aqua mediated indium(iii) chloride catalyzed synthesis...
TRANSCRIPT
Chapter IV
128
CHAPTER IV AQUA MEDIATED INDIUM(III) CHLORIDE CATALYZED
SYNTHESIS OF FUSED PYRIMIDINES AND PYRAZOLES
IV.1: INTRODUCTION IV.1.1: Indium Trichloride: A versatile catalyst Indium metal has drawn considerable attention due to its diverse physical properties. Unlike most other metals, indium is non-toxic, stable to air and moisture which helps in the recovery and recycling of the catalyst.1 The lower first ionisation potential of this metal makes it ideal to participate in Single electron transfer (SET) reactions.2 It is an ideal catalyst or reagent for the C-C bond formation. Recently, indium trichloride has evolved as a mild and water tolerant Lewis acid imparting high regio-, chemo- and diastereoselectivity in various organic transformations. Indium trichloride has advantages of low catalyst loading, moisture stability and catalyst recycling. It has been used in many organic transformations in recent years. A brief review of indium trichloride mediated reactions is given below. Strecker Reaction: Synthesis of α-aminonitrile Indium(III) chloride catalyzed Strecker reaction of aldehyde, amine and trimethylsilylcyanide in water has been reported (eq. 1).3 Simple aromatic and heteroaromatic aldehydes react well under this reaction condition.
RCHO R1NH2 TMSCN InCl3 (20 mol %)H2O, r.t.
CNR NH
R1 ...(1)+ +
Mannich Reaction: Synthesis of β-aminocarbonyl compounds One pot three component reaction of aldehydes, amines and silyl enolates has been reported in water for the synthesis of β-amino carbonyls using InCl3 (eq. 2).4 The reactions with aliphatic ketones, and 1,2-dicarbonyl compounds also gave the β-amino carbonyl compounds, but the yields were poor.
Chapter IV
129
PhCHOInCl3 (20 mol %)
H2O, r.t.NH
PhO
Ph
PhPhNH2
OTMS
Ph...(2)+ +
Pechmann condensation Indium(III) chloride has been used as an efficient catalyst in the Pechmann condensation of phenols with β-ketoesters and leads to the formation of coumarin derivatives in excellent yields (eq. 3).5
R OH R1
OOEt
O InCl3 (10 mol%)O OR
R1
...(3)+
Synthesis of 2-aminochromenes and indolylchromenes A simple and convenient method for the synthesis of new 2-aminochromenes and indolyl chromenes via an indium trichloride catalyzed, three component reaction in aqueous media has been described by Perumal et al. (eqs. 4, 5).6 They have also reported one pot synthesis of new (2-amino-3-cyano-4H-chromen-4-yl) phosphonic acid diethyl esters (eq. 6)7 and 3-pyranyl indoles catalyzed by InCl3 in ethanol (eq. 7).8
CHO
OHCNCN
NH
COOEt
CH3H3C
EtOOC
H2O:EtOH, 1:1 O NH2
CNX XInCl3 (20 mol %)
...(4)+
CHO
OH
CNCN
X
N
R3
R1
R2N
R3
R1
R2
O
CN
NH2
H2O ...(5)
X
+ +InCl3 (20 mol %)
CHO
OH
CNCN
O NH2
CNPO
OO
XX
InCl3EtOHP
OEtEtO OEt
...(6)+ +
Chapter IV
130
CNCN Ethanol, Reflux
ArCHO InCl3NH NH
OCN O
NCAr CN
NH2
...(7)+ +
Three component coupling of kojic acid, aldehydes and 1,3-diones has been achieved in the presence of InCl3 under solvent-free conditions to afford the corresponding dihydropyrano[3,2-b]chromenedione derivatives in good yields (eq. 8).9
O
OArCHO
O
O
HOOH
InCl3 (10 mol%)120oC
O
O
HOO
Ar O...(8)
+ +
An efficient synthesis of 4H-benzo[f]chromenes by one pot four component coupling of aromatic aldehydes, β-naphthol, β-oxodithioesters and primary alcohols has been reported in the presence of InCl3 (eq. 9).10 This transformation presumably proceeds via domino Knoevenagel condensation/ Michael addition/ intramolecular cyclodehydration/ transesterification sequence creating four new bonds and one stereocenter in a single operation.
ArCHOOH
MeSS
Ar1O
ROHO
SOR
Ar1
Ar
80oC
InCl3(10 mol%) ...(9)+ + +
Synthesis of 3-aminobenzofurans Chen and co-workers11 have reported synthesis of 2-aryl-3-aminobenzofuran derivatives via indium trichloride catalyzed reaction of arylglyoxal monohydrates, phenols and p-toluenesulfonamide (eq. 10).
O
OHOH
R1 R3
R2
OHTsNH2
InCl3 (10 mol %)
CH2Cl2O
R2
R3
NHTs
R1
...(10)+ +
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131
Synthesis of xanthene derivatives 9-(N-arylamine)xanthene derivatives have been synthesized by the reaction of cyclohexanone, morpholine and salicylaldehydeimines in the presence of InCl3 by Perumal and co-workers (eq. 11).12
O
NH
O
OH
C N R1
R2
InCl3 (20 mol%)r.t., 20-40 min O N
HN
R2
R1
O
...(11)+ +
Indium(III) chloride catalyzed one pot synthesis of tetrahydrobenzo[a]xanthene-11-one derivatives (eq. 12)13 and 9-aryl/alkyl-3,3,6,6-tetramethyl-1,2,3,4,5,6,7,8-octahydro xanthene-1,8-diones (eq. 13)14 has been reported under solvent-free condition.
OHO
RCHOO
+O
+
ORInCl3 ...(12)
Solvent-free, 120oC O
ORCHO
InCl3Solvent-free, 100oC
O
O
OR2 ....(13)+
Synthesis of pyrroles and imidazoles A convenient and general approach towards the synthesis of substituted pyrroles from propargylic acetates, silyl enol ethers and primary amines, catalyzed by indium trichloride was described by Lin et al. (eq. 14).15
OAcR1
R4
OTMSR3
R2
R5NH2InCl3 (10 mol%)
PhCl, Reflux N
R1
R3
R5
R4
R2 ...(14)+ +
Sharma and co-workers have reported the synthesis of 2,4,5-trisubstituted imidazoles and 1,2,4,5-tetrasubstituted imidazoles at room temperature utilising InCl3 as catalyst (eqs. 15,16)16 in high yields.
Chapter IV
132
Ar
OAr
ORCHO NH4OAc InCl3 (10 mol%)
MeOH, r.t. NH
NAr
ArR ...(15)+ +
Ar
OAr
ORCHO NH4OAc InCl3 (10 mol%)
MeOH, r.t. NNAr
ArRR1NH2
R1
...(16)+ + +
Synthesis of quinolines Highly functionalized 4-methyl-1H-quinolin-2-ones were synthesised from coumarin, hydrazine and isatin catalyzed by InCl3 under microwave irradiation by Siddiqui et al. (eq. 17).17
NH
O
OR4
O O
R3
R2
R1NH2NH2 MW N O
R3
R2
R1
HN
NHO
R4
...(17)InCl3++
Synthesis of spirooxindoles Perumal et al. have reported a simple method for the one pot three component syntheses of spirooxindoles under conventional and solvent-free microwave irradiation (eq. 18).18
NH
O
O CNX
X = CN, COOEt
HOInCl3/ SiO2/ MW
orInCl3, CH3CN, Reflux
NHO
OX
H2N
...(18)+ +
Synthesis of chromeno[2,3-d]pyrimidinones and diazabenzo[b]fluorenones
Synthesis of chromeno[2,3-d]pyrimidinones and diazabenzo[b]fluorenones has been reported by cyclocondensation of aldehydes, cyclic-1,3-diketones and 1,3-dimethylbarbituric acid in presence of InCl3 under solvent-free conditions (eq. 19).19
Chapter IV
133
RCHO
O O
NN
O
OO
O
OInCl3Solvent-free
NN O
O
O
OR
NN O
O
O
R O100oC
...(19)+
IV.1.2: Pyrido[2,3-d]pyrimidines Organic compounds containing pyrimidine scaffold as a core unit are known to exhibit various biological and pharmaceutical activities,20 such as antiviral,21 antibacterial,22-23 antitumor,24 anti-inflammatory,25 antifungal,26-27 and antileishmanial activity.28 Pyrido [2,3-d]pyrimidines are a class of naturally occurring fused uracils. They have received enormous attention over the past years due to their wide range of pharmacological activities, such as antibacterial,29 antitumor,30-31 antihypertensive,32 cardiotonic,33 bronchiodilator,34 vasodilator,35 antiallergic,36 antimalarial,37 analgesic,38-39 antifungal,40 and CNS depressant41 properties.
Moreover, appropriately functionalized pyrido[2,3-d]pyrimidines (Figure IV.1) exhibit variety of promising pharmacological activities, such as potent inhibitor of dihydrofolate reductase (I),42 in treatment of diarrhea (II),43 specific inhibitor of cyclin dependent kinase 4 (III),44 and induces apoptosis of K562 cells.45
N
HN N
N
N ON
N NH
O
O
O
Br
N
N N
CH3NH2
H2N
NH
OMeOMe
OMe
I II III
Figure IV.1: Some biologically active pyrido[2,3-d]pyrimidine frameworks.
Chapter IV
134
Compounds having pyrido[2,3-d]pyrimidine as a central core unit have also been identified as a new class of fibroblast growth factor receptor (FGFR3) tyrosine kinase inhibitors.46-47 Consequently, there has been a lot of interest in the synthesis of these heterocyclic moieties. Chauhan et al.48 have synthesized a series of dihydropyrido[2,3-d]pyrimidines and screened their in vitro antileishmanial activity profile in promastigote and amastigote models (eq. 20).
