Pd Catalyzed CN Bond Forming Reactions of 6

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Pd Catalyzed C-N Bond Forming Reactions of 6-Bromo-2-cyclopropyl-3(pyridyl-3-ylmethyl)-4-quinazolin-(3H)-one at Room Temperature Narender Pottabathinia,* Ramesh Garlapatia, Venkateshwarlu Gurrama, Suresh Poudapallya, Pavan Kumar Machirajub and Somesh Sharmaa a

Medicinal Chemistry Division, GVK Biosciences Pvt. Ltd, 28A, IDA Nacharam, Hyderabad, AP, India-500076; bInformatics Division, GVK Biosciences Pvt. Ltd, Plot 79, IDA Mallapur, Hyderabad, AP, India-500076 Abstract: Background: Quinazolinones are important subunits of many compounds that are of biological and pharmaceutical interest including anticancer, antimicrobial, anti-inflammatory, anti-tubercular, antiHIV, and as an analgesic. Quinazolin[3H]-4-one systems were found to have distinctive biological Narender Pottabathini functions. On the other hand, 2,3-disubstituted quinazolin[3H]-4-one derivatives substitution with various heterocyclic moieties displayed conspicuous anti-tubercular activity. Considering the much broder range of pharmacological properties, several useful approaches to the construction of modified quinazolinones have been developed with the help of Pd/L systems. Methods: Various amines, Pd(OAc)2, Pd2(dba)3, Pd(dba)2, ligands, PtBu3, DavePhos, XantPhos, triphenylphosphine and dppf, were utilised to assess the C-N reaction results. For analysis HNMR, LCMS and HRMS were used. Results: After screening different conditions, Pd(dba)2, PtBu3, NaOtBu in THF was proved to be the best catalyst/ligand system for Pd-catalyzed amination at room temperature. We evaluated the generality of the methodology with variety of amines (aryl, heteroaryl and alkyl amines) participated in the Pd-catalyzed amination reactions. We reported the synthesis of twenty four analogues utilizing these conditions. We have also investigated what cycle differences might exist in the usage of two different Pd sources, Pd(dba)2 and Pd2(dba)3. It is known that dba (dibenzylideneacetone) can competitively inhibit the catalytic cycles, also were interested to find out if in these cases it is inhibiting the catalytic cycle and assess that dba is responsible for the difference in yields. In silico analysis is utilized to evaluate the diversity of the set of compounds against shape space (PMI), polar surface area (PSA) calculations and relevant drug like properties (viz. HBA, HBD, PSA, mol. wt., log P and Log D). Conclusion: In summary, we have developed a room temperature C-N bond formation reaction with simple catalyst system. We have thoroughly investigated the effect of dba in the amination reactions.

Keywords: Cheminformatics, effect of dba, evaluation with various amines, modified quinazolinones, room temperature amination, screening studies. 1. INTRODUCTION Quinazolinones are important subunits of many compounds that are of biological and pharmaceutical interest including anticancer, antimicrobial [1], anti-inflammatory [2], anti-tubercular [3], anti-HIV [4], and as an analgesic [5] (Fig. 1). Quinazolin[3H]-4-one systems were found to have distinctive biological functions [6-8]. On the other hand, 2,3disubstituted quinazolin[3H]-4-one derivatives substitution with various heterocyclic moieties displayed conspicuous anti-tubercular activity [9]. Considering the much broader range of pharmacological properties, several useful approaches to the construction of modified quinazolinones have been developed and published in the literature [10, 11]. *Address correspondence to this author at the Medicinal, and Informatics Divisions, GVK Biosciences Pvt. Ltd. 28A, IDA Nacharam, Hyderabad 500076, Andhra Pradesh, India; Tel: +91 40 66281275; Fax: (+) 91 40 66281505; E-mail: [email protected] 2213-3372/16 $58.00+.00

