CC BY ND NC 4.0 · SynOpen 2018; 02(01): 0001-0005
DOI: 10.1055/s-0036-1591869
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Synthesis of Functionalized Dihydropyrido[2,3-d]pyrimidines in Aqueous Medium

Saeed Balalaie*
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
,
Hamed Esmaeilabadi
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
,
Saber Mehrparvar
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
,
Frank Rominger
Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
,
Fatima Hamdan
Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
,
Hamid Reza Bijanzadeh
Department of Biophysics, Tarbiat Modares University, ­Tehran, Iran
› Author Affiliations
We gratefully acknowledge the Iran National Science Foundation (INSF) for financial support.
Further Information

Publication History

Received: 08 August 2017

Accepted after revision: 27 November 2017

Publication Date:
18 January 2018 (online)

 

Dedicated to Prof. Dr. Uli Kazmaier on the occasion of his birthday

Abstract

Synthesis of functionalized 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one from a cascade reaction between 3-formylchromone, malononitrile, diammonium hydrogen phosphate, and aromatic aldehydes in aqueous media is described.


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One of the fundamental challenges and ultimate goals for organic chemists is to perform reactions under green reaction conditions, such as carrying out the reactions in water to reduce use of organic solvents and to develop environmentally friendly processes.[1] [2] Designing a novel post-transformational reaction in aqueous medium to access functionalized compounds has received much interest in the synthesis of organic compounds.[3,4]

2-Aminopyridines are known skeletons in organic and medicinal chemistry.[5] Methods for the synthesis of 2-aminopyridines involve the reaction of 2-halopyridines with amines using metal catalysts.[6] [7] [8] [9] Since in some cases, amination leads to a mixture of products and the reported methods are often not applicable at large scale, developing new and mild methods for the preparation of 2-aminopyridines is still desirable. Certain 2-amino-3-cyano-pyridines show bioactivity, and different approaches for their synthesis have been reported.[10] In particular, 3-formyl chromone has been used as a starting material for the synthesis 2-amino-3-cyano-pyridines through ring opening.[11] Such compounds have a potential for cyclization to access heterocyclic skeletons such as quinazolinones.[12] [13] Recently, Langer reported the synthesis of 2,3-dihydroquinazolinones using 2-aminobenzonitriles in the presence of a base in aqueous medium.[14] Quinazolinones have extensive biological properties such as anticancer, antibacterial, antihypertensive, antidiabetic, anti-inflammatory, anticonvulsant, and antiallergic activities.[15,16] In Figure [1], the structures of some bioactive compounds containing the quinazolinone skeleton are shown.

Zoom Image
Figure 1 The structure of some bioactive compounds with quinazolinone skeleton

In view of the importance of functionalized quinazolinones,[17] we report herein the synthesis of 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one through a post-transformation of a multicomponent reaction in water with diammonium hydrogen phosphate (DAHP)[18] as a source of nitrogen (Scheme [1]). The three-component reaction of chromone carbaldehyde, malononitrile, and diammonium hydrogen phosphate (DHAP) in water led to functionalized 2-aminopyridines 4ac and their subsequent reaction with aromatic aldehydes in the presence of potassium phosphate in water led to the desired 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones 6ao.

Zoom Image
Scheme 1 Synthesis of 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones 6ao

At first, 3-formylchromones 1ac were synthesized based on a known reaction of 2-hydroxyacetophenes and Meldrum’s acid, and the study began with designing a model three-component reaction of 3-formylchromone 1a, malononitrile 2, and a source of nitrogen 3 in water at room temperature or 50 °C. Under all reaction conditions, the isolated product was compound 4a. As shown in Table [1], diammonium hydrogen phosphate (DAHP), ammonium acetate, and ammonia solution were used as the sources of nitrogen. Comparison of the yield of the product and reaction temperature showed that DAHP was the most suitable nitrogen source and the optimal temperature was 50 °C. Meanwhile, the molar ratio of DAHP was investigated and the best yield was obtained with 1.5 equiv of DAHP (93% yield). The reaction was also carried out in ethanol, but using water resulted in a better yield. The driving force of the reaction is the precipitation of the product from water. After optimizing the reaction conditions, the scope and limitations were studied using different 3-formylchromones 1ac, malononitrile, and diammonium hydrogen phosphate. The desired products 4ac were synthesized under the optimized conditions and the results are summarized in Scheme [2] and Table [1].[19]