NN
O
O NH2
RCHOO O AcOH, Heat N
N NHO
OCOCH3
R
...(20)+ +
A series of pyrido[2,3-d]pyrimidine derivatives were synthesized by KF-Al2O3
catalyzed reaction of arylaldehyde, malononitrile and 4-amino-2,6-dihydroxy pyrimidine in ethanol at 80oC (eq. 21).49 Pyrido[2,3-d]pyrimidines have also been synthesized via L-proline catalyzed one pot three component domino coupling of 6-amino-1,3-dimethyl uracil, aldehydes and dialkyl acetylenedicarboxylates (eq. 22).50
NN
NN N
OH
HO
ArCN
NH2
OH
HO NH2
ArCHO CNCN
KF/ Al2O3 ...(21)+ +
NN
O
O
COOR
COORNH2R1CHO L-Proline (10 mol%)
EtOH, RefluxN
N NH
O
O
COOR
COOR
R1
...(22)+ +
Herrera et al. have synthesized substituted tetrahydropyrido[4,3-d]pyrimidines via one pot reaction of 1-benzylpiperidin-4-one with different nitriles in the presence of triflic anhydride (eq. 23).51
N
O
CH2Ph
2 RCN Tf2ON N
N R
RTf
...(23)+
Chapter IV
135
Bazgir and co-workers have reported a p-TSA catalyzed cyclo-condensation reaction of barbituric acids, aromatic aldehydes and 6-aminouracils for the synthesis of pyrido[2,3-d:6,5-d]dipyrimidines in refluxing water (eq. 24).52
NN
O
X
R
RNH2
N NY
O O
R1 R1 p-TSAH2O, Reflux
NN NH N
N
OO
X YR1R
RAr
R1
X = O, S; R = H, Me; R1 = H, Me; Y = O, S
....(24)ArCHO+ +
Synthesis of pyrazolo[4’,3’:5,6]pyrido[2,3-d]pyrimidines has been reported by reactions of aldehydes, 3-methyl-1-phenyl-1H-pyrazol-5-amine and 1-methyl barbituric acid in water under microwave irradiation (eq. 25).53
ArCHO N NO
O O
H CH3
NH NH
NO
O
ArCH3H2ON
NNH2
PhNN
PhMW
...(25)+ +
Hassan et al. have reported synthesis of polycyclic pyrimido[4,5-b]quinolines and pyrido[2,3-d]pyrimidines by reaction of 6-amino-1,3-dimethyluracil with equimolar amounts of cyclic ketones or cyclic 1,3-diketones and aromatic aldehydes (eq. 26).54
NN
O
O NH2ArCHO N
NH
O
O NH
ArN
N
O
O N
ArODMFReflux
or ...(26)++
A variety of pyrimido[4,5-b]quinoline and indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives were also synthesized via three component reaction of an aldehyde, aminopyrimidine-2,4-dione and 5,5-dimethyl-1,3-cyclohexanedione or 1,3-indanedione in ionic liquid 1-(n-butyl)-3-methylimidazolium bromide ([bmim]Br) by Shi et al.55 and in water promoted by p-TSA by Singh et al.56 A series of pyridopyrimidine derivatives were also synthesized in presence of acetic acid and evaluated for their biological properties (eqs. 27-29).57
Chapter IV
136
R1HNArCHO N
N
O
O NH2R
RHN
NNR
R
O
OAr
O
OR1HN
O
...(29)+ +110oCAcOH
ArCHO NN
O
O NH2R
R HNN
NR
R
O
OAr
O
OO O
O ...(28)++ 110oC
AcOH
O
O
ArCHO NN
O
O NH2R
R
O
HNN
NR
R
O
OAr
...(27)+ + 110oCAcOH
IV.1.3: Pyrazolo[3,4-b]pyridines
The pyrazolo[3,4-b]pyridine moieties represent important building blocks in natural products and synthetic bioactive compounds,58 which show activities such as anxiolytic,59 inhibitors of xanthine oxidases,60 cholesterol formation-inhibiting compounds,61 potent and selective inhibitors of A1 adenosine receptors,62 phosphodiesterase 4 (PDE4) inhibitors in immune and inflammatory cells,63 glycogen synthase kinase-3(GSK-3) inhibitors64 and p38α kinase inhibitors.65 Furthermore, these compounds can be used as promising luminescent materials66 and as fluorescent sensors.67 Indenopyridine compounds show a wide range of biological activities such as calcium antagonistic,68 antioxidant,69 antihistamine and antidepressant activities,70 and also act as phosphodiesterase (PDE) inhibitors71 and NK-1 and dopamine receptor ligands.72 Tomasik et al. have described the synthesis of 1H-pyrazolo[3,4-b]quinolines by the reaction of anilines and 4-(benzylidene)-1,3-disubstituted pyrazol-5-ones (eq. 30)73 and by reaction of 5-(arylamino)pyrazoles with aromatic aldehydes under microwave irradiation (eq. 31).74
Chapter IV
137
O NN
PhR
NH2
R1N N
NR1
Ph
R
ZnCl2...(30)+
N NN
R2
R1
ZnCl2NH N
N
R1
R2
ArCHO
Ar
MW ...(31)+
6-Amino-4-aryl-5-cyanopyrazolo[3,4-b]pyridines were synthesized by Shi and co-workers via three component reaction of aromatic aldehydes, malononitrile and 5-amino-3-methyl-1-phenylpyrazole using sodium 1-dodecanesulfonic (SDS) as catalyst in aqueous media (eq. 32).75
ArCHO CNCN
SDS
N NN
NC
H2N
Ar
PhN N
PhNH2
...(32)H2O, 90oC+ +
Reactions of 5-amino-3-methyl pyrazole with cyanothioacetamide and aldehydes led to the formation of pyrazolo[3,4-b]pyridines under microwave irradiation (eq. 33),76 reactions with dimedone and aldehydes afforded 3,7,7-trimethyl-4,7,8,9-tetrahydro-2H-pyrazolo[3,4-b]quinolin-5(6H)-ones (eq. 34),77 reactions with β-tetralone and aldehydes yielded 6,8-dihydro-5H-benzo[f]pyrazolo[3,4-b]quinolines in a solvent-free reaction (eq. 35) and reactions with benzylidine-α-tetralone gave the 6,10-dihydro-5H-benzo[h]pyrazolo[3,4-b]quinolines (eq. 36).78
ArCHOCN
NH2S
MWN N
NNC
H2N
Ar
PhN N
PhNH2
...(33)+ +
NHNNHArCHO
ArO
O
O
N NHNH2
EthanolReflux
...(34)+ +
Chapter IV
138
N NN
R
Ph
ArCHO
Ar
N NPh
R
NH2
O 120oC ...(35)+ +
N NN
R
Ph
Ar
N NPh
R
NH2
OAr 120oC ...(36)+
Tu and co-workers have synthesized a series of 5-aryl-1,5,6,7,8,9-hexahydro-2H-pyrazolo[5,4-b]quinolin-6-one dervatives by the three component one pot reaction of 5-amino-3-methyl-1-phenylpyrazole with aromatic aldehydes and 1,3-cyclohexanediones under microwave irradiation in ethylene glycol (eq. 37).79 Recently, Chebanov and co-workers presented the similar three component synthesis of unexpected pyrazolopyridines under basic conditions (eq. 38).80
NHN
N
Ph
ArCHO
Ar
MW
O
O RR Ehtylene glycol
O
RRN N
PhNH2 ...(37)+ +
NH
N NArCHO
ArO
O RR
O
RR
N NH
Ph
NH2
Et3N, EtOHMW
EtOH, t-BuOKMW
EtOHSonication
Ph
NN NH
RR
O
OHAr
Ph
NHNH
N
ArO
RR
Ph
...(38)+ +
Heterocyclization of 5-aminopyrazole, cyclic ketones and aldehydes led to the formation of annulated pyrazolo[3,4-b]pyridines (eq. 39).81,82
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139
Wu et al. have reported preparation of 4-aryl-3-methyl-1-phenyl-1H-benzo[g]pyrazolo [3,4-b]quinoline-5,10-diones using sulfamic acid as catalyst under solvent-free condition and using I2 or diammonium hydrogen phosphate ((NH4)2HPO4) as catalyst in water (eq. 40).83-85
N NN
PhArCHO
ArO
O
O
OOH
N NPh
NH2...(40)
++
Quiroga et al. have reported three component condensation of aldehydes, 5-amino-3-methyl-1-phenylpyrazole and 1,3-indanedione for the synthesis of indeno[2’,1’:5,6] pyrido[2,3-c]pyrazole derivatives (eq. 41).86 [bmim]Br,87 L-Proline,88 sodium dodecylsulfate89 and microwave irradiation90 are also known to catalyze the above synthesis of indeno[2’,1’:5,6]pyrido[2,3-c]pyrazole derivatives.
O
ORCHO N N
PhNH2
NNN
OR
Ph
DMF...(41)+ +
It can be inferred from the above review that pyrazolopyridines, pyridopyrimidines and indenopyridines have broad utility and various methods have been reported for their synthesis. However, there is no report on the generalized synthesis of all these derivatives. The catalytic potential of indium trichloride, briefly reviewed in IV.1.1,
ArCHO
N N NH2Ph
HN N
HO
NH2n
O
n =2, 3, 7
AcOHMW
NHN
N
HOn
Ar
...(39)
TFA
NN
Nn
ArPh
+
Chapter IV
140
spurred us to study the application of indium trichloride as a catalyst for the synthesis of these privileged structures. IV.2: RESULTS AND DISCUSSION In view of our work aimed at developing environmentally benign strategies for the synthesis of heterocyclic compounds with high diversity, we report in this chapter a new, convenient, diversity-oriented and highly efficient protocol for the synthesis of novel pyrimidine-2,4-diones, pyrimido[4,5-b]quinolines, pyrimido[2,3-d]pyrimidines, pyrazolo[3,4-b]quinolin-5-ones and pyrazolo[4,3-e]pyridines via three component condensation of aldehydes, 1,3-dicarbonyl compounds and electron-rich amino heterocycles like 6-amino-1,3-dimethyl uracil and 3-methyl-1-phenyl-1H-pyrazol-5-amine catalyzed by indium trichloride in water under reflux. IV.2.1: Synthesis of pyrimidine-2,4-diones, pyrimido[4,5-b]quinolines and
pyrimido[2,3-d]pyrimidines In order to optimize the ideal reaction conditions for the synthesis of pyrimido[4,5-b] quinoline derivatives, initially a reaction of 4-chlorobenzaldehyde (Ia) (1.0 mmol), 6-amino-1,3-dimethyl uracil (1.0 mmol) and dimedone (IIa) (1.0 mmol) was carried out in water in the absence of any catalyst under reflux. TLC analysis using petroleum ether: ethyl acetate (60:40, v/v) as eluent showed mixture of products besides the presence of starting materials, so the reaction was discontinued (run 1). The above model reaction was then performed in presence of various catalysts such as NaBr, LiBr, AlCl3, InCl3,
CeCl3, and TMSCl (20 mol%) in water under reflux to explore the suitable reaction conditions. The reactions performed using 20 mol% of NaBr, LiBr and AlCl3 as catalysts, were found to be incomplete and gave complex reaction mixtures (Table IV.1, runs 2-4). The reaction of 4-chlorobenzaldehyde (Ia) (1.0 mmol), 6-amino-1,3-dimethyl uracil (1.0 mmol) and dimedone (IIa) (1.0 mmol) was then conducted in presence of InCl3 (20 mol%) in water under reflux. The reaction was found to be complete after 15 min as
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141
analysed by TLC using petroleum ether: ethyl acetate (60:40, v/v) as eluent. The solid product was filtered, washed with ethanol and characterised by IR, NMR and mass spectral analysis and was identified to be 6-amino-5-[(4-chlorophenyl)-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIa, 92%) which was not the targeted pyrimido[4,5-b]quinoline (Table IV.1, run 5) (eq. 42).
+ NN
O
O NH2
+
NH2
ON
N
O
O OH
InCl3, H2OReflux, 15 min
O O...(42)
Cl
CHO
Cl
Ia IIa IIIa The IR spectrum of IIIa showed broad absorption band at 3368 cm-1 due to O-H stretch. Absorption due to NH2 was observed at 3202 cm-1. C=O stretch of carbonyls were observed at 1696 and 1594 cm-1 (Figure IV.2, page 164). In the 1H NMR spectrum of compound IIIa (Figure IV.3, page 165), one singlet appeared at δ 12.56 for one OH proton. The four protons appeared as doublets at δ 7.21 and 7.05 with J = 8.8 Hz, showing para substitution of aromatic ring. The NH2 proton was observed as singlet at δ 6.33. The methine proton appeared at δ 5.52 as a singlet. The NCH3 protons of 6-aminouracil residue appeared as singlets at δ 3.48 and 3.26 respectively. Two doublets appeared at δ 2.47 and 2.40 due to the methylene protons (CHa.HbCMe2) which are mutually coupled (AB system). The methylene protons adjacent to carbonyl group (CHa.CHbCO) which are also mutually coupled appeared as another set of doublets at δ 2.38 and 2.25, while two singlets appeared at δ 1.18 and 1.08 for six protons of two methyl groups (CMe2). 13C NMR of compound IIIa showed nineteen signals (Figure IV.4, page 166) corresponding to nineteen non-equivalent carbons present in the compound as given in the experimental spectral data. MS (ESI): m/z = 418.14 [M++H], 420.14 [(M++H)+2] (Figure IV.5, page 167). The structure of IIIa has been unambiguously confirmed by single crystal X-ray analysis (Figure IV.6).
Chapter IV
142
Figure IV.6: ORTEP of compound 6-amino-5-[(4-chlorophenyl)-(2-hydroxy-4,4-
dimethyl-6-oxo-cyclohex-1-enyl)-methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIa) represented as 40% thermal probability ellipsoid
In order to confirm if the unexpected product 6-amino-5-[(4-chlorophenyl)- (2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIa) could be cyclized to give pyrimido[4,5-b]quinoline derivative, a reaction of IIIa (1.0 mmol) and InCl3 (20 mol%) was carried out under reflux in water. TLC analysis using petroleum ether: ethyl acetate (60:40, v/v) as eluent showed the formation of a new spot after 15 min besides the presence of the starting material IIIa. The reflux was continued and after another 30 min. The reaction was found to be complete. The reaction was worked up and gave a white solid. The isolated product was characterized to be 5-(4-chlorophenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (IVa) by m.p. spectral analyses (run 6) (eq. 43).