The recent development in cross-coupling reactions using transition-metal-catalysis affords effective methods for the formation of aryl carbon-heteroatom bonds [12-14]. The invention of various ligands and different Palladium sources lead to the success in this type of catalysis to form the bonds between carbon and heteroatoms, such as nitrogen, oxygen, sulphur, silicon and boron [15-17]. In continuation Hartwig and Buchwald introduced many new ligands for effective metal mediated transformations [18, 19]. There has been less amount of work carried out for synthesizing modified quinazolines and quinazolinones with Palladium mediated C-N and C-C bond formations [20, 21]. Palladium mediated amination reactions have become an important type of transformations to construct a wide variety of C-N bonds [22]. Lakshman et al. and other groups carried out C-N bond forming reactions of nucleosides [23, 24]. In our recent studies, we have extensively screened the Pd catalyst and ligand systems to understand the best conditions for C-N and C-C © 2016 Bentham Science Publishers

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Current Organocatalysis, 2016, Vol. 3, No. 2

Pottabathini et al.

O

O NH

N

H N

N

CN

N

2-Cyanoquinazolinone

O

O HO O

Febrifugine

O

OH

NH O

N

S

N

N

O

N

OH

Methaquilone

Raltitrexed

Fig. (1). Biologically active quinazolinones. Ph

PPh2 N

tBu

Cy P

Cy

tBu

P

O

L1

L2

3

XantPhos L3

P

Ph

P

PPh2 DavePhos

Ph

Fe

tBu

PtBu

P

Ph dppf

Triphenylphosphinetriphenylphosphine

L4

L5

Fig. (2). Five ligands selected for the analysis.

bond-formation reactions of 2,3-disubstituted quinazolinones and nucleosides [25, 26]. In our present work, we tried to evaluate the room temperature amination of 6-bromo-2-cyclopropyl-3-(pyridyl-3ylmethyl) quinazolin-4(3H)-one. In addition to it we compared the effect of dba in Pd2(dba)3 with Pd(dba)2 in amination [27, 28]. The resultant products were also subjected to in silico analysis to evaluate the diversity of the set of compounds against shape space (PMI), polar surface area (PSA) calculations and relevant drug like properties (viz. HBA, HBD, PSA, mol. wt., log P and log D). 2. MATERIALS AND METHODS Thin-layer chromatography was performed on 250 μ silica plates and column chromatographic purifications were performed on 100-200 mesh silica gel. All amines, Pd(OAc)2, Pd2(dba)3, Pd(dba)2, ligands, PtBu3, DavePhos, XantPhos, triphenylphosphine and dppf, all other reagents were obtained from commercial suppliers and were used without further purification. THF was distilled over Na and benzophenone and then stored over Na. Prior to each reaction THF was freshly distilled. For synthesis of compound 1 as well as their precursors, please see the Supporting Information. 1H NMR spectra were collected either at 400 MHz or at 300 MHz and spectra are referenced to residual protio solvent. 13C NMR spectra collected either at 100 MHz or at 75 MHz, are referenced to the carbon resonance of the deuterated solvent. Spectra were obtained either in deacidified CDCl3 (deacidification was performed by percolating the solvent through a bed of solid NaHCO3 and basic alumina) or in DMSO-d6 (see specific compound descriptions below). High resolution mass spectrometry was performed at the Mass Spectrometry Laboratory at GVK

