MHz, CDCl3) δ: 6.99 (s, 1H), 7.13-7.15 (m, 1H), 7.37 (dd, J1 = 4.8 Hz, J2 = 0.8 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.58 (dd, J1 = 4.0 Hz, J2 = 0.8 Hz, 1H), 7.86-7.92 (m, 2H) , 8.51 (d, J = 8.8 Hz, 1H), 8.86 (s, 1H) ; 13C NMR (100MHz, CDCl3) δ: 96.5, 114.9, 118.5, 125.1, 125.4, 126.0, 127.7, 128.4, 134.2, 136.1, 136.3, 146.7, 149.5, 152.1; HRMS calcd for C14H10N3S: 252.0595 [M+H], found: 252.0599. 3bb: white solid; 1H NMR (400MHz, CDCl3) δ: 7.72 (t, J = 7.6 Hz, 1H), 8.02-8.09 (m, 2H), 8.36 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 9.14(s, 1H); 13C NMR (100MHz, CDCl3) δ: 85.9, 112.7, 115.3, 119.2, 127.0, 128.9, 135.6, 135.9, 145.0, 155.4; HRMS calcd for C11H7N4: 195.0671 [M+H], found: 195.0674. 3dd: yellow solid; 1H NMR (400MHz, CDCl3) δ: 2.91 (s, 3H), 6.70 (d, J = 2.4 Hz, 1H), 7.51-7.55 (m, 1H), 7.88 (td, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 8.03-8.05 (m, 2H), 8.49 (d, J = 8.4 Hz, 1H); 13C NMR (100MHz, CDCl3) δ: 22.5, 98.7, 115.1, 118.1, 125.0, 126.9, 133.8, 136.0, 142.6, 144.9, 158.6; HRMS calcd for C11H10N3: 184.0875 [M+H], found: 184.0868. 3ee: yellow solid; 1H NMR (400MHz, CDCl3) δ: 2.53 (s, 3H), -7.46 (m,

1H), 7.78-7.82 (m, 1H), 7.95-7.97 (m, 1H), 8.38 (d, J = 9.6 Hz, 1H); 13C NMR (100MHz, CDCl3) δ: 14.6, 22.5, 98.2, 114.7, 117.8, 124.3, 126.8, 133.7, 135.8, 145.6, 152.6, 158.3; HRMS calcd for C12H12N3: 198.1031 [M+H], found: 198.1034. 3gg: yellow solid; 1 H NMR (400MHz, CDCl3) δ: 2.89 (s, 3H), 6.96 (s, 1H), 7.377.41 (m, 1H), 7.46-7.51 (m, 3H), 7.84-7.88 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 8.04-8.06 (m, 2H), 8.56 (d, J = 8.0 Hz, 1H); 13C NMR (100MHz, CDCl3) δ: 22.5, 95.6, 115.2, 118.1, 124.8, 126.3, 126.8, 128.6, 128.7, 133.2, 133.6, 135.9, 146.0, 153.9, 158.6; HRMS calcd for C17H14N3: 260.1188 [M+H], found: 260.1185. 3jj: yellow solid; 1H NMR (400MHz, CDCl3) δ: 0.90-0.94 (m, 2H), 1.04-1.08 (m, 2H), 2.11-2.15 (m, 1H), 2.81 (s, 3H), 6.28 (s, 1H), 7.12 (td, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.95 (dd, J1 = 8.8 Hz, J2 = 5.6 Hz, 1H), 8.01 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H); 13C NMR (100MHz, CDCl3) δ: 9.0, 10.0, 22.5, 95.0, 101.2, 101.4, 112.8, 113.1, 114.6, 129.6, 129.7, 137.4, 145.7, 157.6, 159.7, 164.3, 166.8; HRMS calcd for C14H13FN3: 242.1094 [M+H], found: 242.1101. 3ll: white solid; 1H NMR (400MHz, CDCl3) δ: 2.59 (s, 3H), 6.62 (s, 1H), 7.40-7.44 (m, 1H), 7.54-7.56 (m, 3H), 7.707.73 (m, 2H), 7.84-7.88 (m, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H); 13C NMR (100MHz, CDCl3) δ: 14.7, 99.3, 114.8, 117.0, 124.3, 128.6, 129.2, 129.5, 129.6, 133.8, 136.6, 137.8, 145.7, 153.0, 159.7; HRMS calcd for C17H14N3: 260.1188 [M+H], found: 260.1191.