NH
ON
N
O
ONH2
ON
N
O
O OH
InCl3, H2OReflux, 45 min
...(43)
Cl Cl
IIIa IVa
Chapter IV
143
We then decided to examine whether IVa could be directly synthesised via three component condensation of 4-chlorobenzaldehyde (Ia) (1.0 mmol), 6-amino-1,3-dimethyl uracil (1.0 mmol) and dimedone (IIa) (1.0 mmol). Therefore, we carried out the above reaction using InCl3 (20 mol%) as catalyst in water under reflux. The reaction progress was monitored by TLC using petroleum ether: ethyl acetate (60:40, v/v) as eluent. TLC analysis of the reaction mixture showed appearence of a new spot after 15 min which corresponded to the product IIIa by co-TLC analysis. However, the reaction was allowed to continue further. Complete disappearance of IIIa was observed after another 45 min of reflux and a new spot appeared which corresponded to IVa by co-TLC (run 7) (eq. 44). The reaction was worked up and 91% of 5-(4-chlorophenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (IVa) was obtained as characterized by m.p. and spectral analyses.
+ NN
O
O NH2 NH
ON
N
O
O+ InCl3, H2O
O O...(44)
Cl
CHO
Cl
Ia IIa IVa
Reflux, 60 min
IR spectrum of compound IVa displayed absorption band at 3488 cm-1 due to NH group. Bands at 1695, 1658 and 1639 cm-1 correspond to C=O stretch of carbonyls (Figure IV.7, page 168). In the 1H spectrum (Figure IV.8, page 169), a singlet for one proton corresponding to NH group appeared at δ 9.02. The four aromatic protons appeared as singlet at δ 7.21. The methine proton appeared at δ 4.83 as a singlet. The NCH3 protons of 6-aminouracil residue appeared as singlets at δ 3.42 and 3.06. The methylene protons (CH2CMe2) appeared as multiplet at δ 2.60-2.47. The methylene protons adjacent to carbonyl group (CH2CO), which are mutually coupled, appeared as a set of doublets at δ 2.22 and 2.04, while two singlets appeared at δ 1.01 and 0.85 for six protons of two methyl groups (CMe2). 13C NMR of compound IVa showed eighteen signals corresponding to eighteen non-equivalent carbons present in the compound (Figure IV.9, page 170).
Chapter IV
144
Reactions of the three components were also conducted using CeCl3 and TMSCl as catalysts in water under reflux. The reactions showed formation of a new product on TLC corresponding to IIIa by co-TLC after 45 min besides the presence of starting materials. The reactions were allowed to continue further under reflux. The reactions were complete after 3 h, using CeCl3 and TMSCl, but yielded a mixture of IIIa and IVa (runs 8, 9). All these results have been summarized in Table IV.1. Table IV.1: Reactions of 6-amino-1,3-dimethyl uracil, 4-chlorobenzaldehyde and
dimedone (molar ratio 1: 1: 1)
Run Catalyst mol% Solvent Temp. Time (%) Yield 1. __ __ H2O Reflux 14 h __a
2. NaBr 20 H2O Reflux 6 h __a 3. LiBr 20 H2O Reflux 6 h __a 4. AlCl3 20 H2O Reflux 6 h __a 5. InCl3 20 H2O Reflux 15 min 92 (IIIa) 6. InCl3 20 H2O Reflux 45 min 91 (IVa)b 7. InCl3 20 H2O Reflux 1 h 91 (IVa) 8. CeCl3 20 H2O Reflux 3 h 70 (IIIa)c 9. TMSCl 20 H2O Reflux 3 h 63 (IIIa)d 10. InCl3 15 H2O Reflux 30 min 79 (IIIa) 11. InCl3 25 H2O Reflux 15 min 92 (IIIa) 12. InCl3 20 EtOH/H2O r.t. 1 h 86 (IIIa) 13. InCl3 20 EtOH/H2O Reflux 1 h 87 (IVa)
a Incomplete reaction with number of spots on TLC b Reaction was performed with IIIa c 18% of IVa was also formed d 21% of IVa was also formed Subsequently, the effect of amount of the catalyst on the reaction time and yield of the product was examined. The above condensation reaction was carried out using 15 mol% and 25 mol% of InCl3. The reaction using 15 mol% of the catalyst required longer time for completion (30 min) and gave inferior yield of IIIa, while on increasing the amount of the catalyst to 25 mol%, no significant improvement in the time or yield of the product, IIIa was observed (Table IV.1, runs 10, 11).
Chapter IV
145
The condensation 4-chlorobenzaldehyde (1.0 mmol), 6-amino-1,3-dimethyl uracil (1.0 mmol) and dimedone (1.0 mmol) could also be achieved in water:ethanol (1:1, v/v) at room temperature in 1 h using 20 mol% of InCl3 to give 86% of uncyclized intermediate product IIIa (Table IV.1, run 12). However, it could not be cyclized further to give the product IVa even after 24 h at room temperature. But the above reaction does undergo cyclization in water: ethanol (1:1, v/v) under reflux though in slightly inferior yields (87%) (Table IV.1, run 13). It is evident from the results summarized in Table IV.1 that the best yield of 6-amino- 5-[(4-chlorophenyl)(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIa) and 5-(4-chlorophenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (IVa) was obtained when 20 mol% of InCl3 is employed as the catalyst in water under reflux. These optimum reaction conditions were chosen for subsequent reactions (eq. 45).
+ NN
O
O NH2
+InCl3, H2O
Reflux
O O...(45)
IIa
orNH
ORN
N
O
ONH2
ORN
N
O
O OHI III IV
RCHO
The possibility to recover and recycle the InCl3 also offers another significant advantage. Because InCl3 is soluble in reaction medium (water) and the products are insoluble in water, the recovered filtrate containing the catalyst could be recycled. Reactions using 6-amino-1,3-dimethyl uracil, 4-chlorobenzaldehyde (Ia) and dimedone (IIa) showed that the recovered filtrate could be successively recycled in subsequent reactions without any significant decrease in yield of IVa. A marginal loss of the yield was observed in first two runs (91% and 89%), while in third and fourth runs the yield dropped to 75% and 65%, respectively. Subsequently, reactions of aromatic, heteroaromatic and aliphatic aldehydes were carried out with 6-amino-1,3-dimethyl uracil and dimedone under the optimised reaction conditions. Reactions with aldehydes like 4-bromobenzaldehyde (Ib), 4-nitrobenzaldehyde (Ic), thiophene-2-carbaldehyde (Id) and isobutyraldehyde (Ie), proceeded satisfactorily to give new intermediate products III, i.e. 6-amino-5- [(4-bromophenyl)(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIb), 6-amino-5-[(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-
Chapter IV
146
enyl)(4-nitrophenyl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIc), 6-amino-5-[(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)(thiophen-2-yl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIId) and 6-amino-5-[1-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)(2-methyl)propyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIe) respectively after 15 min (Table IV.2, runs 14-17). However, if the reactions were continued further for the time indicated in Table IV.2, pyrimidoquinolines IV, i.e. 5-(4-bromophenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (IVb), 1,3,8,8-tetramethyl-5-(4-nitrophenyl)-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (IVc) and 1,3,8,8-tetramethyl-5-(thiophen-2-yl)-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (IVd) could be obtained in high yields (runs 18-20, Table IV.2). However our attempts to get the corresponding cyclized product from 6-amino-5-[1-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-(2-methyl)-propyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIe) proved to be futile. The reactions carried out with 4-hydroxybenzaldehyde (If) and 4-methoxybenzaldehyde (Ig), under otherwise similar conditions, afforded only the cyclized pyrimidoquinoline derivatives i.e. 5-(4-hydroxyphenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (IVe) and 5-(4-methoxy phenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (IVf) (Table IV.2, runs 21-22). Table IV.2: Synthesis of 6-amino-5-[aryl-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-
enyl)methyl]-1,3-dimethyl-1H-pyrimidine-2,4-diones (III) and 5-aryl-1,3, 8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-triones (IV)a
Run R (RCHO) Product Time (min) (%) Yield 14. 4-BrC6H4 (Ib) IIIb 15 92 15. 4-O2NC6H4 (Ic) IIIc 15 93 16. Thiophen-2-yl (Id) IIId 15 91 17. (CH3)2CH (Ie) IIIe 15 92 18. 4-BrC6H4 (Ib) IVb 60 90 19. 4-O2NC6H4 (Ic) IVc 60 91 20. Thiophen-2-yl (Id) IVd 90 89 21. 4-HOC6H4 (If) IVe 60 90 22. 4-CH3OC6H4 (Ig) IVf 60 89
aReactions were carried out using equimolar amounts of 6-amino-1,3-dimethyl uracil, aldehyde and dimedone in presence of 20 mol% of InCl3 as catalyst in water under reflux
Chapter IV
147
A plausible mechanism for the formation of pyrimido[4,5-b]quinoline derivatives is proposed in Scheme IV.1. The reaction proceeded via a reaction sequence of condensation, addition, cyclization and dehydration. The first step is believed to be the InCl3 catalyzed Knoevenagel condensation between the aldehyde and cyclic 1,3-diketone to generate adduct A, which acts as Michael acceptor. The 6-amino-1,3-dimethyl uracil adds to adduct A in a Michael type manner to generate an open chain cintermediate III. Intermediate III undergoes intramolecular cyclization by the reaction of nucleophilic addition of amino function to carbonyl group followed by dehydration to give the pyrimido[4,5-b]quinoline IV. Evidence supporting this proposed mechanism came from the observation that when IIIa was refluxed in water in presence of InCl3 (20 mol%), IVa was obtained (Table IV.1, run 6).
N
N
O
O OO
HRInCl3 O
HR
InCl3OH
RO
O
RO
O
InCl3-H2O
H2N O
OR
N
N
O
O NH HO
OR
N
N
O
O NH2 O
NH
OR
N
N
O
O OHNH
OR
N
N
O
O
-H2O
InCl3
InCl3
H
OR
N
N
O
O NH2 HO
HH
H
Scheme IV.1
III
IV
IIa
A
Furthermore, condensation of 6-amino-1,3-dimethyl uracil, cyclohexane-1,3-dione (IIb) and aldehydes like 4-chlorobenzaldehdye (Ia) and 4-nitrobenzaldehyde (Ic) yielded the corresponding stable dihydropyrimido[4,5-b]quinolines i.e. 5-(4-chlorophenyl)-1,3-dimethyl-7,8,9,10-tetrahydropyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H)-trione (Va) and 1,3-dimethyl-5-(4-nitrophenyl)-7,8,9,10-tetrahydropyrimido[4,5-b]quinoline-2,4,6(1H, 3H,5H)-trione (Vb) respectively in good yields (runs 23-24) (eq. 46) (Table IV.3). Our attempts to isolate the intermediate products in these reactions were not successful.
Chapter IV
148
The reactions of 6-amino-1,3-dimethyl uracil, 5-methyl-cyclohexane-1,3-dione (IIc) and aldehydes i.e. 4-chlorobenzaldehdye (Ia) 4-bromobenzaldehyde (Ib) and 4-nitrobenzaldehyde (Ic) in water under reflux in presence of 20 mol% InCl3 gave 5-(4-chlorophenyl)-1,3,8-trimethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2, 4,6-trione (VIa), 5-(4-bromophenyl)-1,3,8-trimethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido [4,5-b]quinoline-2,4,6-trione (VIb) and 5-(4-nitrophenyl)-1,3,8-trimethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (VIc) respectively (Table IV.3, runs 25-27) (eq. 46).