Biosciences Pvt Ltd. LC-MS analyses were performed with electrospray ionization (ESI), and operated in the positive ion mode. LC analysis was performed using a diode array detector. 3. EXPERIMENTAL PROCEDURE 3.1. Procedure for the Amination 2a-2x In a dry, screw-cap vial, equipped with a stirring bar, were placed bromo quinazolinone, compound 1 (50 mg, 0.07 mmol), the amine (300 mol%), and NaOt Bu (150 mol%) in anhydrous THF (2 mL). The vial was flushed with argon gas for a few minutes and Pd(dba)2 (10 mol%) and tri tert-butyl phosphine (15 mol%) were added. The vial was sealed with a Teflon-lined cap, and the mixture was stirred at rt for 36 h. After 36 h, the solvent was evaporated under reduced pressure, and dried under high vacuum. Flash column chromatography on silica gel afforded the various products (for specific details, see the individual compound headings). 4. RESULT AND DISCUSSION To begin with, we synthesized scaffold 1 with the known procedures [29]. (Synthetic procedure for the preparation of 1 shown in supporting information) Herein we wanted to understand the influence of Pd-catalyst/ligand at the C-6 position of 6-bromo-2,3-disubstitutedquinzolinone for C-N bond formation at room temperature in greater detail and to evaluate much wider scope which was not reported earlier. Pd(OAc)2, Pd(dba)2 and Pd2(dba)3 were selected as Pd sources, in combination with five ligands (L1-L5; Fig. 2). The optimization experiments were performed with p-toluidine. The initial screening results are shown in Table 1.

Pd Catalyzed C-N Bond Forming Reactions

Table 1.


3

Optimization of C-N bond forming reactions, b. O Br

N N 1

N

p-Toluidine Catalyst, Ligand, NaOtBu

O

H N

N

N

N

THF, rt, time 2a

Entry

Catalyst System, Conditions, t=36h, rt

Yield (%)c

1

10 mol% Pd2(dba)3/ 15 mol% DavePhos (L1)

71

2

10 mol% Pd2(dba)3/ 15 mol% PtBu3 (L2)

84

3

t

10 mol% Pd(dba)2/ 15 mol% P Bu3 (L2) t

95

4

10 mol% Pd(OAc)2 / 15 mol% P Bu3 (L2)

14

5

10 mol% Pd(OAc)2 / 15 mol% XantPhos (L3)

4

6

10 mol% Pd2(dba)3/ 15 mol% dppf (L4)

12

7

10 mol% Pd(OAc)2 / 15 mol% PPh3 (L5)

15

[a] Reaction conditions (entries 1-7) 6-bromo-3-(pyridyl-3-ylmethyl) quinazolin-4(3H)-one (1) precursor 0.0711mM in anhydrous THF, 3.0 molar equiv p-toluidine, 1.5 molar equiv of NaOtBu. [b] Reactions were conducted in closed vial sparged with argon [c] % yields refer to isolated and purified products.

The initial attempts with Pd2(dba)3 with L1 resulted in 71% yield (entry 1). The combination of Pd(OAc)2, with L2 (entry 4), L3 (entries 5), L5 (entry 7) ligands resulted in low yields. The combination of Pd2(dba)3 with L4 (entry 6) also resulted in low yield. Among these initial screening reactions, 10 mol% Pd(dba)2/15 mol% L2/1.5molar eq of NaOtBu in THF at room temperature was proven to be the best (95%, entry 3) and 10 mol% Pd2(dba)3/15 mol% L2/ NaOtBu in THF was resulted as the next best catalyst/ligand system (84%, entry 2) for Pd-catalyzed aminaton. The combination of Pd(dba)2 with L2 with different bases and solvents were also screened and the results are tabulated in Table 2. We initially examined the influence of the nature of base on the conversion for the reactions using THF as solvent and 10 mol % Pd(dba)2/15 mol% L2 as the catalyst/ligand system. NaOtBu was superior to K3PO4, and Cs2CO3. Among the solvents THF was much superior to 1,2-DME, 1,4-dioxane, DMF and THP; where reaction mixture was insoluble in toluene and the reaction in tert-BuOH was ineffective. The total reaction time for all reactions were 36 h. After ascertaining the optimal conditions, in the next stage we evaluated the generality of the methodology with variety of amines shown in Table 3. A wide assortment of aryl, heteroaryl and alkyl amines participated in the Pd-catalyzed amination reactions. We reported the synthesis of twenty four analogues utilizing these conditions. The electron rich amines like p-toluidine (entry 1), pmethoxy aniline (entry 6), and 2,6-dimethoxy aniline (entry 8) resulted in excellent yields. The amino naphthalene resulted in 83% yield (entry 16). We were pleased to observe that reactions of amines with electron-deficient groups like 4-cyanoaniline (entry 4), fluorinated substituents like 2fluoroaniline, 4-fluoroaniline, 2-trifluoromethyl and 2-fluoro benzyl amines (entries 9, 10, 14 and 15) also resulted in good yields. However, the reactions were also efficient with aliphatic amines (entries 20-24). Nevertheless, reactions with