Zoom Image
Scheme 2Synthesis of functionalized 2-aminopyridines 4ac through three-component reaction in water

Table 1 Optimization of Reaction Conditions for the Synthesis of Functionalized 2-Aminopyridine 4a

Entry

Solvent

Nitrogen source (molar ratio)

Temp. (°C)

Yield (%)

1

H2O

(NH4)2HPO4 (0.5)

50

78

2

H2O

(NH4)2HPO4 (1.0)

50

90

3

H2O

(NH4)2HPO4 (0.5)

RT

70

4

H2O

(NH4)2HPO4 (1.0)

RT

74

5

H2O

(NH4)2HPO4 (1.5)

RT

79

6

H2O

(NH4)2HPO4 (1.5)

50

93

7

H2O

ammonium acetate (1.0)

50

88

8

H2O

ammonium acetate (1.0)

RT

83

9

H2O

ammonia 25% (0.5)

50

70

10

EtOH

ammonium acetate (0.5)

50

75

11

EtOH

ammonia 25% (1.0)

50

72

The structures of compounds 4ac were deduced from their 1H and 13C NMR spectroscopic and ESI-HRMS data. For compound 4a as a representative example, the 1H NMR spectrum consisted of singlets for the –OH and –NH2 protons at δ = 10.25 and 7.81 ppm, respectively. The H-2 and H-4 of the pyridine ring resonated at δ = 8.11 and 8.47 ppm. The proton decoupled 13C NMR spectrum of 4a showed 13 distinct resonances, consistent with the proposed structure. The carbonyl carbon of the unsaturated ketone resonated at δ = 192.2 ppm. The structure of 4a was subsequently confirmed by single-crystal X-ray crystallographic analysis (Figure [2]). Compound 4a can form effective intermolecular hydrogen bonding in the crystal structure between the -NH2 and -CN groups and the pyridine nitrogen (see the Supporting Information)

Zoom Image
Figure 2 ORTEP structure of 4a

After the synthesis of compounds 4ac, the model reaction was carried out using 4a and benzaldehyde in water and in the presence of different bases, when the desired 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one 6a was isolated. In an effort to optimize the reaction, different bases such as trimethylamine, diisopropylethylamine, L-proline, potassium hydroxide, potassium carbonate, DAHP, cesium carbonate and potassium phosphate were studied, with the best yield being obtained with potassium phosphate. After finding the most suitable base, the model reaction was investigated in a range of solvents such as acetonitrile, ethanol, and DMF as well as water. However, in all cases, the yield of the desired product was lower compared with using water as the solvent. The model reaction was then investigated using varying amounts of potassium phosphate as the base and the optimum yield of 86% was obtained with 1.5 equivalents. Subsequently, the influence of the reaction temperature was investigated and it was found that 100 °C resulted in the best yield. Thus, the optimal reaction conditions for the synthesis of 6a involved conducting the reaction in water with 1.5 equivalents of potassium phosphate at 100 °C (Table [2]).

Table 2 Optimization of the Reaction Conditions for the Synthesis of 6a a

Entry

Base

Concentration (molar ratio)

Temp. (°C)

Yield (%)

1

Et3N

1

100

72

2

DIPEA

1

100

75

3

l-Proline

1

100

52

4

NaOH

1

100

47

5

(NH4)2HPO4

1

100

50

6

Cs2CO3

1

100

62

7

K2CO3

1

100

59

8

K3PO4

0.2

100

43

9

K3PO4

0.5

100

56

10

K3PO4

1.5

100

86

11

K3PO4

2

100

86

12

K3PO4

1.2

RT

47

13

K3PO4

1.2

50

65

a Reaction conditions: 2-aminopyridine (1 mmol, 239 mg), benzaldehyde (1.2 mmol, 127 mg), K3PO4 (1.5 mmol, 340 mg) in H2O (6 mL). In all cases, the reaction time was 7 h.