ArCHOO O
NN
O
O NH2H2O, Reflux
InCl3NH
OArN
N
O
O...(46)
Va-b (R1 = H)IIb (R1 = H)I
+ +
R1
R1
IIc (R1 = Me) VIa-c (R1 = Me) Table IV.3: InCl3 catalyzed three component synthesis of pyrimidoquinoline/
pyridopyrimidine derivativesa Run Ar
(ArCHO) 1,3-Dicarbonyl compound Product Time
(min) (%) Yield
23. 4-ClC6H4 (Ia) Cyclohexane-1,3-dione (IIb) Va 45 92 24. 4-O2NC6H4(Ic) Cyclohexane-1,3-dione (IIb) Vb 60 93 25. 4-ClC6H4 (Ia) 5-Methyl-cyclohexane-1,3-dione (IIc) VIa 50 91 26. 4-BrC6H4 (Ib) 5-Methyl-cyclohexane-1,3-dione (IIc) VIb 60 91 27. 4-O2NC6H4 (Ic) 5-Methyl-cyclohexane-1,3-dione (IIc) VIc 60 92 28. 4-ClC6H4 (Ia) Indane-1,3-dione (IId) VIIa 60 88 29. 4-O2NC6H4 (Ic) Indane-1,3-dione (IId) VIIb 60 90 30. 4-CH3C6H4 (Ih) Indane-1,3-dione (IId) VIIc 60 87 31. 3-O2NC6H4 (Ii) Indane-1,3-dione (IId) VIId 60 89
aReactions were carried out using equimolar amounts of 6-amino-1,3-dimethyl uracil, aldehyde and 1,3-dicarbonyl compounds in presence of 20 mol% of InCl3 as catalyst in water under reflux Further to realize the generality and versatility of the protocol, this novel procedure was extended for the synthesis of indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives by one pot condensation of 6-amino-1,3-dimethyl uracil (1.0 mmol), indane-1,3-dione (IId) (1.0
Chapter IV
149
mmol) and aldehydes (1.0 mmol) like 4-chlorobenzaldehdye (Ia), 4-nitrobenzaldehyde (Ic), 4-methylbenzaldehyde (Ih), and 3-nitrobenzaldehyde (Ii), in aqueous media under reflux in the presence of InCl3 (20 mol%). The reactions underwent successful completion affording 5-(4-chlorophenyl)-1,3-dimethyl-1H-indeno[2',1':5,6]pyrido[2,3-d] pyrimidine-2,4,6-trione (VIIa), 1,3-dimethyl-5-(4-nitrophenyl)-1H-indeno[2',1':5,6]pyrido [2,3-d]pyrimidine-2,4,6-trione (VIIb), 1,3-dimethyl-5-(4-methylphenyl)-1H-indeno[2',1': 5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (VIIc) and 1,3-dimethyl-5-(3-nitrophenyl)-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (VIId) in good yields (eq. 47) (Table IV.3, runs 28-31).
O
OArCHO N
N
O
O NH2
InCl3H2O, Reflux N
OArN
N
O
O...(47)
I IId VIIa-d
+ +
IV.2.2: Synthesis of pyrazolo[3,4-b]quinoline and pyrazolo[4,3-e]pyridine derivatives The protocol employed for the three component condensation described in Section IV.2.1 was investigated further for the condensation of 3-methyl-1-phenyl-1H-pyrazol-5-amine, aromatic aldehydes and cyclohexane-1,3-dione. A reaction of 4-chlorobenzaldehdye (1.0 mmol), cyclohexane-1,3-dione (IIb) (1.0 mmol) and 3-methyl-1-phenyl-1H-pyrazol-5-amine (1.0 mmol) was attempted in aqueous media under reflux in the presence of InCl3 (20 mol%). The reaction progress was monitored by TLC using petroleum ether: ethyl acetate (60:40, v/v) as eluent. The reaction was complete in 45 min and 4-(4-chlorophenyl)-3-methyl-1-phenyl-1,4,6,7,8,9-hexahydropyrazolo[3,4-b]quinolin-5-one (VIIIa, 89%) was obtained after work up (run 32). Similarly, reaction of 4-nitrobenzaldehyde (Ib) under otherwise identical conditions proceeded readily to give 3-methyl-4-(4-nitrophenyl)-1-phenyl-1,4,6,7,8,9-hexahydropyrazolo[3,4-b]quinolin-5-one (VIIIb) (Table IV.4, run 33) (eq. 48).
O OArCHO N N NH2
Ph NHN
NPh
OAr
H2O, RefluxInCl3 ...(48)
IIbI VIIIa-b
+ +
Chapter IV
150
The condensation could also be achieved successfully when cyclic diketone cyclohexane-1,3-dione was replaced with indane-1,3-dione (IId) for reaction with 3-methyl-1-phenyl-1H-pyrazol-5-amine and aromatic aldehydes such as 4-chlorobenzaldehdye (Ia), 4-nitrobenzaldehyde (Ic) and 4-methoxybenzaldehyde (Ig) (eq. 49). The reaction underwent successful condensation using 20 mol% of InCl3 in water under reflux to afford 4-(4-chlorophenyl)-3-methyl-1-phenyl-1H-indeno[1,2-b]pyrazolo[4,3-e]pyridin-5-one (IXa), 3-methyl-4-(4-nitrophenyl)-1-phenyl-1H-indeno[1,2-b]pyrazolo[4,3-e]pyridin-5-one (IXb) and 4-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-indeno[1,2-b]pyrazolo[4,3-e]pyridin-5-one (IXc), respectively in high yields (Table IV.4, runs 34-36).
ArCHO N N NH2
Ph
O
OH2O, Reflux
InCl3N
NN
Ph
OAr...(49)
IIdI IXa-c
+ +
The cyclocondensation of five membered cyclopentane-1,3-dione (IIe) with 3-methyl-1-phenyl-1H-pyrazol-5-amine and aromatic aldehydes viz. 4-chlorobenzaldehyde (Ia) and 4-trifluoromethylbenzaldehyde (Ij) under optimized conditions afforded the corresponding novel derivatives viz. 4-(4-chlorophenyl)-3-methyl-1-phenyl-6,7-dihydrocyclopenta[e]pyrazolo[3,4-b]pyridin-5(1H)-one (Xa) and 3-methyl-1-phenyl-4-(4-(trifluoromethyl)phenyl)-6,7-dihydrocyclopenta[e]pyrazolo[3,4-b]pyridin-5(1H)-one (Xb), respectively (eq. 50) (Table IV.4, runs 37-38).
O O NN
NPh
OAr
ArCHO N N NH2
PhH2O, Reflux
InCl3 ...(50)
IIeI Xa-b
+ +
The scope of the protocol was further explored by investigating the condensation of 3-methyl-1-phenyl-1H-pyrazol-5-amine and aromatic aldehydes with another cyclic 1,3-dicarbonyl compound, i.e. 2-hydroxy-1,4-naphthoquinone (IIf). Reactions of 4-chlorobenzaldehdye (Ia), 4-nitrobenzaldehyde (Ic), 4-methoxybenzaldehyde (Ig), 3-nitrobenzaldehyde (Ii), 4-fluorobenzaldehdye (Ik) and benzaldehyde (Il) were carried out in water under reflux in presence of 20 mol% of InCl3.
Chapter IV
151
Table IV.4: InCl3 catalyzed synthesis of pyrazole derivatives via three component reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine, aromatic aldehydes and cyclic-1,3-dicarbonyl compoundsa
Run Ar (ArCHO)
1,3-Dicarbonyl compound Product Time (min)
(%) Yield
32. 4-ClC6H4 (Ia) Cyclohexane-1,3-dione (IIb) VIIIa 45 89 33. 4-O2NC6H4(Ic) Cyclohexane-1,3-dione (IIb) VIIIb 45 91 34. 4-ClC6H4 (Ia) Indane-1,3-dione (IId) IXa 60 89 35. 4-O2NC6H4 (Ic) Indane-1,3-dione (IId) IXb 45 93 36. 4-CH3OC6H4 (Ig) Indane-1,3-dione (IId) IXc 60 87 37. 4-ClC6H4 (Ia) Cyclopentane-1,3-dione (IIe) Xa 45 88 38. 4- F3CC6H4 (Ij) Cyclopentane-1,3-dione (IIe) Xb 60 92 39. 4-ClC6H4 (Ia) 2-Hydroxy-1,4-naphthoquinone (IIf) XIa 60 87 40. 4-O2NC6H4 (Ic) 2-Hydroxy-1,4-naphthoquinone (IIf) XIb 45 90 41. 4-CH3OC6H4 (Ig) 2-Hydroxy-1,4-naphthoquinone (IIf) XIc 50 89 42. 3-O2NC6H4 (Ii) 2-Hydroxy-1,4-naphthoquinone (IIf) XId 45 91 43. 4-FC6H4 (Ik) 2-Hydroxy-1,4-naphthoquinone (IIf) XIe 60 89 44. C6H5 (Il) 2-Hydroxy-1,4-naphthoquinone (IIf) XIf 60 86
aReactions were carried out using equimolar amounts of 3-methyl-1-phenyl-1H-pyrazol-5-amine, aldehyde and 1,3-dicarbonyl compounds in presence of 20 mol% of InCl3 as catalyst in water under reflux The reactions were complete in 45-60 min yielding 4-(4-chlorophenyl)-3-methyl-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XIa), 3-methyl-4-(4-nitro phenyl)-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XIb), 4-(4-methoxy phenyl)-3-methyl-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XIc), 3-methyl-4-(3-nitrophenyl)-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XId), 4-(4-fluorophenyl)-3-methyl-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XIe) and 3-methyl-1,4-diphenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XIf) respectively (eq. 51) (Table IV.4, runs 39-44).