hetero aryl amines resulted in moderate yields from 21% to 25% (entries 17-19). There was a substantial difference between the yields (9%) in optimization reactions performed using Pd2(dba)3 (entry 2) and Pd(dba)2 (entry 3) conditions for C-N bond formation in Table 1. We were interested in finding out what cycle differences might exist in the usage of two different Pd sources, Pd(dba)2 and Pd2(dba)3. It is known that dba (dibenzylideneacetone) can competitively inhibit the catalytic cycles, also we wanted to find out if in these cases it is inhibiting the catalytic cycle and assess that dba is responsible for the difference in yields [30, 31]. For this, we conducted three different experiments with p-toluidine (electron neutral), pmethoxyaniline (electron rich) and p-fluoroaniline (electron withdrawing) with Pd(dba)2 under the best optimal conditions. These results are shown in blue color in Fig. (3). Reactions using Pd2(dba)3 with the three amines observed lowering of conversion. In 4-fluoroaniline case, it was still lower compared with the remaining two amines. These results are shown in yellow color. Similarly, we have conducted the reactions under optimized conditions with Pd(dba)2 and additionally added equivalents of dba based upon the stoichiometry of Pd2(dba)3. Here in this case also observed the conversions were suppressed more or less to the level of Pd2(dba)3. These results are shown in red color. Although, Pd2(dba)3 slightly better in two of the cases. In the pfluoroaniline case it is almost equal. Fig. (3) shows the % of conversion from the reaction mixtures with 3 different amines utilizing three different catalyst systems. The UPLC analysis of these experiments can be found in the Supporting Information. 5. CHEMINFORMATICS Using in silico methods the skeletal diversity of modified quinazolin-4(3H)-one analogue are assessed using chemical descriptors. The different analogues have different points on

4


Table 2.

Pottabathini et al.

Base and solvent screening. p-Toluidine Pd(dba)2, PtBu3 (L2) Base

O Br

N

N

O

H N

Solvent, T°C, time

N

N

N N 2a

1 Entry

Variable Conditions

Time in h

% 2a Formed

1

K3PO 4

36

26a

2

NaOtBu

36

95a

3

Cs2CO3

36

57a

4

1,4-Dioxane

36

58b

5

1,2-DME

36

65b

6

Toluene

-

Insolubleb

7

tert-BuOH

36

NRb

8

THF

36

95b

9

THP

36

85b

10

DMF

36

53b

[a] Reaction conditions (entries 1-3) Bromoquinazoline (1) 0.0711mM in anhydrous solvent, 3.0 molar equiv p-toluidine, 10 mol% of Pd(dba)2, 15mol% PtBu3, 1.5 molar equiv of base, THF and % yields refer to isolated and purified products. [b] Reaction conditions (entries 4-10) Bromoquinazoline (1) 0.0711mM in anhydrous solvent, 3.0 molar equiv ptoluidine, 10 mol% of Pd(dba)2, 15 mol% PtBu3, 1.5 molar equiv of NaOtBu, solvents and % yields refer to isolated and purified products.

Table 3.

Evaluation of the scope of amination reaction of 6-bromo-3-(pyridyl-3-ylmethyl) quinazolin-4(3H)-one (3) using various amines.a

R1

O

H N

R2 R2

PtBu

Br

Pd(dba)2, 3 (L2) NaOtBu, THF

N

N

R1

N

rt, 36 h

N

O N N

N

2a - 2x

1 Entry

Amine

Product

Yield [%]

2a

97

2b

96

2c

93

2d

71

NH2

1 NH2

2 NH2

3 NH2

4 NC



5

Table 3. Contd…… Entry

Amine

Product

Yield [%]

2e

70

2f

84

2g

82

2h

90

2i

85

2j

82

2k

83

2l

65

2m

48

2n

79

2o

88

2p

83

2q

25

O NH2

5

NH2

6 O O NH2

7

O

NH2

8 O NH2

9 F

NH2

10 F Cl NH2

11 N

N

NH2

12

Cl

13

N NH2 CF3

14

NH2 F

15

NH2

NH2

16

H2N

17 N

6


Pottabathini et al.