After finding suitable reaction conditions for the synthesis of 6a, the scope of the reaction was explored using different functionalized 2-aminopyridines and aromatic aldehydes. The product 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones 6ao were obtained in moderate to good yields and with no side reactions (Table [3]). A characteristic resonance for all of these compounds in the 1H NMR spectra was a singlet at δ = 5.90–6.10 ppm assigned to the aliphatic methine proton and also a distinctive peak in the 13C NMR spectra for the sp3 carbon at δ = 64.0–65.0 ppm. The 13C NMR spectra of 6ao exhibited characteristic signals in the δ = 161.0–163.0 and 192.0–195.0 ppm region associated with the carbonyl carbons of the amide and ketone moieties. There is a suitable disposition for hydrogen bonding between the carbonyl group and the phenolic hydroxyl, with the latter resonating at δ = 10.20–10.50 ppm in the 1H NMR spectra.[20]

Table 3 Synthesis of 2,3-Dihydropyrido[2,3-d]pyrimidin-4(1H)-one 6ao in Aqueous Mediuma

Product

X

Ar

Yield (%)

6a

H

4-ClC6H4

82

6b

H

4-MeOC6H4

61

6c

H

4-BrC6H4

80

6d

H

4-O2NC6H4

61

6e

H

C6H5

79

6f

H

4-FC6H4

81

6g

H

4-NCC6H4

77

6h

H

2- ClC6H4

83

6i

Cl

4-ClC6H4

71

6j

Br

4-ClC6H4

67

6k

H

2-BrC6H4

73

6l

H

4-MeC6H4

65

6m

Cl

4-MeOC6H4

56

6n

H

3-pyridyl

71

6o

H

2-thienyl

89

a In all cases, the reaction time was 7 h.

Subsequently, we investigated one-pot reaction conditions for the reaction model without separation of 4a and the second reaction was carried out by adding potassium phosphate to the aqueous reaction medium. This led to formation of the desired product 6a with a lower yield of 70% compared with 86%.

In conclusion, we have reported a novel approach to access functionalized 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones 6ao in good yields through sequential reaction of functionalized 2-aminopyridines 4ac, which were synthesized through a three-component reaction in water in which diammonium hydrogen phosphate was used as a source of nitrogen in the reaction mixture. The current strategy offers advantages such as moderate to good yields, purity of products, simple work-up, and use of an environmentally benign solvent.