O
ON
O
O
NN
Ph
ArOH
ArCHO N N NH2
PhH2O, Reflux
InCl3 ...(51)
I IIf XIa-f
+ +
Chapter IV
152
The structures of all the synthesized compounds (VIII-XI) have been assigned based on spectral data. IR spectrum of compound Xa showed absorption band at 1707 cm-1 due to C=O stretch of carbonyl functionality (Figure IV.10, page 171). 1H NMR spectrum of compound Xa (Figure IV.11, page 172), showed usual pattern of singlets, doublets, and multiplets for nine aromatic protons at δ 8.22-7.24. The multiplet at δ 3.35-3.25 corresponds to methylene protons (CH2CMe2) and the methylene protons adjacent to carbonyl group (CH2CO) were observed as multiplet at δ 2.81-2.78. The methyl protons of Xa appeared as singlet at δ 2.10. 13C NMR spectrum of compound Xa displayed nineteen signals corresponding to nineteen non-equivalent carbons present in the compound. Carbon of carbonyl functionality appeared at δ 201.86 (Figure IV.12, page 173). MS (ESI): m/z = 374.16 [M++H], 376.17 [(M++H)+2] (Figure IV.13, page 174). In conclusion, we have described a facile, environmentally benign one pot three component method for the synthesis of pyrimidine/ pyrazole annulated heterocyclic systems using 20 mol% InCl3 as catalyst in water. The advantages of this method include operational simplicity, high yields and the reusability of the reaction media. IV.3: EXPERIMENTAL All the chemicals were purchased from Sigma-Aldrich and were used as received. Thin layer chromatography (GF254 coated aluminium plates) was used to monitor reaction progress. Melting points were determined on a Tropical labequip apparatus and are uncorrected. IR (KBr) spectra were recorded on Perkin-Elmer FTIR spectrophotometer and the values are expressed as νmaxcm-1. Mass spectral data were recorded on JEOL-AccuTOF JMS-T100 mass spectrometer having a DART source. The 1H NMR and 13C NMR spectra were recorded on Jeol JNM ECX-400P at 400 and 100 MHz, respectively using TMS as an internal standard. The chemical shift values are recorded on δ scale and the coupling constants (J) are in Hertz (Hz). General procedure for the synthesis of pyrimidine-2,4-diones (III) In a typical experiment, a mixture of aldehyde (1.0 mmol), 6-amino-1,3-dimethyl uracil (1.0 mmol), dimedone (1.0 mmol), InCl3 (20 mol%) and 10 mL of water was placed in
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153
a 50 mL round-bottomed flask and the mixture was stirred under reflux. The reaction was complete within 15 min as analyzed by TLC using petroleum ether: ethyl acetate (60:40) as eluent. The reaction mixture was allowed to cool to room temperature. The precipitate formed was collected by filtration at pump, washed with water and cold ethanol to yield pyrimidine-2,4-diones (IIIa-e). The products were characterized by spectral data. Spectral Data 6-Amino-5-[(4-chlorophenyl)(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl) methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIa, C21H24ClN3O4) White solid; Yield: 92%; M.p.: 190-192°C; IR (KBr) νmax, cm-1: 3368, 3202, 1696, 1594, 1512, 1345; 1H NMR (400 MHz, CDCl3): δ = 12.56 (s, 1H, OH), 7.21 (d, 2H, J = 8.8 Hz, Ar), 7.05 (d, 2H, J = 8.8 Hz, Ar), 6.33 (s, 2H, NH2), 5.52 (s, 1H, CH), 3.48 (s, 3H, NMe), 3.26 (s, 3H, NMe), 2.47 and 2.40 (AB system, J = 17.6 Hz, 2H, CH2), 2.38 and 2.25 (AB system, J = 16.8 Hz, 2H, CH2), 1.18 (s, 3H, CMe), 1.08 (s, 3H, CMe); 13C NMR (100 MHz, CDCl3): δ = 200.78, 177.26, 164.45, 154.00, 150.64, 137.45, 131.52, 128.34, 127.87, 114.19, 89.87, 50.07, 44.33, 33.16, 31.40, 29.65, 29.56, 28.57, 27.34; MS (ESI) m/z calcd. for C21H24ClN3O4: 417.14, found: 418.14 [M++H], 420.14 [(M++H)+2]. 6-Amino-5-[(4-bromophenyl)(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl) methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIb, C21H24BrN3O4) White solid; Yield: 92%; M.p.: 185-187°C; IR (KBr) νmax, cm-1: 3366, 3203,1695, 1592, 1513, 1344; 1H NMR (400 MHz, CDCl3): δ = 12.73 (s, 1H, OH), 7.37 (d, 2H, J = 8.0 Hz, Ar), 7.01 (d, 2H, J = 8.0 Hz, Ar), 6.33 (s, 2H, NH2), 5.38 (s, 1H, CH), 3.31 (s, 3H, NMe), 3.05 (s, 3H, NMe), 2.34 (s, 2H, CH2), 2.24 (s, 2H, CH2), 1.06 (s, 3H, CMe), 0.99 (s, 3H, CMe); 13C NMR (100 MHz, DMSO-d6): δ = 199.32, 176.09, 163.62, 154.72, 150.15, 139.50, 130.74, 128.78, 118.27, 113.49, 87.47, 49.48, 43.52, 32.74, 31.47, 30.33, 28.74, 28.03, 27.15; MS (ESI) m/z calcd. for C21H24BrN3O4: 461.09, found: 462.12 [M++H], 464.12 [(M++H)+2].
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6-Amino-5-[(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)(4-nitrophenyl) methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIc, C21H24N4O6) White solid; Yield: 93%; M.p.: 168-170°C; IR (KBr) νmax, cm-1: 3366, 3203,1695, 1592, 1513, 1344; 1H NMR (400 MHz, CDCl3): δ = 12.51 (s, 1H, OH), 8.11 (d, 2H, J = 8.8 Hz, Ar), 7.29 (d, 2H, J = 8.8 Hz, Ar), 6.37 (s, 2H, NH2), 5.61 (s, 1H, CH), 3.50 (s, 3H, NMe), 3.25 (s, 3H, NMe), 2.45-2.32 ( m, 4H, CH2), 1.20 (s, 3H, CMe), 1.09 (s, 3H, CMe); 13C NMR (100 MHz, CDCl3): δ = 200.73, 177.49, 164.44, 154.16, 150.51, 147.45, 146.13, 127.35, 123.55, 113.72 ,89.45, 58.43, 49.97, 44.34, 33.95, 31.44, 29.64, 28.62, 27.39; MS (ESI) m/z calcd. for C21H24N4O6 : 428.16, found: 429.18 [M++H]. 6-Amino-5-[(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)(thiophen-2-yl) methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIId, C19H23N3O4S)
White solid; Yield: 91%; M.p.: 218-220°C; IR (KBr) νmax, cm-1: 3368, 2924,1695, 1659, 1597, 1514, 1463; 1H NMR (400 MHz, CDCl3): δ = 12.95 (s, 1H, OH), 7.09-7.08 (m, 1H, Ar), 6.87-6.84 (m, 1H, Ar), 6.66-6.65 (m, 1H, Ar), 6.37 (s, 2H, NH2), 5.69 (s, 1H, CH), 3.47 (s, 3H, NMe), 3.29 (s, 3H, NMe), 2.44-2.39 (m, 2H, CH2), 2.35-2.23 (m, 2H, CH2), 1.18 (s, 3H, CMe), 1.07 (s, 3H, CMe); 13C NMR (100 MHz, CDCl3): δ = 198.67, 176.52, 163.50, 154.15, 150.05, 145.62, 126.34, 123.67, 123.42, 114.83, 87.89, 49.26, 43.59, 30.96, 30.33, 29.10, 28.02, 27.71, 26.43; MS (ESI) m/z calcd. for C19H23N3O4S: 389.14, found: 390.19 [M++H]. 6-Amino-5-[1-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-(2-methyl)propyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIe, C18H27N3O4) White solid; Yield: 92%; M.p.: 230-232°C; IR (KBr) νmax, cm-1: 3380, 3208,1690, 1591, 1508, 1366; 1H NMR (400 MHz, CDCl3): δ = 13.13 (s, 1H, OH), 7.17 (d, 2H, NH2), 3.46 (d, J = 11.0 Hz, 1H, CH), 3.32 (s, 3H, NMe), 3.15 (s, 3H, NMe), 2.90-2.87 (m, 1H, CH), 2.35-2.09 (m, 4H, CH2), 0.97 (s, 6H, CH3), 0.78 (d, J = 6.6 Hz, 3H, CH(CH3)2), 0.73 (d, J = 6.6 Hz, 3H, CH(CH3)2); MS (ESI) m/z calcd. for C18H27N3O4 : 349.20, found: 350.21 [M++H].
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General procedure for the synthesis of pyrimidine/ pyrazole derivatives (IV-XI) A mixture of aldehyde (1.0 mmol), 6-amino-1,3-dimethyl uracil or 3-methyl-1-phenyl-1H-pyrazol-5-amine (1.0 mmol), dimedone or cyclohexane-1,3-dione or indane-1,3-dione or cyclopentane-1,3-dione or 5-methyl-cyclohexane-1,3-dione or 2-hydroxy-1,4-naphthoquinone (1.0 mmol), InCl3 (20 mol%) and 10 mL of water was placed in a 50 mL round-bottomed flask and stirred under reflux for an appropriate time as mentioned in Table IV.2/ Table IV.3/ Table IV.4. The progress of the reaction was monitored by TLC (eluent: methanol: chloroform). After completion of the reaction, the reaction mixture was allowed to cool at room temperature. The precipitate formed was collected by filtration at pump, washed with water and ethanol to obtain pure pyrimidine/ pyrazole derivatives (IV-XI). The products were characterized by m.p., IR, NMR and mass spectra. The aqueous filtrate containing InCl3 was used as such for investigating the recyclability of the catalyst. 5-(4-Chlorophenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b] quinoline-2,4,6-trione (IVa, C21H22ClN3O3) White solid; Yield: 91%; M.p.: 290-292°C (Lit. 281-283°C);55 IR (KBr) νmax, cm-1: 3488, 3389, 2964, 1695, 1658, 1639, 1505; 1H NMR (400 MHz, DMSO-d6): δ = 9.02 (s, 1H, NH), 7.21 (s, 4H, Ar), 4.83 (s, 1H, CH), 3.42 (s, 3H, NMe), 3.06 (s, 3H, NMe), 2.60-2.47 (m, 2H, CH2), 2.22 (d, 1H, J = 16.8 Hz, CH), 2.04 (d, 1H, J = 16.8 Hz, CH), 1.01 (s, 3H, CMe), 0.85 (s, 3H, CMe); 13C NMR (100 MHz, DMSO-d6): δ = 194.59, 160.69, 150.54, 149.75, 145.32, 143.96, 130.39, 129.58, 127.64, 111.24, 89.66, 49.97, 33.60, 32.12, 30.25, 29.03, 27.64, 26.46. 5-(4-Bromophenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b] quinoline-2,4,6-trione (IVb, C21H22BrN3O3) White solid; Yield: 90%; M.p.: 290-292°C (Lit. 281-283°C);55 IR (KBr) νmax, cm-1: 3381, 3063, 2959, 1702, 1661, 1642, 1595; 1H NMR (400 MHz, DMSO-d6): δ = 9.05 (s, 1H, NH), 7.40 (d, 2H, J = 16.8 Hz, Ar), 7.20 (d, 2H, J = 16.8 Hz, Ar), 4.80 (s, 1H, CH), 3.42 (s, 3H, NMe), 3.07 (s, 3H, NMe), 2.54-2.48 ( m, 2H, CH2), 2.20 ( d, 1H, J = 16.8 Hz, CH), 2.03 ( d, 1H, J = 16.8 Hz, CH), 1.04 (s, 3H, CMe), 0.88 (s, 3H, CMe).
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1,3,8,8-Tetramethyl-5-(4-nitrophenyl)-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b] quinoline-2,4,6-trione (IVc, C21H22N4O5)
White solid; Yield: 91%; M.p.: 222-224°C; IR (KBr) νmax, cm-1: 3448, 3224, 2959, 1700, 1667, 1642, 1496; 1H NMR (400 MHz, CDCl3): δ = 8.08 (d, 2H, J = 8.8 Hz, Ar), 7.52 (d, 2H, J = 8.8 Hz, Ar), 6.35 (s, 1H, NH), 5.19 (s, 1H, CH), 3.50 (s, 3H, NMe), 3.23 (s, 3H, NMe), 2.50 and 2.26 ( AB system, J = 17.6 Hz, 2H, CH2), 2.27 and 2.14 ( AB system, J = 16.8 Hz, 2H, CH2), 1.09 (s, 3H, CMe), 0.98 (s, 3H, CMe); 13C NMR (100 MHz, DMSO-d6): δ = 194.78, 163.62, 154.65, 150.14, 149.03, 145.42, 127.74, 123.12, 113.32, 87.15, 56.01, 33.63, 31.17, 30.38, 28.07; MS (ESI) m/z calcd. for C21H22N4O5: 410.15, found: 411.16 [M++H]. 1,3,8,8-Tetramethyl-5-(thiophen-2-yl)-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b] quinoline-2,4,6-trione (IVd, C19H21N3O3S) White solid; Yield: 89%; M.p.: 296-298°C (Lit. 295-296°C)81; IR (KBr) νmax, cm-1: 3299, 3239, 2944, 1702, 1661, 1494; 1H NMR (400 MHz, DMSO-d6): δ = 9.18 (s, 1H, NH), 7.17-7.21 (m, 1H, Ar), 6.83-6.75 (m, 2H, Ar), 7.21-7.10 (m, 1H, Ar), 5.20 (s, 1H, CH), 3.41 (s, 3H, NMe), 3.15 (s, 3H, NMe), 2.61-2.42 (m, 2H, CH), 2.21 ( d, 1H, J = 16.4 Hz, CH), 2.03 ( d, 1H, J = 16.4 Hz, CH), 1.06 (s, 3H, CMe), 0.97 (s, 3H, CMe). 5-(4-Hydroxyphenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b] quinoline-2,4,6-trione (IVe, C21H23N3O4)
White solid; Yield: 90%; M.p.: >300°C; IR (KBr) νmax, cm-1: 3414, 3224, 2959, 1691, 1665, 1641, 1493; 1H NMR (400 MHz, DMSO-d6): δ = 9.05 (s, 1H, OH), 8.92 (s, 1H, NH), 6.98 (d, 2H, J = 8.8 Hz, Ar), 6.54 (d, 2H, J = 8.8 Hz, Ar), 4.75 (s, 1H, CH), 3.42 (s, 3H, NMe), 3.07 (s, 3H, NMe), 2.59-2.49 (m, 2H, CH2), 2.20 (d, 1H, J = 16.8 Hz, CH), 2.03 (d, 1H, J = 16.1 Hz, CH), 1.01 (s, 3H, CMe), 0.87 (s, 3H, CMe); 13C NMR (100 MHz, DMSO-d6): δ = 194.57, 160.69, 155.42, 150.54, 149.07, 143.55, 137.03, 128.48, 114.39, 112.08, 90.52, 50.12, 32.65, 32.10, 30.14, 29.11, 27.62, 26.43; MS (ESI) m/z calcd. for C21H23N3O4: 381.16, found: 382.16 [M++H].