Table 3. Contd…… Entry

Amine

Product

Yield [%]

2r

21

2s

23

2t

77

2u

89

2v

57

2w

68

2x

88

H2N

18

N

O N

19 H2N O

20

NH

21

NH

NH2

22

23

24

N

NH2

NH2

a. Reaction conditions (entries 1-24) Bromoquinazoline (1) 0.0711mM in anhydrous solvent, 3.0 molar equiv amines, 1.5 molar equiv of NaOtBu at room temperature and % yields refer to isolated and purified products.

Fig. (3). Comparison of the formation of 2a with p-toluidine, 2f with 4-methoxyaniline and 2j with 4-fluoroaniline, using 10 mol% Pd(dba)2, 10 mol% Pd2(dba)3, and 10 mol% Pd(dba)2 with 10 mol% dba. The reactions were performed with 15 mol% PtBu3, 1.5 eq NaOtBu, THF at room temperature. The formation of 2a, 2f and 2j were determined by UPLC.

the chemical space indicating that each analogue has unique set of drug likeness properties. Chemical space plots of these compounds that corresponded to a set of six key descriptors (i.e. polar surface area (PSA), hydrogen bond acceptor (HBA), solubility, hydrogen bond donor (HBD), log D and

Alog P) relative to FDA approved 1011 drugs (dark green dots), as reported in the GOSTAR database (Figs. 5-8) [32]. C-6 modified quinazolin-4(3H)-one derivatives were compaired with FDA approved drugs by considering the molecular shape of the compounds in two-dimensional trian-



7

Fig. (4). PMI plot of our group of molecules relative to1011 FDA-approved drugs. The PMI calculations involved aligning each molecule to principal moment axes by using SYBYL and the normalized PMI values were calculated by using in-house software.

gular graphs (Fig. 4) using normalized principal moment of inertia (NPR) analysis derived by Schwartz and Sauer [33]. The three-dimensional molecular shape can fit to the suitable cavities in the active site of protein and in turn modulate the biological activity. Principal moments of inertia (PMI) is a topological descriptor and normalized ratios of the principal moments of inertia (NPR) is used to elucidate the molecular shape of the compounds. The PMI of the compound in the three directions are calculated and normalized PMI values calculated using inhouse software. The vertices of the isosceles triangle of the NPR plot relate to the shapes of sphere, rod and disk respectively, these shapes signifies the overall shape of compounds. Commercial compounds tend to occupy the lefthand edge of the PMI plot; that is, they adopt shapes that fall in between rods and discs. Our collections of molecules have the shapes which fall into the area of rods. From the NPR analysis, the each dot in the graph represents the diversity in molecular shape associated with quinazolin-4(3H)-one derivative which in turn increses the likelihood of a wide range of biological activity. Apart from the analysis of drug likeness properties, Shape and space properties the polar surface area (PSA) is also determined. PSA is useful for prediction of various other molecular characteristics. PSA is combination of molecular surface area along with atomic charges i.e. oxygen and nitrogen. PSA determines the hydrogen binding strength of a polar fragment, the polarity changes with orientation, the PSA of small molecules varies with orientation of polar groups. The orientation of polar groups plays a vital role in hydrogen bond interactions of small molecules with protein, which in turn responsible for biological activity. Small molecules with PSA greater than 140 Å2 has less cell permeability [34, 35]. PSA in combination with rotatable bonds has shown good correlation with the oral bioavailability [36]. PSA has shown very good correlations with intestinal absorption, blood - brain barrier (BBB) penetration and several other drug characteristics. Hence, the selected polar surface areas of 2f, 2i, 2l and 2m were plotted in Fig. (9).