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Supporting Information

  • References and Notes

  • 1 Cioc RC. Ruijter E. Orru RV. A. Green Chem. 2014; 16: 2958; and references cited therein
    • 4a Green Chemistry: Synthesis of Bioactive Heterocycles. Ameta KL. Dandia A. Springer; India: 2014
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    • 4c Balalaie S. Mirzaie S. Nikbakht A. Hamdan F. Rominger F. Navari R. Bijanzadeh HR. Org. Lett. 2017; 19: 6124
    • 5a Hilton S. Naud S. Caldwell J. Boxall K. Burns S. Anderson VE. Antoni L. Allen CE. Pearl LH. Oliver AW. Aherne GW. Garrett MD. Collins I. Bioorg. Med. Chem. 2010; 459
    • 5b Yonezawa S. Tamura Y. Kooriyama Y. Sakaguchi G. PCT Int. Appl. WO2010047372, 2010
    • 5c Steinig AG. Mulvihill MJ. Wang J. Werner DS. Weng Q. Kan J. Coate H. Chen X. U. S. Pat. Appl. US2009197862, 2009
    • 6a Goldstein DM. Gong L. Michoud C. Palmer WS. Sidduri A. PCT Int. Appl. WO 2008028860, 2008
    • 6b Kling A. Backfisch G. Delzer J. Geneste H. Graef C. Hornberger W. Lange UE. W. Lauterbach A. Seitz W. Subkowski T. Bioorg. Med. Chem. 2003; 11: 1319
    • 6c Bolliger JL. Oberholzer M. Frech CM. Adv. Synth. Catal. 2011; 353: 945
    • 7a Yang BH. Buchwald SL. J. Organomet. Chem. 1999; 576: 125
    • 7b Hartwig JF. In Modern Amination Methods . Ricci A. Wiley-VCH; Weinheim, Germany: 2000
    • 7c Muci AR. Buchwald SL. Top. Curr. Chem. 2002; 219: 131
    • 7d Zim D. Buchwald SL. Org. Lett. 2003; 5: 2413
    • 7e Urgaonkar S. Verkade JG. J. Org. Chem. 2004; 69: 9135
    • 7f Maiti D. Buchwald SL. J. Am. Chem. Soc. 2009; 131: 17423
    • 7g Shen Q. Hartwig JF. Org. Lett. 2008; 10: 4109
  • 8 Poola B. Choung W. Nantz MH. Tetrahedron 2008; 64: 10798
  • 9 Londregan AT. Jennings S. Wei L. Org. Lett. 2010; 12: 5254
    • 10a Dissanayake AA. Staples RJ. Odom AL. Adv. Synth. Catal. 2014; 356: 1811
    • 10b Ghorbani-Vaghei R. Toghraei-Semiromi Z. Karimi-Namib R. C. R. Chim. 2013; 16: 1111
    • 10c Gouda MA. Berghot MA. Abd El Ghani GE. Khalil AM. Synth. Commun. 2014; 44: 297
    • 11a Ibrahim MA. El-Sayed Ali T. El-Gohary NM. El-Kazak AM. Eur. J. Chem. 2013; 4: 311
    • 11b Abdel-Rahman AH. Hammouda MA. A. El-Desoky SI. Heteroat. Chem. 2005; 16: 20
    • 11c Plaskon AS. Grygorenko OO. Ryabukhlin SV. Tetrahedron 2012; 68: 2743
    • 11d Balalaie S. Derakhshan-Panaha F. Zolfigol MA. Rominger F. Synlett 2018; 29: 89
    • 12a Chai H. Li J. Yang L. Lu H. Zhang Q. Shi D. RSC Adv. 2014; 4: 44811
    • 12b Wu J. Du X. Ma J. Zhang Y. Shi Q. Luo L. Song B. Yangab S. Huab D. Green Chem. 2014; 16: 3210
    • 12c Liu X. Fu H. Jiang Y. Zhao Y. Angew. Chem. Int. Ed. 2009; 48: 348
  • 13 Kalaria PN. Satasia SP. Avalani JR. Raval DK. Eur. J. Med. Chem. 2014; 83: 655
    • 14a Oschatz S. Brunzel T. Wu XF. Langer P. Org. Biomol. Chem. 2015; 13: 1150
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    • 18b Balalaie S. Bararjanian M. Hekmat S. Salehi P. Synth. Commun. 2006; 36: 2549
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    • 18d Balalaie S. Abdolmohammadi S. Bijanzadeh HR. Amani AM. Mol. Diversity 2008; 12: 85
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  • 19 General Procedure for the Synthesis of Functionalized 2-Aminopyridines 4a–c:To a solution of 3-formylchromone (1 mmol, 174 mg) and malononitrile (1 mmol, 66 mg) in water (10 mL) was added diammonium hydrogen phosphate (926 mg, 20% equiv) and the reaction mixture was stirred at room temperature for 30 min. After formation of the desired chromonyl malononitrile (monitoring by TLC, eluent: n-hexane/EtOAc, 3:1). The reaction mixture was stirred at 50 °C for 3 h. The precipitate was filtered and was washed with water and ethanol.2-Amino-5-(2-hydroxybenzoyl)nicotinonitrile (4a)Yield: 222 mg (93%); yellow powder; m.p. 198–200 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 6.90–6.97 (m, 2 H, H-Ar), 7.33 (d, J = 7.5 Hz, 1 H, H-Ar), 7.38–7.43 (m, 1 H, H-Ar), 7.81 (br. s, 2 H, N-H), 8.11 (d, J = 2.4 Hz, 1 H, H-Py), 8.47 (d, J = 2.4 Hz, 1 H, H-Py), 10.25 (br. s, 1 H, -OH). 