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5-(4-Methoxyphenyl)-1,3,8,8-tetramethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b] quinoline-2,4,6-trione (IVf, C22H25N3O4) White solid; Yield: 89%; M.p.: >300°C (Lit. >300°C);55 IR (KBr) νmax, cm-1: 3283, 3227, 3096, 2954, 1701, 1661, 1640, 1496; 1H NMR (400 MHz, DMSO-d6): δ = 8.95 (s, 1H, NH), 7.11 (d, 2H, J = 8.8 Hz, Ar), 6.72 (d, 2H, J = 8.8 Hz, Ar), 4.79 (s, 1H, CH), 3.64 (s, 3H, OMe), 3.42 (s, 3H, NMe), 3.07 (s, 3H, NMe), 2.55-2.48 ( m, 2H, CH2), 2.21 ( d, 1H, J = 16.8 Hz, CH), 2.03 (d, 1H, J = 16.1 Hz, CH), 1.01 (s, 3H, CMe), 0.87 (s, 3H, CMe). 5-(4-Chlorophenyl)-1,3-dimethyl-7,8,9,10-tetrahydropyrimido[4,5-b]quinoline-2,4,6 (1H,3H,5H)-trione (Va, C19H18ClN3O3) White solid; Yield: 92%; M.p.: 279-281°C (Lit. 310-313°C);55 IR (KBr) νmax, cm-1: 3234, 3152, 2924, 1617, 1601, 1524; 1H NMR (400 MHz, DMSO-d6): δ = 9.10 (s, 1H, NH), 7.21 (s, 4H, Ar), 4.88 (s, 1H, CH), 3.43 (s, 3H, NMe), 3.07 (s, 3H, NMe), 2.79-2.72 (m, 1H, CH), 2.60-2.48 (m, 1H, CH), 2.28-2.17 (m, 2H, CH), 1.94-1.90 ( m, 1H, CH), 1.82-1.75 (m, 1H, CH); 13C NMR (100 MHz, DMSO-d6): δ = 194.80, 160.87, 151.76, 150.54, 145.42, 143.82, 130.37, 129.48, 127.66, 112.32, 89.69, 36.56, 33.28, 30.25, 27.62, 26.43, 20.65. 1,3-Dimethyl-5-(4-nitrophenyl)-7,8,9,10-tetrahydropyrimido[4,5-b]quinoline-2,4,6 (1H,3H,5H)-trione (Vb, C19H18N4O5) White solid; Yield: 93%; M.p.: >300°C (Lit. 301-303°C);55 IR (KBr) νmax, cm-1: 3349, 1698, 1662; 1H NMR (400 MHz, DMSO-d6): δ = 9.21 (s, 1H, NH), 8.05 (d, 2H, J = 8.8 Hz, Ar), 7.49 (d, 2H, J = 8.8 Hz, Ar), 4.96 (s, 1H, CHAr), 3.44 (s, 3H, NMe), 3.05 (s, 3H, NMe), 2.73-2.48 (m, 2H, CH2), 2.23-2.20 (m, 2H, CH2), 1.91-1.76 (m, 2H, CH2). 5-(4-Chlorophenyl)-1,3,8-trimethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b] quinoline-2,4,6-trione (VIa, C20H20ClN3O3) White solid; Yield: 91%; M.p.: 268-270°C; IR (KBr) νmax, cm-1: 3298, 3237, 2967, 1700, 1651, 1611, 1498; 1H NMR (400 MHz, DMSO-d6): δ = 9.05 (s, 1H, NH), 7.21
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(s, 4H, Ar), 4.83 (s, 1H, CHAr), 3.43 (s, 3H, NMe), 3.06 (s, 3H, NMe), 2.75-2.69 (m, 1H, CH), 2.47-2.43 (m, 1H, CH), 2.34-2.29 (m, 1H, CH), 2.26-2.18 (m, 1H, CH), 2.02-1.96 (m, 1H, CH), 0.95 (d, 3H, J = 6.6 Hz, CHMe); 13C NMR (100 MHz, DMSO-d6) δ = 194.61, 160.68, 150.63, 150.53, 145.34, 143.87, 130.38, 129.59, 127.62, 111.91, 89.52, 44.35, 33.96, 33.64, 30.25, 28.40, 27.65, 20.24; MS (ESI) m/z calcd. for C20H20ClN3O3: 385.12, found: 386.18 [M++H], 388.17 [(M++H)+2]. 5-(4-Bromophenyl)-1,3,8-trimethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b] quinoline-2,4,6-trione (VIb, C20H20BrN3O3) White solid; Yield: 91%; M.p.: >300°C; IR (KBr) νmax, cm-1: 3301, 3236, 2923, 1700, 1663, 1648, 1609, 1498; 1H NMR (400 MHz, DMSO d6): δ = 9.04 (s, 1H, NH), 7.35 (d, 2H, J = 8.8 Hz, Ar), 7.16 (d, 2H, J = 8.8 Hz, Ar), 4.81 (s, 1H, CHAr), 3.42 (s, 3H, NMe), 3.06 (s, 3H, NMe), 2.74-2.69 (m, 1H, CH), 2.48-2.41 (m, 1H, CH), 2.35-2.28 (m, 1H, CH), 2.25-2.17 (m, 1H, CH), 2.01-1.95 (m, 1H, CH), 0.94 (d, 3H, J = 6.6 Hz, CHMe); 13C NMR (100 MHz, DMSO-d6): δ = 194.56, 160.64, 150.60, 150.50, 145.75, 143.84, 130.50, 129.99, 118.87, 111.82, 89.44, 44.33, 33.96, 33.73, 30.22, 28.38, 27.61, 20.23; MS (ESI) m/z calcd. for C20H20BrN3O3: 429.06, found: 430.10 [M++H], 432.10 [M++H +2]. 5-(4-Nitrophenyl)-1,3,8-trimethyl-5,8,9,10-tetrahydro-1H,7H-pyrimido[4,5-b]quinoline-2,4,6-trione (VIc, C20H20N4O5)
White solid; Yield: 92%; M.p.: 268-270°C; IR (KBr) νmax, cm-1: 3221, 1685, 1701, 1663, 1498; 1H NMR (400 MHz, DMSO d6): δ = 9.13 (s, 1H, NH), 8.05 (d, 2H, J = 8.8 Hz, Ar), 7.49 (d, 2H, J = 8.8 Hz, Ar), 4.96 (s, 1H, CHAr), 3.44 (s, 3H, NMe), 3.05 (s, 3H, NMe), 2.77-2.72 (m, 1H, CH), 2.51-2.44 (m, 1H, CH), 2.34-2.29 (m, 1H, CH), 2.24-2.19 (m, 1H, CH), 2.02-1.96 (m, 1H, CH), 0.95 (d, 3H, J = 6.6 Hz, CHMe); 13C NMR (100 MHz, DMSO-d6): δ = 194.57, 160.65, 153.84, 151.11, 150.50, 145.74, 144.14, 129.07, 122.98, 111.25, 88.87, 44.25, 34.72, 34.00, 30.32, 28.36, 27.64, 20.24; MS (ESI) m/z calcd. for C20H20N4O5: 396.14, found: 397.16 [M++H].
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5-(4-Chlorophenyl)-1,3-dimethyl-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (VIIa, C22H14ClN3O3) White solid; Yield: 88%; M.p.: >300°C (Lit. >300°C);55 IR (KBr) νmax, cm-1: 2925, 1712, 1664, 1575, 1494; 1H NMR (400 MHz, CDCl3): δ = 7.94 (d, 1H, J = 7.32 Hz, Ar), 7.66-7.61 (m, 2H, Ar), 7.54 -7.50 (m, 1H, Ar), 7.45 (d, 2H, J = 8.0 Hz, Ar), 7.17 (d, 2H, J = 8.0 Hz, Ar), 3.87 (s, 3H, NMe), 3.33 (s, 3H, NMe); 13C NMR (100 MHz, CDCl3) δ = 188.50, 168.65, 160.11, 155.61, 151.61, 150.93, 140.66, 136.49, 135.04, 134.82, 134.50, 132.93, 132.72, 132.52, 128.39, 128.16, 123.93, 123.74, 121.99, 106.99, 30.70, 28.56. 1,3-Dimethyl-5-(4-nitrophenyl)-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (VIIb, C22H14N4O5) White solid; Yield: 90%; M.p.: 252-254°C (Lit. 254-256°C);55 IR (KBr) νmax, cm-1: 2956, 1718, 1670, 1568, 1503; 1H NMR (400 MHz, CDCl3): δ = 8.30 (d, 2H, J = 8.8 Hz, Ar), 8.01 (d, 1H, J = 8.0 Hz, Ar), 7.69-7.54 (m, 5H, Ar), 3.74 (s, 3H, NMe), 3.16 (s, 3H, NMe). 1,3-Dimethyl-5-(4-methylphenyl)-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (VIIc, C23H17N3O3) White solid; Yield: 87%; M.p.: >300°C (Lit. >300°C);55 IR (KBr) νmax, cm-1: 2926, 1714, 1669, 1569, 1498; 1H NMR (400 MHz, CDCl3): δ = 7.94 (d, 1H, J = 7.32 Hz, Ar), 7.65-7.60 (m, 2H, Ar), 7.53-7.49 (m, 1H, Ar), 7.29 (d, 2H, J = 8.0 Hz, Ar), 7.13 (d, J = 8.0 Hz, 2H, Ar), 3.88 (s, 3H, NMe), 3.33 (s, 3H, NMe), 2.41 (s, 3H, CH3). 1,3-Dimethyl-5-(3-nitrophenyl)-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (VIId, C22H14N4O5) White solid; Yield: 89%; M.p.: >300°C (Lit. >300°C);55 IR (KBr) νmax, cm-1: 2927, 1718, 1671, 1569, 1500; 1H NMR (400 MHz, CDCl3): δ = 8.36-8.33 (m, 1H, Ar), 8.11 (s, 1H, Ar), 7.98 (d, 1H, J = 7.3 Hz, Ar), 7.69-7.52 (m, 5H, Ar), 3.90 (s, 3H, NMe), 3.32 (s, 3H, NMe).