Fig. (5). Molecular Weight Vs AlogP Vs HBA.

Fig. (6). Molecular Weight Vs AlogP Vs HBD.

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Fig. (7). Molecular Weight Vs AlogP Vs LogD.

Pottabathini et al.

Fig. (9). Surface electrostatic potential of a representative set of our compounds, that is, compounds 2f, 2i, 2l and 2m. The surface electrostatic profiles were calculated by projecting the GasteigerMarsili charge distribution on to a Connolly surface that was generated by using the MOLCAD tool in SYBYL.

diversity of the set of compounds against shape space (PMI), polar surface area (PSA) calculations and relevant drug like properties (viz. HBA, HBD, PSA, mol. wt., log P and Log D). CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS The authors are grateful to GVK Biosciences Pvt. Ltd., for the financial support and encouragement. We thank Prof. Mahesh K. Lakshman, Chemistry Division, The City College and City University of New York, USA. For his invaluable guidance and support. Fig. (8). Molecular Weight Vs AlogP Vs PSA. In silico analysis of 24 molecules (dark-blue spots) in a chemical-space plot that corresponds to a set of six drug-likeness properties (PSA, solubility, HBA, HBD, log A and log D), relative to 1011 FDA-approved drugs (light-red dots), as reported in the GOSTAR database (GVK Bioscience proprietary database).

Surface electrostatic potentials of the compounds were calculated by applying the Gasteiger-Marsili charge distribution onto a Connolly surface generated via the MOLCAD tool. The PSA of the synthesized compounds are in the acceptable range i.e. 140 Å2 and more than 70 Å2 indicating that the compounds have varied electron densities and shapes. From these studies it is clear that our compounds to be potential biologically active analogues over a wide range of therapeutic targets.

SUPPLEMENTARY MATERIAL Supplementary material is available on the publisher’s web site along with the published article. LIST OF ABBREVIATIONS 1,2-DME

=

Dimethoxyethane

1

=

Proton Nuclear Magnetic Resonance

Cs2CO3

=

Caesium carbonate

dba

=

dibenzylideneacetone

DMF

=

Dimethylformamide

dppf

=

1,1'-Bis(diphenylphosphino)ferrocene

FDA

=

Food and Drug Administration

H NMR

CONCLUSION

GOSTAR =

GVKBIO Structural activity Relationship

In summary, we have developed a room temperature C-N bond formation reaction with simple catalyst system. We have thoroughly investigated the effect of dba in the amination reactions. In silico analysis is utilized to evaluate the

HBA

=

Hydrogen bonding acceptor

HBD

=

Hydrogen bonding donor

HIV

=

Human Immunodeficiency Virus


K3PO4

=

Tripotassium phosphate

MHz

=

Mega Hertz

mol. Wt

=

Molecular weight

t

NaO Bu

=

Sodium tertiary butoxide

NPR

=

Normalized ratios of the principal moments of inertia

Pd(dba)2

=

Bis(dibenzylideneacetone)palladium(0)

Pd(OAc)2

=

Palladium (II) acetate

Pd

=

Palladium

Pd2(dba)3

=

Tris(dibenzylideneacetone)dipalladium(0)

PMI

=

Principal moments of inertia

PPh3

=

Triphenylphosphine

PSA

=

Polar surface area

t

P Bu3

=

Tri tertiary butyl phosphine

rt

=

room temperature

tert-BuOH =

tert-Butyl alcohol

THF

=

Tetrahydrofuran

THP

=

Tetrahydropyran

UPLC

=

Ultra Performance Liquid Chromatography


[11]

[12]

[13] [14] [15] [16] [17]

[18]

[19] [20]

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[4]

[5]

[6]

[7]

[8] [9]

[10]

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Revised: September 09, 2015

Accepted: September 14, 2015