13C NMR (75 MHz, DMSO-d 6): δ = 88.9, 116.1, 116.6, 119.3, 121.8, 124.7, 130.1, 133.0, 143.9, 155.6, 156.0, 161.3, 192.1. HRMS (EI): m/z calcd. for C13H9N3O2 [M]+ 239.0675; found: 239.0675.Colorless crystal (lamina); dimensions 0.150 × 0.120 × 0.010 mm3; crystal system triclinic; space group P1; Z=2; a=3.7932(9) Å, b=8.0333(19) Å, c=19.135(5) Å, α = 79.772(6)°, β = 89.384(6)°, γ = 79.103(6)°; V=563.3(2) Å3; ρ = 1.410 g/cm3; T = 200(2) K; θ max= 27.514°; radiation Mo Kα, λ = 0.71073 Å; 0.5° ω-scans with a CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 2.20 and a completeness of 85.6% to a resolution of 0.77 Å, 4556 reflections measured, 2073 unique (R(int)=0.0453), 1868 observed (I > 2σ(I)). Intensities were corrected for Lorentz and polarization effects, an empirical absorption correction was applied using SADABS based on the Laue symmetry of the reciprocal space, μ=0.10mm–1, T min=0.55, T max=0.96. The structure was refined against F2 with a full-matrix least-squares algorithm using the SHELXL-2014/7 (Sheldrick, 2014) software, 168 parameters were refined, hydrogen atoms were treated using appropriate riding models, except H12 of the hydroxy group, which was refined isotropically. Goodness of fit 1.12 for observed reflections, final residual values R1(F) = 0.049, wR(F2)=0.130 for observed reflections, residual electron density –0.27 to 0.24 eÅ–3.21 CCDC 1496174 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif21
  • 20 General Procedure for the Synthesis of Functionalized 2,3-Dihydropyrido[2,3-d]pyrimidin-4(1H)-one 6a–o:A mixture of functionalized 2-amino-pyridine 4ac (1 mmol), aromatic aldehyde 5al (1.2 mmol), and potassium phosphate (1.5 mmol, 340 mg) in water (10 mL) was heated for 7 h at 100 °C. The precipitate was washed with water and ethanol. 2-(4-Chlorophenyl)-6-(2-hydroxybenzoyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (6a):Yellow solid; m.p. 290–293 °C.IR: 3183, 3075, 1681, 1600 cm–1; 1H NMR (300 MHz, DMSO-d 6): δ = 6.00 (s, CH, 1 H), 6.95 (t, J = 7.2 Hz, 2 H, Ar-H), 7.30–7.45 (m, 6 H, Ar-H), 8.14 (s, 1 H, Py-H), 8.53 (s, 1 H, Py-H), 8.80 (s, 1 H, NH), 8.99 (br. s, 1 H, NH), 10.23 (br. s, 1 H, OH). 13C NMR (75 MHz, DMSO-d6 ): δ = 64.6, 107.6, 116.5, 119.1, 123.6, 125.4, 128.2, 128.6, 129.7, 132.6, 133.2, 137.1, 140.7, 155.4, 155.9, 158.9, 161.7, 193.4. HRMS (ESI): m/z [M–H] calcd. for C20H13 35ClN3O3: 378.066563; found: 378.06552.6-(2-Hydroxybenzoyl)-2-(4-nitrophenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (6d):Yellow solid; m.p. 265–268 °C. IR: 3419, 3183, 1688 cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 6.14 (s, CH, 1 H), 6.94–6.95 (t, J = 7.2 Hz, 1 H, Ar-H), 7.29–7.39 (m, 1 H, Ar-H), 7.69 (d, J = 7.0 Hz, 1 H, Ar-H), 8.08–8.27 (m, 4 H, Ar-H), 8.45–8.46 (d, J = 7.0 Hz, 1 H, Ar-H), 8.54 (s, 1 H, Py-H), 8.96 (s, 1 H, Py-H), 9.13 (s, 1 H, NH), 10.05 (s, 1 H, NH), 10.14 (s, 1 H, OH). 13C NMR (75 MHz, DMSO-d6 ): δ = 64.4, 116.5, 119.3, 123.2, 124.0, 125.4, 127.6, 130.2, 130.5, 136.1, 138.5, 147.5, 148.8, 150.8, 155.7, 161.7, 192.3. HRMS (ESI): m/z [M–H] calcd. for C20H13N4O5: 389.08906; found: 389.08908
    • 21a Program SADABS 2012/1 for absorption correction; Sheldrick, G. M.; Bruker Analytical X-ray-Division, Madison, Wisconsin, 2012.
    • 21b Program SHELXL-2014/7; Sheldrick, G. M, 2014; for structure refinement; Acta. Cryst. 2015, C71, 3-8.