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4-(4-Chlorophenyl)-3-methyl-1-phenyl-1,4,6,7,8,9-hexahydrapyrazolo[3,4-b]quinolin-5-one (VIIIa, C23H20ClN3O)79 White solid; Yield: 91%; M.p.: 180-182°C; IR (KBr) νmax, cm-1: 3246, 3159, 2953, 1617, 1602, 1525, 1468; 1H NMR (400 MHz, DMSO-d6): δ = 9.52 (s, 1H, NH), 7.54-7.48 (m, 4H, Ar), 7.40-7.35 (m, 1H, Ar), 7.27-7.17 (m, 4H, Ar), 5.02 (s, 1H, CH), 3.46-3.37 (m, 1H, CH2), 2.71-2.63 (m, 1H, CH2), 2.59-2.51 (m, 1H, CH2), 2.29-2.11 (m, 2H, CH2), 1.86 (s, 3H, CH3), 1.81-1.70 (m, 1H, CH2). 3-Methyl-4-(4-nitrophenyl)-1-phenyl-1,4,6,7,8,9-hexahydropyrazolo[3,4-b]quinolin-5-one (VIIIb, C23H20N4O3) 79 White solid; Yield: 89%; M.p.: 175-178°C; IR (KBr) νmax, cm-1: 3233, 3159, 2922, 2854, 1615, 1599, 1520, 1463; 1H NMR (400 MHz, DMSO-d6): δ = 9.63 (s, 1H, NH), 8.11 (d, 2H, J = 8.8 Hz, Ar), 7.53-7.47 (m, 6H, Ar), 7.40-7.36 (m, 1H, Ar), 5.17 (s, 1H, CH), 3.45-3.38 (m, 1H, CH2), 2.70-2.64 (m, 1H, CH2), 2.61-2.53 (m, 1H, CH2), 2.22-2.10 (m, 2H, CH2), 1.84 (s, 3H, CH3), 1.80-1.76 (m, 1H, CH2); 13C NMR (100 MHz, DMSO-d6): δ = 194.36, 155.12, 154.01, 146.02, 145.51, 138.03, 136.22, 129.42, 128.89, 127.09, 123.39, 123.32, 109.72, 102.80, 36.83, 36.07, 27.35, 20.93, 12.01. 4-(4-Chlorophenyl)-3-methyl-1-phenyl-1H-indeno[1,2-b]pyrazolo[4,3-e]pyridin-5-one (IXa, C26H16ClN3O) White solid; Yield: 89%; M.p.: 270-272°C (Lit. 271-272°C);88 IR (KBr) νmax, cm-1: 2924, 1710, 1597, 1573, 1558, 1503; 1H NMR (400 MHz, CDCl3): δ = 8.41 (d, 2H, J = 8.0 Hz, Ar), 8.28 (d, 2H, J = 7.3 Hz, Ar), 8.01 (d, 1H, J = 7.3 Hz, Ar), 7.66-7.60 (m, 4H, Ar), 7.57-7.52 (m, 2H, Ar), 7.48-7.44 (m, 1H, Ar), 7.38-7.32 (m, 1H, Ar), 2.05 (s, 3H, CH3). 3-Methyl-4-(4-nitrophenyl)-1-phenyl-1H-indeno[1,2-b]pyrazolo[4,3-e]pyridin-5-one (IXb, C26H16N4O3) White solid; Yield: 93%; M.p.: >300°C (Lit. 318-319°C);88 IR (KBr) νmax, cm-1: 3061, 1708, 1566, 1519, 1503; 1H NMR (400 MHz, CDCl3): δ = 8.41 (d, 2H, J = 8.0 Hz, Ar),
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8.28 (d, 2H, J = 8.8 Hz, Ar), 8.01 (d, 1H, J = 7.3 Hz, Ar), 7.65-7.52 (m, 7H, Ar), 7.48 (t, 1H, J 1,2 = 8.8 Hz, Ar), 1.99 (s, 3H, CH3). 4-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-indeno[1,2-b]pyrazolo[4,3-e]pyridin-5-one (IXc, C27H19N3O2) White solid; Yield: 87%; M.p.: 220-222°C (Lit. 222-224°C);88 IR (KBr) νmax, cm-1: 2927, 1710, 1609, 1559, 1511; 1H NMR (400 MHz, CDCl3): δ = 8.29-8.26 (m, 2H, Ar), 7.99-7.96 (m, 1H, Ar), 7.63-7.50 (m, 4H, Ar), 7.45-7.31 (m, 4H, Ar), 7.06-7.03 (m, 2H, Ar), 3.90 (s, 3H, OCH3), 2.04 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ = 189.99, 165.11, 160.37, 152.73, 146.03, 145.92, 142.28, 138.92, 137.32, 134.56, 131.34, 130.43, 128.98, 126.25, 124.50, 123.32, 121.49, 121.30, 119.93, 115.69, 113.31, 55.28, 15.13. 4-(4-Chlorophenyl)-3-methyl-1-phenyl-6,7-dihydrocyclopenta[e]pyrazolo[3,4-b] pyridin-5(1H)-one (Xa, C22H16ClN3O) White solid; Yield: 88%; M.p.: 181-183°C; IR (KBr) νmax, cm-1: 2925, 1707, 1575, 1552, 1487; 1H NMR (400 MHz, CDCl3): δ = 8.22 (d, 2H, J = 8.0 Hz, Ar), 7.54-7.47 (m, 4H, Ar), 7.32-7.24 (m, 3H, Ar), 3.35-3.25 (m, 2H, CH2), 2.81-2.78 (m, 2H, CH2), 2.10 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): δ = 201.86, 174.60, 152.51, 144.63, 143.60, 138.44, 133.88, 131.31, 130.37, 129.08, 128.79, 127.59, 125.82, 121.48, 120.66, 115.02, 36.30, 27.88, 14.68; MS (ESI) m/z calcd. for C22H16ClN3O: 373.09, found, 374.16 [M++H], 376.17 [(M++H)+2]. 3-Methyl-1-phenyl-4-(4-(trifluoromethyl)phenyl)-6,7-dihydrocyclopenta[e]pyrazolo [3,4-b]pyridin-5(1H)-one (Xb, C23H16F3N3O) White solid; Yield: 92%; M.p.: 240-242°C; IR (KBr) νmax, cm-1: 2923, 1712, 1563, 1463; 1H NMR (400 MHz, CDCl3): δ = 8.23 (m, 2H, Ar), 7.78 (d, 2H, J = 8.04 Hz, Ar), 7.55-7.49 (m, 4H, Ar), 7.35-7.31 (m, 1H, Ar), 3.37-3.34 (m, 2H, CH2), 2.82-2.77 (m, 2H, CH2), 2.05 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ = 202.78, 174.84, 153.17, 145.13, 144.00, 138.67, 136.80, 131.90, 130.92, 129.17, 129.05, 126.54, 125.03, 124.99, 124.95, 124.92, 121.65, 115.55, 36.77, 28.44, 15.00; MS (ESI) m/z calcd. for C23H16F3N3O: 407.12, found: 408.16 [M++H].
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4-(4-Chlorophenyl)-3-methyl-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10- dione (XIa, C27H16ClN3O2)
Yellow solid; Yield: 87%; M.p.: 279-281°C (Lit. 278-280°C);80 IR (KBr) νmax, cm-1: 2924, 1685, 1554; 1H NMR (400 MHz, CDCl3): δ = 8.26 (m, 2H, Ar), 7.92–7.23 (m, 1H, Ar), 7.57–7.32 (m, 10H, Ar), 2.04 (s, 3H, CH3). 3-Methyl-4-(4-nitrophenyl)-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XIb, C27H16N4O4 )
Yellow solid; Yield: 90%; M.p.: >300°C (Lit. 326-328°C);80 IR (KBr) νmax, cm-1: 2924, 1682, 1665, 1561; 1H NMR (400 MHz, CDCl3): δ = 8.84 (d, 1H, J = 8.0 Hz, Ar), 8.43 (d, 2H, J = 8.4 Hz, Ar), 8.30 (d, 2H, J = 8.0 Hz, Ar), 8.19 (d, 1H, J = 7.6 Hz, Ar), 7.88 (t, 1H, J1,2 = 8.0 Hz, Ar), 7.64-7.60 (m, 3H, Ar), 7.52-7.43 (m, 2H, Ar), 7.26-7.25 (m, 1H, Ar), 1.96 (s, 3H, CH3). 4-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XIc, C28H19N3O3)
Yellow solid; Yield: 89%; M.p.: 272-274°C (Lit. 274-275°C);80 IR (KBr) νmax, cm-1: 2924, 1631, 1508; 1H NMR (400 MHz, CDCl3): δ = 8.83 (d, 1H, J = 8.0 Hz, Ar), 8.32 (d, 2H, J = 7.3 Hz, Ar), 8.16 (d, 1H, J = 8 Hz, Ar), 7.86-7.82 (m, 1H, Ar), 7.62-7.58 (m, 3H, Ar), 7.41-7.18 (m, 3H, Ar), 7.06 (d, 2H, J = 8.4 Hz, Ar), 3.94 (s, 3H, OMe), 2.02 (s, 3H, CH3). 3-Methyl-4-(3-nitrophenyl)-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XId, C27H16N4O4)
Yellow solid; Yield: 91%; M.p.: 288-290°C (Lit. 288-289°C);80 IR (KBr) νmax, cm-1: 2925, 1684, 1559; 1H NMR (400 MHz, CDCl3): δ = 8.82 (d, 1H, J = 8.1 Hz, Ar), 8.39 (d, 1H, J = 8.0 Hz, Ar), 8.28 (d, 2H, J = 8.04 Hz, Ar), 8.20-8.15 (m, 2H, Ar), 7.73-7.69 (m, 1H, Ar), 7.65-7.58 (m, 4H, Ar), 7.42-7.40 (m, 1H, Ar), 7.25 (s, 1H, Ar), 1.93 (s, 3H).
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163
4-(4-Fluorophenyl)-3-methyl-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XIe, C27H16FN3O2) Yellow solid; Yield: 89%; M.p.: 280-282°C (Lit. 281-283°C);80 IR (KBr) νmax, cm-1: 2926, 1679, 1563; 1H NMR (400 MHz, CDCl3): δ = 8.82 (d, 1H, J = 8.1 Hz, Ar), 8.31 (d, 2H, J = 7.3 Hz, Ar), 8.17 (d, 1H, J = 8.0 Hz, Ar), 7.85-7.83 (m, 1H, Ar), 7.63 (t, 3H, J1,2 = 8.4 Hz, Ar), 7.42 (t, 1H, J1,2 = 8.4 Hz, Ar), 7.29-7.20 (m, 4H, Ar), 1.98 (s, 3H). 3-Methyl-1,4-diphenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-dione (XIf, C27H17N3O2) Yellow solid; Yield: 86%; M.p.: 264-266°C (Lit. 266-267°C);88 IR (KBr) νmax, cm-1: 2925, 1678, 1559); 1H NMR (400 MHz, CDCl3): δ = 8.82 (d, 1H, J = 8.0 Hz, Ar), 8.30 (d, 2H, J = 7.3 Hz, Ar), 8.15 (d, 1H, J = 6.6 Hz, Ar), 7.88-7.85 (m, 1H, Ar), 7.61-7.49 (m, 6H, Ar), 7.40-7.36 (m, 1H, Ar), 7.28-7.26 (m, 2H, Ar), 1.92 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): δ = 180.54, 179.96, 153.70, 152.22, 150.48, 146.62, 138.66, 137.33, 136.00, 135.98, 131.69, 131.34, 129.21, 129.1, 128.41, 127.26, 127.00, 126.47, 121.47, 119.7, 116.8, 14.28.