  • References and Notes

  • 1 Cioc RC. Ruijter E. Orru RV. A. Green Chem. 2014; 16: 2958; and references cited therein
    • 4a Green Chemistry: Synthesis of Bioactive Heterocycles. Ameta KL. Dandia A. Springer; India: 2014
    • 4b Balalaie S. Ramezani KejaniR. Ghabraie E. Darvish F. Rominger F. Hamdan F. Bijanzadeh HR. J. Org. Chem. 2017; 82: 12141
    • 4c Balalaie S. Mirzaie S. Nikbakht A. Hamdan F. Rominger F. Navari R. Bijanzadeh HR. Org. Lett. 2017; 19: 6124
    • 5a Hilton S. Naud S. Caldwell J. Boxall K. Burns S. Anderson VE. Antoni L. Allen CE. Pearl LH. Oliver AW. Aherne GW. Garrett MD. Collins I. Bioorg. Med. Chem. 2010; 459
    • 5b Yonezawa S. Tamura Y. Kooriyama Y. Sakaguchi G. PCT Int. Appl. WO2010047372, 2010
    • 5c Steinig AG. Mulvihill MJ. Wang J. Werner DS. Weng Q. Kan J. Coate H. Chen X. U. S. Pat. Appl. US2009197862, 2009
    • 6a Goldstein DM. Gong L. Michoud C. Palmer WS. Sidduri A. PCT Int. Appl. WO 2008028860, 2008
    • 6b Kling A. Backfisch G. Delzer J. Geneste H. Graef C. Hornberger W. Lange UE. W. Lauterbach A. Seitz W. Subkowski T. Bioorg. Med. Chem. 2003; 11: 1319
    • 6c Bolliger JL. Oberholzer M. Frech CM. Adv. Synth. Catal. 2011; 353: 945
    • 7a Yang BH. Buchwald SL. J. Organomet. Chem. 1999; 576: 125
    • 7b Hartwig JF. In Modern Amination Methods . Ricci A. Wiley-VCH; Weinheim, Germany: 2000
    • 7c Muci AR. Buchwald SL. Top. Curr. Chem. 2002; 219: 131
    • 7d Zim D. Buchwald SL. Org. Lett. 2003; 5: 2413
    • 7e Urgaonkar S. Verkade JG. J. Org. Chem. 2004; 69: 9135
    • 7f Maiti D. Buchwald SL. J. Am. Chem. Soc. 2009; 131: 17423
    • 7g Shen Q. Hartwig JF. Org. Lett. 2008; 10: 4109
  • 8 Poola B. Choung W. Nantz MH. Tetrahedron 2008; 64: 10798
  • 9 Londregan AT. Jennings S. Wei L. Org. Lett. 2010; 12: 5254
    • 10a Dissanayake AA. Staples RJ. Odom AL. Adv. Synth. Catal. 2014; 356: 1811
    • 10b Ghorbani-Vaghei R. Toghraei-Semiromi Z. Karimi-Namib R. C. R. Chim. 2013; 16: 1111
    • 10c Gouda MA. Berghot MA. Abd El Ghani GE. Khalil AM. Synth. Commun. 2014; 44: 297
    • 11a Ibrahim MA. El-Sayed Ali T. El-Gohary NM. El-Kazak AM. Eur. J. Chem. 2013; 4: 311
    • 11b Abdel-Rahman AH. Hammouda MA. A. El-Desoky SI. Heteroat. Chem. 2005; 16: 20
    • 11c Plaskon AS. Grygorenko OO. Ryabukhlin SV. Tetrahedron 2012; 68: 2743
    • 11d Balalaie S. Derakhshan-Panaha F. Zolfigol MA. Rominger F. Synlett 2018; 29: 89
    • 12a Chai H. Li J. Yang L. Lu H. Zhang Q. Shi D. RSC Adv. 2014; 4: 44811
    • 12b Wu J. Du X. Ma J. Zhang Y. Shi Q. Luo L. Song B. Yangab S. Huab D. Green Chem. 2014; 16: 3210
    • 12c Liu X. Fu H. Jiang Y. Zhao Y. Angew. Chem. Int. Ed. 2009; 48: 348
  • 13 Kalaria PN. Satasia SP. Avalani JR. Raval DK. Eur. J. Med. Chem. 2014; 83: 655
    • 14a Oschatz S. Brunzel T. Wu XF. Langer P. Org. Biomol. Chem. 2015; 13: 1150
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  • 19 General Procedure for the Synthesis of Functionalized 2-Aminopyridines 4a–c:To a solution of 3-formylchromone (1 mmol, 174 mg) and malononitrile (1 mmol, 66 mg) in water (10 mL) was added diammonium hydrogen phosphate (926 mg, 20% equiv) and the reaction mixture was stirred at room temperature for 30 min. After formation of the desired chromonyl malononitrile (monitoring by TLC, eluent: n-hexane/EtOAc, 3:1). The reaction mixture was stirred at 50 °C for 3 h. The precipitate was filtered and was washed with water and ethanol.2-Amino-5-(2-hydroxybenzoyl)nicotinonitrile (4a)Yield: 222 mg (93%); yellow powder; m.p. 198–200 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 6.90–6.97 (m, 2 H, H-Ar), 7.33 (d, J = 7.5 Hz, 1 H, H-Ar), 7.38–7.43 (m, 1 H, H-Ar), 7.81 (br. s, 2 H, N-H), 8.11 (d, J = 2.4 Hz, 1 H, H-Py), 8.47 (d, J = 2.4 Hz, 1 H, H-Py), 10.25 (br. s, 1 H, -OH). 13C NMR (75 MHz, DMSO-d 6): δ = 88.9, 116.1, 116.6, 119.3, 121.8, 124.7, 130.1, 133.0, 143.9, 155.6, 156.0, 161.3, 192.1. HRMS (EI): m/z calcd. for C13H9N3O2 [M]+ 239.0675; found: 239.0675.Colorless crystal (lamina); dimensions 0.150 × 0.120 × 0.010 mm3; crystal system triclinic; space group P1; Z=2; a=3.7932(9) Å, b=8.0333(19) Å, c=19.135(5) Å, α = 79.772(6)°, β = 89.384(6)°, γ = 79.103(6)°; V=563.3(2) Å3; ρ = 1.410 g/cm3; T = 200(2) K; θ max= 27.514°; radiation Mo Kα, λ = 0.71073 Å; 0.5° ω-scans with a CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 2.20 and a completeness of 85.6% to a resolution of 0.77 Å, 4556 reflections measured, 2073 unique (R(int)=0.0453), 1868 observed (I > 2σ(I)). Intensities were corrected for Lorentz and polarization effects, an empirical absorption correction was applied using SADABS based on the Laue symmetry of the reciprocal space, μ=0.10mm–1, T min=0.55, T max=0.96. The structure was refined against F2 with a full-matrix least-squares algorithm using the SHELXL-2014/7 (Sheldrick, 2014) software, 168 parameters were refined, hydrogen atoms were treated using appropriate riding models, except H12 of the hydroxy group, which was refined isotropically. Goodness of fit 1.12 for observed reflections, final residual values R1(F) = 0.049, wR(F2)=0.130 for observed reflections, residual electron density –0.27 to 0.24 eÅ–3.21 CCDC 1496174 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif21