Chapter IV
164
NH2
O
N
NO
OOH
Cl
Figur
e IV.2:
IR Sp
ectra of
Com
poun
d IIIa
Chapter IV
165
NH2
O
N
NO
OOH
Cl Figur
e IV.3:
1 H Sp
ectra of
Com
poun
d IIIa
Chapter IV
166
NH2
O
N
NO
OOH
Cl
Figur
e IV.4:
13C Sp
ectra of
Com
poun
d IIIa
Chapter IV
167
NH2
O
N
NO
OOH
Cl
Figur
e IV.5:
Mass
Spect
ra of
Com
poun
d IIIa
Chapter IV
168
N H
O
N
NO
O
Cl
Figur
eIV.7:
IR Sp
ectra of
Com
poun
d IVa
Chapter IV
169
N H
O
N
NO
O
Cl
Figur
e IV.8:
1 H Sp
ectra of
Com
poun
d IVa
Chapter IV
170
N H
O
N
NO
O
Cl
Figur
e IV.9:
13C Sp
ectra of
Com
poun
d IVa
Chapter IV
171
NNN
Ph
O
Cl
Figur
e IV.10: IR Sp
ectra of
Com
poun
d Xa
Chapter IV
172
NNN
Ph
O
Cl
Figur
e IV.11: 1H
Spect
ra of
Com
poun
d Xa
Chapter IV
173
NNN
Ph
O
Cl
Figur
e IV.12: 1
3 C Sp
ectra of
Com
poun
d Xa
Chapter IV
174
NNN
Ph
O
Cl
Figur
e IV.13: M
ass Sp
ectra of
Com
poun
d Xa
Chapter IV
175
X-ray crystallographic study of 6-amino-5-[(4-chlorophenyl)-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIa) The single crystals suitable for X-ray diffraction were grown by vapour diffusion of hexane into chloroform solution of the compound 6-amino-5-[(4-chlorophenyl)-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-methyl]-1,3-dimethyl-1H-pyrimidine-2,4-dione (IIIa) at room temperature. X-ray intensity data was collected on an Oxford Diffraction Xcalibur CCD diffractometer with graphite monochromated Mo Kα radiation (λ = 0.71073 Å) at temperature 293(2) K. A total of 12561 reflections were measured out of which 4901 were unique. The data were corrected for Lorentz and polarization effects. No absorption correction was applied. The structure was solved by direct methods using SIR-9291 and refined by full-matrix least-squares method on F2 (SHELXL-97).92 All calculations were carried out using the WinGX package of the crystallographic programs.93 For the molecular graphics, the program ORTEP-394 was used. The non hydrogen atoms were refined anisotropically. All hydrogen atoms were fixed geometrically. The final residual index are; R = 0.0603, wR = 0.1477 for the observed and R = 0.0713, R = 0.1542 for all the reflections using 302 parameters and zero restraints. The unit cell parameters obtained for the single crystals are: a = 13.8997(14) Å, α = 90°; b = 10.5405(14) Å, β = 94.867(9)°; c = 17.1542(15) Å, γ = 90° and volume = 2504.2(5) Å3, which clearly indicates that it exhibits monoclinic crystal system with the space group of P21/c. Crystallographic data collection and experimental details are summarized in Table V.5. The selected bond lengths and bond angles are listed in Table V.6 and Table V.7 respectively. The thermal ellipsoids were drawn at 40% probability and hydrogen atoms are omitted for the sake of clarity (Figure IV.6).
Chapter IV
176
Table IV.5: Crystal data and structure refinement for IIIa
Identification code Shelxl Empirical formula C22H25Cl4N3O4 Formula weight 537.25 Temperature 293(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 21/c Unit cell dimensions a = 13.8997(14) Å α = 90° b = 10.5405(14) Å β = 94.867(9)° c = 17.1542(15) Å γ = 90° Volume 2504.2(5) Å3 Z 4 Density (calculated) 1.425 Mg/m3 Absorption coefficient 0.506 mm-1 F(000) 1112 Crystal size 0.20 x 0.18 x 0.14 mm3 Theta range for data collection 3.07 to 26.00° Index ranges -17<=h<=16, -12<=k<=13, -21<=l<=21 Reflections collected 12561 Independent reflections 4901 [R(int) = 0.0200] Completeness to theta = 26.00° 99.8 % Max. and min. transmission 0.9325 and 0.9055 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4901 / 0 / 302 Goodness-of-fit on F2 1.054 Final R indices [I>2sigma(I)] R1 = 0.0603, wR2 = 0.1477 R indices (all data) R1 = 0.0713, wR2 = 0.1542 Largest diff. peak and hole 0.591 and -0.724 e.Å-3
Chapter IV
177
Table IV.6: Bond lengths for compound IIIa Bond length [Å] Bond length [Å] C(1)-C(2) 1.367(4) C(13)-H(13B) 0.9600 C(1)-C(6) 1.371(4) C(13)-H(13C) 0.9600 C(1)-Cl(1) 1.741(3) C(14)-C(15) 1.511(4) C(2)-C(3) 1.378(4) C(14)-H(14A) 0.9700 C(2)-H(2) 0.9300 C(14)-H(14B) 0.9700 C(3)-C(4) 1.384(4) C(15)-O(4) 1.238(3) C(3)-H(3) 0.9300 C(16)-C(21) 1.383(3) C(4)-C(5) 1.386(4) C(16)-C(17) 1.402(3) C(4)-C(7) 1.533(3) C(17)-O(1) 1.249(3) C(5)-C(6) 1.384(4) C(17)-N(1) 1.396(3) C(5)-H(5) 0.9300 C(18)-N(1) 1.457(3) C(6)-H(6) 0.9300 C(18)-H(18A) 0.9600 C(7)-C(16) 1.522(3) C(18)-H(18B) 0.9600 C(7)-C(8) 1.522(3) C(18)-H(18C) 0.9600 C(7)-H(7) 0.9800 C(19)-O(2) 1.214(3) C(8)-C(9) 1.358(3) C(19)-N(1) 1.372(3) C(8)-C(15) 1.438(3) C(19)-N(2) 1.374(3) C(8)-H(8) 0.9800 C(20)-N(2) 1.470(4) C(9)-O(3) 1.325(3) C(20)-H(20A) 0.9600 C(9)-C(10) 1.493(4) C(20)-H(20B) 0.9600 C(10)-C(11) 1.524(4) C(20)-H(20C) 0.9600 C(10)-H(10A) 0.9700 C(21)-N(3) 1.328(3) C(10)-H(10B) 0.9700 C(21)-N(2) 1.379(3) C(11)-C(13) 1.525(4) C(22)-Cl(4) 1.733(4) C(11)-C(12) 1.526(4) C(22)-Cl(2) 1.753(4) C(11)-C(14) 1.528(4) C(22)-Cl(3) 1.752(4) C(12)-H(12A) 0.9600 C(22)-H(22) 0.9800 C(12)-H(12B) 0.9600 N(3)-H(3A) 0.8600 C(12)-H(12C) 0.9600 N(3)-H(3B) 0.8600 C(13)-H(13A) 0.9600
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178
Table IV.7: Bond angles for compound IIIa
Bond Angle [°] Bond Angle [°] C(2)-C(1)-C(6) 120.9(2) C(9)-C(8)-H(8) 89.9 C(2)-C(1)-Cl(1) 119.0(2) C(15)-C(8)-H(8) 89.9 C(6)-C(1)-Cl(1) 120.1(2) C(7)-C(8)-H(8) 89.9 C(1)-C(2)-C(3) 119.5(3) O(3)-C(9)-C(8) 124.1(2) C(1)-C(2)-H(2) 120.3 O(3)-C(9)-C(10) 111.7(2) C(3)-C(2)-H(2) 120.2 C(8)-C(9)-C(10) 124.2(2) C(2)-C(3)-C(4) 121.7(3) C(9)-C(10)-C(11) 114.2(2) C(2)-C(3)-H(3) 119.2 C(9)-C(10)-H(10A) 108.7 C(4)-C(3)-H(3) 119.1 C(11)-C(10)-H(10A) 108.7 C(3)-C(4)-C(5) 117.1(2) C(9)-C(10)-H(10B) 108.7 C(3)-C(4)-C(7) 120.1(2) C(11)-C(10)-H(10B) 108.7 C(5)-C(4)-C(7) 122.3(2) H(10A)-C(10)-H(10B) 107.6 C(6)-C(5)-C(4) 121.9(3) C(10)-C(11)-C(13) 109.4(3) C(6)-C(5)-H(5) 119.0 C(10)-C(11)-C(12) 110.8(2) C(4)-C(5)-H(5) 119.0 C(13)-C(11)-C(12) 108.9(3) C(1)-C(6)-C(5) 118.8(3) C(10)-C(11)-C(14) 107.1(2) C(1)-C(6)-H(6) 120.6 C(13)-C(11)-C(14) 110.8(2) C(5)-C(6)-H(6) 120.6 C(12)-C(11)-C(14) 109.9(3) C(16)-C(7)-C(8) 114.88(19) C(11)-C(12)-H(12A) 109.5 C(16)-C(7)-C(4) 112.91(19) C(11)-C(12)-H(12B) 109.5 C(8)-C(7)-C(4) 115.02(19) H(12A)-C(12)-H(12B) 109.5 C(16)-C(7)-H(7) 104.1 C(11)-C(12)-H(12C) 109.5 C(8)-C(7)-H(7) 104.1 H(12A)-C(12)-H(12C) 109.5 C(4)-C(7)-H(7) 104.1 H(12B)-C(12)-H(12C) 109.5 C(9)-C(8)-C(15) 118.5(2) C(11)-C(13)-H(13A) 109.4 C(9)-C(8)-C(7) 124.9(2) C(11)-C(13)-H(13B) 109.5 C(15)-C(8)-C(7) 116.6(2) H(13A)-C(13)-H(13B) 109.5
Chapter IV
179
Table IV.7: Bond angles for compound IIIa
Bond Angle [°] Bond Angle [°] C(11)-C(13)-H(13C) 109.5 O(2)-C(19)-N(1) 121.8(3) H(13A)-C(13)-H(13C) 109.5 O(2)-C(19)-N(2) 121.8(3) H(13B)-C(13)-H(13C) 109.5 N(1)-C(19)-N(2) 116.4(2) C(15)-C(14)-C(11) 113.6(2) N(2)-C(20)-H(20A) 109.4 C(15)-C(14)-H(14A) 108.9 N(2)-C(20)-H(20B) 109.5 C(11)-C(14)-H(14A) 108.8 H(20A)-C(20)-H(20B) 109.5 C(15)-C(14)-H(14B) 108.8 N(2)-C(20)-H(20C) 109.5 C(11)-C(14)-H(14B) 108.9 H(20A)-C(20)-H(20C) 109.5 H(14A)-C(14)-H(14B) 107.7 H(20B)-C(20)-H(20C) 109.5 O(4)-C(15)-C(8) 122.2(2) N(3)-C(21)-N(2) 116.3(2) O(4)-C(15)-C(14) 119.0(2) N(3)-C(21)-C(16) 123.6(2) C(8)-C(15)-C(14) 118.8(2) N(2)-C(21)-C(16) 120.0(2) C(21)-C(16)-C(17) 119.5(2) Cl(4)-C(22)-Cl(2) 110.6(2) C(21)-C(16)-C(7) 121.4(2) Cl(4)-C(22)-Cl(3) 110.4(2) C(17)-C(16)-C(7) 119.0(2) Cl(2)-C(22)-Cl(3) 110.54(19) O(1)-C(17)-N(1) 117.7(2) Cl(4)-C(22)-H(22) 108.4 O(1)-C(17)-C(16) 125.1(2) Cl(2)-C(22)-H(22) 108.4 N(1)-C(17)-C(16) 117.1(2) Cl(3)-C(22)-H(22) 108.4 N(1)-C(18)-H(18A) 109.5 C(19)-N(1)-C(17) 124.0(2) N(1)-C(18)-H(18B) 109.5 C(19)-N(1)-C(18) 116.3(2) H(18A)-C(18)-H(18B) 109.5 C(17)-N(1)-C(18) 119.6(2) N(1)-C(18)-H(18C) 109.4 C(19)-N(2)-C(21) 122.3(2) H(18A)-C(18)-H(18C) 109.5 C(19)-N(2)-C(20) 116.9(2) H(18B)-C(18)-H(18C) 109.5 C(21)-N(2)-C(20) 120.6(2) O(2)-C(19)-N(1) 121.8(3) C(21)-N(3)-H(3A) 120.0 O(2)-C(19)-N(2) 121.8(3) C(21)-N(3)-H(3B) 120.0 N(1)-C(19)-N(2) 116.4(2) H(3A)-N(3)-H(3B) 120.0 N(2)-C(20)-H(20A) 109.4
Chapter IV
180
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