  • 20 General Procedure for the Synthesis of Functionalized 2,3-Dihydropyrido[2,3-d]pyrimidin-4(1H)-one 6a–o:A mixture of functionalized 2-amino-pyridine 4ac (1 mmol), aromatic aldehyde 5al (1.2 mmol), and potassium phosphate (1.5 mmol, 340 mg) in water (10 mL) was heated for 7 h at 100 °C. The precipitate was washed with water and ethanol. 2-(4-Chlorophenyl)-6-(2-hydroxybenzoyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (6a):Yellow solid; m.p. 290–293 °C.IR: 3183, 3075, 1681, 1600 cm–1; 1H NMR (300 MHz, DMSO-d 6): δ = 6.00 (s, CH, 1 H), 6.95 (t, J = 7.2 Hz, 2 H, Ar-H), 7.30–7.45 (m, 6 H, Ar-H), 8.14 (s, 1 H, Py-H), 8.53 (s, 1 H, Py-H), 8.80 (s, 1 H, NH), 8.99 (br. s, 1 H, NH), 10.23 (br. s, 1 H, OH). 13C NMR (75 MHz, DMSO-d6 ): δ = 64.6, 107.6, 116.5, 119.1, 123.6, 125.4, 128.2, 128.6, 129.7, 132.6, 133.2, 137.1, 140.7, 155.4, 155.9, 158.9, 161.7, 193.4. HRMS (ESI): m/z [M–H] calcd. for C20H13 35ClN3O3: 378.066563; found: 378.06552.6-(2-Hydroxybenzoyl)-2-(4-nitrophenyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (6d):Yellow solid; m.p. 265–268 °C. IR: 3419, 3183, 1688 cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 6.14 (s, CH, 1 H), 6.94–6.95 (t, J = 7.2 Hz, 1 H, Ar-H), 7.29–7.39 (m, 1 H, Ar-H), 7.69 (d, J = 7.0 Hz, 1 H, Ar-H), 8.08–8.27 (m, 4 H, Ar-H), 8.45–8.46 (d, J = 7.0 Hz, 1 H, Ar-H), 8.54 (s, 1 H, Py-H), 8.96 (s, 1 H, Py-H), 9.13 (s, 1 H, NH), 10.05 (s, 1 H, NH), 10.14 (s, 1 H, OH). 13C NMR (75 MHz, DMSO-d6 ): δ = 64.4, 116.5, 119.3, 123.2, 124.0, 125.4, 127.6, 130.2, 130.5, 136.1, 138.5, 147.5, 148.8, 150.8, 155.7, 161.7, 192.3. HRMS (ESI): m/z [M–H] calcd. for C20H13N4O5: 389.08906; found: 389.08908
    • 21a Program SADABS 2012/1 for absorption correction; Sheldrick, G. M.; Bruker Analytical X-ray-Division, Madison, Wisconsin, 2012.
    • 21b Program SHELXL-2014/7; Sheldrick, G. M, 2014; for structure refinement; Acta. Cryst. 2015, C71, 3-8.

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Figure 1 The structure of some bioactive compounds with quinazolinone skeleton
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Scheme 1 Synthesis of 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones 6ao
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Scheme 2Synthesis of functionalized 2-aminopyridines 4ac through three-component reaction in water
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Figure 2 ORTEP structure of 4a